Splice acceptor site disruption of a disease-associated gene using adenosine deaminase base editors, including for the treatment of genetic disease

Abstract

The invention features compositions and methods for treating, reducing, or ameliorating the debilitating effects of Amyotrophic Lateral Sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). Provided herein are compositions and methods of using improved new base editors (e.g., adenosine base editors) comprising a polynucleotide programmable nucleotide binding domain and a nucleobase editing domain in conjunction with a guide polynucleotide to disrupt normal transcription of a gene associated with a genetic disease or condition, e.g. ALS, or SBMA by modifying a target gene associated with the genetic disorder or condition with a base editor system provided herein.

Description

SPLICE ACCEPTOR SITE DISRUPTION OF A DISEASE-ASSOCIATED GENE USING ADENOSINE DEAMINASE BASE EDITORS, INCLUDING FOR THE TREATMENT OF GENETIC DISEASE CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 805,271 filed on February 13, 2019; U.S. Provisional Application No. 62 / 852,228 filed on May 23, 2019; U.S. Provisional Application No. 62 / 852,224 filed on May 23, 2019; U.S. Provisional Application No. 62 / 873,140 filed on July 11, 2019; U.S. Provisional Application No. 62 / 873,144 filed on July 11, 2019; U.S. Provisional Application 62 / 931,722 filed November 6, 2019; U.S. Provisional Application 62 / 941,569 filed November 27, 2019; U.S. Provisional Application No. 62 / 966,526 filed on January 27, 2020, the disclosures of which are hereby incorporated by reference in their entirety. INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Absent any indication otherwise, publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entireties. BACKGROUND OF THE DISCLOSURE Targeted editing of nucleic acid sequences, for example, the targeted cleavage or the targeted modification of genomic DNA is a highly promising approach for the study of gene function and also has the potential to provide new therapies for human genetic diseases. Currently available base editors include cytidine base editors (e.g., BE4) that convert target C+G base pairs to TA and adenine base editors (e.g., ABE7.10) that convert A«T to G-C. There is a need in the art for improved base editors capable of inducing modifications within a target sequence with greater specificity and efficiency. SUMMARY OF THE DISCLOSURE The invention provides compositions comprising novel adenine base editors (e.g., ABER) that have increased efficiency and methods of using base editors comprising adenosine deaminase variants for editing a target sequence. In some aspects, provided herein, is a method of treating a neurological disorder in a subject in need thereof, the method comprising: administering to the subject (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase modification at a splice site of a target gene associated with the neurological disorder in the subject, thereby treating the neurological disorder in the subject. In some embodiments, the adenosine deaminase comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 ora corresponding substitution thereof. In some embodiments, the single nucleobase modification results in alternative splicing of a transcript encoded by the target gene. In some embodiments, the alternative splicing generates a truncated or nonfunctional protein encoded by the target gene. In some embodiments, the single nucleobase modification results in reduced expression of the target gene in the subject. In some embodiments, the target gene is a superoxide dismutase 1 (SODI) gene and wherein the neurological disease is Amyotrophic Lateral Sclerosis (ALS). In some embodiments, the target gene is an androgen receptor (AR) gene and wherein the neurological disease is spinal and bulbar muscular atrophy (SBMA). In some aspects, provided herein, is a method of treating Amyotrophic Lateral Sclerosis (ALS) in a subject in need thereof, the method comprising: administering to the subject (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the base editor comprises a programmable DNA binding domain and a deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase modification at a splice site of a superoxide dismutase 1 (SODJ) gene in the subject, thereby treating ALS in the subject. In some aspects, provided herein, is a method of treating Amyotrophic Lateral Sclerosis (ALS) in a subject in need thereof, the method comprising: administering to the subject (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the base editor comprises a programmable DNA binding domain and a deaminase domain, wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase modification in a superoxide dismutase 1 (SOD!) gene in the subject and wherein the single nucleobase modification results in a premature stop codon in the SOD! gene, thereby treating ALS in the subject. In some embodiments, the deaminase is an adenosine deaminase comprising an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding substitution thereof. In some embodiments, the single nucleobase modification is an A-to-G modification. In some embodiments, the single nucleobase modification is at a splice acceptor site of the SOD! gene. In some embodiments, the splice site is a splice acceptor site 5' of an exon of the SOD! gene. In some embodiments, the exon of the SOD gene is exon 3 corresponding to SEQ ID NO: 3, or a variant thereof. In some embodiments, the exon 3 of the SOD gene is adjacent to the splice acceptor AG at nucleotide position 6828 of the SOD polynucleotide sequence as numbered in SEQ ID NO: 3, or a variant thereof. In some embodiments, the exon of the SOD! gene is exon 4 corresponding to SEQ ID NO: 3, or a variant thereof. In some embodiments, the single nucleobase modification generates a transcription product lacking exons 3-5 of the human SOD! gene corresponding to SEQ ID NO: 3, or a variant thereof. In some embodiments, expression of the SOD / gene is reduced by at least 40% in the subject after the administration. In some embodiments, guide polynucleotide comprises a nucleic acid sequence complementary to a splice acceptor nucleic acid sequence or a splice donor nucleic acid sequence of the SOD! gene. In some embodiments, the guide polynucleotide comprises any one of the nucleic acid sequences selected from Table 19 or Table 23. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence selected from the group consisting of 5-UUAAAGGAAAGUAAUGGACCAGU-3', 5'-UAAAUAGGCUGUACCAGUGCAGG- 3' 5'-UUCAUUAUUAGGCAUGUUGGAGA-3’, 5'- AAAUAGGCUGUACCAGUGCAGGU-3', 5-UAUUAGGCAUGUUGGAGACUUGG-3', and a complementary sequence thereof. In some aspects, provided herein, is a method of treating spinal and bulbar muscular atrophy (SBMA) in a subject, the method comprising: administering to the subject (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the base editor comprises a programmable DNA binding domain and a deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase modification at a splice site of an androgen receptor (4R) gene in the subject, thereby treating SBMA in the subject. In some aspects, provided herein, is a method of treating spinal and bulbar muscular atrophy (SBMA) in a subject, the method comprising: administering to the subject (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and a deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase modification in an androgen receptor (AR) gene in the subject and wherein the single nucleobase modification results in a premature stop codon in the AR gene, thereby treating SBMA in the subject. In some embodiments, the nucleobase modification results in a CAG-TAG codon change in the AR gene. In some embodiments, the codon change is in exon 1 or exon 2 in the AR gene. In some embodiments, the deaminase is an adenosine deaminase comprising an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2. In some embodiments, the single nucleobase modification is an A-to-G modification. In some embodiments, the A-to-G nucleobase modification is at a splice acceptor site of the AR gene. In some embodiments, the splice site is a splice acceptor site 5’ of an exon of the AR gene. In some embodiments, the exon of the AR gene is exon 2 corresponding to SEQ ID NO: 4, or a variant thereof. In some embodiments, the splice site is a splice donor site 3' of an exon of the AR gene. In some embodiments, the exon of the AR gene is exon 1 corresponding to SEQ ID NO: 4, or a variant thereof. In some embodiments, the expression of the AR gene is reduced by at least 40% in the subject after the administration. In some embodiments, guide polynucleotide comprises a nucleic acid sequence complementary to a splice acceptor nucleic acid sequence or a splice donor nucleic acid sequence of the AR gene. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence selected from Table 41A or 41B. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence selected from the group consisting of 5'- ACUUACCGCAUGUCCCCGUAAGG-3', 5'- AGUGCAGUUAGGGCUGGGAAGGG-3 / , 5'- AAGUGCAGUUAGGGCUGGGAAGG-3' and a complement thereof, In some embodiments, the subject is a mammal or a human. In some embodiments, the administering is performed through delivery to a cell of the central nervous system (CNS) of the subject. In some embodiments, the cell is a motor neuron. In some aspects, provided herein, is a method of modifying a target gene or a regulatory element thereof associated with a neurological disorder, the method comprising: contacting the target gene or regulatory element thereof with (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase alteration at a splice site of the target gene. In some embodiments, the adenosine deaminase comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2. In some embodiments, the single nucleobase alteration results in alternative splicing of a transcript encoded by the target gene, a truncated and / or nonfunctional protein encoded by the target gene, and / or reduced expression of the target gene when expressed in a cell. In some embodiments, the target gene is a superoxide dismutase 1 (SOD!) gene and wherein the neurological disease is Amyotrophic Lateral Sclerosis (ALS). In some embodiments, the target gene is an androgen receptor (AR) gene and wherein the neurological disease is spinal and bulbar muscular atrophy (SBMA), In some aspects, provided herein, is a method of modulating expression of a superoxide dismutase (SOD!) gene, the method comprising: contacting a SOD! gene or a regulatory element thereof with (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the base editor comprises a programmable DNA binding domain and a deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase alteration at a splice site of a superoxide dismutase 1 (SOD) gene. In some aspects, provided herein, is a method of modifying a superoxide dismutase (SOD) gene, the method comprising: contacting the SOD! gene or a regulatory element thereof with (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase alteration in a superoxide dismutase 1 (SOD) gene in the subject and wherein the single nucleobase alteration results in a premature stop codon in the SODI gene. In some embodiments, the single nucleobase alteration is an A-to-G alteration. In some embodiments, the nucleobase alteration is at a splice acceptor site of the SOD gene. In some embodiments, the splice site is a splice acceptor site 5° of an exon of the SOD! gene. In some embodiments, the exon of the SOD! gene is exon 3 corresponding to SEQ ID NO: 3, or a variant thereof. In some embodiments, the exon 3 of the SOD gene is adjacent to the splice acceptor at nucleotide position 6828 of the SOD polynucleotide sequence as numbered in SEQ ID NO: 3, or a variant thereof. In some embodiments, the exon of the SOD / gene is exon 4 corresponding to SEQ ID NO: 3, or a variant thereof. In some embodiments, the single nucleobase alteration generates a transcription product lacking exons 3-5 of the SOD! gene corresponding to SEQ ID NO: 3, or a variant thereof. In some embodiments, guide polynucleotide comprises a nucleic acid sequence complementary to a splice acceptor nucleic acid sequence or a splice donor nucleic acid sequence of the SODI gene. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence selected from Table 19 or Table 23. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence selected form the group consisting of 5'- UUAAAGGAAAGUAAUGGACCAGU-3, 5'-UAAAUAGGCUGUACCAGUGCAGG-3', 5'-UUCAUUAUUAGGCAUGUUGGAGA-3', 5-AAAUAGGCUGUACCAGUGCAGGU-3', S.UAUUAGGCAUGUUGGAGACUUGG-3" In some aspects, provided herein, is a method of modulating expression of an androgen receptor (AR) gene, the method comprising: contacting the AR gene or a regulatory element thereof with (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the base editor comprises a programmable DNA binding domain and a deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase alteration at a splice site of an androgen receptor (AR) gene. In some aspects, provided herein, is a method of modifying an androgen receptor (AR) gene, the method comprising: contacting the AR gene or a regulatory element thereof with (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the base editor comprises a programmable DNA binding domain and a deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase alteration in an androgen receptor (AR) gene in the subject and wherein the single nucleobase alteration results in a premature stop codon in the AR gene. In some embodiments, the deaminase is an adenosine deaminase comprising an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2. In some embodiments, the deaminase is a cytidine deaminase. In some embodiments, the single nucleobase alteration is a C-to-T alteration. In some embodiments, the nucleobase alteration results in a CAG-TAG codon change in the AR gene. In some embodiments, the codon change is in exon 1 or exon 2 in the AR gene. In some embodiments, the single nucleobase alteration is an A-to-G alteration. In some embodiments, the A-to-G nucleobase alteration is at a splice acceptor site of the AR gene. In some embodiments, the splice site is a splice acceptor site 5’ of an exon of the AR gene. In some embodiments, the exon of the AR gene is exon 2 corresponding to SEQ ID NO: 4, or a variant thereof. In some embodiments, the splice site is a splice donor site 3’ of an exon of the AR gene. In some embodiments, the exon of the AR gene is exon 1 corresponding to SEQ ID NO: 4, or a variant thereof. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence selected from Table 41A or 41B. In some embodiments, guide polynucleotide comprises a nucleic acid sequence complementary to a splice acceptor nucleic acid sequence or a splice donor nucleic acid sequence of the AR gene. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence selected from Table 41A or 41B. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence selected from the group consisting of 5'-ACUUACCGCAUGUCCCCGUAAGG-3, 5'- AGUGCAGUUAGGGCUGGGAAGGG-3, 5'- AAGUGCAGUUAGGGCUGGGAAGG-3' and a complement thereof. In some embodiments, the contacting is in a cell. In some embodiments, the single nucleobase modification results in less than 15% indels in a genome of the cell. In some embodiments, the single nucleobase modification results in less than 5% indels in a genome of the cell. In some embodiments, the single nucleobase modification results in less than 2% indels in a genome of the cell. In some embodiments, the cell is a mammalian cell or a human cell. In some embodiments, the cell is a central nervous system cell. In some embodiments, the cell is a motor neuron. In some embodiments, the contacting is in a population of cells. In some embodiments, at least 40% of the population of cells comprise the single nucleobase modification after the contacting. In some embodiments, at least 50% of the population of cells comprise the single nucleobase modification after the contacting. In some embodiments, at least 60% of the population of cells comprise the single nucleobase modification after the contacting. In some embodiments, at least 85% of the population of cells are viable after the contacting. In some embodiments, the population of cells are mammalian cells or human cells. In some embodiments, the population of cells are central nervous system cells. In some embodiments, the population of cells are motor neurons. In some embodiments, the adenosine deaminase comprises a TadA deaminase. In some embodiments, the adenosine deaminase is TadA7.10. In some embodiments, the adenosine deaminase is a TadA comprising comprises a V28S mutation or a T166R mutation as numbered in SEQ ID NO: 2 or a corresponding mutation thereof. In various aspects and embodiments provided herein, the adenosine deaminase comprises one or more of the following mutations: Y147T, Y147R, Q154S, Y123H, and Q154R as numbered in SEQ ID NO: 2 or a corresponding mutation thereof. In various aspects and embodiments provided herein, the adenosine deaminase comprises a combination of mutations selected from the group consisting of: Y147T + Q154R; Y147T + Q154S; Y147R + Q154S; V82S + Q154S; V82S + Y147R; V82S + Q154R; V82S + Y123H; I76Y + V82S; V82S + YI123H + Y147T, V82S + Y123H + Y147R; V828 + Y123H + Q154R; Y147R + QI154R +Y123H; Y147R + Q154R + I76Y; Y147R + Q154R + T166R; Y123H + Y147R + Q154R +176Y; V82S + Y123H + Y147R + Q154R; and I76Y + V82S + Y123H + Y147R + Q154R as numbered in SEQ ID NO: 2 or corresponding mutations thereof, In some embodiments, the adenosine deaminase comprises a deletion of the C terminus beginning at a residue selected from the group consisting of 149, 150, 151, 152, 153, 154, 155, 156, and 157. In some embodiments, the adenosine deaminase comprises a TadA dimer. In some embodiments, the adenosine deaminase comprises an adenosine deaminase monomer. In various aspects and embodiments above, the polynucleotide programmable DNA binding domain is a Cas9 domain. In some embodiments, the Cas9 domain is a Cas9 nickase domain. In some embodiments, the Cas9 domain comprises a SpCas9 domain. In some embodiments, the SpCas9 domain comprises a D10A and / or a H840A amino acid substitution as numbered in SEQ ID NO: 1 or corresponding amino acid substitutions thereof. In some embodiments, the Cas9 domain comprises a SaCas9 domain. In some embodiments, the Cas9 domain has specificity for an altered PAM. In some embodiments, the Cas9 domain has specificity for a PAM sequence selected from the group consisting of NGG, NGA, NGCG, NGN, NNGRRT, NNNRRT, NGCG, NGCN, NGTN, and NGC, wherein Nis A, G, C,or T and wherein Ris A or G. In some aspects, provided herein, is a population of cells produced by the method described herein. In some aspects, provided herein, is a base editor system that comprises (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the base editor comprises a programmable DNA binding domain and a deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase modification at a splice site of a superoxide dismutase 1 (SOD / ). In some aspects, provided herein, is a base editor system that comprises (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the base editor comprises a programmable DNA binding domain and a deaminase domain, wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase modification in a superoxide dismutase 1 (§OD / ) gene and wherein the single nucleobase modification results in a premature stop codon in the SOD! gene. In some embodiments, the deaminase is an adenosine deaminase comprising an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2. In some embodiments, the deaminase is a cytidine deaminase. In some embodiments, the single nucleobase modification is an A-to-G modification. In some embodiments, the A-to-G nucleobase modification is at a splice acceptor site of the SOD / gene. In some embodiments, the splice site is a splice acceptor site 5' of an exon of the SOD / gene. In some embodiments, the exon of the SOD gene is exon 3 corresponding to SEQ ID NO: 3, or a variant thereof. In some embodiments, the exon 3 of the SOD / gene is adjacent to the splice acceptor AG at nucleotide position 6828 of the SOD! polynucleotide sequence as numbered in SEQ ID NO: 3, or a variant thereof. In some embodiments, the alternative splicing of the SOD! transcript generates a transcription product lacking exons 3-5 of the SOD! gene corresponding to SEQ ID NO: 3, or a variant thereof. In some embodiments, the exon of the SOD! gene is exon 4 corresponding to SEQ ID NO: 3, or a variant thereof. In some embodiments, guide polynucleotide comprises a nucleic acid sequence complementary to a splice acceptor nucleic acid sequence or a splice donor nucleic acid sequence of the SOD / gene. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence selected from Table 19 or Table 23. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence selected form the group consisting of 5'- UUAAAGGAAAGUAAUGGACCAGU-3 / , 5'-UAAAUAGGCUGUACCAGUGCAGG-3', 5'-UUCAUUAUUAGGCAUGUUGGAGA-3', 5'-AAAUAGGCUGUACCAGUGCAGGU-3', 5'-UAUUAGGCAUGUUGGAGACUUGG-3', and a complementary sequence thereof. In some aspects, provided herein, is a base editor system that comprises (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the base editor comprises a programmable DNA binding domain and a deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase modification at a splice site of an androgen receptor (AR) gene. In some aspects, provided herein, is a base editor system that comprises (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and a deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase modification in an androgen receptor (AR) gene in the subject and wherein the single nucleobase modification results in a premature stop codon in the AR gene. In some embodiments, the deaminase is an adenosine deaminase comprising an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2. In some embodiments, the deaminase is a cytidine deaminase. In some embodiments, the single nucleobase modification is a C-to-T modification. In some embodiments, the single nucleobase modification results in a CAG-TAG codon change in the AR gene. In some embodiments, the codon change is in exon 1 or exon 2 in the AR gene corresponding to SEQ ID NO: 4, or a variant thereof. In some embodiments, the single nucleobase modification is an A-to-G modification. In some embodiments, the A-to-G nucleobase modification is at a splice acceptor site of the AR gene. In some embodiments, the splice site is a splice acceptor site 5' of an exon of the AR gene. In some embodiments, the exon of the AR gene is exon 2 corresponding to SEQ ID NO: 4, or a variant thereof. In some embodiments, the splice site is a splice donor site 3” of an exon of the AR gene. In some embodiments, the exon of the AR gene is exon 1 corresponding to SEQ ID NO: 4, or a variant thereof, In some embodiments, guide polynucleotide comprises a nucleic acid sequence complementary to a splice acceptor nucleic acid sequence or a splice donor nucleic acid sequence of the AR gene. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence selected from Table 41A or 41B. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence selected from the group consisting of 5'- ACUUACCGCAUGUCCCCGUAAGG-3', 5'- AGUGCAGUUAGGGCUGGGAAGGG-3 / , 5'- AAGUGCAGUUAGGGCUGGGAAGG-3' and a complement thereof, In some embodiments, the adenosine deaminase comprises a TadA deaminase. In some embodiments, the adenosine deaminase is TadA7.10. In some embodiments, the adenosine deaminase is a TadA comprising comprises a V28S mutation or a T166R mutation as numbered in SEQ ID NO: 2 or a corresponding mutation thereof. In some embodiments, the adenosine deaminase comprises one or more of the following mutations: Y147T, Y147R, Q1548, Y123H, and Q154R as numbered in SEQ ID NO: 2 or a corresponding mutation thereof. In some embodiments, the adenosine deaminase comprises a combination of mutations selected from the group consisting of: Y147T + Q154R; Y147T + Q154S; Y147R + Q1548; V82S + Q154S; V82S + Y147R; V82S + Q154R; V82S + Y123H; I76Y + V82S; V82S + Y123H + Y147T,; V82S + Y123H + Y147R; V82S + Y123H + Q154R; Y147R + Q154R +Y123H; Y147R + Q154R + I76Y; Y147R + Q154R + T166R; Y123H + Y147R + QI154R +176Y; V82S + Y123H + Y147R + Q154R; and I76Y + V82S + Y123H + Y147R + Q154R as numbered in SEQ ID NO: 2 or corresponding mutations thereof. In some embodiments, the adenosine deaminase comprises a deletion of the C terminus beginning at a residue selected from the group consisting of 149, 150, 151, 152, 153, 154, 155, 156, and 157. In some embodiments, the adenosine deaminase comprises a TadA dimer. In some embodiments, the adenosine deaminase comprises an adenosine deaminase monomer. In some embodiments, the polynucleotide programmable DNA binding domain is a Cas9 domain. In some embodiments, the Cas9 domain is a Cas9 nickase domain. In some embodiments, the Cas9 domain comprises a SpCas9 domain. In some embodiments, the SpCas9 domain comprises a D10A and / or a H840A amino acid substitution as numbered in SEQ ID NO: lor corresponding amino acid substitutions thereof. In some embodiments, the Cas9 domain comprises a SaCas9 domain. In some embodiments, the Cas9 domain has specificity for an altered PAM. In some embodiments, the Cas9 domain has specificity for a PAM sequence selected from the group consisting of NGG, NGA, NGCG, NGN, NNGRRT, NNNRRT, NGCG, NGCN, NGTN, and NGC, wherein Nis A, G, C, or T and wherein R is A or G. In some aspects, provided herein, is a vector comprising the nucleic acid sequence encoding the polynucleotide programmable DNA binding domain and the nucleic acid sequence encoding the adenosine deaminase domain in the base editor system described herein. In some embodiments, the vector further comprises the nucleic acid sequence encoding the guide polynucleotide. In some embodiments, the vector is a viral vector. In some aspects, provided herein, is a cell comprising the base editor system or the vector described herein. In some embodiments, the cell is a mammalian cell, a human cell, or a motor neuron. In some embodiments, the cell is in vivo, ex vivo, or in vitro. In some embodiments, the cell is an autologous cell isolated from a subject. In some embodiments, the cell is an allogeneic cell. In some aspects, provided herein, is a population of cells comprising the base editor system or the vector described herein. In some embodiments, the population of cells is mammalian cells, human cells, or motor neurons. In some embodiments, the population of cells is in vivo, ex vivo, or in vitro. In some embodiments, the cell is an autologous cell isolated from a subject. In some aspects, provided herein, is a pharmaceutical composition comprising the base editor, the vector, or the cell described herein and a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical composition described herein further comprises a lipid. In another embodiment, the pharmaceutical composition described herein further comprises a virus. In some aspects, provided herein, is a kit comprising the base editor system or the vector described herein. In various embodiments of the methods described herein, at least one nucleotide of the guide polynucleotide comprises a non-naturally occurring modification. In various embodiments of the methods described herein, at least one nucleotide of the nucleic acid sequence comprises a non-naturally occurring modification. In various embodiments of the methods described herein, at least one nucleotide of the nucleic acid sequence of the base editor system comprises a non-naturally occurring modification. In some embodiments, the non-naturally occurring modification is a chemical modification. In some embodiments, the chemical modification is a 2’-O-methylation. In some embodiments, the nucleic acid sequence comprises a phosphorothioate, The description and examples herein illustrate embodiments of the present disclosure in detail. It is to be understood that this disclosure is not limited to the particular embodiments described herein and as such can vary. Those of skill in the art will recognize that there are numerous variations and modifications of this disclosure, which are encompassed within its scope. The practice of some embodiments disclosed herein employ, unless otherwise indicated, conventional techniques of immunology, biochemistry, chemistry, molecular biology, microbiology, cell biology, genomics and recombinant DNA, which are within the skill of the art. See for example Sambrook and Green, Molecular Cloning: A Laboratory Manual, 4th Edition (2012); the series Current Protocols in Molecular Biology (F. M. Ausubel, ef al. eds.); the series Methods In Enzymology (Academic Press, Inc.), PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Culture of Animal Cells: A Manual of Basic Technique and Specialized Applications, 6th Edition (R.L Freshney, ed. (2010). The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. Although various features of the present disclosure can be described in the context of a single embodiment, the features can also be provided separately or in any suitable combination. Conversely, although the present disclosure can be described herein in the context of separate embodiments for clarity, the present disclosure can also be implemented in a single embodiment. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. The features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and in view of the accompanying drawings as described hereinbelow. Definitions The following definitions supplement those in the art and are directed to the current application and are not to be imputed to any related or unrelated case, e.g., to any commonly owned patent or application. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present disclosure, the preferred materials and methods are described herein. Accordingly, the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs. The following references provide one of skill with a general definition of many of the terms used in this invention: Singleton ez al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger ez al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or,” unless stated otherwise, and is understood to be inclusive. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting. As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or composition of the present disclosure, and vice versa. Furthermore, compositions of the present disclosure can be used to achieve methods of the present disclosure. The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, 7.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, such as within 5-fold or within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term “about” meaning within an acceptable error range for the particular value should be assumed. Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49. or 50. Reference in the specification to “some embodiments,” “an embodiment,” “one embodiment” or “other embodiments” means that a particular feature, structure, or characteristic described in connection with the embodiments is included in at least some embodiments, but not necessarily all embodiments, of the present disclosures. By “abasic base editor” is meant an agent capable of excising a nucleobase and inserting a DNA nucleobase (A, T, C, or G). Abasic base editors comprise a nucleic acid glycosylase polypeptide or fragment thereof. In one embodiment, the nucleic acid glycosylase is a mutant human uracil DNA glycosylase comprising an Asp at amino acid 204 (e.g., replacing an Asn at amino acid 204) in the following sequence, or corresponding position in a uracil DNA glycosylase, and having cytosine-DNA glycosylase activity, or active fragment thereof. In one embodiment, the nucleic acid glycosylase is a mutant human uracil DNA glycosylase comprising an Ala, Gly, Cys, or Ser at amino acid 147 (e.g., replacing a Tyr at amino acid 147) in the following sequence, or corresponding position in a uracil DNA glycosylase, and having thymine-DNA glycosylase activity, or an active fragment thereof. The sequence of exemplary human uracil-DNA glycosylase, isoform 1, follows: 1 mgvfclgpwg lgrklrtpgk gplgllsrlc gdhlgaipak kapaggeepg tppssplsae 61 gldrigrnka aallrlaarn vpvgfgeswk khlsgefgkp yfiklmgfva eerkhytvyp 121 pphqvftwtqg medikdvkvv ilggdpyhgp ngahglefsv qrpvppppsl eniykelstd 181 iedfvhpghg dlsgwakggv lllmavltvr ahganshker gwegftdavv swlngnsngl 241 vfllwgsyaq kkgsaidrkr hhvlqtahps plsvyrgffg crhfsktnel lgksgkkpid 301 wkel The sequence of human uracil-DNA glycosylase, isoform 2, follows: 1 miggktlysf fspsparkrh apspepavqg tgvagvpees gdaaaipakk apaggeepgt 61 ppssplsaeq ldrigrnkaa allrlaarnv pvgfgeswkk hlsgefgkpy fiklmgfvae 121 erkhytvypp phgvftwtam cdikdvkvvi lggdpyhgpn qgahglefsvg rpvppppsle 181 niykelstdi edfvhpghgd lsgwakqgvl llnavltvra hganshkerg wegftdavvs 241 wlngnsnglv fllwgsyagk kgsaidrkrh hvlgtahpsp lsvyrgffgc rhfsktnell 301 gksgkkpidw kel In other embodiments, the abasic editor is any one of the abasic editors described in PCT / TP2015 / 080958 and US20170321210, which are incorporated herein by reference. In particular embodiments, the abasic editor comprises a mutation at a position shown in the sequence above in bold with underlining or at a corresponding amino acid in any other abasic editor or uracil deglycosylase known in the art. In one embodiment, the abasic editor comprises a mutation at Y147, N204, L272, and / or R276, or corresponding position. In another embodiment, the abasic editor comprises a Y147A or Y147G mutation, or corresponding mutation. In another embodiment, the abasic editor comprises a N204D mutation, or corresponding mutation. In another embodiment, the abasic editor comprises a L272A mutation, or corresponding mutation. In another embodiment, the abasic editor comprises a R276E or R276C mutation, or corresponding mutation. By “adenosine deaminase” is meant a polypeptide or fragment thereof capable of catalyzing the hydrolytic deamination of adenine or adenosine. In some embodiments, the deaminase or deaminase domain is an adenosine deaminase catalyzing the hydrolytic deamination of adenosine to inosine or deoxy adenosine to deoxyinosine. In some embodiments, the adenosine deaminase catalyzes the hydrolytic deamination of adenine or adenosine in deoxyribonucleic acid (DNA). The adenosine deaminases (e.g., engineered adenosine deaminases, evolved adenosine deaminases) provided herein may be from any organism, such as a bacterium. In some embodiments, the adenosine deaminase is a TadA deaminase. In some embodiments, the TadA deaminase is TadA variant. In some embodiments, the TadA variant is a TadA*8. In some embodiments, the deaminase or deaminase domain is a variant of a naturally occurring deaminase from an organism, such as a human, chimpanzee, gorilla, monkey, cow, dog, rat, or mouse. In some embodiments, the deaminase or deaminase domain does not occur in nature. For example, in some embodiments, the deaminase or deaminase domain is at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75% at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9% identical to a naturally occurring deaminase. For example, deaminase domains are described in International PCT Application Nos. PCT / 2017 / 045381 (WO 2018 / 027078) and PCT / US2016 / 058344 (WO 2017 / 070632), each of which is incorporated herein by reference for its entirety. Also, see Komor, A.C, et al., “Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage” Nature 533, 420-424 (2016); Gaudelli, NM., et al., “Programmable base editing of AT to GC in genomic DNA without DNA cleavage” Nature 551, 464-471 (2017); Komor, A.C., ef al, “Improved base excision repair inhibition and bacteriophage Mu Gam protein yields C:G-to-T:A base editors with higher efficiency and product purity” Science Advances 3:eaa04774 (2017) ), and Rees, HA, et al., “Base editing: precision chemistry on the genome and transcriptome of living cells.” Nat Rev Genet. 2018 Dec;19(12):770-788. doi: 10.1038 / s41576-018-0059-1, the entire contents of which are hereby incorporated by reference. A wild type TadA(wt) adenosine deaminase has the following sequence (also termed TadA reference sequence): MSEVEFSHEYWMRHALTLAKRAWDEREVPVGAVLVHNNRVIGEGWNRPIGRHDPTAHAE IMA LRQGGLVMQONYRLIDATLYVTLEPCVMCAGAMIHSRIGRVVFGARDAKTGAAGSLMDVLHHP GMNHRVEITEGILADECAALLSDFFRMRRQEIKAQKKAQSSTD (SEQ ID NO: 2). In some embodiments, the adenosine deaminase comprises an alteration in the following sequence: MSEVEFSHEY WMRHALTLAK RARDEREVPV GAVLVLNNRV IGEGWNRAIG LHDPTAHAEI MALRQGGLVM QNYRLIDATL YVTFEPCVMC AGAMIHSRIG RVVFGVRNAK TGAAGSLMDV LHYPGMNHRV EITEGILADE CAALLCYFFR MPRQVENAQK KAQSSTD (also termed TadA*7.10). In some embodiments, TadA*7.10 comprises at least one alteration. In some embodiments, TadA*7.10 comprises an alteration at amino acid 82 and / or 166. In particular embodiments, a variant of the above-referenced sequence comprises one or more of the following alterations: Y147T, Y147R, Q154S, Y123H, V82S, T166R, and / or Q154R. The alteration Y123H is also referred to herein as H123H (the alteration H123Y in TadA*7.10 reverted back to Y123H (wt)). In other embodiments, a variant of the TadA*7.10 sequence comprises a combination of alterations selected from the group consisting of: Y147T + Q154R; Y147T + Q154S; Y147R + Q154S; V82S + Q154S; V82S + Y147R; V828 + Q154R; V82S + YI123H; 176Y + V82S; V82S + Y123H + Y147T, V82S + Y123H + Y147R; V82S + Y123H + QI154R; Y147R + Q154R +Y123H; Y147R + Q154R + I76Y; Y147R + Q154R + T166R, Y123H + Y147R + Q154R + 176Y; V82S + Y123H + Y147R + Q154R,; and I76Y + V82S + Y123H + Y147R + Q154R. In other embodiments, the invention provides adenosine deaminase variants that include deletions, e.g., TadA*8, comprising a deletion of the C terminus beginning at residue 149, 150, 151, 152, 153, 154, 155, 156, or 157. In other embodiments, the adenosine deaminase variant is a TadA (e.g., Tad A*8) monomer comprising one or more of the following alterations: Y147T, Y147R, Q154S, Y123H, V82S, T166R, and / or Q154R. In other embodiments, the adenosine deaminase variant is TadA (e.g., TadA*8) a monomer comprising a combination of alterations selected from the group consisting of: Y147T + QI54R; Y147T + Q154S; Y147R + Q154S; V82S + Q1548S; V82S + Y147R; V82S + QI54R; V82S + Y123H; I76Y + V82S; V82S + Y123H + Y147T, V82S + Y123H + Y147R; V82S + Y123H + Q154R; Y147R + Q154R +Y123H; Y147R + Q154R + I76Y; Y147R + QI54R + T166R; Y123H + Y147R + Q154R + 176Y; V82S + Y123H + Y147R + Q154R; and I76Y + V82S + Y123H + Y147R + Q154R. In still other embodiments, the adenosine deaminase variant is a homodimer comprising two adenosine deaminase domains (e.g., TadA*8) each having one or more of the following alterations Y147T, Y147R, Q154S, Y123H, V82S, T166R, and / or Q154R. In other embodiments, the adenosine deaminase variant is a homodimer comprising two adenosine deaminase domains (e.g., TadA*8) each having a combination of alterations selected from the group consisting of: Y147T + Q154R; Y147T + Q154S; Y147R + Q154S; V82S + Q154S; V82S + Y147R; V82S + Q154R, V82S + Y123H, I76Y + V82S; V82S + Y123H + Y147T; V82S + Y123H + Y147R; V82S + Y123H + Q154R; Y147R + Q154R +Y123H; Y147R + Q154R + 176Y; Y147R + Q154R + T166R; Y123H + Y147R + Q154R + 176Y; V82S + Y123H + Y147R + Q154R; and I76Y + V82S + Y123H + Y147R + Q154R. In other embodiments, the adenosine deaminase variant is a heterodimer comprising a wild-type TadA adenosine deaminase domain and an adenosine deaminase variant domain (e.g., TadA*8) comprising one or more of the following alterations Y147T, Y147R, Q154S, Y123H, V82S, T166R, and / or Q154R. In other embodiments, the adenosine deaminase variant is a heterodimer comprising a wild-type TadA adenosine deaminase domain and an adenosine deaminase variant domain (e.g. TadA*8) comprising a combination of alterations selected from the group consisting of: Y147T + Q154R; Y147T + Q154S; Y147R + Q154S; V82S + Q154S; V82S + Y147R; V82S + Q154R; V82S + Y123H; I76Y + V82S; V82S + Y123H + Y147T; V82S + Y123H + Y147R; V82S + Y123H + Q154R; Y147R + Q154R +Y123H; Y147R + Q154R + I76Y; Y147R + Q154R + T166R; Y123H + Y147R + Q154R + 176Y; V82S + Y123H + Y147R + Q154R; and I76Y + V82S + Y123H + Y147R + Q154R. In other embodiments, the adenosine deaminase variant is a heterodimer comprising a TadA*7.10 domain and an adenosine deaminase variant domain (e.g., Tad A*8) comprising one or more of the following alterations Y147T, Y147R, Q154S, Y123H, V82S, T166R, and / or Q154R. In other embodiments, the adenosine deaminase variant is a heterodimer comprising a TadA*7.10 domain and an adenosine deaminase variant domain (e.g. TadA*8) comprising a combination of the following alterations: Y147T + Q154R; Y147T + Q154S; Y147R + Q154S; V82S + Q154S; V82S + Y147R; V82S + Q154R; V82S + Y123H; I76Y + V82S; V82S + Y123H + Y147T; V82S + Y123H + Y147R; V82S + Y123H + Q154R; Y147R + Q154R +Y123H, Y147R + Q154R + I76Y; Y147R + Q154R + T166R; Y123H + Y147R + Q154R + 176Y; V82S + Y123H + Y147R + Q154R; or I76Y + V82S + Y123H + Y147R + Q154R. In one embodiment, the adenosine deaminase is a TadA*8 that comprises or consists essentially of the following sequence or a fragment thereof having adenosine deaminase activity: MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMA LRQGGLVMQONYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYP GMNHRVEITEGILADECAALLCTFFRMPROVENAQKKAQSSTD. In some embodiments, the TadA*8 is truncated. In some embodiments, the truncated TadA*8 is missing 1, 2,3, 4, 5.6, 7, 8,9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 19, or 20 N-terminal amino acid residues relative to the full length TadA*8. In some embodiments, the truncated TadA*8 is missing 1, 2,3, 4, 5.6, 7,8,9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 19, or 20 C-terminal amino acid residues relative to the full length TadA*8. In some embodiments the adenosine deaminase variant is a full-length TadA*8. In particular embodiments, an adenosine deaminase heterodimer comprises a TadA*8 domain and an adenosine deaminase domain selected from one of the following: In particular embodiments, an adenosine deaminase heterodimer comprises a TadA*8 domain and an adenosine deaminase domain selected from one of the following: Escherichia coli TadA: MRRAFITGVFFLSEVEFSHEYWMRHALTLAKRAWDEREVPVGAVLVHNNRVIGEGWNRPIGR HDPTAHAE IMALRQGGLVMONYRLIDATLYVTLEPCVMCAGAMIHSRIGRVVFGARDAKTGA AGSLMDVLHHPGMNHRVEITEGILADECAALLSDFFRMRRQE IKAQKKAQSSTD E.coli TadA (N-terminal truncated): MSEVEFSHEYWMRHALTLAKRAWDEREVPVGAVLVHNNRVIGEGWNRPIGRHDPTAHAE TMA LRQGGLVMQONYRLIDATLYVTLEPCVMCAGAMIHSRIGRVVFGARDAKTGAAGSLMDVLHHP GMNHRVEITEGILADECAALLSDFFRMRRQOE IKAQKKAQSSTD Staphylococcus aureus (S. aureus) TadA: MGSHMTNDIYFMTLAIEEAKKAAQLGEVPIGAIITKDDEVIARAHNLRETLQOPTAHAEHIA IERAAKVLGSWRLEGCTLYVTLEPCVMCAGT IVMSRIPRVVYGADDPKGGCSGSLMNLLQQS NFNHRAIVDKGVLKEACSTLLTTFFKNLRANKKSTN Bacillus subtilis (B. subtilis) TadA: MTQDELYMKEAIKEAKKAEEKGEVPIGAVLVINGEI IARAHNLRETEQRSIAHAEMLVIDEA CKALGTWRLEGATLYVTLEPCPMCAGAVVLSRVEKVVFGAFDPKGGCSGTLMNLLQEERFNH QAEVVSGVLEEECGGMLSAFFRELRKKKKAARKNLSE Salmonella typhimurium (S. typhimurium) TadA: MPPAFITGVTSLSDVELDHEYWMRHALTLAKRAWDEREVPVGAVLVHNHRVIGEGWNRPIGR HDPTAHAE IMALRQGGLVLONYRLLDTTLYVTLEPCVMCAGAMVHSRIGRVVFGARDAKTGA AGSLIDVLHHPGMNHRVEIIEGVLRDECATLLSDFFRMRRQEIKALKKADRAEGAGPAV Shewanella putrefaciens (S. putrefaciens) TadA: MDE YWMQVAMOMAFEKAEAAGEVPVGAVLVKDGQQIATGYNLSISQHDPTAHAEILCLRSAGK KLENYRLLDATLYITLEPCAMCAGAMVHSRIARVVYGARDEKTGAAGTVVNLLQHPAFNHQV EVTSGVLAEACSAQLSRFFKRRRDEKKALKLAQRAQQGIE Haemophilus influenzae F3031 (H. influenzae) TadA: MDAAKVRSEFDEKMMRYALELADKAEALGEIPVGAVLVDDARNIIGEGWNLSIVQSDPTAHA EITALRNGAKNIQONYRLLNSTLYVTLEPCTMCAGAILHSRIKRLVFGASDYKTGAIGSRFHF FDDYKMNHTLEITSGVLAEECSQKLSTFFOKRREEKKIEKALLKSLSDK Caulobacter crescentus (C. crescentus) TadA: MRTDESEDQDHRMMRLALDAARAAAFAGETPVGAVILDPSTGEVIATAGNGPIAAHDPTAHA EIAAMRAAAAKLGNYRLTDLTLVVTLEPCAMCAGAISHARIGRVVEGADDPKGGAVVHGPKE FAQPTCHWRPEVTGGVLADESADLLRGFFRARRKAKI Geobacter sulfurreducens (G. sulfurreducens) TadA: MSSLKKTPIRDDAYWMGKAIREAAKARARDEVPIGAVIVRDGAVIGRGHNLREGSNDPSAHA EMIATRQAARRSANWRLTGATLYVTLEPCLMCMGAIILARLERVVFGCYDPKGGAAGSLYDL SADPRLNHQVRLSPGVCQEECGTMLSDFFRDLRRRKKAKATPALFIDERKVPPEP TadA*7.10 MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRATIGLHDPTAHAE TMA LRQGGLVMQONYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYP GMNHRVEITEGILADECAALLCYFFRMPROVEFNAQKKAQSSTD Additional TadA7.10 or TadA7.10 variants contemplated as a component of a heterodimer with a Tad A *8 include: GSSGSETPGTSESATPESSGSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGE GWNRAIGLHDPTAHAE IMALRQGGLVMQONYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVEG VRNAKTGAAGSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD TadA7.10 CP65 TAHAE IMALRQGGLVMONYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVEFGVRNAKTGAAGS LMDVLHYPGMNHRVEITEGILADECAARLLCYFFRMPRQVFNAQKKAQSSTDGSSGSETPGTS ESATPESSGSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDP TadA7.10 CP83 YRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYPGMNHRVEITE GILADECAALLCYFFRMPRQVFNAQKKAQSSTDGSSGSETPGTSESATPESSGSEVEFSHEY WMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMALRQGGLVMON TadA7.10 CP136 MNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTDGSSGSETPGTSESATPESSG SEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMAL ROGGLVMONYRLIDATLYVIFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYPG TadA7.10 C-truncate GSSGSETPGTSESATPESSGSEVEFSHEYWMRHALT LAKRARDEREVPVGAVLVLNNRVIGE GWNRAIGLHDPTAHAE IMALRQGGLVMQONYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVEG VRNAKTGAAGSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQVEN TadA7.10 C-truncate 2 GSSGSETPGTSESATPESSGSEVEFSHEYWMRHALT LAKRARDEREVPVGAVLVLNNRVIGE GWNRAIGLHDPTAHAEIMALRQGGLVMQONYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVEG VRNAKTGAAGSIMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQ TadA7.10 delta59-66+C-truncate GSSGSETPGTSESATPESSGSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGE GWNRAHAE IMALRQGGLVMONYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVEGVRNAKTGA AGSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQVEN TadA7.10 delta 59-66 GSSGSETPGTSESATPESSGSEVEFSHEYWMRHALT LAKRARDEREVPVGAVLVLNNRVIGE GWNRAHAE IMALRQGGLVMONYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGA AGSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQVEFNAQKKAQSSTD. In some embodiments, the adenosine deaminase variant comprises an alteration in TadA7.10. In some embodiments, TadA7.10 comprises an alteration at amino acid 82 or 166. In particular embodiments, a variant in the above-referenced sequence comprises one or more of the following alterations: Y147T, Y147R, Q154S, Y123H, V82S, T166R, and Q154R. In other embodiments, the adenosine deaminase variant comprises a combination of alterations selected from the group consisting of Y147R + Q154R +Y123H; Y147R + Q154R +176Y; Y147R + Q154R + T166R; Y147T + Q154R; Y147T + Q154S; and Y123H + Y147R + Q154R + I76Y. In other embodiments, the invention provides adenosine deaminase variants that include deletions, e.g., TadA7.10 comprising a deletion of the C terminus beginning at residue 149, 150, 151, 152, 153, 154, 155, 156, or 157. In other embodiments, the adenosine deaminase variant is a Tad A monomer comprising one or more of the following alterations: Y147T, Y147R, Q154S, Y123H, V82S, T166R, Q154R. In other embodiments, the adenosine deaminase variant is a monomer comprising the following alterations: Y147R + QI154R +Y123H; Y147R + Q154R + 176Y; Y147R + Q154R + T166R; Y147T + Q154R,; Y147T + Q154S; and Y123H + Y147 R + Q154R + I76Y. In still other embodiments, the adenosine deaminase variant is a homodimer comprising two adenosine deaminase domains each having one or more of the following alterations Y147T, Y147R, Q154S, Y123H, V828, T166R, Q154R. In other embodiments, the adenosine deaminase variant is a heterodimer comprising a wild-type adenosine deaminase domain or a TadA7.10 domain and an adenosine deaminase variant domain comprising one or more of the following alterations Y147T, Y147R, Q154S, Y123H, V82S, T166R, Q154R. In other embodiments, the adenosine deaminase variant is a heterodimer comprising a TadA7.10 domain and an adenosine deaminase variant of TadA7.10 comprising the following alterations: Y147R + Q154R +Y123H, Y147R + Q154R + I76Y, Y147R + Q154R + T166R, Y147T + Q154R,; Y147T + Q154S; and Y123H + Y147R + Q154R + 176Y. “Administering” is referred to herein as providing one or more compositions described herein to a patient or a subject. By way of example and without limitation, composition administration, e.g., injection, can be performed by intravenous (i.v.) injection, sub-cutaneous (s.c.) injection, intradermal (i.d.) injection, intraperitoneal (i.p.) injection, or intramuscular (i.m.) injection. One or more such routes can be employed. Parenteral administration can be, for example, by bolus injection or by gradual perfusion over time. In some embodiments, parenteral administration includes infusing or injecting intravascularly, intravenously, intramuscularly, intraarterially, intrathecally, intratumorally, intradermally, intraperitoneally, transtracheally, subcutaneously, subcuticularly, intraarticularly, subcapsularly, subarachnoidly and intrasternally. Alternatively, or concurrently, administration can be by the oral route. By “agent” is meant any small molecule chemical compound, antibody, nucleic acid molecule, or polypeptide, or fragments thereof. By “alteration” is meant a change (e.g. increase or decrease) in the structure, expression levels or activity of a gene or polypeptide as detected by standard art known methods such as those described herein. As used herein, an alteration includes a change in a polynucleotide or polypeptide sequence or a change in expression levels, such as a 10% change, a 25% change, a 40% change, a 50% change, or greater. By “ameliorate” is meant decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease. By “analog” is meant a molecule that is not identical, but has analogous functional or structural features. For example, a polynucleotide or polypeptide analog retains the biological activity of a corresponding naturally-occurring polynucleotide or polypeptide, while having certain modifications that enhance the analog's function relative to a naturally occurring polynucleotide or polypeptide. Such modifications could increase the analog's affinity for DNA, efficiency, specificity, protease or nuclease resistance, membrane permeability, and / or half-life, without altering, for example, ligand binding. An analog may include an unnatural nucleotide or amino acid. By "base editor (BE)" or “nucleobase editor (NBE)" is meant an agent that binds a polynucleotide and has nucleobase modifying activity. In various embodiment, the base editor comprises a nucleobase modifying polypeptide (e.g, a deaminase) and a nucleic acid programmable nucleotide binding domain in conjunction with a guide polynucleotide (e.g., guide RNA). In various embodiments, the agent is a biomolecular complex comprising a protein domain having base editing activity, i.e., a domain capable of modifying a base (e.g., A, T, C, G, or U) within a nucleic acid molecule (e.g., DNA). In some embodiments, the polynucleotide programmable DNA binding domain is fused or linked to a deaminase domain. In one embodiment, the agent is a fusion protein comprising a domain having base editing activity. In another embodiment, the protein domain having base editing activity is linked to the guide RNA (e.g., via an RNA binding motif on the guide RNA and an RNA binding domain fused to the deaminase). In some embodiments, the domain having base editing activity is capable of deaminating a base within a nucleic acid molecule. In some embodiments, the base editor is capable of deaminating one or more bases within a DNA molecule. In some embodiments, the base editor is capable of deaminating an adenosine (A) within DNA. In some embodiments, the base editor is an adenosine base editor (ABE). By “cytidine deaminase” is meant a polypeptide or fragment thereof capable of catalyzing a deamination reaction that converts an amino group to a carbonyl group. In some embodiments the cytidine deaminase has at least about 85% identity to APOBEC or AID. In one embodiment, the cytidine deaminase converts cytosine to uracil or 5-methylcytosine to thymine. PmCDAI, which is derived from Petromyzon marinus (Petromyzon marinus cytosine deaminase 1, “PmCDA1”), AID (Activation-induced cytidine deaminase; AICDA), which is derived from a mammal (e.g., human, swine, bovine, horse, monkey etc.), and APOBEC are exemplary cytidine deaminases. In some embodiments, the base editor is a reprogrammable base editor fused to a deaminase (e.g, an adenosine deaminase or cytidine deaminase). In some embodiments, the base editor is a Cas9 fused to a deaminase (e.g., an adenosine deaminase or cytidine deaminase). In some embodiments, the base editor is a nuclease-inactive Cas9 (dCas9) fused to a deaminase (e.g., an adenosine deaminase or cytidine deaminase). In some embodiments, the Cas9 is a circular permutant Cas9 (e.g., spCas9 or saCas9). Circular permutant Cas9s are known in the art and described, for example, in Oakes et al., Cell 176, 254-267, 2019. In some embodiments, the base editor is fused to an inhibitor of base excision repair, for example, a UGI domain, or a dISN domain. In some embodiments, the fusion protein comprises a Cas9 nickase fused to a deaminase and an inhibitor of base excision repair, such as a UGI or dISN domain. In other embodiments, the base editor is an abasic base editor. In some embodiments, the base editor is an adenosine base editor (ABE). In some embodiments, an adenosine deaminase is evolved from TadA. In some embodiments, the base editors of the present invention comprise a napDNAbp domain with an internally fused catalytic (e.g., deaminase) domain. In some embodiments, the napDNAbp is a Cas12a (Cpf1) with an internally fused deaminase domain. In some embodiments, the napDNAbp is a Cas12b (c2c1) with an internally fused deaminase domain. In some embodiments, the napDNAbp is a Casl2c (c2c3) with an internally fused deaminase domain. In some embodiments, the napDNAbp is a Casl2d (CasX) with an internally fused deaminase domain. In some embodiments, the napDNAbp is a Cas12e (CasY) with an internally fused deaminase domain. In some embodiments, the napDNAbp is a Cas12g with an internally fused deaminase domain. In some embodiments, the napDNAbp is a Cas12h with an internally fused deaminase domain. In some embodiments, napDNAbp is a Cas12i with an internally fused deaminase domain. In some embodiments, the base editor is a catalytically dead Cas12 (dCas12) fused to a deaminase domain. In some embodiments, the base editor is a Casl2 nickase (nCas12) fused to a deaminase domain. In some embodiments, base editors are generated (e.g., ABE8) by cloning an adenosine deaminase variant (e.g., Tad A*8) into a scaffold that includes a circular permutant Cas9 (e.g., spCAS9 or saCAS9) and a bipartite nuclear localization sequence. Circular permutant Cas9s are known in the art and described, for example, in Oakes ef a / ., Cell 176, 254-267, 2019. Exemplary circular permutants follow where the bold sequence indicates sequence derived from Cas9, the italics sequence denotes a linker sequence, and the underlined sequence denotes a bipartite nuclear localization sequence. CPS (with MSP “NGC=Pam Variant with mutations Regular Cas9 likes NGG” PID=Protein Interacting Domain and “D10A” nickase): EIGKATAKYFFYSNIMNFFKTE I TLANGE IRKRPLIE TNGE TGE IVWDKGRDFATVRKVLSM PQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWDPKKY GGFMQPTVAY SVLVVAKVEK GKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLI IKLPKYSLFELENGRKRM LASAKFLOKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISE FSKRVILADANLDKVLSAYNKHRDKPIREQAENIIHLFTLTNLGAPRAFKYFDTTIARKEYR STKEVLDATLIHQSITGLYE TRIDLSQLGGDGGSGGSGGSGGSGGSGGSGGMDKKYSIGLAT GTNSVGWAVITDE YKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGE TAEATRLKRTARRRYT RRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDEVAYHEKYPTI YHLRKKLVDS TDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQLVQTYNQLFE ENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLA EDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNTE ITKAPLSASM IKRYDEHHQDLTLLKALVRQQLPEKYKE IFFDQSKNGYAGY IDGGASQEEFYKFIKPILEKM DGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLKDNREKIEKILT FRIPYYVGPLARGNSRFAWMTRKSEE TI TPWNFEEVVDKGASAQSFIERMTNFDKNLPNEKV LPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQLKEDYF KKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVLTLTLFEDREM IEERLKTYAHLFDDKVMKQLKRRRY TGWGRLSRKLINGIRDKQSGKTILDFLKSDGFANRNF MQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDE LVKVMGRHK PENIVIEMARENQTTQKGOKNSRERMKRIEEGIKELGSQILKEHPVENTQLONEKLYLYYLQ NGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDS IDNKVLTRSDKNRGKSDNVPSEEVVKKM KNYWRQLLNAKLI TQRKFDNLTKAERGGLSE LDKAGFIKRQLVE TRQI TKHVAQILDSRMNT KYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVRE INNYHHAHDAYLNAVVGTALIKKY PK LESEFVYGDYKVYDVRKMIAKSEQEGADKRTADGSEFESPKKKRKV* In some embodiments, the ABES is selected from a base editor from Table 6-9, 13, or 14 infra. In some embodiments, ABER contains an adenosine deaminase variant evolved from TadA. In some embodiments, the adenosine deaminase variant of ABES is a TadA*8 variant as described in Table 7, 9, 13 or 14 infra. In some embodiments, the adenosine deaminase variant is TadA*7.10 variant (e.g. TadA*8) comprising one or more of an alteration selected from the group of Y147T, Y147R, Q1548S, Y123H, V828, T166R, and / or Q154R. In various embodiments, ABE8 comprises TadA*7.10 variant (e.g. TadA*8) with a combination of alterations selected from the group consisting of Y147T + Q154R; Y147T + Q1548; Y147R + Q1548; V82S + Q154S; V828 + Y147R; V82S + Q154R; V82S + Y123H; 176Y + V82S; V82S + Y123H + Y147T, V82S + Y123H + Y147R; V82S + Y123H + QI154R; Y147R + Q154R +Y123H; Y147R + Q154R + I76Y; Y147R + Q154R + T166R,; Y123H + Y147R + Q154R + 176Y; V82S + Y123H + Y147R + Q154R; and I76Y + V82S + Y123H + Y147R + Q154R. In some embodiments ABES is a monomeric construct. In some embodiments, ABES is a heterodimeric construct. In some embodiments, the ABES8 base editor comprises the sequence: MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAETIMA LRQGGLVMQONYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYP GMNHRVEITEGILADECAALLCTFFRMPROVENAQKKAQSSTD. In some embodiments, the polynucleotide programmable DNA binding domain is a CRISPR associated (e.g, Cas or Cpfl) enzyme. In some embodiments, the base editor is a catalytically dead Cas9 (dCas9) fused to a deaminase domain. In some embodiments, the base editor is a Cas9 nickase (nCas9) fused to a deaminase domain. In some embodiments, the base editor is fused to an inhibitor of base excision repair (BER). In some embodiments, the inhibitor of base excision repair is a uracil DNA glycosylase inhibitor (UGI). In some embodiments, the inhibitor of base excision repair is an inosine base excision repair inhibitor. Details of base editors are described in International PCT Application Nos. PCT / 2017 / 045381 (WO 2018 / 027078) and PCT / US2016 / 058344 (WO 2017 / 070632), each of which is incorporated herein by reference for its entirety. Also see Komor, A.C, et al, “Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage” Nature 533, 420-424 (2016); Gaudelli, N.M., ef al., “Programmable base editing of A+T to G+C in genomic DNA without DNA cleavage” Nature 551, 464-471 (2017); Komor, A.C, et al, “Improved base excision repair inhibition and bacteriophage Mu Gam protein yields C:G-to-T:A base editors with higher efficiency and product purity” Science Advances 3:eaa04774 (2017), and Rees, HA, et al., “Base editing: precision chemistry on the genome and transcriptome of living cells.” Nat Rev Genet. 2018 Dec;19(12):770-788. doi: 10.1038 / s41576-018-0059-1, the entire contents of which are hereby incorporated by reference. By way of example, a cytidine base editor as used in the base editing compositions, systems and methods described herein has the following nucleic acid sequence (8877 base pairs), (Addgene, Watertown, MA.; Komor AC, et al., 2017, Sci Adv., 30;3(8):eaa04774. doi: 10.1126 / sciadv.aa04774) as provided below. Polynucleotide sequences having at least 95% or greater identity to the BE4 nucleic acid sequence are also encompassed. L atatgccaag tacgccccct attgacgtca atgacggtaa atggcccgec tggcattatg 61 cccagtacat gaccttatgg gactttccta cttggcagta catctacgta ttagtcatcg 121 ctattaccat ggtgatgcgg ttttggcagt acatcaatgg gcgtggatag cggtttgact 181 cacggggatt tccaagtctc caccccattg acgtcaatgg gagtttgttt tggcaccaaa 241 atcaacggga ctttccaaaa tgtcgtaaca actccgcccc attgacgcaa atgggcggta 301 ggcgtgtacg gtgggaggtc tatataagca gagctggttt agtgaaccgt cagatccgcet 361 agagatccgc ggccgctaat acgactcact atagggagag ccgccaccat gagctcagag 421 actggcccag tggctgtgga ccccacattg agacggcgga tcgagcccca tgagtttgag 481 gtattcetteg atccgagaga getcecgcaay gagacctgee tgctttacga aattaattgg 541 gggggccgge actccatttyg gegacataca tcacagaaca ctaacaagca cgtcgaagte 601 aacttcatcy agaagttcac gacagaaaga tatttctgte cgaacacaag gtgcagecatt 661 acctggttte tcagetggay cecatgegge gaatgtagta gggccatcac tgaattcctg 721 tcaaggtatc cccacgtcac tctgtttatt tacatcgcaa ggctgtacca ccacgctgac 781 ccccgcaatc gacaaggcct gcgggatttg atctcttcag gtgtgactat ccaaattatg 841 actgagcagg agtcaggata ctgctggaga aactttgtga attatagccc gagtaatgaa 901 gcccactgge ctaggtatcc ccatctgtgg gtacgactgt acgttcttga actgtactgce 961 atcatactgg gcetgectce ttgtctcaac attctgagaa ggaagcagcece acagctgaca 1021 ttctttacca tcgectcttca gtcttgtcat taccagegac tgcccccaca cattctectgg 1081 gccaccgggt tgaaatctgg tggttcttet ggtggtteta gecggcagega gactcccggg 1141 acctcagagt ccgccacacce cgaaagttct ggtggttett ctggtggttce tgataaaaag 1201 tattctattyg gtttagccat cggcactaat tccgttggat gggetgtcat aaccgatgaa 1261 tacaaagtac cttcaaagaa atttaaggtg ttggggaaca cagaccgtca ttcgattaaa 1321 aagaatctta tcggtgccct cctattcgat agtggcgaaa cggcagaggce gactcgecctg 1381 aaacgaaccg ctcggagaag gtatacacgt cgcaagaacc gaatatgtta cttacaagaa 1441 atttttagca atgagatggc caaagttgac gattctttct ttcaccgttt ggaagagtcc 1501 ttccttgtcg aagaggacaa gaaacatgaa cggcacccca tctttggaaa catagtagat 1561 gaggtggcat atcatgaaaa gtacccaacyg atttatcacc tcagaaaaaa gctagttgac 1621 tcaactgata aagcggacct gaggttaate tacttggetc ttgeccatat gataaagtte 1681 cgtgggcact ttetcattga gggtgatcta aatccggaca acteggatgt cgacaaactyg 1741 ttcatccagt tagtacaaac ctataatcag ttgtttgaag agaaccctat aaatgcaagt 1801 ggcgtggatg cgaaggctat tcttagcgecc cgcctctcta aatcccgacg gctagaaaac 1861 ctgatcgcac aattacccgg agagaagaaa aatgggttgt tcggtaacct tatagcgctce 1921 tcactaggcc tgacaccaaa ttttaagtcg aacttcgact tagctgaaga tgccaaattg 1981 cagcttagta aggacacgta cgatgacgat ctcgacaatc tactggcaca aattggagat 2041 cagtatgcgg acttattttt ggctgccaaa aaccttageg atgcaatcct cctatctgac 2101 atactgagag ttaatactga gattaccaag gcgccgttat ccgettcaat gatcaaaagg 2161 tacgatgaac atcaccaaga cttgacactt ctcaaggccc tagtccgtca gcaactgcct 2221 gagaaatata aggaaatatt ctttgatcag tcgaaaaacg ggtacgcagg ttatattgac 2281 ggcggagcga gtcaagagga attctacaag tttatcaaac ccatattaga gaagatggat 2341 gggacggaag agttgcttgt aaaactcaat cgcgaagatc tactgcgaaa gcagcggact 2401 ttcgacaacg gtagcattcc acatcaaatc cacttaggcg aattgcatgce tatacttaga 2461 aggcaggagg atttttatcc gttcctcaaa gacaatcgtg aaaagattga gaaaatccta 2521 acctttcgca taccttacta tgtgggaccc ctggcccgag ggaactctcg gttecgcatgg 2581 atgacaagaa agtccgaaga aacgattact ccatggaatt ttgaggaagt tgtcgataaa 2641 ggtgcgtcag ctcaatcgtt catcgagagyg atgaccaact ttgacaagaa tttaccgaac 2701 gaaaaagtat tgcctaagca cagtttactt tacgagtatt tcacagtgta caatgaactc 2761 acgaaagtta agtatgtcac tgagggcatyg cgtaaacccg cctttcetaag cggagaacag 2821 aagaaagcaa tagtagatct gttattcaag accaaccgeca aagtgacagt taagcaattg 2881 aaagaggact actttaagaa aattgaatgc ttcgattctg tcgagatctc cggggtagaa 2941 gatcgattta atgcgtcact tggtacgtat catgacctcc taaagataat taaagataag 3001 gacttcctgg ataacgaaga gaatgaagat atcttagaag atatagtgtt gactcttacc 3061 ctctttgaag atcgggaaat gattgaggaa agactaaaaa catacgctca cctgttegac 3121 gataaggtta tgaaacagtt aaagaggcgt cgctatacgg gctggggacyg attgtcgegyg 3181 aaacttatca acgggataag agacaagcaa agtggtaaaa ctattctcga ttttctaaag 3241 agcgacggct tcgccaatag gaactttatg cagctgatcc atgatgactc tttaacctte 3301 aaagaggata tacaaaaggc acaggtttcc ggacaagggg actcattgca cgaacatatt 3361 gcgaatctty ctggttcgee agccatcaaa aagggcatac tccagacagt caaagtagtg 3421 gatgagctag ttaaggtcat gggacgtcac aaaccggaaa acattgtaat cgagatggca 3481 cgcgaaaatc aaacgactca gaaggggcaa aaaaacagtc gagagcggat gaagagaata 3541 gaagagggta ttaaagaact gggcagccag atcttaaagg agcatcctgt ggaaaatacc 3601 caattgcaga acgagaaact ttacctctat tacctacaaa atggaaggga catgtatgtt 3661 gatcaggaac tggacataaa ccgtttatct gattacgacg tcgatcacat tgtaccccaa 3721 tectttttga aggacgatte aatcgacaat aaagtgetta cacgetcgga taagaaccga 3781 gggaaaagty acaatgttce aagcgaggaa gtcgtaaaga aaatgaagaa ctattggcgg 3841 cagctcctaa atgecgaaact gataacgcaa agaaagtteg ataacttaac taaagctgag 3901 aggggtggct tgtctgaact tgacaaggcec ggatttatta aacgtcaget cgtggaaacc 3961 cgccaaatca caaagcatgt tgcacagata ctagattccc gaatgaatac gaaatacgac 4021 gagaacgata agctgattcg ggaagtcaaa gtaatcactt taaagtcaaa attggtgtcg 4081 gacttcagaa aggattttca attctataaa gttagggaga taaataacta ccaccatgcg 4141 cacgacgctt atcttaatgc cgtcgtaggg accgcactca ttaagaaata cccgaagcta 4201 gaaagtgagt ttgtgtatgg tgattacaaa gtttatgacg tccgtaagat gatcgcgaaa 4261 agcgaacagg agataggcaa ggctacagcc aaatacttct tttattctaa cattatgaat 4321 ttctttaaga cggaaatcac tctggcaaac ggagagatac gcaaacgacc tttaattgaa 4381 accaatgggg agacaggtga aatcgtatgg gataagggcc gggacttcge gacggtgaga 4441 aaagttttgt ccatgcccca agtcaacata gtaaagaaaa ctgaggtgca gaccggagygg 4501 ttttcaaagyg aatcgattct tccaaaaagg aatagtgata agctcatcge tcgtaaaaag 4561 gactgggacc cgaaaaagta cggtggcttc gatagcccta cagttgcecta ttctgteccta 4621 gtagtggcaa aagttgagaa gggaaaatcc aagaaactga agtcagtcaa agaattattg 4681 gggataacga ttatggagcg ctcgtctttt gaaaagaacc ccatcgactt ccttgaggcg 4741 aaaggttaca aggaagtaaa aaaggatctc ataattaaac taccaaagta tagtctgttt 4801 gagttagaaa atggccgaaa acggatgttyg gectagegecg gagagettca aaaggggaac 4861 gaactcgcac taccgtctaa atacgtgaat ttectgtatt tagegtcecca ttacgagaag 4921 ttgaaaggtt cacctgaaga taacgaacag aagcaacttt ttgttgagea gcacaaacat 4981 tatctcgacy aaatcataga gcaaattteg gaattcagta agagagtcat cctagctgat 5041 gccaatctgg acaaagtatt aagcgcatac aacaagcaca gggataaacc catacgtgag 5101 caggcggaaa atattatcca tttgtttact cttaccaacc tcggcgctcc agccgcattce 5161 aagtattttg acacaacgat agatcgcaaa cgatacactt ctaccaagga ggtgctagac 5221 gcgacactga ttcaccaatc catcacggga ttatatgaaa ctcggataga tttgtcacag 5281 cttgggggtyg actctggtgg ttcectggagga tctggtggtt ctactaatct gtcagatatt 5341 attgaaaagg agaccggtaa gcaactggtt atccaggaat ccatcctecat gctcccagag 5401 gaggtggaag aagtcattgg gaacaagccg gaaagcgata tactcgtgca caccgcctac 5461 gacgagagca ccgacgagaa tgtcatgctt ctgactagcg acgcccctga atacaagcct 5521 tgggctctygyg tcatacagga tagcaacggt gagaacaaga ttaagatgct ctctggtggt 5581 tctggaggat ctggtggttc tactaatctg tcagatatta ttgaaaagga gaccggtaag 5641 caactggtta tccaggaatc catcctcatg ctcccagagg aggtggaaga agtcattggg 5701 aacaagccgg aaagcgatat actcgtgcac accgcctacg acgagagcac cgacgagaat 5761 gtcatgcttc tgactagcga cgcccctgaa tacaagcctt gggctctggt catacaggat 5821 agcaacggtg agaacaagat taagatgctc tctggtggtt ctcccaagaa gaagaggaaa 5881 gtctaaccygyg tcatcatcac catcaccatt gagtttaaac ccgctgatca gecctegactyg 5941 tgcettectag ttgccageca totgttgttt geoccctecce cgtgecttee ttgaccctgg 6001 aaggtgccac tcccactgte ctttectaat aaaatgagga aattgcatcy cattgtctga 6061 gtaggtgtca ttctattety gggggtgggy tggggcagga cagcaagygy gaggattggg 6121 aagacaatag caggcatgct ggggatgcgg tgggctctat ggcttctgag gcggaaagaa 6181 ccagctgggg ctcgataccg tcgacctcta gctagagctt ggcgtaatca tggtcatagce 6241 tgtttcctgt gtgaaattgt tatccgctca caattccaca caacatacga gccggaagca 6301 taaagtgtaa agcctagggt gcctaatgag tgagctaact cacattaatt gcgttgeget 6361 cactgccege tttccagtcg ggaaacctgt cgtgccaget geattaatga atcggccaac 6421 gcgcggggag aggcggtttg cgtattggge gectettecge ttectegetce actgactcge 6481 tgcgctcggt cgttcggetg cggegagegg tatcagetca ctcaaaggcy gtaatacggt 6541 tatccacaga atcaggggat aacgcaggaa agaacatgtg agcaaaaggc cagcaaaagg 6601 ccaggaaccyg taaaaaggcc gegttgctgyg cgtttttcca taggctccege cccectgacg 6661 agcatcacaa aaatcgacgc tcaagtcaga ggtggcgaaa cccgacagga ctataaagat 6721 accaggcgtt tccccctgga agctccctcg tgcgectctce tgttcecgacce ctgccgetta 6781 ccggatacct gtccgeccttt ctcecttecgg gaagecgtgge gectttctcat agctcacgct 6841 gtaggtatct cagttcggtg taggtcgttc gctccaagct gggectgtgtg cacgaacccc 6901 ccgttcagcc cgaccgctgc gecttatccg gtaactatcg tcttgagtcce aacccggtaa 6961 gacacgactt atcgccactg gcagcagcca ctggtaacag gattagcaga gcgaggtatyg 7021 taggceggtgce tacagagtte ttgaagtggt ggcctaacta cggetacact agaagaacag 7081 tatttggtat ctgcgctety ctgaagecag ttaccttegg aaaaagagtt ggtagectett 7141 gatccggcaa acaaaccace gctggtageg gtggtttttt tgtttgcaag cagcagatta 7201 cgcgcagaaa aaaaggatct caagaagatc ctttgatctt ttctacgggg tctgacgecte 7261 agtggaacga aaactcacgt taagggattt tggtcatgag attatcaaaa aggatcttca 7321 cctagatcct tttaaattaa aaatgaagtt ttaaatcaat ctaaagtata tatgagtaaa 7381 cttggtctga cagttaccaa tgcttaatca gtgaggcacc tatctcagcg atctgtctat 7441 ttcgttcatc catagttgce tgactccceg tcgtgtagat aactacgata cgggagggct 7501 taccatctgg ccccagtgct gcaatgatac cgcgagaccc acgctcaccyg gctccagatt 7561 tatcagcaat aaaccagcca gccggaaggg ccgagcgeag aagtggtect gcaactttat 7621 ccgcctccat ccagtctatt aattgttgecc gggaagetag agtaagtagt tcgecagtta 7681 atagtttgcy caacgttgtt gccattgcta caggcatcgt ggtgtcacge tcgtegtttg 7741 gtatggcttc attcagctce ggttcccaac gatcaaggeg agttacatga tcececcatgt 7801 tgtgcaaaaa agcggttagc tccttcggtc cteccgatcgt tgtcagaagt aagttggccg 7861 cagtgttatc actcatggtt atggcagcac tgcataattc tcttactgtc atgccatccg 7921 taagatgctt ttctgtgact ggtgagtact caaccaagtc attctgagaa tagtgtatgce 7981 ggcgaccgag ttgctcttgc ccggcgtcaa tacgggataa taccgcgeca catagcagaa 8041 ctttaaaagt gcetcatcatt ggaaaacgtt ctteggggeg aaaactctca aggatcttac 8101 cgctgttgag atccagttcyg atgtaaccea ctegtgeace caactgatcet tcagcatctt 8161 ttactttcac cagecgtttct gggtgagcaa aaacaggaag gcaaaatgcec gcaaaaaagq 8221 gaataagggc gacacggaaa tgttgaatac tcatactett ccttttteaa tattattgaa 8281 gcatttatca gggttattgt ctcatgagcg gatacatatt tgaatgtatt tagaaaaata 8341 aacaaatagg ggttccgcgc acatttcccc gaaaagtgcc acctgacgtc gacggatcgg 8401 gagatcgatc tcccgatccc ctagggtcga ctctcagtac aatctgctct gatgccgeat 8461 agttaagcca gtatctgctc cctgcttgtg tgttggaggt cgctgagtag tgcgcgagca 8521 aaatttaagc tacaacaagg caaggcttga ccgacaattg catgaagaat ctgcttaggg 8581 ttaggcgttt tgcgctgctt cgcgatgtac gggccagata tacgegttga cattgattat 8641 tgactagtta ttaatagtaa tcaattacgg ggtcattagt tcatagccca tatatggagt 8701 tccgegttac ataacttacg gtaaatggcce cgcctggetg accgcccaac gacccccgec 8761 cattgacgtc aataatgacg tatgttccca tagtaacgcc aatagggact ttccattgac 8821 gtcaatgggt ggagtattta cggtaaactyg cccacttggc agtacatcaa gtgtatc BE4 amino acid sequence: MSSETGPVAVDPTLRRRIEPHEFEVFFDPRELRKETCLLYEINWGGRHSIWRHTSQNTNKHV EVNFIEKFTTERYFCPNTRCSITWFLSWSPCGECSRAITEFLSRYPHVTLFIYIARLYHHAD PRNRQGLRDLISSGVTIQIMTEQESGYCWRNFVNYSPSNEAHWPRYPHLWVRLYVLELYCII LGLPPCLNILRRKQPQLTFFTIALQSCHYQRLPPHILWATGLKSGGSSGGSSGSETPGTSES ATPESSGGSSGGSDKKYSIGLAIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGA LLFDSGETAEATRLKRTARRRYTRRKNRICYLQEI FSNEMAKVDDS FFHRLEESFLVEEDKK HERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDL NPDNSDVDKLFIQLVQTYNQLFEENP INASGVDAKAILSARLSKSRRLENLIAQLPGEKKNG LFGNLIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSD AILLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYA GYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAT LRRQEDFYPFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEET ITPWNFEEVVDK GASAQSFIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKK AIVDLLFKTNRKVTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLD NEENEDILEDIVLTLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGI RDKQSGKTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPA IKKGILQTVKVVDELVKVMGRHKPENIVIEMARENQTTQKGOKNSRERMKRIEEGIKELGSQ ILKEHPVENTQLONEKLYLYYLONGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDS IDNKV LTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIK RQLVETRQITKHVAQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVRE INN YHHAHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNI MNFFKTEITLANGEIRKRPLIETNGETGE IVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGG FSKESILPKRNSDKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGI TIMERSSFEKNPIDFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELAL PSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEITEQISEFSKRVILADANLDKV LSAYNKHRDKPIREQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSI TGLYETRIDLSQLGGDSGGSGGSGGSTNLSDITEKETGKQLVIQESILMLPEEVEEVIGNKP ESDILVHTAYDESTDENVMLLTSDAPEYKPWALVIQDSNGENKIKMLSGGSGGSGGSTNLSD IIEKETGKQLVIQESILMLPEEVEEVIGNKPESDILVHTAYDESTDENVMLLTSDAPEYKPW ALVIQDSNGENKIKMLSGGSPKKKRK By way of example, the adenine base editor (ABE) as used in the base editing compositions, systems and methods described herein has the nucleic acid sequence (8877 base pairs), (Addgene, Watertown, MA; Gaudelli NM, et al., Nature. 2017 Nov 23;551(7681):464- 471. doi: 10.1038 / nature24644; Koblan LW, et al., Nat Biotechnol. 2018 Oct;36(9):843-846. doi: 10.1038 / nbt.4172.) as provided below. Polynucleotide sequences having at least 95% or greater identity to the ABE nucleic acid sequence are also encompassed. ATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTARATGGCCCGCCTGGCATTATGCCCAGTAC AT GACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGC GG TTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGAT TTCCARAGTCTCCACCCCAT mG ACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCC cc ATTGACGCARATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACC GT CAGATCCGCTAGAGATCCGCGGCCGCTAATACGACTCACTATAGGGAGAGCCGCCACCATGARACGGA CA GCCGACGGAAGCGAGTTCGAGTCACCAAAGAAGAAGCGGARAGTCTCTGAAGTCGAGTTTAGCCACGA GT ATTGGATGAGGCACGCACTGACCCTGGCARAGCGAGCATGGGATGARAGAGAAGTCCCCGTGGGCGCC GT GCTGGTGCACAACAATAGAGTGATCGGAGAGGGATGGARCAGGCCAATCGGCCGCCACGACCCTACCG CA CACGCAGAGATCATGGCACTGAGGCAGGGAGGCCTGGTCATGCAGAATTACCGCCTGATCGATGCCAC cc TGTATGTGACACTGGAGCCATGCGTGATGTGCGCAGGAGCARTGATCCACAGCAGGATCGGARAGAGTG GT GTTCGGAGCACGGGACGCCARAGACCGGCGCAGCAGGCTCCCTGATGGATGTGCTGCACCACCCCGGCA TG AACCACCGGGTGGAGATCACAGAGGGAATCCTGGCAGACGAGTGCGCCGCCCTGCTGAGCGATTTCTT TA GAATGCGGAGACAGGAGATCAAGGCCCAGAAGAAGGCACAGAGCTCCACCGACTCTGGAGGATCTAGC GG AGGATCCTCTGGAAGCGAGACACCAGGCACAAGCGAGTCCGCCACACCAGAGAGCTCCGGCGGCTCCT cc GGAGGATCCTCTGAGGTGGAGTTTTCCCACGAGTACTGGATGAGACATGCCCTGACCCTGGCCAAGAG GC CACGCGATGAGAGGGAGGTGCCTGTGGGAGCCGTGCTGGTGCTGAACAATAGAGTGATCGGCGAGGGC mG GRACAGAGCCATCGGCCTGCACGACCCAACAGCCCATGCCGARATTATGGCCCTGAGACAGGGCGGCC mG GTCATGCAGAACTACAGACTGATTGACGCCACCCTGTACGTGACATTCGAGCCTTGCGTGATGTGCGC OG GCGCCATGATCCACTCTAGGATCGGCCGCGTGGTGTTTGGCGTGAGGAACGCARRARCCGGCGCCGCA cc CTCCCTGATGGACGTGCTGCACTACCCCGGCATGAATCACCGCGTCGARATTACCGAGGGAATCCTGG CA GATGAATGTGCCGCCCTGCTGTGCTATTTCTTTCGGATGCCTAGACAGGTGTTCAATGCTCAGAAGAA GG CCCAGAGCTCCACCGACTCCGGAGGATCTAGCGGAGGCTCCTCTGGCTCTGAGACACCTGGCACAAGC GA GAGCGCAACACCTGAAAGCAGCGGGGGCAGCAGCGGGGGGTCAGACAAGAAGTACAGCATCGGCCTGG oc ATCGGCACCAACTCTGTGGGCTGGGCCGTGATCACCGACGAGTACARGGTGCCCAGCARAGARATTCAA GG TGCTGGGCAACACCGACCGGCACAGCATCAAGAAGRACCTGATCGGAGCCCTGCTGTTCGACAGCGGC GA AACAGCCGAGGCCACCCGGCTGAAGAGAACCGCCAGARGAAGATACACCAGACGGAAGAACCGGATCT GC TATCTGCAAGAGATCTTCAGCAACGAGATGGCCAAGGTGGACGACAGCTTCTTCCACAGACTGGAAGA GT CCTTCCTGGTGGARGAGGATAAGAAGCACGAGCGGCACCCCATCTTCGGCARCATCGTGGACGAGGTG acc CTACCACGAGAAGTACCCCACCATCTACCACCTGAGAAAGAAACTGGTGGACAGCACCGACAAGGCCG AC CTGCGGCTGATCTATCTGGCCCTGGCCCACATGATCAAGTTCCGGGGCCACTTCCTGATCGAGGGCGA co TGAACCCCGACAARCAGCGACGTGGACAAGCTGTTCATCCAGCTGGTGCAGACCTACAACCAGCTGTTC GA GGAAAARCCCCATCAACGCCAGCGGCGTGGACGCCARGGCCATCCTGTCTGCCAGACTGAGCAAGAGCA GA CGGCTGGAARATCTGATCGCCCAGCTGCCCGGCGAGAAGARAGAATGGCCTGTTCGGARACCTGATTGC oc TGAGCCTGGGCCTGACCCCCRACTTCAAGAGCAACTTCGACCTGGCCGAGGATGCCARACTGCAGCTG AGC CRAGGACACCTACGACGACGACCTGGACAACCTGCTGGCCCAGATCGGCGACCAGTACGCCGACCTGT TT CTGGCCGCCAAGAACCTGTCCGACGCCATCCTGCTGAGCGACATCCTGAGAGTGARCACCGAGATCAC OA AGGCCCCCCTGAGCGCCTCTATGATCAAGAGATACGACGAGCACCACCAGGACCTGACCCTGCTGRAA cc TCTCGTGCGGCAGCAGCTGCCTGAGAAGTACARAGAGATTTTCTTCGACCAGAGCAAGAACGGCTACG co GGCTACATTGACGGCGGAGCCAGCCAGGAAGAGTTCTACARGTTCATCAAGCCCATCCTGGARAAGAT GG ACGGCACCGAGGAACTGCTCGTGAAGCTGAACAGAGAGGACCTGCTGCGGARAGCAGCGGACCTTCGAC AR CGGCAGCATCCCCCACCAGATCCACCTGGGAGAGCTGCACGCCATTCTGCGGCGGCAGGAAGATTTTT AC CCATTCCTGAAGGACARACCGGGARARAGATCGAGAAGATCCTGACCTTCCGCATCCCCTACTACGTGGG a 4 CTCTGGCCAGGGGAARCAGCAGATTCGCCTGGATGACCAGARAGAGCGAGGARACCATCACCCCCTGG AD CTTCGAGGAAGTGGTGGACARAGGGCGCTTCCGCCCAGAGCTTCATCGAGCGGATGACCARCTTCGATA AG AACCTGCCCAACGAGAAGGTGCTGCCCARGCACAGCCTGCTGTACGAGTACTTCACCGTGTATAARCGA GC TGACCAAAGTGARATACGTGACCGAGGGAATGAGAAAGCCCGCCTTCCTGAGCGGCGAGCAGARARRG cc CATCGTGGACCTGCTGTTCAAGACCAACCGGARAGTGACCGTGAAGCAGCTGAAAGAGGACTACTTCA AG AAAATCGAGTGCTTCGACTCCGTGGARATCTCCGGCGTGGAAGATCGGTTCAACGCCTCCCTGGGCAC AT ACCACGATCTGCTGAAARATTATCAAGGACAAGGACTTCCTGGACAATGAGGAAAACGAGGACATTCTG GA AGATATCGTGCTGACCCTGACACTGTTTGAGGACAGAGAGATGATCGAGGARCGGCTGAAAACCTATG cc CACCTGTTCGACGACAAAGTGATGAAGCAGCTGAAGCGGCGGAGATACACCGGCTGGGGCAGGCTGAG oc GGAAGCTGATCAACGGCATCCGGGACAAGCAGTCCGGCRAGACAARTCCTGGATTTCCTGAAGTCCGAC 8G CTTCGCCRACAGARACTTCATGCAGCTGATCCACGACGACAGCCTGACCTTTARAGAGGACATCCAGA RAD GCCCAGGTGTCCGGCCAGGGCGATAGCCTGCACGAGCACATTGCCAATCTGGCCGGCAGCCCCGCCAT TA AGAAGGGCATCCTGCAGACAGTGAAGGTGGTGGACGAGCTCGTGARAGTGATGGGCCGGCACAAGCCC GA GAACATCGTGATCGAAATGGCCAGAGAGAACCAGACCACCCAGAAGGGACAGAAGAACAGCCGCGAGA GA ATGAAGCGGATCGAAGAGGGCATCAAAGAGCTGGGCAGCCAGATCCTGAAAGAACACCCCGTGGARRA CA CCCAGCTGCAGAACGAGAAGCTGTACCTGTACTACCTGCAGAATGGGCGGGATATGTACGTGGACCAG GA ACTGGACATCAACCGGCTGTCCGACTACGATGTGGACCATATCGTGCCTCAGAGCTTTCTGARGGACG AC TCCATCGACRACARAGGTGCTGACCAGAAGCGACAAGAACCGGGGCAAGAGCGACARACGTGCCCTCCGA AG AGGTCGTGAAGAAGATGAAGARACTACTGGCGGCAGCTGCTGAACGCCAAGCTGATTACCCAGAGARAAG e CGACRATCTGACCAAGGCCGAGAGAGGCGGCCTGAGCGRAACTGGATAAGGCCGGCTTCATCARGAGAC AG CTGGTGGAAACCCGGCAGATCACARAGCACGTGGCACAGATCCTGGACTCCCGGATGAACACTAAGTA CG ACGAGAATGACAAGCTGATCCGGGAAGTGAAAGTGATCACCCTGAAGTCCARGCTGGTGTCCGATTTC [oi] GAAGGATTTCCAGTTTTACARAGTGCGCGAGATCAACAACTACCACCACGCCCACGACGCCTACCTGA AC GCCGTCGTGGGAACCGCCCTGATCAAAAAGTACCCTAAGCTGGARAGCGAGTTCGTGTACGGCGACTA CA AGGTGTACGACGTGCGGAAGATGATCGCCAAGAGCGAGCAGGARATCGGCARGGCTACCGCCAAGTAC TT CTTCTACAGCAACATCATGAARCTTTTTCAAGACCGAGATTACCCTGGCCAACGGCGAGATCCGGAAGC GG CCTCTGATCGAGACARAACGGCGAAACCGGGGAGATCGTGTGGGATARGGGCCGGGATTTTGCCACCGT aC GGAARGTGCTGAGCATGCCCCAAGTGAATATCGTGARARAGACCGAGGTGCAGACAGGCGGCTTCAGC AD AGAGTCTATCCTGCCCRAGAGGAACAGCGATAAGCTGATCGCCAGARAGARGGACTGGGACCCTARGA AG TACGGCGGCTTCGACAGCCCCACCGTGGCCTATTCTGTGCTGGTGGTGGCCARAGTGGARRAGGGCAA GT CCAAGAARCTGAAGAGTGTGRAAGAGCTGCTGGGGATCACCATCATGGARAAGARGCAGCTTCGAGAAG AR TCCCATCGACTTTCTGGAAGCCAAGGGCTACARAGAAGTGARARAGGACCTGATCATCARGCTGCCTA AG TACTCCCTGTTCGAGCTGGARAACGGCCGGAAGAGAATGCTGGCCTCTGCCGGCGAACTGCAGAAGGG AD ACGAACTGGCCCTGCCCTCCARATATGTGAACTTCCTGTACCTGGCCAGCCACTATGAGAAGCTGAAG [op CTCCCCCGAGGATAATGAGCAGAAACAGCTGTTTGTGGARCAGCACAAGCACTACCTGGACGAGATCA TC GAGCAGATCAGCGAGTTCTCCAAGAGAGTGATCCTGGCCGACGCTAATCTGGACARAGTGCTGTCCGC oT ACAACAAGCACCGGGATAAGCCCATCAGAGAGCAGGCCGAGAATATCATCCACCTGTTTACCCTGACC AD TCTGGGAGCCCCTGCCGCCTTCAAGTACTTTGACACCACCATCGACCGGARGAGGTACACCAGCACCA RAD GAGGTGCTGGACGCCACCCTGATCCACCAGAGCATCACCGGCCTGTACGAGACACGGATCGACCTGTC mc AGCTGGGAGGTGACTCTGGCGGCTCARAAAGAACCGCCGACGGCAGCGAATTCGAGCCCAAGARAGAAG AG GAAAGTCTAACCGGTCATCATCACCATCACCATTGAGTTTAAACCCGCTGATCAGCCTCGACTGTGCC TT CTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCC AC TGTCCTTTCCTAATAARATGAGGARATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGG GT GGGGTGGGGCAGGACAGCARGGGGGAGGAT TGGGARGACAATAGCAGGCATGCTGGGGATGCGGTGGG CT CTATGGCTTCTGAGGCGGARRGAACCAGCTGGGGCTCGATACCGTCGACCTCTAGCTAGAGCTTGGCG TA ATCATGGTCATAGCTGTTTCCTGTGTGARATTGTTATCCGCTCACAATTCCACACRACATACGAGCCG CGA AGCATARAGTGTAAAGCCTAGGGTGCCTAATGAGTGAGCTAACTCACATTAARTTGCGTTGCGCTCACT GC CCGCTTTCCAGTCGGGARARCCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGC GC TTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGC GA GCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAA CA TGTGAGCAARAGGCCAGCARRAGGCCAGGAACCGTARARRGGCCGCGTTGCTGGCGTTTTTCCATAGG CT CCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTAT AR AGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGG AT ACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGT ne GGTGTAGGTCGTTCGCTCCARAGCTGGGCTGTGTGCACGARCCCCCCGTTCAGCCCGACCGCTGCGCCT TA TCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGG TA ACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAARCTACGGC TA CACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGARARAGAGTTGGTA acc TCTTGATCCGGCARACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCG CA GAAAARAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACACTCAGTGGAACGAARRAC mC ACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAAT GA AGTTTTAAATCAATCTARAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGA GG CACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATARCT Al GATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTC CA GATTTATCAGCAATARACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCARCTTTATCCGC oT CCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGT AAGTAGTTCGCCAGTTAATAGTTTGCGCAAC GT TGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTT cc CAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCC GA TCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTT AC TGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGT GAGTACTCAACCAAGTCATTCTGAGAATAGT GT ATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTT RAD AAGTGCTCATCATTGGRRAACGTTCTTCGGGGCGRARARACTCTCAAGGATCTTACCGCTGTTGAGATCC AG TTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGT GA GCARRARACAGGAAGGCARARATGCCGCAARARAGGGAATARGGGCGACACGGARATGTTGAATACTCAT AC TCTTCCTTTTTCRAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAA TG TATTTAGAAARARATAAACAAATAGGGGTTCCGCGCACATTTCCCCGARRAGTGCCACCTGACGTCGACG GA TCGGGAGATCGATCTCCCGATCCCCTAGGGTCGACTCTCAGTACAATCTGCTCTGATGCCGCATAGTT AA GCCAGTATCTGCTCCCTGCTTGTGTGTTGGAGGTCGCTGAGTAGTGCGCGAGCARAATTTAAGCTACA AC AAGGCAAGGCTTGACCGACAATTGCATGAAGAATCTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCG AT GTACGGGCCAGATATACGCGTTGACATTGATTATTGACTAGTTATTAATAGTAATCARTTACGGGGTC AT TAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTARATGGCCCGCCTGGCTGACCG oc CAACGACCCCCGCCCATTGACGTCARATAATGACGTATGTTCCCATAGTAACGCCARTAGGGACTTTCC AT TGACGTCAATGGGTGGAGTATT TACGGTAAACTGCCCACTTCGGCAGTACATCAAGTCGTATC By “base editing activity” is meant acting to chemically alter a base within a polynucleotide. In one embodiment, a first base is converted to a second base. In one embodiment, the base editing activity is cytidine deaminase activity, e.g., converting target C+Gto T*A. In another embodiment, the base editing activity is adenosine or adenine deaminase activity, e.g., converting A+T to G+C. In another embodiment, the base editing activity is cytidine deaminase activity, e.g., converting target C+G to T+A and adenosine or adenine deaminase activity, e.g., converting AT to G+C. In some embodiments, base editing activity is assessed by efficiency of editing. Base editing efficiency may be measured by any suitable means, for example, by sanger sequencing or next generation sequencing. In some embodiments, base editing efficiency is measured by percentage of total sequencing reads with nucleobase conversion effected by the base editor, for example, percentage of total sequencing reads with target A.T base pair converted to a G.C base pair. In some embodiments, base editing efficiency is measured by percentage of total cells with nucleobase conversion effected by the abse editor, when base editing is performed in a population of cells. The term “base editor system” refers to a system for editing a nucleobase of a target nucleotide sequence. In various embodiments, the base editor system comprises (1) a polynucleotide programmable nucleotide binding domain (e.g., Cas9); (2) a deaminase domain (e.g., an adenosine deaminase or a cytidine deaminase) for deaminating said nucleobase; and (3) one or more guide polynucleotide (e.g., guide RNA). In some embodiments, the polynucleotide programmable nucleotide binding domain is a polynucleotide programmable DNA binding domain. In some embodiments, the base editor is an adenine or adenosine base editor (ABE). In some embodiments, the base editor system is ABES. In some embodiments, a base editor system may comprise more than one base editing component. For example, a base editor system may include more than one deaminase. In some embodiments, a base editor system may include one or more adenosine deaminases. In some embodiments, a single guide polynucleotide may be utilized to target different deaminases to a target nucleic acid sequence. In some embodiments, a single pair of guide polynucleotides may be utilized to target different deaminases to a target nucleic acid sequence. The deaminase domain and the polynucleotide programmable nucleotide binding component of a base editor system may be associated with each other covalently or non- covalently, or any combination of associations and interactions thereof. For example, in some embodiments, a deaminase domain can be targeted to a target nucleotide sequence by a polynucleotide programmable nucleotide binding domain. In some embodiments, a polynucleotide programmable nucleotide binding domain can be fused or linked to a deaminase domain. In some embodiments, a polynucleotide programmable nucleotide binding domain can target a deaminase domain to a target nucleotide sequence by non-covalently interacting with or associating with the deaminase domain. For example, in some embodiments, the deaminase domain can comprise an additional heterologous portion or domain that is capable of interacting with, associating with, or capable of forming a complex with an additional heterologous portion or domain that is part of a polynucleotide programmable nucleotide binding domain. In some embodiments, the additional heterologous portion may be capable of binding to, interacting with, associating with, or forming a complex with a polypeptide. In some embodiments, the additional heterologous portion may be capable of binding to, interacting with, associating with, or forming a complex with a polynucleotide. In some embodiments, the additional heterologous portion may be capable of binding to a guide polynucleotide. In some embodiments, the additional heterologous portion may be capable of binding to a polypeptide linker. In some embodiments, the additional heterologous portion may be capable of binding to a polynucleotide linker. The additional heterologous portion may be a protein domain. In some embodiments, the additional heterologous portion may be a K Homology (KH) domain, a MS2 coat protein domain, a PP7 coat protein domain, a SfMu Com coat protein domain, a steril alpha motif, a telomerase Ku binding motif and Ku protein, a telomerase Sm7 binding motif and Sm7 protein, or an RNA recognition motif, A base editor system may further comprise a guide polynucleotide component. It should be appreciated that components of the base editor system may be associated with each other via covalent bonds, noncovalent interactions, or any combination of associations and interactions thereof. In some embodiments, a deaminase domain can be targeted to a target nucleotide sequence by a guide polynucleotide. For example, in some embodiments, the deaminase domain can comprise an additional heterologous portion or domain (e.g. polynucleotide binding domain such as an RNA or DNA binding protein) that is capable of interacting with, associating with, or capable of forming a complex with a portion or segment (e.g., a polynucleotide motif) of a guide polynucleotide. In some embodiments, the additional heterologous portion or domain (e.g., polynucleotide binding domain such as an RNA or DNA binding protein) can be fused or linked to the deaminase domain. In some embodiments, the additional heterologous portion may be capable of binding to, interacting with, associating with, or forming a complex with a polypeptide. In some embodiments, the additional heterologous portion may be capable of binding to, interacting with, associating with, or forming a complex with a polynucleotide. In some embodiments, the additional heterologous portion may be capable of binding to a guide polynucleotide. In some embodiments, the additional heterologous portion may be capable of binding to a polypeptide linker. In some embodiments, the additional heterologous portion may be capable of binding to a polynucleotide linker. The additional heterologous portion may be a protein domain. In some embodiments, the additional heterologous portion may be a K Homology (KH) domain, a MS2 coat protein domain, a PP7 coat protein domain, a SfMu Com coat protein domain, a sterile alpha motif, a telomerase Ku binding motif and Ku protein, a telomerase Sm7 binding motif and Sm?7 protein, or an RNA recognition motif. In some embodiments, a base editor system can further comprise an inhibitor of base excision repair (BER) component. It should be appreciated that components of the base editor system may be associated with each other via covalent bonds, noncovalent interactions, or any combination of associations and interactions thereof. The inhibitor of BER component may comprise a BER inhibitor. In some embodiments, the inhibitor of BER can be a uracil DNA glycosylase inhibitor (UGI). In some embodiments, the inhibitor of BER can be an inosine BER inhibitor. In some embodiments, the inhibitor of BER can be targeted to the target nucleotide sequence by the polynucleotide programmable nucleotide binding domain. In some embodiments, a polynucleotide programmable nucleotide binding domain can be fused or linked to an inhibitor of BER. In some embodiments, a polynucleotide programmable nucleotide binding domain can be fused or linked to a deaminase domain and an inhibitor of BER. In some embodiments, a polynucleotide programmable nucleotide binding domain can target an inhibitor of BER to a target nucleotide sequence by non-covalently interacting with or associating with the inhibitor of BER. For example, in some embodiments, the inhibitor of BER component can comprise an additional heterologous portion or domain that is capable of interacting with, associating with, or capable of forming a complex with an additional heterologous portion or domain that is part of a polynucleotide programmable nucleotide binding domain. In some embodiments, the inhibitor of BER can be targeted to the target nucleotide sequence by the guide polynucleotide. For example, in some embodiments, the inhibitor of BER can comprise an additional heterologous portion or domain (e.g, polynucleotide binding domain such as an RNA or DNA binding protein) that is capable of interacting with, associating with, or capable of forming a complex with a portion or segment (e.g., a polynucleotide motif) of a guide polynucleotide. In some embodiments, the additional heterologous portion or domain of the guide polynucleotide (e.g., polynucleotide binding domain such as an RNA or DNA binding protein) can be fused or linked to the inhibitor of BER. In some embodiments, the additional heterologous portion may be capable of binding to, interacting with, associating with, or forming a complex with a polynucleotide. In some embodiments, the additional heterologous portion may be capable of binding to a guide polynucleotide. In some embodiments, the additional heterologous portion may be capable of binding to a polypeptide linker. In some embodiments, the additional heterologous portion may be capable of binding to a polynucleotide linker. The additional heterologous portion may be a protein domain. In some embodiments, the additional heterologous portion may be a K Homology (KH) domain, a MS2 coat protein domain, a PP7 coat protein domain, a SfMu Com coat protein domain, a sterile alpha motif, a telomerase Ku binding motif and Ku protein, a telomerase Sm7 binding motif and Sm7 protein, or an RNA recognition motif. The term “Cas9” or “Cas9 domain” refers to an RNA guided nuclease comprising a Cas9 protein, or a fragment thereof (e.g., a protein comprising an active, inactive, or partially active DNA cleavage domain of Cas9, and / or the gRNA binding domain of Cas9). A Cas9 nuclease is also referred to sometimes as a Casnl nuclease or a CRISPR (clustered regularly interspaced short palindromic repeat) associated nuclease. CRISPR is an adaptive immune system that provides protection against mobile genetic elements (viruses, transposable elements and conjugative plasmids). CRISPR clusters contain spacers, sequences complementary to antecedent mobile elements, and target invading nucleic acids. CRISPR clusters are transcribed and processed into CRISPR RNA (ctRNA). In type II CRISPR systems correct processing of pre-crRNA requires a trans-encoded small RNA (tracrRNA), endogenous ribonuclease 3 (mc) and a Cas9 protein. The tracrRNA serves as a guide for ribonuclease 3-aided processing of pre-crRNA. Subsequently, Cas9 / crRNA / tractRNA endonucleolytically cleaves linear or circular dsDNA target complementary to the spacer. The target strand not complementary to crRNA is first cut endonucleolytically, then trimmed 3'-5" exonucleolytically. In nature, DNA-binding and cleavage typically requires protein and both RNAs. However, single guide RNAs (“sgRNA”, or simply “gNRA”) can be engineered 0 as to incorporate aspects of both the crRNA and tracrRNA into a single RNA species. See, e.g., Jinek M., et al., Science 337:816-821(2012), the entire contents of which is hereby incorporated by reference. Cas9 recognizes a short motif in the CRISPR repeat sequences (the PAM or protospacer adjacent motif) to help distinguish self versus non-self. Cas9 nuclease sequences and structures are well known to those of skill in the art (see, e.g., “Complete genome sequence of an M1 strain of Streptococcus pyogenes.” Ferretti ef al., Proc. Natl. Acad. Sci. U.S.A. 98:4658-4663(2001); “CRISPR RNA maturation by trans- encoded small RNA and host factor RNase IIL.” Deltcheva E., ef al., Nature 471:602- 607(2011); and “A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity.” Jinek M., et al., Science 337:816-821(2012), the entire contents of each of which are incorporated herein by reference). Cas9 orthologs have been described in various species, including, but not limited to, S. pyogenes and S. thermophilus. Additional suitable Cas9 nucleases and sequences will be apparent to those of skill in the art based on this disclosure, and such Cas9 nucleases and sequences include Cas9 sequences from the organisms and loci disclosed in Chylinski, Rhun, and Charpentier, “The tractRNA and Cas9 families of type II CRISPR-Cas immunity systems” (2013) RNA Biology 10:5, 726-737; the entire contents of which are incorporated herein by reference. An exemplary Cas9, is Streptococcus pyogenes Cas9 (spCas9), the amino acid sequence of which is provided below: MDKKYSIGLDIGTNSVGWAVITDDYKVPSKKFKVLGNTDRHS IKKNLIGALLFGSGETAEAT RLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVD EVAYHEKYPTIYHLRKKLADSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLEL QLVQIYNQLFEENPINASRVDAKAILSARLSKSRRLENLIAQLPGEKRNGLFGNLIALSLGL TPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNS EITKAPLSASMIKRYDEHHQDLTLLKALVRQQOLPEKYKEIFFDOSKNGYAGYIDGGASQEEF YKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLK DNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMT NFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRK VTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGAYHDLLKI IKDKDFLDNEENEDILEDIV LTLTLFEDRGMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDF LKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGHSLHEQIANLAGSPATIKKGILQTVKIV DELVKVMGHKPENIVIEMARENQTTQKGOKNSRERMKRIEEGIKELGSQILKEHPVENTQLQ NEKLYLYYLONGRDMYVDQELDINRLSDYDVDHIVPQSFIKDDS IDNKVLTRSDKNRGKSDN VPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKHV AQILDSRMNTKYDENDKL IREVKVITLKSKLVSDFRKDFQFYKVRE INNYHHAHDAYLNAVV GTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQREIGKATAKYFFYSNIMNFFKTEITLANG EIRKRPLIETNGETGEIVWDKGRDFATVRKVL.SMPQVNIVKKTEVQTGGFSKESILPKRNSD KLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPI DFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASH YEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIR EQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQL GGD (single underline: HNH domain; double underline: RuvC domain) A nuclease-inactivated Cas9 protein may interchangeably be referred to as a “dCas9” protein (for nuclease-“dead” Cas9) or catalytically inactive Cas9. Methods for generating a Cas9 protein (or a fragment thereof) having an inactive DNA cleavage domain are known (See, e.g., Jinek et al., Science. 337:816-821(2012); Qi et al., “Repurposing CRISPR as an RNA-Guided Platform for Sequence-Specific Control of Gene Expression” (2013) Cell. 28;152(5):1173-83, the entire contents of each of which are incorporated herein by reference). For example, the DNA cleavage domain of Cas9 is known to include two subdomains, the HNH nuclease subdomain and the RuvC1 subdomain. The HNH subdomain cleaves the strand complementary to the gRNA, whereas the RuvC1 subdomain cleaves the non-complementary strand. Mutations within these subdomains can silence the nuclease activity of Cas9. For example, the mutations D10A and H840A completely inactivate the nuclease activity of S. pyogenes Cas9 (Jinek et al., Science. 337:816-821(2012); Qi et al., Cell. 28,152(5):1173-83 (2013)). In some embodiments, a Cas9 nuclease has an inactive (e.g., an inactivated) DNA cleavage domain, that is, the Cas9 is a nickase, referred to as an “nCas9” protein (for “nickase” Cas9). In some embodiments, proteins comprising fragments of Cas9 are provided. For example, in some embodiments, a protein comprises one of two Cas9 domains: (1) the gRNA binding domain of Cas9; or (2) the DNA cleavage domain of Cas9. In some embodiments, proteins comprising Cas9 or fragments thereof are referred to as “Cas9 variants.” A Cas9 variant shares homology to Cas9, or a fragment thereof. For example, a Cas9 variant is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% identical to wild-type Cas9. In some embodiments, the Cas variant may have 1,2, 3,4,5,6,7,8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more amino acid changes compared to wild-type Cas9. In some embodiments, the Cas9 variant comprises a fragment of Cas9 (e.g., a gRNA binding domain or a DNA-cleavage domain), such that the fragment is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% identical to the corresponding fragment of wild-type Cas9. In some embodiments, the fragment is at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% identical, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% of the amino acid length of a corresponding wild-type Cas9. In some embodiments, the fragment is at least 100 amino acids in length. In some embodiments, the fragment is at least 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, or at least 1300 amino acids in length. In some embodiments, wild-type Cas9 corresponds to Cas9 from Streptococcus pyogenes (NCBI Reference Sequence: NC_017053.1, nucleotide and amino acid sequences as follows). ATGGATAAGAAATACTCAATAGGCTTAGATATCGGCACAAATAGCGTCGGATGGGCGGTGAT CACTGATGATTATAAGGTTCCGTCTARARAGTTCAAGGTTCTGGGAAATACAGACCGCCACA GTATCAAAAAARATCTTATAGGGGCTCTTTTATTTGGCAGTGGAGAGACAGCGGAAGCGACT CGTCTCAAACGGACAGCTCGTAGAAGGTATACACGTCGGAAGAATCGTATTTGTTATCTACA GGAGATTTTTTCARATGAGATGGCGARAGTAGATGATAGTTTCTTTCATCGACTTGAAGAGT CTTTTTTGGTGGAAGARGACARGAAGCATGARCGTCATCCTATTTTTGGAAATATAGTAGAT GAAGTTGCTTATCATGAGAAATATCCAACTATCTATCATCTGCGAAAAAAATTGGCAGATTC TACTGATARAGCGGATTTGCGCTTAATCTATTTGGCCTTAGCGCATATGATTAAGTTTCGTG GTCATTTTTTGATTGAGGGAGATTTARATCCTGATAATAGTGATGTGGACAAACTATTTATC CAGTTGGTACARATCTACAATCAATTATTTGAAGAAAACCCTATTAACGCAAGTAGAGTAGA TGCTAAAGCGATTCTTTCTGCACGATTGAGTAAAT CAAGACGATTAGAAAATCTCATTGCTC AGCTCCCCGGTGAGAAGAGAAATGGCTTGTTTGGGAATCTCATTGCTTTGTCATTGGGATTG ACCCCTAATTTTAAATCAAATTTTGATTTGGCAGAAGATGCTAAATTACAGCTTTCAAAAGA TACTTACGATGATGATTTAGATAATTTATTGGCGCAAATTGGAGATCAATATGCTGATTTGT TTTTGGCAGCTAAGAATTTATCAGATGCTATTTTACTTTCAGATATCCTAAGAGTAAATAGT GAAATAACTAAGGCTCCCCTATCAGC TTCAATGATTAAGCGCTACGATGAACATCATCAAGA CTTGACTCTTTTAAAAGCTTTAGTTCGACAACAACTTCCAGAAAAGTATAAAGAAATCTTTT TTGATCAATCAAARAACGGATATGCAGGTTATATTGATGGGGGAGCTAGCCAAGAAGAATTT TATAAATTTATCAAACCAATTTTAGAAAAAATGGATGGTACTGAGGAATTATTGGTGAAACT AAATCGTGAAGATTTGCTGCGCAAGCAACGGACCTTTGACAACGGCTCTATTCCCCATCARA TTCACTTGGGTGAGCTGCATGCTATTTTGAGAAGACAAGAAGACTTTTATCCATTTTTAARA GACAATCGTGAGAAGATTGAARAAATCTTGACTTTTCGAATTCCTTATTATGTTGGTCCATT GGCGCGTGGCAATAGTCGTTTTGCATGGATGACTCGGAAGTCTGAAGARACAATTACCCCAT GGAATTTTGAAGAAGTTGTCGATAAAGGTGCTTCAGCTCAATCATTTATTGAACGCATGACA AACTTTGATAAAAATCTTCCAAATGAAARAGTACTACCAAAACATAGTTTGCTTTATGAGTA TTTTACGGTTTATAACGAATTGACAAAGGTCAARATATGTTACTGAGGGAATGCGAAAACCAG CATTTCTTTCAGGTGAACAGARGAAAGCCATTGTTGATTTACTCTTCARAACARATCGAAAA GTAACCGTTAAGCAATTAAAAGAAGATTATTTCAAAARRATAGAATGTTTTGATAGTGTTGA AATTTCAGGAGTTGAAGATAGATTTAATGCTTCATTAGGCGCCTACCATGATTTGCTARAAA TTATTAAAGATAARGATTTTTTGGATAATGAAGAARATGAAGATATCTTAGAGGATATTGTT TTAACATTGACCTTATTTGAAGATAGGGGGATGATTGAGGAAAGACTTAAAACATATGCTCA CCTCTTTGATGATAAGGTGATGAAACAGCTTAAACGTCGCCGTTATACTGGTTGGGGACGTT TGTCTCGAAAATTGATTAATGGTAT TAGGGATAAGCAATCTGGCAAAACAATATTAGATTTT TTGAAATCAGATGGTTTTGCCAATCGCAATTTTATGCAGCTGATCCATGATGATAGTTTGAC ATTTAAAGAAGATATTCAAAAAGCACAGGTGTCTGGACAAGGCCATAGTTTACATGAACAGA TTGCTAACTTAGCTGGCAGTCCTGCTATTAAAAAAGGTATTTTACAGACTGTAARAATTGTT GATGAACTGGTCAAAGTAATGGGGCATAAGCCAGAAAATATCGTTATTGAAATGGCACGTGA AAATCAGACAACTCAAARGGGCCAGAARRATTCGCGAGAGCGTATGAAACGAATCGAAGAAG GTATCARAGAATTAGGAAGTCAGATTCTTAAAGAGCATCCTGTTGAARATACTCAATTGCAA AATGAAAAGCTCTATCTCTATTATCTACAAAATGGAAGAGACATGTATGTGGACCAAGAATT AGATATTAATCGTTTAAGTGATTATGATGTCGATCACATTGTTCCACAAAGTTTCATTAAAG ACGATTCAATAGACAATAAGGTACTAACGCGTTCTGATAAAAATCGTGGTAAATCGGATAAC GTTCCAAGTGAAGAAGTAGTCAAAAAGATGARAAACTATTGGAGACAACTTCTAAACGCCAA GTTAATCACTCAACGTAAGTTTGATAATTTAACGAAAGCTGAACGTGGAGGTTTGAGTGAAC TTGATAAAGCTGGTTTTATCAAACGCCAATTGGTTGAAACTCGCCAAATCACTAAGCATGTG GCACAAATTTTGGATAGTCGCATGAATACTARATACGATGAAAATGATAAACTTATTCGAGA GGTTAAAGTGATTACCTTAAAATCTARATTAGTTTCTGACTTCCGAARAGATTTCCAATTCT ATAAAGTACGTGAGATTAACAATTACCATCATGCCCATGATGCGTATCTARATGCCGTCGTT GGAACTGCTTTGATTAAGAAATATCCAAAACTTGAATCGGAGTTTGTCTATGGTGATTATAA ACT TIATGATGTI ICG TAAAATGAT TCC IARC TCG AGC AAG ANA TACGCGCABRAGCARCCGCAN AATATTTCTTTTACTCTAATATCATGAACTTCTTCAAAACAGAAATTACACTTGCAAATGGA GAGATTCGCAAACGCCCTCTAATCGARACTAATGGGGAAACTGGAGAAATTGTCTGGGATAA AGGGCGAGATTTTGCCACAGTGCGCAAAGTATTGTCCATGCCCCAAGTCAATATTGTCAAGA AARCAGARGTACAGACAGGCGGATTCTCCAAGGAGTCAATTTTACCAAAAAGARATTCGGAC AAGCTTATTGCTCGTAAAARAGACTGGGATCCAAAAAAATATGGTGGTTTTGATAGTCCAAC GGTAGCTTATTCAGTCCTAGTGGTTGCTAAGGT GGAAAAAGGGAAATCGAAGAAGTTAAAAT CCGTTAAAGAGTTACTAGGGATCACAATTATGGAAAGAAGTTCCTTTGAAAAARATCCGATT GACTTTTTAGAAGCTARAGGATATAAGGAAGTTAAAARAGACTTAATCATTARACTACCTAA ATATAGTCTTTTTGAGT TAGAAAACGGTCGTAAACGGATGCTGGCTAGTGCCGGAGAATTAC AARAAGGAAATGAGCTGGCTCTGCCAAGCAAATATGTGAATTTTTTATATTTAGCTAGTCAT TATGAAAAGT TGAAGGGTAGTCCAGAAGATAACGAACAAARACAATTGTTTGTGGAGCAGCA TAAGCATTATTTAGATGAGATTATTGAGCAAATCAGTGAATTTTCTAAGCGTGTTATTTTAG CAGATGCCAATTTAGATARAGTTCTTAGTGCATATAACAAACATAGAGACAAACCAATACGT GAACAAGCAGARAAATATTATTCATTTATTTACGTTGACGAATCTTGGAGCTCCCGCTGCTTT TAAATATTTTGATACAACAATTGATCGTAAACGATATACGTCTACAAAAGAAGTTTTAGATG CCACTCTTATCCATCAATCCATCACTGGTCTTTATGAARACACGCATTGATTTGAGTCAGCTA CGCACCTCICTCA MDKKYSIGLDIGTNSVGWAVITDDYKVPSKKFKVLGNTDRHS IKKNLIGALLFGSGETAEAT RLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVD EVAYHEKYPTIYHLRKKLADSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLEL QLVQIYNQLFEENPINASRVDAKAILSARLSKSRRLENLIAQLPGEKRNGLFGNLIALSLGL TPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNS EITKAPLSASMIKRYDEHHQDLTLLKALVRQQOLPEKYKEIFFDOSKNGYAGYIDGGASQEEF YKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLK DNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMT NFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRK VIVKQLKEDYFKKIECFDSVEISGVEDRFNASLGAYHDLLKIIKDKDFLDNEENEDILEDIV LTLTLFEDRGMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDF LKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGHSLHEQIANLAGSPATIKKGILQTVKIV DELVKVMGHKPENIVIEMARENQTTQKGOKNSRERMKRIEEGIKELGSQILKEHPVENTQLQ NEKLYLYYLONGRDMYVDQELDINRLSDYDVDHIVPQSFIKDDS IDNKVLTRSDKNRGKSDN VPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVETRQI TKHV AQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVRE INNYHHAHDAYLNAVV GTALIKKYPKIESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANG EIRKRPLIETNGETGE IVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSD KLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPI DFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASH YEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIR EQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQL GGL (single underline: HNH domain; double underline: RuvC domain) In some embodiments, wild-type Cas9 corresponds to, or comprises the following nucleotide and / or amino acid sequences: ATGGATAAARAGTATTCTATTGGTTTAGACATCGGCACTAATTCCGTTGGATGGGCTGTCAT AACCGATGAATACAAAGTACCTTCAAAGAAATTTAAGGTGTTGGGGAACACAGACCGTCATT CGATTAAARAGAATCTTATCGGTGCCCTCCTATTCGATAGTGGCGAAACGGCAGAGGCGACT CGCCTGAAACGAACCGCTCGGAGAAGGTATACACGTCGCAAGAACCGAATATGTTACTTACA AGAAATTTTTAGCAATGAGATGGCCAAAGTTGACGATTCTTTCTTTCACCGTTTGGAAGAGT CCTTCCTTGTCGAAGAGGACARGAAACATGARCGGCACCCCATCTTTGGARACATAGTAGAT GAGGTGGCATATCATGAAAAGTACCCAACGATTTATCACCTCAGAAAAAAGCTAGTTGACTC AACTGATAAAGCGGACCTGAGGTTAATCTACTTGGCTCTTGCCCATATGATAAAGTTCCGTG GGCACTTTCTCATTGAGGGTGATCTAAATCCGGACAACTCGGATGTCGACARACTGTTCATC CAGTTAGTACAAACCTATAATCAGTTGTTTGAAGAGAACCCTATAAATGCAAGTGGCGTGGA TGCGAAGGCTATTCTTAGCGCCCGCCTCTCTARATCCCGACGGCTAGAARACCTGATCGCAC AATTACCCGGAGAGAAGAARAATGGGTTGTTCGGTAACCTTATAGCGCTCTCACTAGGCCTG ACACCAAATTTTAAGTCGAACTTCGACTTAGCTGAAGATGCCARATTGCAGCTTAGTAAGGA CACGTACGATGACGATCTCGACAATCTACTGGCACAAATTGGAGATCAGTATGCGGACTTAT TTTTGGCTGCCAARAACCTTAGCGATGCAATCCTCCTATCTGACATACTGAGAGTTAATACT GAGATTACCAAGGCGCCGTTATCCGCTTCAATGATCAAARAGGTACGATGAACATCACCAAGA CTTGACACTTCTCAAGGCCCTAGTCCGTCAGCAACTGCCTGAGAAATATAAGGAAATATTCT TTGATCAGTCGAARAACGGGTACGCAGGTTATATTGACGGCGGAGCGAGTCAAGAGGAATTC TACAAGTTTATCARACCCATATTAGAGAAGATGGATGGGACGGAAGAGTTGCTTGTAAAACT CAATCGCGAAGATCTACTGCGRAAAGCAGCGGACTTTCGACAACGGTAGCATTCCACATCAAA TCCACTTAGGCGAATTGCATGCTATACTTAGAAGGCAGGAGGATTTTTATCCGTTCCTCAAA GACAATCGTGARAAAGATTGAGAARATCCTAACCTTTCGCATACCTTACTATGTGGGACCCCT GGCCCGAGGGAACTCTCGGTTCGCATGGATGACAAGAARAGT CCGAAGARACGATTACTCCAT GCAATTITCGAGCGAACT IG TCCGATAAMMGE TCC TCAGC TCAATCETICATCGAGACGATCGACC AACTTTGACAAGAATTTACCGAACGAAARAGTATTGCCTAAGCACAGTTTACTTTACGAGTA TTTCACAGTGTACAATGAACTCACGAAAGTTAAGTATGTCACTGAGGGCATGCGTAAACCCG CCTTTCTAAGCGGAGAACAGAAGAAAGCAATAGTAGATCTGTTATTCAAGACCAACCGCAAA GTGACAGTTAAGCAATTGAAAGAGGACTACTTTAAGAAAATTGAATGCTTCGATTCTGTCGA GATCTCCGGGGTAGAAGATCGATTTAATGCGTCACTTGGTACGTATCATGACCTCCTARAGA TAATTAAAGATAAGGACTTCCTGGATAACGAAGAGAATGAAGATATCTTAGAAGATATAGTG TTGACTCTTACCCTCTTTGAAGATCGGGARATGATTGAGGAAAGACTAAAAACATACGCTCA CCTGTTCGACGATAAGGTTATGAAACAGTTARAGAGGCGTCGCTATACGGGCTGGGGACGAT TGTCGCGGAAACTTATCAACGGGATAAGAGACAAGCAAAGTGGTAAAACTATTCTCGATTTT CTAAAGAGCGACGGCTTCGCCAATAGGAACTTTATGCAGCTGATCCATGATGACTCTTTAAC CTTCAAAGAGGATATACARAAGGCACAGGTTTCCGGACAAGGGGACTCATTGCACGAACATA TTGCGAATCTTGCTGGTTCGCCAGCCATCAAARAGGGCATACTCCAGACAGTCARAGTAGTG GATGAGCTAGTTAAGGTCATGGGACGTCACARACCGGARAACATTGTAATCGAGATGGCACG CGAAAATCAAACGACTCAGAAGGGGCAAAARARCAGT CGAGAGCGGATGAAGAGAATAGAAG AGGGTATTARAGAACTGGGCAGCCAGATCTTAAAGGAGCATCCTGTGGARAATACCCAATTG CAGAACGAGAAACTTTACCTCTATTACCTACAARATGGAAGGGACATGTATGTTGATCAGGA ACTGGACATAAACCGTTTATCTGATTACGACGTCGATCACATTGTACCCCAATCCTTTTTGA AGGACGATTCAATCGACAATAAAGTGCTTACACGCTCGGATAAGAACCGAGGGAARAGTGAC AATGTTCCAAGCGAGGARGTCGTARAGARRATGAAGAACTATTGGCGGCAGCTCCTAAATGC GAAACTGATAACGCAAAGAAAGTTCGATAACTTAACTAAAGCTGAGAGGGGTGGCTTGTCTG AACTTGACAAGGCCGGATTTATTAAACGTCAGCTCGTGGAAACCCGCCAAATCACAAAGCAT GTTGCACAGATACTAGATTCCCGAATGAATACGAAATACGACGAGAACGATAAGCTGATTCG GGAAGTCAAAGTAATCACTTTAAAGTCAAAATTGGTGTCGGACTTCAGAAAGGATTTTCAAT TCTATAAAGTTAGGGAGATARATAACTACCACCATGCGCACGACGCTTATCTTAATGCCGTC GTAGGGACCGCACTCATTAAGAAATACCCGAAGCTAGAAAGTGAGTTTGTGTATGGTGATTA CAAAGTTTATGACGTCCGTAAGATGATCGCGAARAGCGAACAGGAGATAGGCAAGGCTACAG CCAAATACTTCTTTTATTCTAACATTATGAATTTCTTTAAGACGGAAATCACTCTGGCAAAC GGAGAGATACGCARACGACCTTTAATTGAAACCAATGGGGAGACAGGTGAAATCGTATGGGA TAAGGGCCGGGACTTCGCGACGGTGAGARAAGTTTTGTCCATGCCCCAAGTCAACATAGTAA AGAARACTGAGGTGCAGACCGGAGGGTTTTCAAAGGAATCGATTCTTCCARAAAAGGAATAGT GATAAGCTCATCGCTCGTAAARAGGACTGGGACCCGAAAAAGTACGGTGGCTTCGATAGCCC TACAGTTGCCTATTCTGTCCTAGTAGTGGCAAAAGTTGAGAAGGGAAAATCCAAGAAACTGA AGTCAGTCAAAGAATTATTGGGGATAACGATTATGGAGCGCTCGTCTTTTGAAAAGAACCCC ATCGACTTCCTTGAGGCGAAAGGTTACAAGGAAGTAAAALAAGGATCTCATAATTAAACTACC AAAGTATAGTCTGTTTGAGTTAGARAATGGCCGARAAACGGATGTTGGCTAGCGCCGGAGAGC TTCAAAAGGGGAACGAACTCGCACTACCGTCTAAATACGTGAATTTCCTGTATTTAGCGTCC CATTACGAGAAGTTGAAAGGTTCACCTGAAGATAACGAACAGAAGCAACTTTTTGTTGAGCA GCACAAACATTATCTCGACGARATCATAGAGCAAATTTCGGAATTCAGTAAGAGAGTCATCC TAGCTGATGCCAATCTGGACAAAGTATTAAGCGCATACAACAAGCACAGGGATAAACCCATA CGTGAGCAGGCGGAAAATATTATCCATTTGTTTACTCTTACCAACCTCGGCGCTCCAGCCGC ATTCAAGTATTTTGACACAACGATAGATCGCAAACGATACACTTCTACCAAGGAGGTGCTAG ACGCGACACTGATTCACCAATCCATCACGGGATTATATGAAACTCGGATAGATTTGTCACAG CTTGGGGGTGACGGATCCCCCAAGAAGAAGAGGAAAGTCTCGAGCGACTACAAAGACCATGA CGGTGATTATARAAGATCATGACATCGATTACALAGGATGACGATGACAAGGCTGCAGGA MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHS IKKNLIGALLFDSGETAEAT RLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVD EVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLEL QLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGL TPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNT EITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDOSKNGYAGYIDGGASQEEF YKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLK DNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMT NFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRK VIVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIV LTLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDF LKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDS LHEHIANLAGSPATKKGILQTVKVV DELVKVMGRHKPENIVIEMARENQTTQKGOKNSRERMKRIEEGIKELGSQILKEHPVENTQL ONEKLYLYYLONGRDMYVDQELDINRLSDYDVDHIVPQS FLKDDS I DNKVLTRSDKNRGKSD NVPSEEVVKKMKNYWRQLINAKLITQRKFDNLTKAERGGLSELDKAGFIKRQILVETRQITKH VAQILDSRMNTKYDENDKLIREVKVITLKSKIVSDFRKDFQFYKVRE INNYHHAHDAYLNAV VGTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLAN GEIRKRPLIETNGETGE IVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNS DKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNP IDFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLAS HYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPI REQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQ LGGD (single underline: HNH domain; double underline: RuvC domain) In some embodiments, wild-type Cas9 corresponds to Cas9 from Streptococcus pyogenes (NCBI Reference Sequence: NC_002737.2 (nucleotide sequence as follows); and Uniprot Reference Sequence: Q99ZW?2 (amino acid sequence as follows). ATGGATAAGAAATACTCAATAGGCTTAGATATCGGCACAAATAGCGTCGGATGGGCGGTGAT CACTGATGAATATAAGGTTCCGTCTARARAGTTCAAGGTTCTGGGAAATACAGACCGCCACA GTATCAAAAAARATCTTATAGGGGCTCTTTTATTTGACAGTGGAGAGACAGCGGAAGCGACT CGTCTCAAACGGACAGCTCGTAGAAGGTATACACGTCGGAAGAATCGTATTTGTTATCTACA GGAGATTTTTTCAAATGAGATGGCGARAGTAGATGATAGTTTCTTTCATCGACTTGAAGAGT CTTTTTTGGTGGAAGAAGACAAGAAGCATGARCGTCATCCTATTTTTGGAAATATAGTAGAT GAAGTTGCTTATCATGAGAAATATCCAACTATCTATCATCTGCGAAAAARATTGGTAGATTC TACTGATAAAGCGGATTTGCGCTTAATCTATTTGGCCTTAGCGCATATGATTAAGTTTCGTG GICATTTTTTGATTGAGGGAGATTTAAATCCTGATAATAGTGATGTGGACARACTATTTATC CAGTTGGTACAAACCTACAATCAATTATTTGAAGAAAACCCTATTAACGCAAGTGGAGTAGA TGCTAAAGCGATTCTTTCTGCACGATTGAGTARATCAAGACGATTAGAARATCTCATTGCTC AGCTCCCCGGTGAGARAGAARAATGGCTTATTTGGGAATCTCATTGCTTTGTCATTGGGTTTG ACCCCTAATTTTAAATCAAATTTTGATTTGGCAGAAGATGCTARATTACAGCTTTCAAAAGA TACTTACGATGATGATTTAGATAATTTATTGGCGCAAATTGGAGATCAATATGCTGATTTGT TTTTGGCAGCTAAGAATTTATCAGATGCTATTTTACTTTCAGATATCCTAAGAGTARATACT GAAATAACTAAGGCTCCCCTATCAGCTTCAATGATTAAACGCTACGATGAACATCATCAAGA CTTGACTCTTTTAAAAGCTTTAGTTCGACAACAACTTCCAGAAAAGTATAAAGAAATCTTTT TTGATCAATCAAARARCGGATATGCAGGTTATATTGATGGGGGAGCTAGCCAAGAAGAATTT TATAAATTTATCARACCAATTTTAGAAARAATGGATGGTACTGAGGAATTATTGGTGAAACT AAATCGTGAAGATTTGCTGCGCAAGCAACGGACCTTTGACAACGGCTCTATTCCCCATCAAA TTCACTTGGGTGAGCTGCATGCTATTTTGAGAAGACAAGAAGACTTTTATCCATTTTTAARA GACAATCGTGAGAAGATTGAARAAATCTTGACTTTTCGAATTCCTTATTATGTTGGTCCATT GGCGCGTGGCAATAGTCGTTTTGCATGGATGACTCGGAAGTCTGAAGARACAATTACCCCAT GGAATTTTGAAGAAGTTGTCGATAAAGGTGCTTCAGCTCAATCATTTATTGAACGCATGACA AACTTTGATAAARATCTTCCARATGARARAGTACTACCAAAACATAGTTTGCTTTATGAGTA TTTTACGGTTTATAACGAATTGACAAAGGTCAAATATGTTACTGAAGGAATGCGAAAACCAG CATTTCTTTCAGGTGARCAGARGAAAGCCATTGTTGATTTACTCTTCAAAACAAATCGAAAA GTAACCGTTAAGCAATTAAAAGAAGATTATTTCAAAAAAATAGAATGTTTTGATAGTGTTGA AATTTCAGGAGTTGAAGATAGATTTAATGCTTCATTAGGTACCTACCATGATTTGCTAAAAA TTATTAAAGATAAAGAT TT TTTGGATAATGAAGAAAATGAAGATATCTTAGAGGATATTGTT TTAACATTGACCTTATTTGAAGATAGGGAGATGATTGAGGAAAGACTTAAAACATATGCTCA CCTCTTTGATGATAAGGTGATGAAACAGCTTAAACGTCGCCGTTATACTGGTTGGGGACGTT TGTCTCGAAAATTGATTAATGGTATTAGGGATAAGCAATCTGGCAAAACAATATTAGATTTT TTGAAATCAGATGGTTTTGCCAATCGCAATTTTATGCAGCTGATCCATGATGATAGTTTGAC ATTTAAAGAAGACATTCAAAAAGCACAAGTGTCTGGACAAGGCGATAGTTTACATGAACATA TTGCAAATTTAGCTGGTAGCCCTGCTATTAAAAAAGGTATTTTACAGACTGTAARAGTTGTT GATGAATTGGTCARAGTAATGGGGCGGCATAAGCCAGAARAATATCGTTATTGAAATGGCACG TGAAAATCAGACAACTCARAAGGGCCAGAAAAATTCGCGAGAGCGTATGAAACGAATCGAAG AAGGTATCARAGAATTAGGAAGTCAGATTCTTAAAGAGCATCCTGTTGAARAATACTCAATTG CAAAATGAAAAGCTCTATCTCTATTATCTCCAARATGGAAGAGACATGTATGTGGACCAAGA ATTAGATATTAATCGTTTAAGTGATTATGATGTCGATCACATTGTTCCACAAAGTTTCCTTA AAGACGATTCAATAGACAATAAGGTCTTAACGCGTTCTGATAAAAATCGTGGTAAATCGGAT AACGTTCCAAGTGAAGAAGTAGTCAAARAGATGAAAAACTATTGGAGACAACTTCTAAACGC CAAGTTAATCACTCAACGTAAGTTTGATAATTTAACGAAAGCTGAACGTGGAGGTTTGAGTG AACTTGATARAGCTGGTTTTATCARACGCCAATTGGTTGAAACTCGCCARATCACTAAGCAT GTGGCACAAATTTTGGATAGTCGCATGAATACTAAATACGATGARAATGATAAACTTATTCG AGAGGTTAAAGTGATTACCTTARAATCTARATTAGTTTCTGACTTCCGAAAAGATTTCCAAT TCTATAAAGTACGTGAGATTAACAATTACCATCATGCCCATGATGCGTATCTAAATGCCGTC GTTGGAACTGCTTTGATTAAGAAATATCCAARACTTGAATCGGAGTTTGTCTATGGTGATTA TAAAGTTTATGATGTTCGTAAAATGATTGCTAAGTCTGAGCAAGARATAGGCAAAGCAACCG CAAAATATTTCTTTTACTCTAATATCATGAACTTCTTCAARACAGAAATTACACTTGCAAAT GGAGAGATTCGCARACGCCCTCTAATCGAAACTAATGGGGAAACTGGAGAAATTGTCTGGGA TAAAGGGCGAGATTTTGCCACAGTGCGCAAAGTATTGTCCATGCCCCAAGTCAATATTGTCA AGAAAACAGAAGTACAGACAGGCGGATTCTCCAAGGAGTCAATTTTACCAAAAAGAAATTCG GACAAGCTTATTGCTCGTAAARAAGACTGGGATCCAARAAAATATGGTGGTTTTGATAGTCC AACGGTAGCTTATTCAGTCCTAGTGGTTGCTRAGGTGGAAAAAGGGAAATCGAAGAAGT TAA AATCCGTTAAAGAGTTACTAGGGATCACAATTATGGAAAGAAGTTCCTTTGAAARAAAATCCG ATTGACTTTTTAGAAGCTARAGGATATAAGGAAGTTAAAAAAGACTTAATCATTAAACTACC TAAATATAGTCTTTTTGAGT TAGAAAACGGTCGTAAACGGATGCTGGCTAGTGCCGGAGAAT TACAAAAAGGAAATGAGCTGGCTCTGCCAAGCAAATATGTGAATTTTTTATATTTAGCTAGT CATTATGAAAAGT TGAAGGGTAGTCCAGAAGATAACGAACAAARAACAATTGTTTGTGGAGCA GCATAAGCATTATTTAGATGAGATTATTGAGCAAATCAGTGAATTTTCTAAGCGTGTTATTT TAGCAGATGCCAATTTAGATAAAGTTCTTAGTGCATATAACAAACATAGAGACAAACCAATA CCIGANCRAAGC AGAR AA TAT IAT TIC AT IIA TT ACCT TIGACGARTOTIGEGAGO TCC CECT TTTTAAATATTTTGATACAACAATTGATCGTAAACGATATACGTCTACAAAAGAAGTTTTAG ATGCCACTCTTATCCATCAATCCATCACTGGTCTTTATGAAACACGCATTGATTTGAGTCAG CrTACCGACGCTCACTCA MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAEAT RLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVD EVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFI QLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGL TPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNT EITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEF YKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLK DNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEET ITPWNFEEVVDKGASAQSFIERMT NFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRK VIVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIV LTLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDF LKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVV DELVKVMGRHKPENIVIEMARENQTTQKGQOKNSRERMKRIEEGIKELGSQILKEHPVENTQL QONEKLYLYYLONGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDKNRGKSD NVPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKH VAQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVRE INNYHHAHDAY LNAV VGTALIKKYPKIESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNEFKTEITLAN GEIRKRPLIETNGETGE IVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNS DKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNP IDFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLAS HYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPI REQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQ LGGD (SEQ ID NO: 1) (single underline: HNH domain; double underline: RuvC domain) In some embodiments, Cas9 refers to Cas9 from: Corynebacterium ulcerans (NCBI Refs: NC_015683.1, NC_017317.1); Corynebacterium diphtheria (NCBI Refs: NC_016782.1, NC_016786.1); Spiroplasma syrphidicola (NCBI Ref: NC_021284.1), Prevotella intermedia NCBI Ref: NC_017861.1); Spiroplasma taiwanense (NCBI Ref: NC_021846.1); Streptococcus iniae (NCBI Ref: NC_021314.1); Belliella baltica (NCBI Ref: NC _018010.1); Psychroflexus torquis] (NCBI Ref: NC _018721.1); Streptococcus thermophilus (NCBI Ref: YP_820832.1), Listeria innocua (NCBI Ref: NP_472073.1), Campylobacter jejuni (NCBI Ref: YP_002344900.1) or Neisseria meningitidis (NCBI Ref: YP 002342100.1) or to a Cas9 from any other organism. In some embodiments, dCas9 corresponds to, or comprises in part or in whole, a Cas9 amino acid sequence having one or more mutations that inactivate the Cas9 nuclease activity. For example, in some embodiments, a dCas9 domain comprises D10A and an H840A mutation or corresponding mutations in another Cas9. In some embodiments, the dCas9 comprises the amino acid sequence of dCas9 (D10A and H840A): MDKKYSIGLAIGTNSVGWAVITDEYRVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAEAT RLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVD EVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFI QLVQTYNQLFEENP INASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGL TPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDATILLSDILRVNT EITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEF YKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHATILRRQEDFYPFLK DNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMT NFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKATIVDLLFKTNRK VIVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKI IKDKDFLDNEENEDILEDIV LTLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDF LKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDS LHEHIANLAGSPATKKGILQTVEVV DELVKVMGRHKPENIVIEMARENQTTOQKGOKNSRERMKRIEEGIKELGSQILKEHPVENTQL ONEKLYLYYLONGRDMYVDQELDINRLSDYDVDAIVPQS FLKDDS IDNKVLTRSDKNRGKSD NVPSEEVVKKMKNYWRQLINAKLITQRKFDNLTKAERGGLSELDKAGFIKRQIVETRQITKH VAQILDSRMNTKYDENDKLIREVKVITLKSKIVSDFRKDFQFYKVRE INNYHHAHDAYLNAV VGTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTETITLAN GEIRKRPLIETNGETGE IVWDKGRDFATVRKVLSMPOVNIVKKTEVOTGGFSKESILPKRNS DKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNP IDFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGE LQKGNELALPSKYVNFLYLAS HYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPI REQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQ LGGD (single underline: HNH domain; double underline: RuvC domain). In some embodiments, the Cas9 domain comprises a D10A mutation, while the residue at position 840 remains a histidine in the amino acid sequence provided above, or at corresponding positions in any of the amino acid sequences provided herein. In other embodiments, dCas9 variants having mutations other than D10A and H840A are provided, which, e.g., result in nuclease inactivated Cas9 (dCas9). Such mutations, by way of example, include other amino acid substitutions at D10 and H840, or other substitutions within the nuclease domains of Cas9 (e.g., substitutions in the HNH nuclease subdomain and / or the RuvC1 subdomain). In some embodiments, variants or homologues of dCas9 are provided which are at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% identical. In some embodiments, variants of dCas9 are provided having amino acid sequences which are shorter, or longer, by about 5 amino acids, by about 10 amino acids, by about 15 amino acids, by about 20 amino acids, by about 25 amino acids, by about 30 amino acids, by about 40 amino acids, by about 50 amino acids, by about 75 amino acids, by about 100 amino acids or more. In some embodiments, Cas9 fusion proteins as provided herein comprise the full- length amino acid sequence of a Cas9 protein, e.g., one of the Cas9 sequences provided herein. In other embodiments, however, fusion proteins as provided herein do not comprise a full-length Cas9 sequence, but only one or more fragments thereof. Exemplary amino acid sequences of suitable Cas9 domains and Cas9 fragments are provided herein, and additional suitable sequences of Cas9 domains and fragments will be apparent to those of skill in the art, It should be appreciated that additional Cas9 proteins (e.g., a nuclease dead Cas9 (dCas9), a Cas9 nickase (nCas9), or a nuclease active Cas9), including variants and homologs thereof, are within the scope of this disclosure. Exemplary Cas9 proteins include, without limitation, those provided below. In some embodiments, the Cas9 protein is a nuclease dead Cas9 (dCas9). In some embodiments, the Cas9 protein is a Cas9 nickase (nCas9). In some embodiments, the Cas9 protein is a nuclease active Cas9. Exemplary catalytically inactive Cas9 (dCas9): DKKYSIGLAIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAEATR LKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDE VAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLEFIQ LVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLT PNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNTE ITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFY KFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLKD NREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMTN FDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKV TVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVL TLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFL KSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVD ELVKVMGRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQLQ NEKLYLYYLONGRDMYVDQELDINRLSDYDVDAIVPQSFLKDDSIDNKVLTRSDKNRGKSDN VPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKHV AQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVREINNYHHAHDAYLNAVV GTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANG EIRKRPLIETNGETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSD KLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPI DFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASH YEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIR EQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQL GGL Exemplary catalytically Cas9 nickase (nCas9): DKKYSIGLAIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAEATR LKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEES FLVEEDKKHERHPIFGNIVDE VAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQ LVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLT PNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNTE ITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFY KFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLKD NREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEET ITPWNFEEVVDKGASAQSFIERMTN FDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKV TVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVL TLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFL KSDGFANRNEMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVD ELVKVMGRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQLQ NEKLYLYYLONGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDKNRGKSDN VPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKHV AQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVREINNYHHAHDAYLNAVV GTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANG EIRKRPLIETNGETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSD KLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPI DFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASH YEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIR EQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQL GC Exemplary catalytically active Cas9: DKKYSIGLDIGTINSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAEATR LKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEES FLVEEDKKHERHPIFGNIVDE VAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQ LVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLEFGNLIALSLGLT PNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDATILLSDILRVNTE ITKAPLSASMIKRYDEHHQDLTLLKALVRQOLPEKYKEIFFDQSKNGYAGY IDGGASQEEFY KFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHATILRRQEDFYPFLKD NREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEET ITPWNFEEVVDKGASAQSFIERMTN FDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKATIVDLLFKTNRKV TVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVL TLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFL KSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVD ELVKVMGRHKPENIVIEMARENQTTQKGQOKNSRERMKRIEEGIKELGSQILKEHPVENTQLQ NEKLYLYYLONGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDKNRGKSDN VPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKHV AQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVRE INNYHHAHDAYLNAVV GTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANG EIRKRPLIETNGETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSD KLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPI DFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASH YEKLKGSPEDNEQKQLEVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIR EQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQL GGD. In some embodiments, Cas9 refers to a Cas9 from archaea (e.g., nanoarchaea), which constitute a domain and kingdom of single-celled prokaryotic microbes. In some embodiments, Cas9 refers to CasX or CasY, which have been described in, for example, Burstein et al., "New CRISPR-Cas systems from uncultivated microbes." Cell Res. 2017 Feb 21. doi: 10.1038 / cr.2017.21, the entire contents of which is hereby incorporated by reference. Using genome-resolved metagenomics, a number of CRISPR-Cas systems were identified, including the first reported Cas9 in the archaeal domain of life. This divergent Cas9 protein was found in little- studied nanoarchaea as part of an active CRISPR-Cas system. In bacteria, two previously unknown systems were discovered, CRISPR-CasX and CRISPR-CasY, which are among the most compact systems yet discovered. In some embodiments, Cas9 refers to CasX, or a variant of CasX. In some embodiments, Cas9 refers to a CasY, or a variant of CasY. It should be appreciated that other RNA-guided DNA binding proteins may be used as a nucleic acid programmable DNA binding protein (napDNAbp), and are within the scope of this disclosure. In particular embodiments, napDNAbps useful in the methods of the invention include circular permutants, which are known in the art and described, for example, by Oakes etal. Cell 176,254-267,2019. An exemplary circular permutant follows where the bold sequence indicates sequence derived from Cas9, the italics sequence denotes a linker sequence, and the underlined sequence denotes a bipartite nuclear localization sequence, CP5 (with MSP “NGC=Pam Variant with mutations Regular Cas9 likes NGG” PID=Protein Interacting Domain and “D10A” nickase): EIGKATAKYFFYSNIMNFFKTE I TLANGE IRKRPLIE TNGE TGE IVWDKGRDFATVRKVLSM PQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWD PKKYGGFMQPTVAY SVLVVAKVEK GKSKKLKSVKELLGI TIMERSSFEKNPIDFLEAKGYKEVKKDLI IKLPKY SLFE LENGRKRM LASAKFLOKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISE FSKRVILADANLDKVLSAYNKHRDKPIREQAENIIHLFTLTNLGAPRAFKYFDTTIARKEYR STKEVLDATLIHQSITGLYE TRIDLSQLGGDGGSGGSGGSGGSGGSGGSGGMDKKY SIGLAT GTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGE TAEATRLKRTARRRY T RRKNRICYLQE IFSNEMAKVDDSFFHRLEE SFLVEEDKKHERHPIFGNIVDEVAYHEKYPTI YHLRKKLVDS TDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQLVQTYNQLFE ENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLA EDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNTE ITKAPLSASM IKRYDEHHQDLTLLKALVRQQLPEKYKE IFFDQSKNGYAGY IDGGASQEEFYKFIKPILEKM DGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLKDNREKIEKILT FRIPYYVGPLARGNSRFAWMTRKSEE TI TPWNFEEVVDKGASAQSFIERMTNFDKNLPNEKV LPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQLKEDYF KKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVLTLTLFEDREM IEERLKTYAHLFDDKVMKQLKRRRY TGWGRLSRKLINGIRDKQSGKTILDFLKSDGFANRNF MQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDE LVKVMGRHK PENIVIEMARENQTTQKGOKNSRERMKRIEEGIKELGSQILKEHPVENTQLONEKLYLYYLQ NGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDS IDNKVLTRSDKNRGKSDNVPSEEVVKKM KNYWRQLLNAKLI TQRKFDNLTKAERGGLSE LDKAGFIKRQLVE TRQI TKHVAQILDSRMNT KYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVRE INNYHHAHDAYLNAVVGTALIKKY PK LESEFVYGDYKVYDVRKMIAKSEQEGADKRTADGSEFESPKKKRKV* Non-limiting examples of a polynucleotide programmable nucleotide binding domain which can be incorporated into a base editor include a CRISPR protein-derived domain, a restriction nuclease, a meganuclease, TAL nuclease (TALEN), and a zinc finger nuclease (ZFN). In some embodiments, the nucleic acid programmable DNA binding protein (napDNADp) of any of the fusion proteins provided herein may be a CasX or CasY protein. In some embodiments, the napDNAbp is a CasX protein. In some embodiments, the napDNAbp is a CasY protein. In some embodiments, the napDNAbp comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at ease 99.5% identical to a naturally-occurring CasX or CasY protein. In some embodiments, the napDNAbp is a naturally-occurring CasX or CasY protein. In some embodiments, the napDNAbp comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at ease 99.5% identical to any CasX or CasY protein described herein. It should be appreciated that Cas12b / C2c1, CasX and CasY from other bacterial species may also be used in accordance with the present disclosure. Cas12b / C2c1 (uniprot.org / uniprot / TOD7A2#2) sp|TOD7A2|C2C1_ALIAG CRISPR-associated endo- nuclease C2cl OS = Alicyclobacillus acido- terrestris (strain ATCC 49025 / DSM 3922 / CIP 106132 / NCIMB 13137 / GD3B) GN=c2cl PE=1 SV=1 MAVKSIKVKLRLDDMPE IRAGLWKLHKEVNAGVRYYTEWLSLLRQENLYRRSPNGDGEQECD KTAEECKAELLERLRARQVENGHRGPAGSDDELLQLARQLYELLVPQAIGAKGDAQQIARKF LSPLADKDAVGGLGIAKAGNKPRWVRMREAGEPGWEEEKEKAETRKSADRTADVLRALADFG LKPLMRVYTDSEMSSVEWKPLRKGQAVRTWDRDMFQQOAIERMMSWESWNQRVGQEYAKLVEQ KNRFEQKNFVGQEHLVHLVNQLQQDMKEASPGLESKEQTAHYVTGRALRGSDKVFEKWGKLA PDAPFDLYDAEIKNVQRRNTRRFGSHDLFAKLAEPEYQALWREDASFLTRYAVYNSILRKLN HAKMFATFTLPDATAHPIWTRFDKLGGNLHQYTFLFNEFGERRHAIRFHKLLKVENGVAREV DDVTVPISMSEQLDNLLPRDPNEPIALYFRDYGAEQHFTGE FGGAKIQCRRDQLAHMHRRRG ARDVYLNVSVRVQSQSEARGERRPPYAAVFRLVGDNHRAFVHFDKLSDYLAEHPDDGKLGSE GLLSGLRVMSVDLGLRTSASISVFRVARKDELKPNSKGRVPFFFPIKGNDNLVAVHERSQLL KLPGETESKDLRAIREERQRTLRQLRTQLAYLRLLVRCGSEDVGRRERSWAKLIEQPVDAAN HMTPDWREAFENELQKLKSLHGICSDKEWMDAVYESVRRVWRHMGKQVRDWRKDVRSGERPK IRGYAKDVVGGNSIEQIEYLERQYKFLKSWSFFGKVSGQVIRAEKGSRFAITLREHIDHAKE DRLKKLADRIIMEALGYVYALDERGKGKWVAKYPPCQLILLEELSEYQFNNDRPPSENNQLM QWSHRGVFQELINQAQVHDLLVGTMYAARFSSRFDARTGAPGIRCRRVPARCTQEHNPEPFPW WLNKFVVEHTLDACPLRADDLIPTGEGEIFVSPFSAEEGDFHQIHADLNAAQNLOORLWSDE DISQIRLRCDWGEVDGELVLIPRLTGKRTADSYSNKVFYTNTGVTYYERERGKKRRKVFAQE KLSEEEAELLVEADEAREKSVVLMRDPSGIINRGNWIRQKEFWSMV NQRIEGYLVKQIRSR VPLQDSACENTGDI CasX (uniprot.org / uniprot / FONNS87; uniprot.org / uniprot / FONHS3) >tr[FONN87[FONN87_SULIH CRISPR-associated Casx protein OS = Sulfolobus islandicus (strain HVE10 / 4) GN = SiH_0402 PE=4 SV=1 MEVPLYNIFGDNYIIQVATEAENSTIYNNKVEIDDEELRNVLNLAYKIAKNNEDAAAERRGK AKKKKGEEGETTTSNIILPLSGNDKNPWTETLKCYNFPTTVALSEVFKNFSQVKECEEVSAP SFVKPEFYEFGRSPGMVERTRRVKLEVEPHYLIIAARAGWVLTRLGKAKVSEGDYVGVNVETP TRGILYSLIONVNGIVPGIKPETAFGLWIARKVVSSVTNPNVSVVRIYTISDAVGONPTTIN GGFSIDLTKLLEKRYLLSERLEAIARNALSISSNMRERYIVLANYIYEYLTG SKRLEDLLY FANRDLIMNLNSDDGKVRDLKLISAYVNGELIRGEG >tr[FONH53[FONHS3_SULIR CRISPR associated protein, Casx OS = Sulfolobus islandicus (strain REY15A) GN=SiRe 0771 PE=4 SV=1 MEVPLYNIFGDNYIIQVATEAENSTIYNNKVEIDDEELRNVLNLAYKIAKNNEDAAAERRGK AKKKKGEEGETTTSNIILPLSGNDKNPWTETLKCYNFPTTVALSEVFKNFSQVKECEEVSAP SFVKPEFYKFGRSPGMVERTRRVKLEVEPHYLIMAAAGWVLTRLGKAKVSEGDYVGVNVETP TRGILYSLIQONVNGIVPGIKPETAFGLWIARKVVSSVTNPNVSVVSIYTISDAVGONPTTIN GGFSIDLTKLLEKRDLLSERLEAIARNALSISSNMRERYIVLANYIYEYLTGSKRLEDLLYF ANRDLIMNLNSDDGKVRDLKLISAYVNGELIRGEG Deltaproteobacteria CasX MEKRINKIRKKLSADNATKPVSRSGPMKTLLVRVMTDDLKKRLEKRRKKPEVMPQVISNNAA NNLRMLLDDYTKMKEAILQVYWQEFKDDHVGLMCKFAQPASKKI DONKLKPEMDEKGNLTTA GFACSQCGQPLFVYKLEQVSEKGKAYTNYFGRCNVAEHEKLILLAQLKPVKDSDEAVTYSLG KFGQRALDFYSIHVTKESTHPVKPLAQIAGNRYASGPVGKALSDACMGTIASFLSKYQDIII EHQKVVKGNQKRLESLRELAGKENLEYPSVTLPPQPHTKEGVDAYNEVIARVRMWVNLNLWQ KLKLSRDDAKPLLRLKGFPSFPVVERRENEVDWWNT INEVKKLIDAKRDMGRVEFWSGVTAEK RNTILEGYNYLPNENDHKKREGSLENPKKPAKRQFGDLLLYLEKKYAGDWGKVFDEAWERID KKIAGLTSHIEREEARNAEDAQSKAVLTDWLRAKASFVLERLKEMDEKEFYACEIQLOKWYG DLRGNPFAVEAENRVVDISGFSIGSDGHS IQYRNLLAWKYLENGKREFYLLMNYGKKGRIRF TDGTDIKKSGKWQGLLYGGGKAKVIDLTFDPDDEQLIILPLAFGTRQGREFIWNDLLSLETG LIKLANGRVIEKTIYNKKIGRDEPALFVALTFERREVVDPSNIKPVNLIGVARGENIPAVIA LTDPEGCPLPEFKDSSGGPTDILRIGEGYKEKQRAIQAAKEVEQRRAGGY SRKFASKSRNLA DDMVRNSARDLFYHAVTHDAVLVFANLSRGFGROGKRTFMTERQY TKMEDWLTAKLAYEGLT SKTYLSKTLAQYTSKTCSNCGFTITYADMDVMLVRLKKTSDGWATTLNNKELKAEYQITYYN RYKRQTVEKELSAELDRLSEESGNNDISKWTKGRRDEALFLLKKRFSHRPVQEQFVCLDCGH EVHAAEQAALNIARSWLEFLNSNSTEFKSYKSGKQPFVGAWQAFYKRRLKEVWKPNA CasY (ncbi.nlm.nih.gov / protein / APG80656.1) >APGB0656.1 CRISPR-associated protein CasY [uncultured Parcubacteria group bacterium] MSKRHPRISGVKGYRLHAQRLEYTGKSGAMRTIKYPLYSSPSGGRTVPREIVSAINDDYVGL YGLSNFDDLYNAEKRNEEKVYSVLDFWYDCVQYGAVFSYTAPGLLKNVAEVRGGSYELTKTL KGSHLYDELQIDKVIKFLNKKE ISRANGSLDKLKKDIIDCFKAEYRERHKDQCNKLADDIKN AKKDAGASLGERQKKLFRDFFGISEQSENDKPSFTNPLNLTCCLLPFDTVNNNRNRGEVLFN KLKEYAQKLDKNEGSLEMWEYIGIGNSGTAFSNFLGEGFLGRLRENKITELKKAMMDITDAW RGOEQEEELEKRLRILAALTIKLREPKFDNHWGGYRSDINGKLSSWLONYINQTVKIKEDLK GHKKDLKKAKEMINRFGESDTKEEAVVSSLLESIEKIVPDDSADDEKPDIPAIAIYRRFLSD GRLTLNRFVQREDVQEALIKERLEAEKKKKPKKRKKKSDAEDEKETIDFKELFPHLAKPLKL VPNFYGDSKRELYKKYKNAAIYTDALWKAVEKIYKSAFSSSLKNSFFDTDFDKDFFIKRLQK IFSVYRREFNTDKWKPIVKNSFAPYCDIVSLAENEVLYKPKQSRSRKSAAIDKNRVRLPSTEN IAKAGIALARELSVAGFDWKDLLKKEEHEEYIDLIELHKTALALLLAVTETQLDISALDFVE NGTVKDFMKTRDGNLVLEGRFLEMFSQSIVFSELRGLAGLMSRKEFITRSAIQTMNGKQAEL LYIPHEFQSAKITTPKEMSRAFLDLAPAEFATSLEPESLSEKSLLKLKOMRYYPHYFGYELT RTGQGIDGGVAENALRLEKSPVKKREIKCKQYKTLGRGONKIVLYVRSSYYQTQFLEWFLHR PKNVQTDVAVSGSFLIDEKKVKTRWNYDALTVALEPVSGSERVFVSQPFTIFPEKSAEEEGQ RYLGIDIGEYGIAYTALEITGDSAKILDONFISDPQLKTLREEVKGLKLDQRRGTFAMPSTK IARIRESLVHSLRNRIHHLALKHKAKIVYELEVSRFEEGKQKIKKVYATLKKADVYSEIDAD KNLQTTVWGKLAVASEISASYTSQFCGACKKLWRAEMQVDETITTQELIGTVRVIKGGTLID AIKDFMRPPIFDENDTPFPKYRDFCDKHHISKKMRGNSCLFICPFCRANADADIQASQTIAL LRYVKEEKKVEDYFERFRKLKNIKVLGCOMKKI The term “Cas12” or “Cas12 domain” refers to an RNA guided nuclease comprising a Casl2 protein or a fragment thereof (e.g., a protein comprising an active, inactive, or partially active DNA cleavage domain of Cas12, and / or the gRNA binding domain of Cas12). Cas12 belongs to the class 2, Type V CRISPR / Cas system. A Casl2 nuclease is also referred to sometimes as a CRISPR (clustered regularly interspaced short palindromic repeat) associated nuclease. The sequence of an exemplary Bacillus hisashii Cas 12b (BhCas12b) Cas 12 domain is provided below: MAPKKKRKVGIHGVPAAATRSFILKIEPNEEVKKGLWKTHEVLNHGIAYYMNILKLIRQEAT YEHHEQDPKNPKKVSKAE IQAELWDFVLKMQKCNS FTHEVDKDEVENILRELYEELVPSSVE KKGEANQLSNKFLYPLVDPNSQSGKGTAS SGRKPRWYNLKIAGDPSWEEEKKKWEEDKKKDP LAKILGKLAEYGLIPLFIPYTDSNEPIVKE IKWMEKSRNQSVRRLDKDMFIQALERFLSWES WNLKVKEEYEKVEKEYKTLEERIKEDIQALKALEQYEKERQEQLLRDTLNTNEYRLSKRGLR GWREIIQKWLKMDENEPSEKYLEVFKDYQRKHPREAGDYSVYEFLSKKENHFIWRNHPEYPY LYATFCEIDKKKKDAKQQATFTLADPINHPLWVRFEERSGSNLNKYRILTEQLHTEKLKKKL TVQLDRLIYPTESGGWEEKGKVDIVLLPSRQFYNQIFLDIEEKGKHAFTYKDESIKFPLKGT LGGARVQFDRDHLRRYPHKVESGNVGRIYFNMTVNIEPTESPVSKSLKIHRDDFPKVVNEKP KELTEWIKDSKGKKLKSGIESLEIGLRVMSIDLGQRQAAAASIFEVVDOKPDIEGKLFFPIK GTELYAVHRASFNIKLPGETLVKSREVLRKAREDNLKLMNQKLNFLRNVLHFQQFEDITERE KRVTKWISRQENSDVPLVYQDELIQIRELMYKPYKDWVAFLKQLHKRLEVEIGKEVKHWRKS LSDGRKGLYGISLKNIDEIDRTRKFLLRWSLRPTEPGEVRRLEPGQRFAIDQLNHLNALKED RLKKMANTIIMHALGYCYDVRKKKWQAKNPACQIILFEDLSNYNPYEERSRFENSKLMKWSR REIPRQVALQGEIYGLQVGEVGAQFSSRFHAKTGSPGIRCSVVTKEKLQDNRFFKNLQREGR LTLDKIAVLKEGDLYPDKGGEKFISLSKDRKCVTTHADINAAQNLQKRFWTRTHGFYKVYCK AYQVDGQTVYIPESKDQKQKIIEEFGEGYFILKDGVYEWVNAGKLKIKKGSSKQSSSELVDS DILKDSFDLASELKGEKLMLYRDPSGNVEFPSDKWMAAGVFFGKLERILISKLTNQYSISTIE DDSSKQSMKRPAATKKAGQAKKKK . Amino acid sequences having at least 85% or greater identity to the BhCas12b amino acid sequence are also useful in the methods of the invention. By “cytidine deaminase” is meant a polypeptide or fragment thereof capable of catalyzing a deamination reaction that converts an amino group to a carbonyl group. In one embodiment, the cytidine deaminase converts cytosine to uracil or S-methylcytosine to thymine. PmCDA1, which is derived from Petromyzon marinus (Petromyzon marinus cytosine deaminase 1, “PmCDA1"), AID (Activation-induced cytidine deaminase; AICDA), which is derived from a mammal (e.g., human, swine, bovine, horse, monkey etc.), and APOBEC are exemplary cytidine deaminases. The term “conservative amino acid substitution” or “conservative mutation” refers to the replacement of one amino acid by another amino acid with a common property. A functional way to define common properties between individual amino acids is to analyze the normalized frequencies of amino acid changes between corresponding proteins of homologous organisms (Schulz, G. E. and Schirmer, R. H., Principles of Protein Structure, Springer-Verlag, New York (1979)). According to such analyses, groups of amino acids can be defined where amino acids within a group exchange preferentially with each other, and therefore resemble each other most in their impact on the overall protein structure (Schulz, G. E. and Schirmer, R. H, supra). Non-limiting examples of conservative mutations include amino acid substitutions of amino acids, for example, lysine for arginine and vice versa such that a positive charge can be maintained; glutamic acid for aspartic acid and vice versa such that a negative charge can be maintained; serine for threonine such that a free ~OH can be maintained; and glutamine for asparagine such that a free -NH, can be maintained. The term “coding sequence” or “protein coding sequence” as used interchangeably herein refers to a segment of a polynucleotide that codes for a protein. The region or sequence is bounded nearer the 5’ end by a start codon and nearer the 3° end with a stop codon. Coding sequences can also be referred to as open reading frames. The term “deaminase” or “deaminase domain,” as used herein, refers to a protein or enzyme that catalyzes a deamination reaction. In some embodiments, the deaminase is an adenosine deaminase, which catalyzes the hydrolytic deamination of adenine to hypoxanthine. In some embodiments, the deaminase is an adenosine deaminase, which catalyzes the hydrolytic deamination of adenosine or adenine (A) to inosine (I). In some embodiments, the deaminase or deaminase domain is an adenosine deaminase catalyzing the hydrolytic deamination of adenosine or deoxyadenosine to inosine or deoxyinosine, respectively. In some embodiments, the adenosine deaminase catalyzes the hydrolytic deamination of adenosine in deoxyribonucleic acid (DNA). The adenosine deaminases (e.g., engineered adenosine deaminases, evolved adenosine deaminases) provided herein can be from any organism, such as a bacterium. In some embodiments, the adenosine deaminase is from a bacterium, such as Escherichia coli, Staphylococcus aureus, Salmonella typhimurium, Shewanella putrefaciens, Haemophilus influenzae, or Caulobacter crescentus. In some embodiments, the adenosine deaminase is a TadA deaminase. In some embodiments, the TadA deaminase is TadA variant. In some embodiments, the TadA variant is a TadA*8. In some embodiments, the deaminase or deaminase domain is a variant of a naturally occurring deaminase from an organism, such as a human, chimpanzee, gorilla, monkey, cow, dog, rat, or mouse. In some embodiments, the deaminase or deaminase domain does not occur in nature. For example, in some embodiments, the deaminase or deaminase domain is at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75% at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9% identical to a naturally occurring deaminase. For example, deaminase domains are described in International PCT Application Nos. PCT / 2017 / 045381 (WO 2018 / 027078) and PCT / US2016 / 058344 (WO 2017 / 070632), each of which is incorporated herein by reference for its entirety. Also, see Komor, A.C, et al., “Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage” Nature 533, 420-424 (2016); Gaudelli, N.M,, ef al., “Programmable base editing of A*T to G*C in genomic DNA without DNA cleavage” Nature 551, 464-471 (2017); Komor, A.C., ef al, “Improved base excision repair inhibition and bacteriophage Mu Gam protein yields C:G-to-T:A base editors with higher efficiency and product purity” Science Advances 3:eaa04774 (2017) ), and Rees, HA, et al., “Base editing: precision chemistry on the genome and transcriptome of living cells.” Nat Rev Genet. 2018 Dec;19(12):770-788. doi: 10.1038 / s41576-018-0059-1, the entire contents of which are hereby incorporated by reference. “Detect” refers to identifying the presence, absence or amount of the analyte to be detected. In one embodiment, a sequence alteration in a polynucleotide or polypeptide is detected. In another embodiment, the presence of indels is detected. By "detectable label" is meant a composition that when linked to a molecule of interest renders the latter detectable, via spectroscopic, photochemical, biochemical, immunochemical, or chemical means. For example, useful labels include radioactive isotopes, magnetic beads, metallic beads, colloidal particles, fluorescent dyes, electron-dense reagents, enzymes (for example, as commonly used in an enzyme linked immunosorbent assay (ELISA)), biotin, digoxigenin, or haptens. By “disease” is meant any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ. The term “effective amount,” as used herein, refers to an amount of a biologically active agent that is sufficient to elicit a desired biological response. The effective amount of an active agent(s) used to practice the present invention for therapeutic treatment of a disease varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an “effective” amount. In one embodiment, an effective amount is the amount of a base editor of the invention (e.g., a fusion protein comprising a programable DNA binding protein, a nucleobase editor and gRNA) sufficient to introduce an alteration in a gene of interest in a cell (e.g., a cell in vitro or in vivo). In some embodiments, an effective amount of a fusion protein provided herein, e.g, of a nucleobase editor comprising a nCas9 domain and a deaminase domain (e.g., adenosine deaminase or cytidine deaminase) may refer to the amount of the fusion protein that is sufficient to induce editing of a target site specifically bound and edited by the nucleobase editor. In one embodiment, an effective amount is the amount of a base editor required to achieve a therapeutic effect (e.g., to reduce or control a disease or a symptom or condition thereof). Such therapeutic effect need not be sufficient to alter a gene of interest in all cells of a subject, tissue or organ, but only to alter a gene of interest in about 1%, 5%, 10%, 25%, 50%, 75% or more of the cells present in a subject, tissue or organ. In some embodiments, an effective amount of a fusion protein provided herein, e.g., of a nucleobase editor comprising a nCas9 domain and a deaminase domain (e.g., adenosine deaminase or cytidine deaminase) refers to the amount of the fusion protein that is sufficient to induce editing of a target site specifically bound and edited by the nucleobase editors described herein. As will be appreciated by the skilled artisan, the effective amount of an agent, e.g, a fusion protein, a nuclease, a hybrid protein, a protein dimer, a complex of a protein (or protein dimer) and a polynucleotide, or a polynucleotide, may vary depending on various factors as, for example, on the desired biological response, e.g., on the specific allele, genome, or target site to be edited, on the cell or tissue being targeted, and / or on the agent being used. By "fragment" is meant a portion of a polypeptide or nucleic acid molecule. This portion contains, at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the entire length of the reference nucleic acid molecule or polypeptide. A fragment may contain 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 nucleotides or amino acids. By “guide RNA” or “gRNA” is meant a polynucleotide which can be specific for a target sequence and can form a complex with a polynucleotide programmable nucleotide binding domain protein (e.g., Cas9 or Cpf1). In an embodiment, the guide polynucleotide is a guide RNA (gRNA). gRNAs can exist as a complex of two or more RNAs, or as a single RNA molecule. gRNAs that exist as a single RNA molecule may be referred to as single-guide RNAs (sgRNAs), though “gRNA” is used interchangeably to refer to guide RNAs that exist as either single molecules or as a complex of two or more molecules. Typically, gRNAs that exist as single RNA species comprise two domains: (1) a domain that shares homology to a target nucleic acid (e.g, and directs binding of a Cas9 complex to the target); and (2) a domain that binds a Cas9 protein. In some embodiments, domain (2) corresponds to a sequence known as atracrRNA, and comprises a stem-loop structure. For example, in some embodiments, domain (2) is identical or homologous to a tractRNA as provided in Jinek ef al., Science 337:816- 821(2012), the entire contents of which is incorporated herein by reference. Other examples of gRNAs (e.g., those including domain 2) can be found in U.S. Provisional Patent Application, U.S.S.N. 61 / 874,682, filed September 6, 2013, entitled "Switchable Cas9 Nucleases and Uses Thereof," and U.S. Provisional Patent Application, U.S.S.N. 61 / 874,746, filed September 6, 2013, entitled "Delivery System For Functional Nucleases," the entire contents of each are hereby incorporated by reference in their entirety. In some embodiments, a gRNA comprises two or more of domains (1) and (2), and may be referred to as an “extended gRNA.” An extended gRNA will bind two or more Cas9 proteins and bind a target nucleic acid at two or more distinct regions, as described herein. The gRNA comprises a nucleotide sequence that complements a target site, which mediates binding of the nuclease / RNA complex to said target site, providing the sequence specificity of the nuclease: RNA complex. “Hybridization” means hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleobases. For example, adenine and thymine are complementary nucleobases that pair through the formation of hydrogen bonds. The term "inhibitor of base repair" or "IBR" refers to a protein that is capable in inhibiting the activity of a nucleic acid repair enzyme, for example a base excision repair (BER) enzyme. In some embodiments, the IBR is an inhibitor of inosine base excision repair. Exemplary inhibitors of base repair include inhibitors of APE1, Endo III, Endo IV, Endo V, Endo VIII, Fpg, hOGGI, hNEILI, T7 Endol, T4PDG, UDG, hSMUGI, and hAAG. In some embodiments, the IBR is an inhibitor of Endo V or hAAG. In some embodiments, the IBR is a catalytically inactive EndoV or a catalytically inactive hAAG. In some embodiments, the base repair inhibitor is an inhibitor of Endo V or hAAG. In some embodiments, the base repair inhibitor is a catalytically inactive EndoV or a catalytically inactive hAAG. In some embodiments, the base repair inhibitor is uracil glycosylase inhibitor (UGI). UGI refers to a protein that is capable of inhibiting a uracil-DNA glycosylase base-excision repair enzyme. In some embodiments, a UGI domain comprises a wild-type UGI or a fragment of a wild-type UGL In some embodiments, the UGI proteins provided herein include fragments of UGI and proteins homologous to a UGI or a UGI fragment. In some embodiments, the base repair inhibitor is an inhibitor of inosine base excision repair. In some embodiments, the base repair inhibitor is a “catalytically inactive inosine specific nuclease” or “dead inosine specific nuclease. Without wishing to be bound by any particular theory, catalytically inactive inosine glycosylases (e.g., alkyl adenine glycosylase (AAG)) can bind inosine, but cannot create an abasic site or remove the inosine, thereby sterically blocking the newly formed inosine moiety from DNA damage / repair mechanisms. In some embodiments, the catalytically inactive inosine specific nuclease can be capable of binding an inosine in a nucleic acid but does not cleave the nucleic acid. Non-limiting exemplary catalytically inactive inosine specific nucleases include catalytically inactive alkyl adenosine glycosylase (AAG nuclease), for example, from a human, and catalytically inactive endonuclease V (EndoV nuclease), for example, from E. coli. In some embodiments, the catalytically inactive AAG nuclease comprises an E125Q mutation or a corresponding mutation in another AAG nuclease. By “increases” is meant a positive alteration of at least 10%, 25%, 50%, 75%, or 100%. An "intein" is a fragment of a protein that is able to excise itself and join the remaining fragments (the exteins) with a peptide bond in a process known as protein splicing. Inteins are also referred to as "protein introns." The process of an intein excising itself and joining the remaining portions of the protein is herein termed "protein splicing" or "intein- mediated protein splicing." In some embodiments, an intein of a precursor protein (an intein containing protein prior to intein-mediated protein splicing) comes from two genes. Such intein is referred to herein as a split intein (e.g., split intein-N and split intein-C). For example, in cyanobacteria, DnaE, the catalytic subunit a of DNA polymerase III, is encoded by two separate genes, dnaE-n and dnaE-c. The intein encoded by the dnaE-n gene may be herein referred as "intein-N." The intein encoded by the dnaE-c gene may be herein referred as "intein-C." Other intein systems may also be used. For example, a synthetic intein based on the dnakE intein, the Cfa-N (e.g., split intein-N) and Cfa-C (e.g., split intein-C) intein pair, has been described (e.g., in Stevens et al., J Am Chem Soc. 2016 Feb. 24; 138(7):2162-5, incorporated herein by reference). Non-limiting examples of intein pairs that may be used in accordance with the present disclosure include: Cfa DnaE intein, Ssp GyrB intein, Ssp DnaX intein, Ter DnaE3 intein, Ter ThyX intein, Rma DnaB intein and Cne Prp8 intein (e.g., as described in U.S. Patent No. 8,394,604, incorporated herein by reference. Exemplary nucleotide and amino acid sequences of inteins are provided. DnaF Intein-N DNA: TGCCTGTCATACGAAACCGAGATACTGACAGTAGAATATGGCCTTCTGCCAATCGGGAAGAT TGTGGAGAAACGGATAGAATGCACAGTTTACTCTGTCGATAACAATGGTAACATTTATACTC AGCCAGTTGCCCAGTGGCACGACCGGGGAGAGCAGGARGTATTCGAATACTGTCTGGAGGAT GGAAGTCTCATTAGGGCCACTAAGGACCACARATTTATGACAGTCGATGGCCAGATGCTGCC TATAGACGAAATCTTTGAGCGAGAGTTGGACCTCATGCGAGTTGACAACCTTCCTAAT DnaE Intein-N Protein: CLSYETEILTVEYGLLPIGKIVEKRIECTVYSVDNNGNIYTQPVAQWHDR GEQEVFEYCLEDGSLIRATKDHKFMTVDGOMLPIDEIFERELDLMRVDNLPN DnaFE Intein-C DNA: ATGATCAAGATAGCTACAAGGARGTATCTTGGCAARACAARACGTTTATGA TATTGGAGTCGAARGAGATCACAACTTTGCTCTGAAGAACGGATTCATAGCTTCTAAT Intein-C: MIKIATRKYLGKQNVYDIGVERDHNFALKNGFIASN Cfa-N DNA: TGCCTGTCTTATGATACCGAGATACTTACCGTTGAATATGGCTTCTTGCCTATTGGAAAGAT TGTCGAAGAGAGAATTGAATGCACAGTATATACTGTAGACAAGAATGGTTTCGTTTACACAC AGCCCATTGCTCAATGGCACAATCGCGGCGAACAAGAAGTATTTGAGTACTGTCTCGAGGAT GGAAGCATCATACGAGCAACTAAAGATCATAAATTCATGACCACTGACGGGCAGATGTTGCC AATAGATGAGATATTCGAGCGGGGCTTGGATCTCAAACAAGTGGATGGATTGCCA Cfa-N Protein: CLSYDTEILTVEYGFLPIGKIVEERIECTVYTVDKNGFVYTQPIAQWHNRGEQEVFEYCLED GSIIRATKDHKEFMTTDGCMLPIDEIFERGLDLKQVDGLP Cfa-C DNA: ATGAAGAGGACTGCCGATGGATCAGAGT TTGAATCTCCCAAGAAGAAGAGGAAAGTAAAGAT AATATCTCGAAARAGTCTTGGTACCCAAAATGTCTATGATATTGGAGTGGAGAAAGATCACA BOTT CCT TOI CAMIAN CETC TCC TAGCOAGOAAD: Cfa-C Protein: MKRTADGSEFESPKKKRKVKIISRKSLGTONVYDIGVEKDHNFLLKNGLVASN Intein-N and intein-C may be fused to the N-terminal portion of the split Cas9 and the C-terminal portion of the split Cas9, respectively, for the joining of the N-terminal portion of the split Cas9 and the C-terminal portion of the split Cas9. For example, in some embodiments, an intein-N is fused to the C-terminus of the N-terminal portion of the split Cas9, i.e., to form a structure of N--[N-terminal portion of the split Cas9]-[intein-N]--C. In some embodiments, an intein-C is fused to the N-terminus of the C-terminal portion of the split Cas9, i.e., to form a structure of N-[intein-C]--[C-terminal portion of the split Cas9]-C. The mechanism of intein-mediated protein splicing for joining the proteins the inteins are fused to (e.g, split Cas9) is known in the art, e.g., as described in Shah et al., Chem Sci. 2014; 5(1):446-461, incorporated herein by reference. Methods for designing and using inteins are known in the art and described, for example by W02014004336, W02017132580, US20150344549, and US20180127780, each of which is incorporated herein by reference in their entirety. The terms “isolated,” “purified,” or "biologically pure" refer to material that is free to varying degrees from components which normally accompany it as found in its native state. "Isolate" denotes a degree of separation from original source or surroundings. "Purify" denotes a degree of separation that is higher than isolation. A "purified" or "biologically pure" protein is sufficiently free of other materials such that any impurities do not materially affect the biological properties of the protein or cause other adverse consequences. That is, a nucleic acid or peptide of this invention is purified if it is substantially free of cellular material, viral material, or culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized. Purity and homogeneity are typically determined using analytical chemistry techniques, for example, polyacrylamide gel electrophoresis or high-performance liquid chromatography. The term "purified" can denote that a nucleic acid or protein gives rise to essentially one band in an electrophoretic gel. For a protein that can be subjected to modifications, for example, phosphorylation or glycosylation, different modifications may give rise to different isolated proteins, which can be separately purified. By "isolated polynucleotide" is meant a nucleic acid (e.g., a DNA) that is free of the genes which, in the naturally-occurring genome of the organism from which the nucleic acid molecule of the invention is derived, flank the gene. The term therefore includes, for example, a recombinant DNA that is incorporated into a vector; into an autonomously replicating plasmid or virus; or into the genomic DNA of a prokaryote or eukaryote; or that exists as a separate molecule (for example, a cDNA or a genomic or cDNA fragment produced by PCR or restriction endonuclease digestion) independent of other sequences. In addition, the term includes an RNA molecule that is transcribed from a DNA molecule, as well as a recombinant DNA that is part of a hybrid gene encoding additional polypeptide sequence. By an "isolated polypeptide" is meant a polypeptide of the invention that has been separated from components that naturally accompany it. Typically, the polypeptide is isolated when it is at least 60%, by weight, free from the proteins and naturally-occurring organic molecules with which it is naturally associated. Preferably, the preparation is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight, a polypeptide of the invention. An isolated polypeptide of the invention may be obtained, for example, by extraction from a natural source, by expression of a recombinant nucleic acid encoding such a polypeptide; or by chemically synthesizing the protein. Purity can be measured by any appropriate method, for example, column chromatography, polyacrylamide gel electrophoresis, or by HPLC analysis. The term “linker”, as used herein, can refer to a covalent linker (e.g., covalent bond), a non-covalent linker, a chemical group, or a molecule linking two molecules or moieties, e.g., two components of a protein complex or a ribonucleocomplex, or two domains of a fusion protein, such as, for example, a polynucleotide programmable DNA binding domain (e.g., dCas9) and a deaminase domain (e.g., an adenosine deaminase, a cytidine deaminase, or an adenosine deaminase and a cytidine deaminase) or a napDNAbp domain (e.g., Cas12b) and a deaminase domain (e.g., an adenosine deaminase or a cytidine deaminase). In particular embodiments, linkers flank a deaminase domain that is inserted within a Cas protein or fragment thereof. A linker can join different components of, or different portions of components of, a base editor system. For example, in some embodiments, a linker can join a guide polynucleotide binding domain of a polynucleotide programmable nucleotide binding domain and a catalytic domain of a deaminase. In some embodiments, a linker can join a CRISPR polypeptide and a deaminase. In some embodiments, a linker can join a Cas9 and a deaminase. In some embodiments, a linker can join a dCas9 and a deaminase. In some embodiments, a linker can join a nCas9 and a deaminase. For example, in some embodiments, a linker can join a Cas12a / Cpfl, Cas12b / C2cl, Cas12¢ / C2c3, Cas12d / CasY, Casl2e / CasX, Casl2g, Cas12h, or Cas12i and a deaminase. In some embodiments, a linker can join a guide polynucleotide and a deaminase. In some embodiments, a linker can join a deaminating component and a polynucleotide programmable nucleotide binding component of a base editor system. In some embodiments, a linker can join an RNA-binding portion of a deaminating component and a napDNAbp component of a base editor system. In some embodiments, a linker can join an RNA-binding portion of a deaminating component and a polynucleotide programmable nucleotide binding component of a base editor system. In some embodiments, a linker can join an RNA-binding portion of a deaminating component and an RNA-binding portion of a polynucleotide programmable nucleotide binding component of a base editor system. A linker can be positioned between, or flanked by, two groups, molecules, or other moieties and connected to each one via a covalent bond or non- covalent interaction, thus connecting the two. In some embodiments, the linker can be an organic molecule, group, polymer, or chemical moiety. In some embodiments, the linker can be a polynucleotide. In some embodiments, the linker can be a DNA linker. In some embodiments, the linker can be an RNA linker. In some embodiments, a linker can comprise an aptamer capable of binding to a ligand. In some embodiments, the ligand may be carbohydrate, a peptide, a protein, or a nucleic acid. In some embodiments, the linker may comprise an aptamer may be derived from a riboswitch. The riboswitch from which the aptamer is derived may be selected from a theophylline riboswitch, a thiamine pyrophosphate (TPP) riboswitch, an adenosine cobalamin (AdoCbl) riboswitch, an S-adenosyl methionine (SAM) riboswitch, an SAH riboswitch, a flavin mononucleotide (FMN) riboswitch, a tetrahydrofolate riboswitch, a lysine riboswitch, a glycine riboswitch, a purine riboswitch, a GImS riboswitch, or a pre-queosinel (PreQ1) riboswitch. In some embodiments, a linker may comprise an aptamer bound to a polypeptide or a protein domain, such as a polypeptide ligand. In some embodiments, the polypeptide ligand may be a K Homology (KH) domain, a MS2 coat protein domain, a PP7 coat protein domain, a SfMu Com coat protein domain, a sterile alpha motif, a telomerase Ku binding motif and Ku protein, a telomerase Sm7 binding motif and Sm7 protein, or an RNA recognition motif. In some embodiments, the polypeptide ligand may be a portion of a base editor system component. For example, a nucleobase editing component may comprise a deaminase domain and an RNA recognition motif. In some embodiments, the linker can be an amino acid or a plurality of amino acids (e.g., a peptide or protein). In some embodiments, the linker can be about 5-100 amino acids in length, for example, about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 20-30, 30- 40, 40-50, 50-60, 60-70, 70-80, 80-90, or 90-100 amino acids in length. In some embodiments, the linker can be about 100-150, 150-200, 200-250, 250-300, 300-350, 350- 400, 400-450, or 450-500 amino acids in length. Longer or shorter linkers can be also contemplated. In some embodiments, a linker joins a gRNA binding domain of an RNA- programmable nuclease, including a Cas9 nuclease domain, and the catalytic domain of a nucleic-acid editing protein (e.g., cytidine or adenosine deaminase). In some embodiments, a linker joins a dCas9 and a nucleic-acid editing protein. For example, the linker is positioned between, or flanked by, two groups, molecules, or other moieties and connected to each one via a covalent bond, thus connecting the two. In some embodiments, the linker is an amino acid or a plurality of amino acids (e.g., a peptide or protein). In some embodiments, the linker is an organic molecule, group, polymer, or chemical moiety. In some embodiments, the linker is 5-200 amino acids in length, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 35, 45, 50, 55, 60, 60, 65, 70, 70, 75, 80, 85, 90, 90, 95, 100, 101, 102, 103, 104, 105, 110, 120, 130, 140, 150, 160, 175, 180, 190, or 200 amino acids in length. Longer or shorter linkers are also contemplated. In some embodiments, the domains of the nucleobase editor are fused via a linker that comprises the amino acid sequence of SGGSSGSETPGTSESATPESSGGS, SGGSSGGSSGSETPGTSESATPESSGGSSGGS, or GGSGGSPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTE PSEGSAPGTSTEPSEGSAPGTSESATPESGPGSEPATSGGSGGS. In some embodiments, domains of the nucleobase editor are fused via a linker comprising the amino acid sequence SGSETPGTSESATPES, which may also be referred to as the XTEN linker. In some embodiments, a linker comprises the amino acid sequence SGGS. In some embodiments, a linker comprises (SGGS)s, (GGGS)n, (GGGGS) n, (Gn, (EAAAK)n, (GGS)n, SGSETPGTSESATPES, or (XP). motif, or a combination of any of these, wherein n is independently an integer between 1 and 30, and wherein X is any amino acid. In some embodiments, nis 1, 2,3,4,5,6,7,8,9, 10, 11, 12, 13, 14, or 15. In some embodiments, the linker is 24 amino acids in length. In some embodiments, the linker comprises the amino acid sequence SGGSSGGSSGSETPGTSESATPES. In some embodiments, the linker is 40 amino acids in length. In some embodiments, the linker comprises the amino acid sequence SGGSSGGSSGSETPGTSESATPESSGGSSGGSSGGSSGGS. In some embodiments, the linker is 64 amino acids in length. In some embodiments, the linker comprises the amino acid sequence SGGSSGGSSGSETPGTSESATPESSGGSSGGSSGGSSGGSSGSETPGTSESATPESSGGS SGGS. In some embodiments, the linker is 92 amino acids in length. In some embodiments, the linker comprises the amino acid sequence PGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPG TSTEPSEGSAPGTSESATPESGPGSEPATS. By “marker” is meant any protein or polynucleotide having an alteration in expression level or activity that is associated with a disease or disorder. The term “mutation,” as used herein, refers to a substitution of a residue within a sequence, e.g., a nucleic acid or amino acid sequence, with another residue, or a deletion or insertion of one or more residues within a sequence. Mutations are typically described herein by identifying the original residue followed by the position of the residue within the sequence and by the identity of the newly substituted residue. Various methods for making the amino acid substitutions (mutations) provided herein are well known in the art, and are provided by, for example, Green and Sambrook, Molecular Cloning: A Laboratory Manual (4th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2012)). In some embodiments, the presently disclosed base editors can efficiently generate an “intended mutation,” such as a point mutation, in a nucleic acid (e.g., a nucleic acid within a genome of a subject) without generating a significant number of unintended mutations, such as unintended point mutations. In some embodiments, an intended mutation is a mutation that is generated by a specific base editor (e.g., cytidine base editor or adenosine base editor) bound to a guide polynucleotide (e.g., gRNA), specifically designed to generate the intended mutation. In general, mutations made or identified in a sequence (e.g., an amino acid sequence as described herein) are numbered in relation to a reference (or wild-type) sequence, i.e., a sequence that does not contain the mutations. The skilled practitioner in the art would readily understand how to determine the position of mutations in amino acid and nucleic acid sequences relative to a reference sequence. The term “non-conservative mutations” involve amino acid substitutions between different groups, for example, lysine for tryptophan, or phenylalanine for serine, etc. In this case, it is preferable for the non-conservative amino acid substitution to not interfere with, or inhibit the biological activity of, the functional variant. The non-conservative amino acid substitution can enhance the biological activity of the functional variant, such that the biological activity of the functional variant is increased as compared to the wild-type protein. The term “nuclear localization sequence,” “nuclear localization signal,” or “NLS” refers to an amino acid sequence that promotes import of a protein into the cell nucleus. Nuclear localization sequences are known in the art and described, for example, in Plank et al., International PCT application, PCT / EP2000 / 011690, filed November 23, 2000, published as W0 / 2001 / 038547 on May 31, 2001, the contents of which are incorporated herein by reference for their disclosure of exemplary nuclear localization sequences. In other embodiments, the NLS is an optimized NLS described, for example, by Koblan ef al., Nature Biotech. 2018 doi:10.1038 / nbt.4172. In some embodiments, an NLS comprises the amino acid sequence KRTADGSEFESPKKKRKYV, KRPAATKKAGQAKKKK, KKTELQTTNAENKTKKL, KRGINDRNFWRGENGRKTR, RKSGKIAAIVVKRPRK, PKKKRKV, or MDSLLMNRRKFLYQFKNVRWAKGRRETYLC. The terms “nucleic acid” and “nucleic acid molecule,” as used herein, refer to a compound comprising a nucleobase and an acidic moiety, e.g., a nucleoside, a nucleotide, or a polymer of nucleotides. Typically, polymeric nucleic acids, e.g., nucleic acid molecules comprising three or more nucleotides are linear molecules, in which adjacent nucleotides are linked to each other via a phosphodiester linkage. In some embodiments, “nucleic acid” refers to individual nucleic acid residues (e.g, nucleotides and / or nucleosides). In some embodiments, “nucleic acid” refers to an oligonucleotide chain comprising three or more individual nucleotide residues. As used herein, the terms “oligonucleotide” and “polynucleotide” can be used interchangeably to refer to a polymer of nucleotides (e.g., a string of at least three nucleotides). In some embodiments, “nucleic acid” encompasses RNA as well as single and / or double-stranded DNA. Nucleic acids may be naturally occurring, for example, in the context of a genome, a transcript, an mRNA, tRNA, rRNA, siRNA, snRNA, a plasmid, cosmid, chromosome, chromatid, or other naturally occurring nucleic acid molecule. On the other hand, a nucleic acid molecule may be a non-naturally occurring molecule, e.g., a recombinant DNA or RNA, an artificial chromosome, an engineered genome, or fragment thereof, or a synthetic DNA, RNA, DNA / RNA hybrid, or including non-naturally occurring nucleotides or nucleosides. Furthermore, the terms “nucleic acid,” “DNA,” “RNA,” and / or similar terms include nucleic acid analogs, e.g., analogs having other than a phosphodiester backbone. Nucleic acids can be purified from natural sources, produced using recombinant expression systems and optionally purified, chemically synthesized, erc. Where appropriate, e.g., in the case of chemically synthesized molecules, nucleic acids can comprise nucleoside analogs such as analogs having chemically modified bases or sugars, and backbone modifications. A nucleic acid sequence is presented in the 5' to 3' direction unless otherwise indicated. In some embodiments, a nucleic acid is or comprises natural nucleosides (e.g., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, and deoxycytidine); nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, S-methylcytidine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7- deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and 2-thiocytidine); chemically modified bases; biologically modified bases (e.g., methylated bases); intercalated bases; modified sugars ( 2'-e.g. fluororibose, ribose, 2'-deoxyribose, arabinose, and hexose); and / or modified phosphate groups (e.g., phosphorothioates and 5'-N- phosphoramidite linkages). The term "nucleic acid programmable DNA binding protein" or "napDNAbp" may be used interchangeably with “polynucleotide programmable nucleotide binding domain” to refer to a protein that associates with a nucleic acid (e.g., DNA or RNA), such as a guide nucleic acid or guide polynucleotide (e.g., gRNA), that guides the napDNAbp to a specific nucleic acid sequence. In some embodiments, the polynucleotide programmable nucleotide binding domain is a polynucleotide programmable DNA binding domain. In some embodiments, the polynucleotide programmable nucleotide binding domain is a polynucleotide programmable RNA binding domain. In some embodiments, the polynucleotide programmable nucleotide binding domain is a Cas9 protein. A Cas9 protein can associate with a guide RNA that guides the Cas9 protein to a specific DNA sequence that is complementary to the guide RNA. In some embodiments, the napDNAbp is a Cas9 domain, for example a nuclease active Cas9, a Cas9 nickase (nCas9), or a nuclease inactive Cas9 (dCas9). Non-limiting examples of nucleic acid programmable DNA binding proteins include, Cas9 (e.g., dCas9 and nCas9), Cas12a / Cpfl, Cas12b / C2cl, Cas12¢ / C2¢3, Cas12d / CasY, Cas12e / CasX, Casl2g, Cas12h, and Cas12i. Non-limiting examples of Cas enzymes include Casl, CaslB, Cas2, Cas3, Cas4, Cas5, Cas5d, Cas5t, Cas5h, Cas5a, Cas6, Cas7, Cas8, Cas8a, Cas8b, Cas8c, Cas9 (also known as Csnl or Csx12), Cas10, Cas10d, Cas12a / Cpfl, Cas12b / C2cl, Cas12¢ / C2c3, Cas12d / CasY, Cas12e / CasX, Casl2g, Cas12h, Casl2i, Csyl, Csy2, Csy3, Csy4, Csel, Cse2, Cse3, Cse4, Cse5e, Cscl, Csc2, Csa$, Csnl, Csn2, Csm1, Csm2, Csm3, Csm4, Csm5, Csm6, Cmrl, Cmr3, Cmr4, Cmr5, Cmr6, Csbl, Csb2, Csb3, Csx17, Csx14, Csx10, Csx16, CsaX, Csx3, Csx1, Csx1S, Csx11, Csfl, Csf2, CsO, Csf4, Csdl, Csd2, Cstl, Cst2, Cshl, Csh2, Csal, Csa2, Csa3, Csa4, Csa5, Type II Cas effector proteins, Type V Cas effector proteins, Type VI Cas effector proteins, CARF, DinG, homologues thereof, or modified or engineered versions thereof. Other nucleic acid programmable DNA binding proteins are also within the scope of this disclosure, although they may not be specifically listed in this disclosure. See, e.g., Makarova ef al. “Classification and Nomenclature of CRISPR-Cas Systems: Where from Here?” CRISPR J. 2018 Oct; 1:325-336. doi: 10.1089 / crispr.2018.0033; Yan ef al, “Functionally diverse type V CRISPR-Cas systems” Science. 2019 Jan 4,363(6422):88-91. doi: 10.1126 / science.aav7271, the entire contents of each are hereby incorporated by reference. The term “nucleobase,” “nitrogenous base,” or “base,” used interchangeably herein, refers to a nitrogen-containing biological compound that forms a nucleoside, which in turn is a component of a nucleotide. The ability of nucleobases to form base pairs and to stack one upon another leads directly to long-chain helical structures such as ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). Five nucleobases — adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U) — are called primary or canonical. Adenine and guanine are derived from purine, and cytosine, uracil, and thymine are derived from pyrimidine. DNA and RNA can also contain other (non-primary) bases that are modified. Non-limiting exemplary modified nucleobases can include hypoxanthine, xanthine, 7-methylguanine, 5,6- dihydrouracil, 5-methylcytosine (m5C), and 5-hydromethylcytosine. Hypoxanthine and xanthine can be created through mutagen presence, both of them through deamination (replacement of the amine group with a carbonyl group). Hypoxanthine can be modified from adenine. Xanthine can be modified from guanine. Uracil can result from deamination of cytosine. A “nucleoside” consists of a nucleobase and a five carbon sugar (either ribose or deoxyribose). Examples of a nucleoside include adenosine, guanosine, uridine, cytidine, 5- methyluridine (m5U), deoxyadenosine, deoxyguanosine, thymidine, deoxyuridine, and deoxycytidine. Examples of a nucleoside with a modified nucleobase includes inosine (I), xanthosine (X), 7-methylguanosine (m7G), dihydrouridine (D), 5-methylcytidine (m5C), and pseudouridine (¥). A “nucleotide” consists of a nucleobase, a five carbon sugar (either ribose or deoxyribose), and at least one phosphate group. The term “nucleic acid programmable DNA binding protein” or “napDNAbp” refers to a protein that associates with a nucleic acid (e.g., DNA or RNA), such as a guide nucleic acid, that guides the napDNAbp to a specific nucleic acid sequence. For example, a Cas12 protein can associate with a guide RNA that guides the Cas12 protein to a specific DNA sequence that is complementary to the guide RNA. In some embodiments, the napDNAbp is a Cas12 domain, for example a nuclease active Cas12 domain. Examples of napDNAbps include, Cas12a / Cpfl, Cas12b / C2cl, Cas12¢ / C2c3, Cas12d / CasY, Cas12e / CasX, Cas12g, Casl12h, and Cas12i. Other napDNAbps are also within the scope of this disclosure, although they may not be specifically listed in this disclosure. See, e.g., Makarova et al. “Classification and Nomenclature of CRISPR-Cas Systems: Where from Here?” CRISPR J. 2018 Oct; 1:325-336. doi: 10.1089 / crispr.2018.0033; Yan et al., “Functionally diverse type V CRISPR-Cas systems” Science. 2019 Jan 4;363(6422):88-91. doi: 10.1126 / science.aav7271, the entire contents of each are hereby incorporated by reference. The terms “nucleobase editing domain” or “nuclecbase editing protein,” as used herein, refers to a protein or enzyme that can catalyze a nucleobase modification in RNA or DNA, such as cytosine (or cytidine) to uracil (or uridine) or thymine (or thymidine), and adenine (or adenosine) to hypoxanthine (or inosine) deaminations, as well as non-templated nucleotide additions and insertions. In some embodiments, the nucleobase editing domain is a deaminase domain (e.g., an adenine deaminase or an adenosine deaminase; or a cytidine deaminase or a cytosine deaminase). In some embodiments, the nucleobase editing domain is more than one deaminase domain (e.g, an adenine deaminase or an adenosine deaminase and a cytidine or a cytosine deaminase). In some embodiments, the nucleobase editing domain can be a naturally occurring nucleobase editing domain. In some embodiments, the nucleobase editing domain can be an engineered or evolved nucleobase editing domain from the naturally occurring nucleobase editing domain. The nucleobase editing domain can be from any organism, such as a bacterium, human, chimpanzee, gorilla, monkey, cow, dog, rat, or mouse. For example, nucleobase editing proteins are described in International PCT Application Nos. PCT / 2017 / 045381 (WO 2018 / 027078) and PCT / US2016 / 058344 (WO 2017 / 070632), each of which is incorporated herein by reference for its entirety. Also see, Komor, A.C, et al., “Programmable editing of a target base in genomic DNA without double- stranded DNA cleavage” Nature 533, 420-424 (2016); Gaudelli, NM, et al., “Programmable base editing of A+T to G=C in genomic DNA without DNA cleavage” Nature 551, 464-471 (2017); and Komor, A.C, et al., “Improved base excision repair inhibition and bacteriophage Mu Gam protein yields C:G-to-T:A base editors with higher efficiency and product purity” Science Advances 3:eaa04774 (2017), the entire contents of which are hereby incorporated by reference. As used herein, “obtaining” as in “obtaining an agent” includes synthesizing, purchasing, or otherwise acquiring the agent. A “patient” or “subject” as used herein refers to a mammalian subject or individual diagnosed with, at risk of having or developing, or suspected of having or developing a disease or a disorder. In some embodiments, the term “patient” refers to a mammalian subject with a higher than average likelihood of developing a disease or a disorder. Exemplary patients can be humans, non-human primates, cats, dogs, pigs, cattle, cats, horses, camels, llamas, goats, sheep, rodents (e.g, mice, rabbits, rats, or guinea pigs) and other mammalians that can benefit from the therapies disclosed herein. Exemplary human patients can be male and / or female. “Patient in need thereof” or “subject in need thereof” is referred to herein as a patient diagnosed with, at risk or having, predetermined to have, or suspected of having a disease or disorder. The terms “pathogenic mutation,” “pathogenic variant,” “disease casing mutation,” “disease causing variant,” “deleterious mutation,” or “predisposing mutation” refers to a genetic alteration or mutation that increases an individual’s susceptibility or predisposition to a certain disease or disorder. In some embodiments, the pathogenic mutation comprises at least one wild-type amino acid substituted by at least one pathogenic amino acid in a protein encoded by a gene. The term “pharmaceutically-acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the compound from one site (e.g., the delivery site) of the body, to another site (e.g., organ, tissue or portion of the body). A pharmaceutically acceptable carrier is “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the tissue of the subject (e.g., physiologically compatible, sterile, physiologic pH, etc.). The terms such as “excipient,” “carrier,” “pharmaceutically acceptable carrier,” “vehicle,” or the like are used interchangeably herein. The term “pharmaceutical composition” can refer to a composition formulated for pharmaceutical use. The terms “protein,” “peptide,” “polypeptide,” and their grammatical equivalents are used interchangeably herein, and refer to a polymer of amino acid residues linked together by peptide (amide) bonds. The terms refer to a protein, peptide, or polypeptide of any size, structure, or function. Typically, a protein, peptide, or polypeptide will be at least three amino acids long. A protein, peptide, or polypeptide can refer to an individual protein or a collection of proteins. One or more of the amino acids in a protein, peptide, or polypeptide can be modified, for example, by the addition of a chemical entity such as a carbohydrate group, a hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, a linker for conjugation, functionalization, or other modifications, etc. A protein, peptide, or polypeptide can also be a single molecule or can be a multi-molecular complex. A protein, peptide, or polypeptide can be just a fragment of a naturally occurring protein or peptide. A protein, peptide, or polypeptide can be naturally occurring, recombinant, or synthetic, or any combination thereof. The term “fusion protein” as used herein refers to a hybrid polypeptide which comprises protein domains from at least two different proteins. One protein can be located at the amino-terminal (N-terminal) portion of the fusion protein or at the carboxy-terminal (C-terminal) protein thus forming an amino-terminal fusion protein or a carboxy-terminal fusion protein, respectively. A protein can comprise different domains, for example, a nucleic acid binding domain (e.g., the gRNA binding domain of Cas9 that directs the binding of the protein to a target site) and a nucleic acid cleavage domain, or a catalytic domain of a nucleic acid editing protein. In some embodiments, a protein comprises a proteinaceous part, e.g, an amino acid sequence constituting a nucleic acid binding domain, and an organic compound, e.g., a compound that can act as a nucleic acid cleavage agent. In some embodiments, a protein is in a complex with, or is in association with, a nucleic acid, e.g., RNA or DNA. Any of the proteins provided herein can be produced by any method known in the art. For example, the proteins provided herein can be produced via recombinant protein expression and purification, which is especially suited for fusion proteins comprising a peptide linker. Methods for recombinant protein expression and purification are well known, and include those described by Green and Sambrook, Molecular Cloning: A Laboratory Manual (4th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2012)), the entire contents of which are incorporated herein by reference. Polypeptides and proteins disclosed herein (including functional portions and functional variants thereof) can comprise synthetic amino acids in place of one or more naturally-occurring amino acids. Such synthetic amino acids are known in the art, and include, for example, aminocyclohexane carboxylic acid, norleucine, a-amino n-decanoic acid, homoserine, S-acetylaminomethyl-cysteine, trans-3- and trans-4-hydroxyproline, 4- aminophenylalanine, 4-nitrophenylalanine, 4-chlorophenylalanine, 4-carboxyphenylalanine, B-phenylserine B-hydroxyphenylalanine, phenylglycine, a-naphthylalanine, cyclohexylalanine, cyclohexylglycine, indoline-2-carboxylic acid, 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid, aminomalonic acid, aminomalonic acid monoamide, N’-benzyl-N’-methyl-lysine, N’,N’-dibenzyl-lysine, 6-hydroxylysine, ornithine, a-aminocyclopentane carboxylic acid, a-aminocyclohexane carboxylic acid, a- aminocycloheptane carboxylic acid, a-(2-amino-2-norbomane)-carboxylic acid, o,y- diaminobutyric acid, a,B-diaminopropionic acid, homophenylalanine, and a-tert-butylglycine. The polypeptides and proteins can be associated with post-translational modifications of one or more amino acids of the polypeptide constructs. Non-limiting examples of post- translational modifications include phosphorylation, acylation including acetylation and formylation, glycosylation (including N-linked and O-linked), amidation, hydroxylation, alkylation including methylation and ethylation, ubiquitylation, addition of pyrrolidone carboxylic acid, formation of disulfide bridges, sulfation, myristoylation, palmitoylation, isoprenylation, farnesylation, geranylation, glypiation, lipoylation and iodination. The term “polynucleotide programmable nucleotide binding domain” or “nucleic acid programmable DNA binding protein (napDNAbp)” refers to a protein that associates with a nucleic acid (e.g., DNA or RNA), such as a guide polynucleotide (e.g., guide RNA), that guides the polynucleotide programmable nucleotide binding domain to a specific nucleic acid sequence. In some embodiments, the polynucleotide programmable nucleotide binding domain is a polynucleotide programmable DNA binding domain. In some embodiments, the polynucleotide programmable nucleotide binding domain is a polynucleotide programmable RNA binding domain. In some embodiments, the polynucleotide programmable nucleotide binding domain is a Cas12 protein. The term "recombinant” as used herein in the context of proteins or nucleic acids refers to proteins or nucleic acids that do not occur in nature, but are the product of human engineering. For example, in some embodiments, a recombinant protein or nucleic acid molecule comprises an amino acid or nucleotide sequence that comprises at least one, at least two, at least three, at least four, at least five, at least six, or at least seven mutations as compared to any naturally occurring sequence. By “reduces” is meant a negative alteration of at least 10%, 25%, 50%, 75%, or 100%. By “reference” is meant a standard or control condition. In one embodiment, the reference is a wild-type or healthy cell. In other embodiments and without limitation, a reference is an untreated cell that is not subjected to a test condition, or is subjected to placebo or normal saline, medium, buffer, and / or a control vector that does not harbor a polynucleotide of interest. A “reference sequence” is a defined sequence used as a basis for sequence comparison. A reference sequence may be a subset of or the entirety of a specified sequence; for example, a segment of a full-length cDNA or gene sequence, or the complete cDNA or gene sequence. For polypeptides, the length of the reference polypeptide sequence will generally be at least about 16 amino acids, at least about 20 amino acids, at least about 25 amino acids, about 35 amino acids, about 50 amino acids, or about 100 amino acids. For nucleic acids, the length of the reference nucleic acid sequence will generally be at least about 50 nucleotides, at least about 60 nucleotides, at least about 75 nucleotides, about 100 nucleotides or about 300 nucleotides or any integer thereabout or therebetween. In some embodiments, a reference sequence is a wild-type sequence of a protein of interest. In other embodiments, a reference sequence is a polynucleotide sequence encoding a wild-type protein, The term "RNA-programmable nuclease," and "RNA-guided nuclease" are used with (e.g., binds or associates with) one or more RNA(s) that is not a target for cleavage. In some embodiments, an RNA-programmable nuclease, when in a complex with an RNA, may be referred to as a nuclease:RNA complex. Typically, the bound RNA(s) is referred to as a guide RNA (gRNA). gRNAs can exist as a complex of two or more RNAs, or as a single RNA molecule. gRNASs that exist as a single RNA molecule may be referred to as single- guide RNAs (sgRNAs), though "gRNA" is used interchangeably to refer to guide RNAs that exist as either single molecules or as a complex of two or more molecules. Typically, gRNAs that exist as single RNA species comprise two domains: (1) a domain that shares homology to a target nucleic acid (e.g., and directs binding of a Cas9 complex to the target); and (2) a domain that binds a Cas9 protein. In some embodiments, domain (2) corresponds to a sequence known as a tracrRNA, and comprises a stem-loop structure. For example, in some embodiments, domain (2) is identical or homologous to a tractRNA as provided in Jinek et ah, Science 337:816-821(2012), the entire contents of which is incorporated herein by reference. Other examples of gRNAs (e.g., those including domain 2) can be found in U.S. Provisional Patent Application, U.S.S.N. 61 / 874,682, filed September 6, 2013, entitled "Switchable Cas9 Nucleases and Uses Thereof," and U.S. Provisional Patent Application, U.S.S.N. 61 / 874,746, filed September 6, 2013, entitled "Delivery System For Functional Nucleases," the entire contents of each are hereby incorporated by reference in their entirety. In some embodiments, a gRNA comprises two or more of domains (1) and (2), and may be referred to as an "extended gRNA." For example, an extended gRNA will, e.g, bind two or more Cas9 proteins and bind a target nucleic acid at two or more distinct regions, as described herein. The gRNA comprises a nucleotide sequence that complements a target site, which mediates binding of the nuclease / RNA complex to said target site, providing the sequence specificity of the nuclease: RNA complex. In some embodiments, the RNA-programmable nuclease is the (CRISPR-associated system) Cas9 endonuclease, for example, Cas9 (Casnl) from Streptococcus pyogenes (see, e.g., "Complete genome sequence of an Ml strain of Streptococcus pyogenes." Ferretti 1.J., et al., Proc. Natl. Acad. Sci. U.S.A. 98:4658-4663(2001); "CRISPR RNA maturation by trans- encoded small RNA and host factor RNase IIL." Deltcheva E., ef al, Nature 471:602- 607(2011). Because RNA-programmable nucleases (e.g., Cas9) use RNA:DNA hybridization to target DNA cleavage sites, these proteins are able to be targeted, in principle, to any sequence specified by the guide RNA. Methods of using RNA-programmable nucleases, such as Cas9, for site-specific cleavage (e.g., to modify a genome) are known in the art (see e.g., Cong, L. et al., Multiplex genome engineering using CRISPR / Cas systems. Science 339, 819-823 (2013); Mali, P. et al, RNA-guided human genome engineering via Cas9. Science 339, 823-826 (2013); Hwang, W.Y. et al, Efficient genome editing in zebrafish using a CRISPR-Cas system. Nature biotechnology 31, 227-229 (2013); Jinek, M. ef al, RNA-programmed genome editing in human cells. eLife 2, e00471 (2013); Dicarlo, J.E. et al, Genome engineering in Saccharomyces cerevisiae using CRISPR-Cas systems. Nucleic acids research (2013); Jiang, W. et al, RNA-guided editing of bacterial genomes using CRISPR-Cas systems. Nature biotechnology 31, 233-239 (2013); the entire contents of each of which are incorporated herein by reference). The term “single nucleotide polymorphism (SNP)” is a variation in a single nucleotide that occurs at a specific position in the genome, where each variation is present to some appreciable degree within a population (e.g., > 1%). For example, at a specific base position in the human genome, the C nucleotide can appear in most individuals, but in a minority of individuals, the position is occupied by an A. This means that there is a SNP at this specific position, and the two possible nucleotide variations, C or A, are said to be alleles for this position. SNPs underlie differences in susceptibility to disease. The severity of illness and the way our body responds to treatments are also manifestations of genetic variations. SNPs can fall within coding regions of genes, non-coding regions of genes, or in the intergenic regions (regions between genes). In some embodiments, SNPs within a coding sequence do not necessarily change the amino acid sequence of the protein that is produced, due to degeneracy of the genetic code. SNPs in the coding region are of two types: synonymous and nonsynonymous SNPs. Synonymous SNPs do not affect the protein sequence, while nonsynonymous SNPs change the amino acid sequence of protein. The nonsynonymous SNPs are of two types: missense and nonsense. SNPs that are not in protein-coding regions can still affect gene splicing, transcription factor binding, messenger RNA degradation, or the sequence of noncoding RNA. Gene expression affected by this type of SNP is referred to as an eSNP (expression SNP) and can be upstream or downstream from the gene. A single nucleotide variant (SNV) is a variation in a single nucleotide without any limitations of frequency and can arise in somatic cells. A somatic single nucleotide variation can also be called a single-nucleotide alteration. By "specifically binds" is meant a nucleic acid molecule, polypeptide, or complex thereof (e.g., a nucleic acid programmable DNA binding domain and guide nucleic acid), compound, or molecule that recognizes and binds a polypeptide and / or nucleic acid molecule of the invention, but which does not substantially recognize and bind other molecules in a sample, for example, a biological sample. Nucleic acid molecules useful in the methods of the invention include any nucleic acid molecule that encodes a polypeptide of the invention or a fragment thereof. Such nucleic acid molecules need not be 100% identical with an endogenous nucleic acid sequence, but will typically exhibit substantial identity. Polynucleotides having “substantial identity” to an endogenous sequence are typically capable of hybridizing with at least one strand of a double-stranded nucleic acid molecule. Nucleic acid molecules useful in the methods of the invention include any nucleic acid molecule that encodes a polypeptide of the invention or a fragment thereof. Such nucleic acid molecules need not be 100% identical with an endogenous nucleic acid sequence, but will typically exhibit substantial identity. Polynucleotides having “substantial identity” to an endogenous sequence are typically capable of hybridizing with at least one strand of a double-stranded nucleic acid molecule. By "hybridize" is meant pair to form a double-stranded molecule between complementary polynucleotide sequences (e.g., a gene described herein), or portions thereof, under various conditions of stringency. (See, e.g., Wahl, G. M. and S. L. Berger (1987) Methods Enzymol. 152:399; Kimmel, A. R. (1987) Methods Enzymol. 152:507). For example, stringent salt concentration will ordinarily be less than about 750 mM NaCl and 75 mM trisodium citrate, preferably less than about 500 mM NaCl and 50 mM trisodium citrate, and more preferably less than about 250 mM NaCl and 25 mM trisodium citrate. Low stringency hybridization can be obtained in the absence of organic solvent, e.g., formamide, while high stringency hybridization can be obtained in the presence of at least about 35% formamide, and more preferably at least about 50% formamide. Stringent temperature conditions will ordinarily include temperatures of at least about 30° C, more preferably of at least about 37° C, and most preferably of at least about 42° C. Varying additional parameters, such as hybridization time, the concentration of detergent, e.g., sodium dodecyl sulfate (SDS), and the inclusion or exclusion of carrier DNA, are well known to those skilled in the art. Various levels of stringency are accomplished by combining these various conditions as needed. In a one: embodiment, hybridization will occur at 30° C in 750 mM NaCl, 75 mM trisodium citrate, and 1% SDS. In another embodiment, hybridization will occur at 37° C in 500 mM NaCl, 50 mM trisodium citrate, 1% SDS, 35% formamide, and 100 pg / ml denatured salmon sperm DNA (ssDNA). In another embodiment, hybridization will occur at 42° C in 250 mM NaCl, 25 mM trisodium citrate, 1% SDS, 50% formamide, and 200 pg / ml ssDNA. Useful variations on these conditions will be readily apparent to those skilled in the art. For most applications, washing steps that follow hybridization will also vary in stringency. Wash stringency conditions can be defined by salt concentration and by temperature. As above, wash stringency can be increased by decreasing salt concentration or by increasing temperature. For example, stringent salt concentration for the wash steps will preferably be less than about 30 mM NaCl and 3 mM trisodium citrate, and most preferably less than about 15 mM NaCl and 1.5 mM trisodium citrate. Stringent temperature conditions for the wash steps will ordinarily include a temperature of at least about 25° C, more preferably of at least about 42° C, and even more preferably of at least about 68° C. In an embodiment, wash steps will occur at 25° C in 30 mM NaCl, 3 mM trisodium citrate, and 0.1% SDS. In a more preferred embodiment, wash steps will occur at 42 C in 15 mM NaCl, 1.5 mM trisodium citrate, and 0.1% SDS. In a more preferred embodiment, wash steps will occur at 68° C in 15 mM NaCl, 1.5 mM trisodium citrate, and 0.1% SDS. Additional variations on these conditions will be readily apparent to those skilled in the art. Hybridization techniques are well known to those skilled in the art and are described, for example, in Benton and Davis (Science 196:180, 1977); Grunstein and Hogness (Proc. Natl. Acad. Sci., USA 72:3961, 1975); Ausubel et al. (Current Protocols in Molecular Biology, Wiley Interscience, New York, 2001); Berger and Kimmel (Guide to Molecular Cloning Techniques, 1987, Academic Press, New York); and Sambrook ef al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, New York. By “split” is meant divided into two or more fragments. A "split Cas9 protein” or “split Cas9" refers to a Cas9 protein that is provided as an N- terminal fragment and a C-terminal fragment encoded by two separate nucleotide sequences. The polypeptides corresponding to the N-terminal portion and the C-terminal portion of the Cas9 protein may be spliced to form a “reconstituted” Cas9 protein. In particular embodiments, the Cas9 protein is divided into two fragments within a disordered region of the protein, e.g., as described in Nishimasu et al., Cell, Volume 156, Issue 5, pp. 935-949, 2014, or as described in Jiang et al. (2016) Science 351: 867-871. PDB file: 5F9R, each of which is incorporated herein by reference. In some embodiments, the protein is divided into two fragments at any C, T, A, or S within a region of SpCas9 between about amino acids A292-G364, F445-K483, or E565-T637, or at corresponding positions in any other Cas9, Cas9 variant (e.g., nCas9, dCas9), or other napDNAbp. In some embodiments, protein is divided into two fragments at SpCas9 T310, T313, A456, $469, or C574. In some embodiments, the process of dividing the protein into two fragments is referred to as “splitting” the protein, In other embodiments, the N-terminal portion of the Cas9 protein comprises amino acids 1-573 or 1-637 S. pyogenes Cas9 wild-type (SpCas9) (NCBI Reference Sequence: NC_002737.2, Uniprot Reference Sequence: Q99ZW2) and the C-terminal portion of the Cas9 protein comprises a portion of amino acids 574-1368 or 638-1368 of SpCas9 wild-type. The C-terminal portion of the split Cas9 can be joined with the N-terminal portion of the split Cas9 to form a complete Cas9 protein. In some embodiments, the C-terminal portion of the Cas9 protein starts from where the N-terminal portion of the Cas9 protein ends. As such, in some embodiments, the C-terminal portion of the split Cas9 comprises a portion of amino acids (551-651)-1368 of spCas9. "(551-651)-1368" means starting at an amino acid between amino acids 551-651 (inclusive) and ending at amino acid 1368. For example, the C- terminal portion of the split Cas9 may comprise a portion of any one of amino acid 551-1368, 552-1368, 553-1368, 554-1368, 555-1368, 556-1368, 557-1368, 558-1368, 559-1368, 560- 1368, 561-1368, 562-1368, 563-1368, 564-1368, 565-1368, 566-1368, 567-1368, 568-1368, 569-1368, 570-1368, 571-1368, 572-1368, 573-1368, 574-1368, 575-1368, 576-1368, 577- 1368, 578-1368, 579-1368, 580-1368, 581-1368, 582-1368, 583-1368, 584-1368, 585-1368, 586-1368, 587-1368, 588-1368, 589-1368, 590-1368, 591-1368, 592-1368, 593-1368, 594- 1368, 595-1368, 596-1368, 597-1368, 598-1368, 599-1368, 600-1368, 601-1368, 602-1368, 603-1368, 604-1368, 605-1368, 606-1368, 607-1368, 608-1368, 609-1368, 610-1368, 611- 1368, 612-1368, 613-1368, 614-1368, 615-1368, 616-1368, 617-1368, 618-1368, 619-1368, 620-1368, 621-1368, 622-1368, 623-1368, 624-1368, 625-1368, 626-1368, 627-1368, 628- 1368, 629-1368, 630-1368, 631-1368, 632-1368, 633-1368, 634-1368, 635-1368, 636-1368, 637-1368, 638-1368, 639-1368, 640-1368, 641-1368, 642-1368, 643-1368, 644-1368, 645- 1368, 646-1368, 647-1368, 648-1368, 649-1368, 650-1368, or 651-1368 of spCas9. In some embodiments, the C-terminal portion of the split Cas9 protein comprises a portion of amino acids 574-1368 or 638-1368 of SpCas9. By "subject" is meant a mammal, including, but not limited to, a human or non- human mammal, such as a bovine, equine, canine, ovine, or feline. Subjects include livestock, domesticated animals raised to produce labor and to provide commodities, such as food, including without limitation, cattle, goats, chickens, horses, pigs, rabbits, and sheep. By "substantially identical" is meant a polypeptide or nucleic acid molecule exhibiting at least 50% identity to a reference amino acid sequence (for example, any one of the amino acid sequences described herein) or nucleic acid sequence (for example, any one of the nucleic acid sequences described herein). In one embodiment, such a sequence is at least 60%, 80% or 85%, 90%, 95% or even 99% identical at the amino acid level or nucleic acid to the sequence used for comparison. Sequence identity is typically measured using sequence analysis software (for example, Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wis. 53705, BLAST, BESTFIT, GAP, or PILEUP / PRETTYBOX programs). Such software matches identical or similar sequences by assigning degrees of homology to various substitutions, deletions, and / or other modifications. Conservative substitutions typically include substitutions within the following groups: glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid, asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine. In an exemplary approach to determining the degree of identity, a BLAST program may be used, with a probability score between e? and e'%° indicating a closely related sequence. COBALT is used, for example, with the following parameters: a) alignment parameters: Gap penalties-11,-1 and End-Gap penalties-5,-1, b) CDD Parameters: Use RPS BLAST on; Blast E-value 0.003; Find Conserved columns and Recompute on, and ¢) Query Clustering Parameters: Use query clusters on; Word Size 4; Max cluster distance 0.8; Alphabet Regular. EMBOSS Needle is used, for example, with the following parameters: a) Matrix: BLOSUM62; b) GAP OPEN: 10; c) GAP EXTEND: 0.5; d) OUTPUT FORMAT: pair; e) END GAP PENALTY: false; f) END GAP OPEN: 10; and 2) END GAP EXTEND: 0.5. The term "target site" refers to a sequence within a nucleic acid molecule that is modified by a nucleobase editor. In one embodiment, the target site is deaminated by a deaminase or a fusion protein comprising a deaminase (e.g., cytidine or adenine deaminase). As used herein, the terms “treat,” treating,” “treatment,” and the like refer to reducing or ameliorating a disorder and / or symptoms associated therewith or obtaining a desired pharmacologic and / or physiologic effect. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated. In some embodiments, the effect is therapeutic, 7.e., without limitation, the effect partially or completely reduces, diminishes, abrogates, abates, alleviates, decreases the intensity of, or cures a disease and / or adverse symptom attributable to the disease. In some embodiments, the effect is preventative, i.e., the effect protects or prevents an occurrence or reoccurrence of a disease or condition. To this end, the presently disclosed methods comprise administering a therapeutically effective amount of a compositions as described herein, By “uracil glycosylase inhibitor” or “UGI” is meant an agent that inhibits the uracil- excision repair system. In one embodiment, the agent is a protein or fragment thereof that binds a host uracil-DNA glycosylase and prevents removal of uracil residues from DNA. In an embodiment, a UGH is a protein, a fragment thereof, or a domain that is capable of inhibiting a uracil-DNA glycosylase base-excision repair enzyme. In some embodiments, a ‘UGI domain comprises a wild-type UGI or a modified version thereof. In some embodiments, a UGI domain comprises a fragment of the exemplary amino acid sequence set forth below. In some embodiments, a UGI fragment comprises an amino acid sequence that comprises at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of the exemplary UGI sequence provided below. In some embodiments, a UGI comprises an amino acid sequence that is homologous to the exemplary UGI amino acid sequence or fragment thereof, as set forth below. In some embodiments, the UGI, or a portion thereof, is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical to a wild- type UGI or a UGI sequence, or portion thereof, as set forth below. An exemplary UGI comprises an amino acid sequence as follows: >splP14739IUNGI_BPPB2 Uracil-DNA glycosylase inhibitor MINLSDIIEKETGKQLVIQESILMLPEEVEEVIGNKPESDILVHTAYDESTDENVMLLTSD APEYKPWALVIQDSNGENKIKML. The term “vector” refers to a means of introducing a nucleic acid sequence into a cell, resulting in a transformed cell. Vectors include plasmids, transposons, phages, viruses, liposomes, and episome. “Expression vectors” are nucleic acid sequences comprising the nucleotide sequence to be expressed in the recipient cell. Expression vectors may include additional nucleic acid sequences to promote and / or facilitate the expression of the of the introduced sequence such as start, stop, enhancer, promoter, and secretion sequences. Any compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein, DNA editing has emerged as a viable means to modify disease states by correcting pathogenic mutations at the genetic level. Until recently, all DNA editing platforms have functioned by inducing a DNA double strand break (DSB) at a specified genomic site and relying on endogenous DNA repair pathways to determine the product outcome in a semi- stochastic manner, resulting in complex populations of genetic products. Though precise, user-defined repair outcomes can be achieved through the homology directed repair (HDR) pathway, a number of challenges have prevented high efficiency repair using HDR in therapeutically-relevant cell types. In practice, this pathway is inefficient relative to the competing, error-prone non-homologous end joining pathway. Further, HDR is tightly restricted to the G1 and § phases of the cell cycle, preventing precise repair of DSBs in post- mitotic cells. As a result, it has proven difficult or impossible to alter genomic sequences in a user-defined, programmable manner with high efficiencies in these populations. Superoxide dismutase 1 (SOD1) is an enzymatic protein encoded by the SOD gene. The SOD1 enzyme is abundant in cells throughout the body. The SOD1 enzyme binds to copper (Cu) and zinc (Zn) to degrade toxic, charged oxygen molecules called superoxide radicals or reactive oxygen species (ROS), which are byproducts of normal cell processes that must be regularly degraded to avoid cell damage, transformation, or death. At least 200 mutations in the SOD gene have been found to cause amyotrophic lateral sclerosis (ALS), a condition characterized by progressive muscle weakness, a loss of muscle mass, and an inability to control movement. Most of these mutations alter one amino acid in the superoxide dismutase enzyme. Worldwide, SOD gene mutations cause 15 to 20 percent of familial ALS. About half of all Americans with ALS caused by SOD! gene mutations have a particular mutation that replaces the amino acid residue alanine (A) with the amino acid residue valine (V) at position 5 in the enzyme, i.e., Ala5Val or A5V. ALS caused by the ASV mutation is generally associated with a shorter life expectancy compared with ALS caused by other genetic mutations. ALS is caused by the death of nerve cells that control muscle movement (motor neurons). It is presently unclear why motor neurons are particularly sensitive to SOD gene mutations, although the large size of these types of neurons may contribute to their being more sensitive to disruption in normal SOD1 enzyme function. Several possible ways in which an altered SOD1 enzyme may cause the death of motor neurons include (i) an increase in harmful superoxide radicals in cells, particularly in lysosomes and / or proteosomes; (ii) increased production of other types of toxic radicals and increased cell death; and / or (iii) accumulation of clumps (aggregates) of misfolded superoxide dismutase that may be toxic to cells. By “SOD protein” is meant a polypeptide or fragment thereof having at least about 95% amino acid sequence identity to NCBI Accession No. NP_000445. An exemplary human SOD1 amino acid sequence is provided below. MATKAVCVLK GDGPVQGIIN FEQKESNGPV KVWGSIKGLT EGLHGFHVHE FGDNTAGCTS 61 AGPHENPLSR KHGGPKDEER HVGDLGNVTA DKDGVADVSI EDSVISLSGD HCIIGRTLVV 121 HEKADDLGKG GNEESTKTGN AGSRLACGVI GIAQ By “SOD! polynucleotide” is meant a nucleic acid molecule encoding a SOD1 protein or fragment thereof. The genomic sequence of an exemplary human SOD polynucleotide, which is available at NCBI Accession No. NC_000021.9:31659622- 31668931 (Homo sapiens chromosome 21, GRCh38.p13 Primary Assembly), is provided below (SEQ ID NO: 3). gtttggggce agagtgggcg aggcgcggag gtctggeocta taaagtagtc geggagacgg 61 ggtgctggtt tgcgtegtag tcocteoctgeag cgtetggggt ttecgttgea gteocteggaa 121 ccaggaccte ggecgtggect agegagttat ggcgacgaag geoegtgtgeg tgctgaaggg 181 cgacggccca gtgcagggea tcatcaattt cgagcagaag gcaagggctg ggacggagge 241 ttgtttgcga ggcecgctecce accecgetegt ccocecccgege acctttgcta ggagegggte 301 gcccgecagg ccteggggee goectggtec agegoecggt cceggeecgt gecgeecggt 361 cggtgcctte geccccageg gtgeggtgec caagtgctga gtcaccggge gggeceggge 421 geggggegty ggaccgagge cgecgegggg ctgggectge gegtggegyg agegegggga 481 gggattgccg cgggccgggy aggggcygggy gcgggegtge tgccctetgt ggtecttggg 541 ccgeccgecge gggtcotgteg tggtgectgg agecggetgtg ctegtcectt gettggecgt 601 gttctegttc ctgagggtce cgeggacacc gagtggegeca gtgcocaggec cageccgggg 661 atggcgactg cgecctgggee cgectggtgt cttegeatce cteteegett tecggettea 721 gcgetctagg tcagggagte ttegettttg tacagetcta aggctaggaa tggtttttat 781 atttttaaaa ggctttggaa aacaaaaata cgcaacagag accgtttgtg tgacactttg 841 cagggaagtt tgctggecte tgttctaggt catgattggyg ctgcaaggge agagaaggta 901 gccttgaaca gaggtccttt tcctectcet aagetccggg agecagaggt ttaactgace 961 cttttgggga tttttgaggg cagtgatctt aactttgggt gcacagttag cttatttgaa 1021 gatcttacta aaaatacacce agagcccaac ctcecgaccaa ttacatcaaa acctgtecta 1081 gtgcagggtg agtattgctg ttttttgaaa gtttccaaaa gtgattttga tgtgcaccta 1141 cgattgagaa ctgtegtttyg aggacagtgy gtggagttte gtatttggaa attagaagac 1201 ctggagtttc cattacaccg aattggcact taataactgt tgtcggagea tttcttaage 1261 cacatttteg taaagtggct ttaaaattgce tetgecagta ggeaggttge taagatggte 1321 agagacaaac ttctgaacga ctettgtaaa atatacagaa atattttcag aacttttate 1381 agtaaaatta caaaacgtgt tgcaaggaag gtgcttgtga taacactgtc cccagaacct 1441 tagtgaagtt accaactggt ggaaaatttt ctettgcact cggettaaaa atcatgaggg 1501 aatatttact atacgaatga gattcagtct ttaaaggggt ttacagaaac gtgagaggac 1561 aggaacagtt agtctgtgta aatgtctgaa atatatgtga gggagataat gagtttagece 1621 tttttettta ataggtctee agattttetyg gaaaaggtte tttggeattt gactccattt 1681 tgctgtttca tttgtcagac ttctttttgt cectctttac ttctccccac ataattcace 1741 agtactagtg ttttgttttt cagaccaagt ctegetetgt cgeccagget ggagtgceagt 1801 ggcgcgatct cagctcactg caacctccge ctcccaggtt caagcaattc toctgectca 1861 geecteceggy tagetgggace tacaggegeg cgecgecacyg cotggcetaat tttttatatt 1921 ttagtagaga cggcegtttea ccatgttgge caggatggte tegatctgtt gacgtegtga 1981 tccacccgec tcggoctcce aaagtgctgg gattacagge gtgagccace cegeccggec 2041 accagtgcta ttettaagac gectetgagg aatcccttet ccctggecat tgagaatceca 2101 tgcatgaacc caggttttcc accttccctg agcagcttge atagttcctt cttttaageg 2161 cctgactteg ttttgtttgy tgecegttgt acctgagaat gagecttgga tagtggagea 2221 ttccagettt ccagatatge agagataata cattggetat cagetacttg gettggecta 2281 ttccgtgttt aaaatcttgg actctttgct agtttttaca gatcagaatt tttcacgtat 2341 taatccagtt ttcoctagett ctettgaaga atttttggag atctettecat actgagectt 2401 cattagccca ggacagtact gctgtagcag ttcatatatt ttttcgcttc ccaggectgt 2461 gttattcact taagttcata gectggtceec tgcagggttyg taccecgagea cagetactta 2521 gatgtcctga atgtattace ggttaaatgg aggtttcaaa gaacctgctg tttttggece 2581 tgtgctcttg ataacagagt gtttgaggga caactttcac atttgagttt ttccaaaatt 2641 aaaggttgta gaagagtcac agtatctatt gtcaaaaaga aaagaattta aaaaggcagce 2701 aattgccagg atacttcatt tgagcaatga tattttccag tggaaagtca catcttaagg 2761 gttaatgccc cttaactgtt ggccgtattt gaaaacaaac caagctaaaa acaagagaca 2821 ctgacatgtt gtatgacggt gtggtgtgga tgttgtgttt attttagtec tgagatctag 2881 ttgtaacttc cttgatttct gtatgtagce acggagcacc attacctgtc accattacct 2941 gaatggctat actgcttget ttcattttgg tagagtggaa aggttaccta ggtttcagtg 3001 cttgaaaaga tttcagaaag cagtagtacg tctggttaga ctagaatcag tcctctcctg 3061 ggggcagtgg aatataatat tttctgactg ctaattaaaa atacctgtga tagccgggcg 3121 tggtggctta cgectgtaat cccagcactt tgggaggccyg agacgggtgg atcacgaggt 3181 cagcagatgg agaccatcct ggctaacacg gtgaaaccce gtctctacta aaaatgcaaa 3241 aaaattagcc gggtgtggtg gtgggcgoct gtagtcccag ctactcagga ggctgaggca 3301 ggagaatggc atgaacctgg gaggcggagce ttgcagtgag ccgagatcat gtcactgeac 3361 tccagcctgg gecgacagage gagactcgtc tcaaaaaaaa aaagaaaaaa acttatgatg 3421 gacacttaaa aacactcact gagtggggag tggagagcag gggtcccagg gtagectgtt 3481 ggacatttec agggcgactt tttetttttt tttttttaaa gtcaagtgag tatgecatat 3541 ggaaaagggt gtgcgtggag aaaaagcaag gggctccaga gtgtaggatg agacatacac 3601 cttttgggtt aaaaaggctg aggcaggaga atggegtgaa ccegggagge ggagettgea 3661 gtgagctgag atcatgccac tgcactccag cctgggcgac agagegagac tcttgtctca 3721 aaataaaaaa cgtttacatg tacatgtata ttcaacatgt acaaatataa cctattcaaa 3781 agtatttact acataaatag gtacttacat tacctattta ctgtaatagt caaagectat 3841 gaagtatcta acactgatgt gtaggtactc actttgcttg ccactctatt aggtgetttt 3901 tatgttattt aatcatgaag cctggccaca gggtgettgt geattgagtg tgggaacaag 3961 attaccatct cccttttgag gacacaggcc tagagcagtt aagcagettg ctggaggtte 4021 actggctaga aagtggtcag cctgggattt ggacacagat ttttecacte ccaagtetgg 4081 ctgettttta cttcactgty aggggtaaag gtaaatcage tgttttettt gttcagaaac 4141 tctctccaac tttgcacttt tcttaaagga aagtaatgga ccagtgaagg tgtggggaag 4201 cattaaagga ctgactgaag geoetgcatgg attecatgtt catgagtttg gagataatac 4261 agcaggtggg tgttgtgctg tgctggtgac ccatacttgt tcaccctagt tagataaaca 4321 gtagagtagce cectaaacgt taaaacccet caacttgttt ttgtttttga gaaagggtet 4381 tgctcetgteg cteaggetgyg agtgcagtgg cgctgtgega teatggetga cettagectt 4441 gacctcccag gotccattga tcctcatgec ttggcccgta gotgggacta caggtacaca 4501 ccaccacgec tggctaattt ttgtattttt ttectagaggt ggggtttcat catgttgece 4561 aggctggtct tgaactgctg ggctcaagtg gtctatccte ctegacctec caaagtgetg 4621 ggattacatg tgtgageccac tgtgectggg aaaacectca acttttettt taaaaaagag 4681 gtcaacttta ttgtatataa gcactgtget aaaattgecag gaactgggac catatectga 4741 tttttgtaat aatgccagca gagtacacac aagaaaagta actgcactag attgtgaaga 4801 ctggggtgga cctgettetyg aaggtccagt gecctttgte ttaagatttg gtgtagtgtg 4861 tctttagaaa ccaaaaaaag agaagaagat caaccttaag attagccaca aaactgggct 4921 ttgataccta ggtgtggaaa agaaagggaa agagttgatg ttttgtetta cageatcatt 4981 gtagaagagg gtgttttttt gtttgtttgt tttttgagac ggagtcttac tctgtggece 5041 aggctggagt gcagtggege gatctcgget cactgeaage tcegectcec gggtteatge 5101 cattctecectg cectcagecce ctgagtaget gggactacag gtgcccgecca cecegectgg 5161 ctaatttttt gtatttttag tagagacggg gtttcactgt gttagccaag atggtctcte 5221 tcctgaccte gtgatccgee tgtctcagec teccaaagtg ctgggattac aggecatgage 5281 caccgcaccc agccagaaga gggtgttttt taaagaaggc aaataggaaa taaaaacttg 5341 ggctcttaac ttttgtaatg atcccaggtg tttgagetgg gggttgaggg tgggtgecte 5401 gagcaaaggg gctgcattta tttgcataat gccatgtaag agtagctcta caccccaaac 5461 acaggcttct tagtgggacc aaagtatgat acaaactgaa gatggaatgc agaggattat 5521 tggtactttg gaatatgctt aaaaaaaatt tttttaaagt atttttaaaa aatcaggcaa 5581 ccecctgaacce agagtaggtt cagagaaact gecaaatttt attttcttaa tttgggattg 5641 gaagcaagtt aacagaagtt tatgagttaa gttgcattta gtgatctttt gecatatttg 5701 agtaataatc tgattttttt gtttatagat ttcttcttaa attaacttta ttcatcttgc 5761 taatttagtt tcaaatagtg atttgtaatg atcagatttg atccatttct gtaattgetg 5821 aaattccccc gagttgcottt ttggctttac cgcctctggt ctgggaggtg attgetctge 5881 tgcttecctgt aacttgectg cctttetece tgtgtgggac teetgegggt gagagegtgg 5941 ctgaagacag ccgtgttatg aaagggecte ctgtgetgte gaggttgtge tetgtgaatg 6001 tcatcccctg gtgcacagca gcaccttcta cacaggatac agttggaatg cegeccccte 6061 gagttgtgta aggcagcage cttggecctt geacataaga tgetgttgaa tattctgect 6121 gcaccaagta aagggcacag atagaactgc ttggcatatg ttgctgggga gatgagtttt 6181 ttgtaaagta tactacgtte ttaagaattt ggatcataac catgggattt taataataga 6241 aaaactgttg aagatcagte tggtccetta tttttacagt gaagaagecca aageccagag 6301 aagggtgtta actttacaag tgtcagacag tagttagaac ttggtggggt tttttttttt 6361 ttttttttga gatggagtet tgectetgtty cecaggetgy agtgcagtgg tgcgatctea 6421 gctcactgca acctctgect cccaggttca agcgattcte ctgcctcage ctactaagta 6481 gctgggacta taggtgegea ccaccacgec tagetaattt ttgtattttt teagtagaga 6541 cagggttttg ctatgetgge caggetggte teaaactect gacctcagat gatccageca 6601 cctcagcttc ccaaagtgct ggggttccag gtgttageca ccatgcctgg ccatagactt 6661 gtttetgtte cettetcact gtggetgtac caaggtgtty cttatcecag aagtegtgat 6721 gcaggtcagc actttctcca tgggaagttt tagcagtgtt tctttttaga atgtatttgg 6781 gaactttaat tcataattta getttttttt cttettetta taaatagget gtaccagtge 6841 aggtectcac tttaatcetce tatccagaaa acacggtggg ccaaaggatg aagagaggta 6901 acaagatgct taactcttgt aataatggcg atagctttct ggagttcata tggtatacta 6961 cttgtaaata tgtgctaaga taattcegtyg tttececcac ctttgetttt gaacttgetg 7021 actcatctaa acccctgcte ccaaatgctg gaatgetttt acttcctggg cttaaaggaa 7081 ttgacaaatg gggacactta aaacgatttg gttttgtage atttattgaa tatagaacta 7141 atacaagtgc caaaggggaa ctaatacagg aaatgtcatg aacagtactg tcaaccacta 7201 gcaaaatcaa tcatcattgt gaaacatagg aagcttctgt agataaaaaa aaaaattgat 7261 actgaaaact agtcgagact ccatttatat gtgtatgttt tctgaaagec tttcagaaaa 7321 atattaaatt taaggacaag atttttatat cagaggcctt gggacatagc tttgttaget 7381 atgccagtaa ttaacaggca taactcagta actgagagtt taccctttgg tacttetgaa 7441 atcaggtgca gccccatcett tcetteccaga geattagtgt gtagacgtga ageecttgttt 7501 gaagagctgt atttagaatg cctagctact tgtttgcaaa tttgtgtcta ctcagtcaag 7561 ttttaattta gctcatgaac taccttgatg tttagtggca tcagecctaa tecatctgat 7621 gctttttcat tattaggcat gttggagact tgggcaatgt gactgctgac aaagatggtg 7681 tggccgatgt gtctattgaa gattctgtga tcetcactete aggagaccat tgcatcattg 7741 gccgcacact ggtggtaagt tttcataaaa ggatatgcat aaaacttctt ctaacataca 7801 gtcatgtatc ttttcacttt gattgttagt cgcggtttct aaagatccag ataaactgta 7861 cttgcagttc aaattaggaa aagcaatttt attggacaat tacggtgaaa atgaattatt 7921 ttatctaggt cagttaagaa cactgttctg ctaagatgca gtaaaaagca ggttacattt 7981 gaccatatta gatctgagtt tggaaaacag aagtagtctt tagttttaaa atggccagat 8041 tttcttgcca ggattgggtt tctcacttgt taaacagaac attttgttaa gtttaaaacc 8101 tgggatggac ttaagtattec atgttcattc atgttecatte aggactgcag gttatcatga 8161 cttgtttaac ttgtgggaag ctgttgtccc aagttatcct ggggaactgc atctggttct 8221 tgcaaaacac caagtagaca ggctctettt taccteccct tgagggeatt aacattcagt 8281 agtcacttcc attcagttaa ccctttattt ttatggtttt tcttgagcca tagttgtaaa 8341 gcagaaaaat catttataaa ggtttgttga acaaaattca aaatactgtt gcttaaagta 8401 ttaagatttt ttaggattat accttactta taggceccgte attcatttgg catgaaattt 8461 tgagttttat tcactttcac tttccttttt ttccaaagca attaaaaaaa ctgccaaagt 8521 aagagtgact gecggaactaa ggttactgta acttaccatyg gaggattaag ggtagegtgt 8581 ggtggtctac aacatagtta tttgggtttt agtatttcat ttagacagca acacttacct 8641 aatgtttaaa ggtaatgtct ttgcaacacc aagaaaaage tttgagtagt agtttctact 8701 tttaaactac taaatattag tatatctcte tactaggatt aatgttattt ttctaatatt 8761 atgaggttct taaacatctt ttgggtattg ttgggaggag gtagtgatta cttgacagee 8821 caaagttatc ttcttaaaat tttttacagyg tecatgaaaa ageagatgac ttgggcaaag 8881 gtggaaatga agaaagtaca aagacaggaa acgctggaag tcgtttgget tgtggtgtaa 8941 ttgggatcge ccaataaaca tteccttgga tgtagtetga ggecccttaa cteatetgtt 9001 atcctgetag ctgtagaaat gtatectgat aaacattaaa cactgtaatc ttaaaagtgt 9061 aattgtgtga ctttttcaga gttgctttaa agtacctgta gtgagaaact gatttatgat 9121 cacttggaag atttgtatag ttttataaaa ctcagttaaa atgtetgttt caatgacctg 9181 tattttgcca gacttaaatc acagatgggt attaaacttg tcagaatttc tttgtecatte 9241 aagcctgtga ataaaaacce tgtatggeac ttattatgag getattaaaa gaatccaaat 9301 tcaaactaaa In the above SOD! genomic nucleic acid sequence, the “ag” splice acceptor site at the 5' end of exon 3 of the SOD1 gene is in bold font. The nucleic acid sequence of exon 3 of the SOD gene is indicated in italics and by double underlining in the above SOD! genomic sequence. The mRNA / cDNA sequence of an exemplary human SOD! polynucleotide, which is available at NCBI Reference Sequence: NM_000454.4, is provided below: gcgtcgtag tctcctgcag cgtctggggt ttccgttgca gtecctcggaa ccaggacctc ggcgtggcct agcgagttat ggcgacgaag geocgtgtgcg tgctgaaggg cgacggecceca gtgcagggca tcatcaattt cgagcagaag gaaagtaatg gaccagtgaa ggtgtgggga agcattaaag gactgactga aggcctgcat ggattccatg ttcatgagtt tggagataat acagcaggct gtaccagtge aggtcctcac tttaatccte tatccagaaa acacggtggg ccaaaggatg aagagaggca tgttggagac ttgggcaatg tgactgctga caaagatggt gtggccgatg tgtctattga agattctgtg atctcactct caggagacca ttgcatcatt ggccgcacac tggtggtcca tgaaaaagca gatgacttgg gcaaaggtgg aaatgaagaa agtacaaaga caggaaacgc tggaagtcgt ttggcttgtg gtgtaattgg gatcgcccaa taaacattcecc cttggatgta gtctgaggec ccttaactca tctgttatcce tgctagctgt agaaatgtat cctgataaac attaaacact gtaatcttaa aagtgtaatt gtgtgacttt ttcagagttg ctttaaagta cctgtagtga gaaactgatt tatgatcact tggaagattt gtatagtttt ataaaactca gttaaaatgt ctgtttcaat gacctgtatt ttgccagact taaatcacag atgggtatta aacttgtcag aatttctttg tcattcaage ctgtgaataa aaaccctgta tggcacttat tatgaggcta ttaaaagaat ccaaattcaa actaaaaaaa aaaaaaaaaa a By “Androgen Receptor (AR) polynucleotide” is meant any polynucleotide encoding an androgen receptor polypeptide. An exemplary androgen receptor polynucleotide is provided below (SEQ ID NO: 4): Homo sapiens androgen receptor (AR), transcript variant 1, mRNA (NM. 000044.6) ATGGALAGCGTGCAGTTAGGGC IGG AACG ETC TAC CC TCG CGC CaTCCARAGACCTACCGAGG AGCTTTCCAGRATCTGTTCCAGAGOCGTGCGCGAAGTGATCCAGAACCCGGGCCCCAGGCACC CAGAGGCCGCGAGCGCAGC ACC TCC CREEL CACGTTTGC TGC TGC TGCAGCAGCAGCAGCAG CAGCAGCAGCAGCAGCAGCAGCAGC AGC AGC AGC AGC AGCAGCAGCAGCAGCAAGAGACTAG CCC CAGGC AGC AGC AGC AGC AGC AGRGTGAGGATGGTTCTCCCCAAGCCCATCETAGAGRCC CCACAGGC TAC CTGETCCTGRATGAGG ALAC AGC AACCTTCACAGCCGCAGTCGGCCCTGRGAG TGCCACCCCGAGAGAGET TGC GTC CCAGLAGCCTGGAGC CGC CERTGRCCGCCAGCAMAGGGRCT GCCGCAGC AGC TGC C AGC AC CTC CGE ACGAGGATGACTCAGCTGCCCCATCCACGTTGTCCC TGCTGGEGC CCC ACT TTC CC CGECTTAAGCAGCTGC TC CGCTGACCTTAAAGACATCCTGAGC GAGGCCAGC ACC ATG AAC TCC TTC AGC AAC AGC AGC AGGAAGCAGTATCCGAAGGCAGCAG CAGCGGRGAGAGCGAGGRAGGCCTCGERGEC TCC C ACT TC CTC CAAGGACAATTACTTAGGGG GC ACT TCGACC ATT TCI GAC AN GCC A AGE AGT IGT TAM GC AC TG TC CGTCTCCATGGEC CTCGGGTGCTGGAGGCCTIGGAGC ATC TCAG TCA CGGG AAC ACC TTCGGCCGGATTGCATCG TA CGCCC CAC TTITIGEGAGT TC CACC CGO IG IG CG TCC CA CTC CT TC GCC CCATTGGCCGAAT GCAAMGGTICTCTIGC TAGACGAC AGC GC ACGO ALG AGC ACTG AAG ATACTGCTGAGTATTCC CCT TTCAAGGGAGGT TAC ACCAANGG EC TAGAA GG GAGAGCC TAGGCTGCTCTGGCAGCEC TGCAGCAGGGAGCTCCGGGACACTTIGARAC TGC GTC TT ACCOTG TCI CTC TACAAGTCCGGAG CACTGGACGAGGC AGO TGCGTAC CAG AGTCGCG AC TACT ACA MTT TCCACTGGCTCTGGCC GGACCGC CGC CC CCT Calo CCoCATC Con CGOTCGC ATC AMAGCTGGAGANCCGTT GGACTACGGCAGCGCCTGERGC GRC TGCGGRLGGCGCAGTGCCGCTATGGGGACCTGGCGAGCC TGCATGGCGCGGETGCAGCGGREACCCGETTCTGGGTCACCCTCAGCCGCCGCTTCCTCATCC TGGCACACTCTCTTCACAGCCGAAGAAGGCCAGTTGTATGGACCGTGTGETGGTGGTGGGRG TGCTGCGCGEC CEG CC lGE Cala ECC a la CCC CCClaCCCoC CACC GAGCTGTAGCCCCCTACGGCTACACTCGGC CCC CTCAGGGGCTGGCGGGCCAGGAAAGCGAC TTCACCGCACCTGATGTGTGGTACCCTGGCGGCATGGTGAGCAGAGTGCCCTATCCCAGTCC CACTTGTGTCARARAAGCGAAATGGGC CCC TGGATGGATAGCTACTCCGGACCTTACGGGGACA TGCGTTTGGAGACTGCCAGGGACCATGTTT TGC CCATTGACTATTACTTTCCACCCCAGAAG ACCTGCCTGATCTGTGGAGATGAAGC TTCTGGETGTCACTATGGAGC TCTCACATGTGGAAG CTGCAAGGTCTTCTTCAAAAGAGCCECTGAAGGGARAACAGAAGTACCTGTGCGCCAGCAGARD ATGATTGCACTATTGATAAATTCCGAAGGAAAAATTGTCCATCTTGTCGTCTTCGGAAATGT TATGAAGCAGGGATGACTCTGGRGAGCCCGEAAGCTGAAGAAACTTGGTAATCTGAAACTACA GGAGGAAGGAGAGGCTTCCAGCACCACCAGCCCCACTGAGGAGACAACCCAGAAGCTGACAG TGTCACACATTGAAGGCTATGAATCTCAGCCCATC TT TCTGAATGTCCTGGAAGCCATTGAG CCAGGTGTAGTGTGTGCTGGACACCACAAC ADC CAGCCCGACTCCTTTGCAGCCTTGCTCTC TAGCCTCAATGAACTGGGAGAGAGACAGUTTGTACACCGTGETCAAGTGGGCCAAGGCCTTGC CTGGCT TCC CGCAACTTACACGTGGACCACCAGATGGCTGTCATTCAGTACTCCTGGATGGGG CTCATGCETCTTIGCCATGGGUTGGCGATCCTTCACCAATGTCAA TCCAGGATGCTCTACTT CGC CC TGATCTGE TT I TCARTGACTAC CCC ATG ACAAGTCCCCCATGTACAGCCAGTCGTG TCCGAATGAGGCACCTCTC TCAAGACTTITGGATGGC TCC AAR TCACCCCCCAGGAATTCCTG TGCATGAAAGCACTGC TACTIC TTC AGC ATT ATTIC CC AGTGGATGGGCTGAAAAATCAAAAATT CTTTGATGAACTTCGAATGAAC TACATCAAGGAACTCGATCGTATCATTGCATGCAAAAGARD AAARATCCCACATCCTGCTCAAGACGCT TCT AC CAGCTCACCALAGCTCCTGGACTCCETGCAG CCT ATTGCGAGAGAGC TGC ATC AGT TC ACT TT TGACCTGCTAATCAAGTCACACATGGTGAG CETGRACT TTC CREAM TGATGGCAGAGATC ATC TCTGTGC AAGTGCCCAAGATCCTTTCTG GGAAAGTCAAGCCCATCTATTTCCACACCCAG BRIEF DESCRIPTION OF THE DRAWINGS FIGs. 1A — 1C depict plasmids. FIG. 1A is an expression vector encoding a TadA7.10-dCas9 base editor. FIG. 1B is a plasmid comprising nucleic acid molecules encoding proteins that confer chloramphenicol resistance (CamR) and spectinomycin resistance (SpectR). The plasmid also comprises a kanamycin resistance gene disabled by two point mutations. FIG. 1C is a plasmid comprising nucleic acid molecules encoding proteins that confer chloramphenicol resistance (CamR) and spectinomycin resistance (SpectR). The plasmid also comprises a kanamycin resistance gene disabled by three point mutations. FIG. 2 is an image of bacterial colonies transduced with the expression vectors depicted in FIG. 1, which included a defective kanamycin resistance gene. The vectors contained ABE7.10 variants that were generated using error prone PCR. Bacterial cells expressing these “evolved” ABE7.10 variants were selected for kanamycin resistance using increasing concentrations of kanamycin. Bacteria expressing ABE7.10 variants having adenosine deaminase activity were capable of correcting the mutations introduced into the kanamycin resistance gene, thereby restoring kanamycin resistance. The kanamycin resistant cells were selected for further analysis. FIGs. 3A and 3B illustrate editing of a regulatory region of the hemoglobin subunit gamma (HGB1) locus, which is a therapeutically relevant site for upregulation of fetal hemoglobin. FIG. 3A is a drawing of a portion of the regulatory region for the HGB1 gene. FIG. 3B quantifies the efficiency and specificity of adenosine deaminase variants. Editing is assayed at the hemoglobin subunit gamma 1 (HGB1) locus in HEK293T cells, which is therapeutically relevant site for upregulation of fetal hemoglobin. The top panel depicts nucleotide residues in the target region of the regulatory sequence of the HGB1 gene. AS, A8, A9, and A11 denote the edited adenosine residues in HGB1. FIG. 4 illustrates the relative effectiveness of adenosine base editors comprising a dCas9 that recognizes a noncanonical PAM sequence. The top panel depicts the coding sequence of the hemoglobin subunit, The bottom panel is a graph demonstrating the efficiency of adenosine deaminase variant base editors with guide RNAs of varying lengths, FIG. 5 is a graph illustrating the efficiency and specificity of ABES base editors. The percent editing at intended target nucleotides and unintended target nucleotides (bystanders) is quantified. FIG. 6 is a graph illustrating the efficiency and specificity of ABES base editors. The percent editing at intended target nucleotides and unintended target nucleotides (bystanders) is quantified. FIGs. 7A — 7D depict eighth generation adenine base editors mediate superior A«T to G+C conversion in human cells. FIG. 7A illustrates an overview of adenine base editing: i) ABES creates an R-loop at a sgRNA-targeted site in the genome; ii) TadA* deaminase chemically converts adenine to inosine via hydrolytic deamination on the ss-DNA portion of the R-loop; iii) D10A nickase of Cas9 nicks the strand opposite of the inosine containing strand; iv) the inosine containing strand can be used as a template during DNA replication; v) inosine preferentially base pairs with cytosine in the context of DNA polymerases; and vi) following replication, inosine may be replaced by guanosine. FIG. 7B illustrates the architecture of ABE8.x-m and ABE8.x-d. FIG. 7C illustrates three perspectives of the £. coli TadA deaminase (PDB 1Z3A) aligned with the S. aureus TadA (not shown) complexed with tRNAArg2 (PDB 2B3J). Mutations identified in eighth round of evolution are highlighted. FIG. 7D are graphs depicting A*T to G+C base editing efficiencies of core ABES constructs relative to ABE7.10 constructs in Hek293T cells across eight genomic sites. Values and error bars reflect the mean and s.d. of three independent biological replicates performed on different days. FIGS 8A-8C depict Cas9 PAM-variant ABE8s and catalytically dead Cas9 ABE8 variants mediate higher AT to G+C conversion than corresponding ABE7.10 variants in human cells. Values and error bars reflect the mean and s.d. of three independent biological replicates performed on different days. FIG. 8A is a graph depicting A*T to G+C conversion in Hek293T cells with NG-Cas9 ABE8s (-NG PAM). FIG. 8B is a graph depiecting A*T to GC conversion in Hek293T cells with Sa-Cas9 ABE8s (-NNGRRT PAM). FIG. 8Cisa graph depiecting A*T to GC conversion in Hek293T cells with catalytically inactivated, dCas9-ABES8s (D10A, H840A in S. pyogenes Cas9). FIGs. 9A-9E depict the comparison between the on- and off-target editing frequencies between ABE7.10, ABEmax and ABEmax with one BPNLS in Hek293T cells. Individual data points are shown and error bars represent s.d. for n=3 independent biological replicates, performed on different days. FIGs 9A and 9B are graphs that depict on-target DNA editing frequencies. FIGs 9C and 9D are graphs that depict sgRNA-guided DNA-off- target editing frequencies. FIG 9E is a graph depicting RNA off-target editing frequencies. FIGs. 10A-10B depict the median A+T to G+C conversion and corresponding INDEL formation of TadA, C-terminal alpha-helix truncation ABE constructs in HEK293T cells. FIG 10A is a heat map depicting A=T to G+C median editing conversion across 8 genomic sites. FIG 10B is a heat map depicting INDEL formation. Delta residue value corresponds to deletion position in TadA. Median value generated from n=3 biological replicate. FIG 11 are heat maps depicting the median A=T to G=C conversion of 40 ABES constructs in HEK293T cells across 8 genomic sites. Median values were determined from two or greater biological replicates. FIG. 12 is a heat map depicting median INDEL % of 40 ABE8 constructs in HEK293T cells across 8 genomic sites. Median values were determined from two or greater biological replicates. FIG. 13 is a graph depicting fold change in editing, ABE8:ABE7. Representation of average ABE8:ABE7 AT to G+C editing in Hek293T cells across all A positions within the target of eight different genomic sites. Positions 2-12 denote location of a target adenine within the 20-nt protospacer with position 20 directly 5° of the -NGG PAM. FIG. 14 depicts a dendrogram of ABE8s. Core ABE8 constructs selected for further studies highlighted in in black. FIG. 15 are heat maps depicting median A*T to G+C conversion of core eight ABE8 constructs in HEK293T cells across 8 genomic sites. Median values were determined from three or greater biological replicates. FIG. 16 is a heat map depicting median INDEL frequency of core 8 ABESs tested at 8 genomic sites in HEK293T cells. FIG. 17 are heat maps depicting median AT to G+C conversion of core NG-ABE8 constructs 9 (-NG PAM) at six genomic sites in HEK293T cells. Median value generated from n=3 biological replicate. FIG. 18 is a heat map depicting median INDEL frequency of core NG-ABESs tested at six genomic sites in HEK293T cells. Median value generated from n=3 biological replicate. FIG. 19 are heat maps depicting median AT to G+C conversion of core Sa-ABE8 constructs (-NNGRRT PAM) at six genomic sites in HEK293T cells. Site positions are numbered -2 to 20 (5’ to 3”) within the 22-nt protospacer. Position 20 is 5° to the NNGRRT PAM. Median value generated from n=3 biological replicate. FIG. 20 is a heat map depicting median INDEL frequency of core Sa-ABE8s tested at 8 genomic sites in HEK293T cells. Median value generated from n=3 biological replicate. FIG. 21 are heat maps depicting median A+T to G*C conversion of core dC9-ABES8- m constructs at eight genomic sites in HEK293T cells. Dead Cas9 (dC9) is defined as D10A and H840A mutations within S. pyogenes Cas9. Median value generated from n>3 biological replicate. FIG. 22 are heat maps depicting median AT to G+C conversion of core dC9-ABE8-d constructs at eight genomic sites in HEK293T cells. Dead Cas9 (dC9) is defined as D10A and H840A mutations within S. pyogenes Cas9. Median value generated from n>3 biological replicate. FIGs. 23A and 23B depict Median INDEL frequency of core dC9-ABES8s tested at 8 genomic sites in HEK293T cells. Median value generated from n>3 biological replicate. FIG. 23A is a heat map depicting indel frequency shown for dC9-ABE8-m variants relative to ABE7.10. FIG. 23B is a heat map depicting indel frequency shown for dC9-ABE8-d variants relative to ABE7.10. FIG. 24 is a graph depicting C+G to T+A editing with Hek293T cells treated with ABESs and ABE7.10. Editing frequencies for each site averaged across all C positions within the target. Cytosines within the protospacer are indicted with shading. FIGs. 25A-25H depict DNA on-target and sgRNA-dependent DNA off-target editing by ABES constructs and ABE8 constructs with TadA mutations to improve specificity for DNA. Individual data points are shown and error bars represent s.d. for n=3 independent biological replicates, performed on different days. FIGs. 25A and 25B are graph depicting on-target DNA editing frequencies for core ABE8 constructs as compared to ABE7. FIGs. 25C and 25D are graphs depicting on-target DNA editing frequencies for ABE8 with mutations that improve RNA off-target editing. FIGs. 25E and 25F are graphs depicting sgRNA-guided DNA-off-target editing frequencies for core ABE 8 constructs as compared to ABET. FIGs. 25G and 25H are graphs depicting sgRNA-guided DNA-off-target editing frequencies for ABE 8 constructs with mutations that improve RNA off-target editing. FIG. 26 is a graph depicting indel frequencies at 12 previously identified sgRNA- dependent Cas9 off-target loci in human cells Individual data points are shown and error bars represent s.d. for n=3 independent biological replicates, performed on different days. FIGs. 27A and 27B depict A+T to G=C conversion and phenotypic outcomes in primary cells. FIG. 27A is a graph depicting A*T to G+C conversion at -198 HBG1 / 2 site in CD34+ cells treated with ABE from two separate donors. NGS analysis conducted at 48 and 144h post treatment. -198 HBG1 / 2 target sequence shown with A7 highlighted. Percent AsT to GC plotted for A7. FIG. 27B is a graph depicting percentage of y-globin formed as a fraction of alpha-globin. Values shown from two different donors, post ABE treatment and erythroid differentiation. FIGs. 28A and 28B depict A+T to G=C conversion of CD34+ cells treated with ABE8 at the -198 promoter site upstream of HBG1 / 2. FIG. 28A is a heat map depicting Ato G editing frequency of ABE8s in CD34+ cells from two donors, where Donor 2 is heterozygous for sickle cell disease, at 48 and 144h post editor treatment. FIG. 28B is a graphical representation of distribution of total sequencing reads which contain either A7 only edits or combined (A7 + A8) edits. FIG. 29 is a heat map depicting INDEL frequency of CD34+ cells treated with ABE8 at the -198 site of the gamma-globin promoter. Frequencies shown from two donors at 48h and 144h time points. FIG. 30 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of untreated differentiated CD34+ cells (donor 1). FIG. 31 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABE7.10-m (donorl) FIG. 32 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABE7.10-d (donorl). FIG. 33 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABES.8-m (donor1) FIG. 34 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABES.8-d (donorl). FIG. 35 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABE8.13-m (donorl). FIG. 36 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABES.13-d (donorl). FIG. 37 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABES8.17-m (donorl). FIG. 38 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABES.17-d (donorl). FIG. 39 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABE8.20-m (donorl). FIG. 40 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABES.20-d (donor 1). FIG. 41 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells untreated (donor 2). Note: donor 2 is heterozygous for sickle cell disease. FIG. 42 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABE7.10-m (donor 2). Note: donor 2 is heterozygous for sickle cell disease. FIG. 43 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABE7.10-d (donor 2). Note: donor 2 is heterozygous for sickle cell disease. FIG. 44 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABES8.8-m (donor 2). Note: donor 2 is heterozygous for sickle cell disease. FIG. 45 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABE8.8-d (donor 2). Note: donor 2 is heterozygous for sickle cell disease. FIG. 46 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABE8.13-m (donor 2). Note: donor 2 is heterozygous for sickle cell disease. FIG. 47 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABES.13-d (donor 2). Note: donor 2 is heterozygous for sickle cell disease. FIG. 48 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABE8.17-m (donor 2). Note: donor 2 is heterozygous for sickle cell disease. FIG. 49 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABES.17-d (donor 2). Note: donor 2 is heterozygous for sickle cell disease. FIG. 50 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABE8.20-m (donor 2). Note: donor 2 is heterozygous for sickle cell disease. FIG. 51A-51E depict editing with ABE8.8 at two independent sites reached over 90% editing on day 11 post erythroid differentiation before enucleation and about 60% of gamma globin over alpha globin or total beta family globin on day 18 post erythroid differentiation. FIG. 51A is a graph depicting an average of ABER.8 editing in 2 healthy donors in 2 independent experiments. Editing efficiency was measured with primers that distinguish HBG1 and HBG2. FIG. 51B is a graph depicting an average of 1 healthy donor in 2 independent experiments. Editing efficiency was measured with primers that recognize both HBGI1 and HBG2. FIG. 51C is a graph depicting editing of ABE8.8 in a donor with heterozygous E6V mutation. FIGs. 51D and 51E are graphs depicting gamma globin increase in the ABES.8 edited cells. FIGs. 52A and 52B depict percent editing using ABE variants to correct sickle cell mutations. FIG. 52A is a graph depicting a screen of different editor variants with about 70% editing in SCD patient fibroblasts. FIG. 52B is a graph depicting CD34 cells from healthy donors edited with a lead ABE variant, targeting a synonymous mutation A13 in an adjacent proline that resides within the editing window and serves as a proxy for editing the SCD mutation. ABES variants showed an average editing frequency around 40% at the proxy Al3. FIGs. 53A and 53B depict RNA amplicon sequencing to detect cellular A-to-I editing in RNA associated with ABE treatment. Individual data points are shown and error bars represent s.d. for n=3 independent biological replicates, performed on different days.FIG. 53A is a graph depicting A-to-I editing frequencies in targeted RNA amplicons for core ABE 8 constructs as compared to ABE7 and Cas9(D10A) nickase control. FIG. 53B is a graph depicting A-to-I editing frequencies in targeted RNA amplicons for ABE8 with mutations that have been reported to improve RNA off-target editing. FIG. 54 is a bar graph depicting the total percent of A-to-G base editing at the splice acceptor target site (AG nucleic acid site) achieved by the adenosine base editors (ABE8 variants) assayed versus controls. The Protospacer PAM sequence for the ABE assessed was NGG ABE. FIG. 55 depicts a diagramic illustration of the exon 3 splice acceptor of the SOD! genomic nucleic acid sequence as a target for A-to-G nucleotide change to cause splice disruption of transcription of SOD exon 3. Shown in the figure are the numeric genomic DNA locations in the region of exon 3 of the SOD! nucleic acid sequence (top), SOD! genomic nucleic acid sequence in the region of exon 3, the intron nucleic acid sequence 5' of exon 3; and the target splice acceptor nucleic acid sequence 5' of exon 3; and the nucleic acid sequence of the corresponding guide RNA (gRNA), with the splice acceptor (“AG”) nucleic acids immediately 5’ of SOD! exon 3 indicated by upward arrows. Also noted in the figure are bystander adenosine (A) nucleobases (boxed) in the intronic sequence in proximity to the AG splice acceptor 5' of SOD! exon 3. FIG. 56 is a table depicting efficiency of target site nucleobase alteration in the target nucleic acid sequence using the base editor systems and methods described herein and following PCR and deep sequencing of DNA. Shown is percentage efficiency of precise A- to-G nucleotide change (alteration) in the target splice acceptor (AG) nucleic acid sequence residing 5' of exon 3 of the SOD / genomic nucleic acid sequence, as detected by deep sequencing (MySeq) following PCR of the genomic DNA in cells in which base editing by had occurred. Each nucleobase, A, C, G, T, is listed vertically along the left edge of the table, and the position in the DNA along the target site nucleic acid (in base pairs (bp)) is shown along the bottom of the table. The table demonstrates about 81% (80.77%) efficiency of A-to-G conversion at the splice acceptor target nucleic acid site (position 6 along the target site) using the ABE8 base editor variants and the systems and methods described herein. The alteration of bystander A nucleobases to G nucleobases (at positions 2, 3, and 4 shown in the box to the left of the targeted A nucleobase of the splice acceptor) was minimal compared with editing of the target A in the splice acceptor nucleic acid sequence. FIGS. 57A-57L are tables depicting efficiency of target site nucleobase alteration in the target nucleic acid sequence using the base editor systems and methods described herein and following PCR and deep sequencing of DNA. Each nucleobase, A, C, G, T, is listed vertically along the left edge of the table, and the position in the DNA along the target site nucleic acid (in base pairs (bp)) is shown along the bottom of the table. See, also, FIG. 56 supra. FIG. 58 is a bar graph depicting the percentage of A-to-G base editing at the target position 6 at the splice acceptor target site (AG nucleic acid site) achieved by the adenosine base editors (ABE variants) with guide 20 assayed versus controls. The Protospacer PAM sequence for the ABE assessed was NGG ABE. FIG. 59 is a bar graph depicting the percentage of A-to-G base editing at the target position 5 (left) and a bar graph depicting the total percent of A-to-G base editing at positions 2, 5,9 (right) at the splice acceptor target site (AG nucleic acid site) achieved by the adenosine base editors (ABE8 variants) with guide 42 assayed versus controls. The Protospacer PAM sequence for the ABE assessed was NGG ABE. FIG. 60A is a bar graph depicting the percentage of A-to-G base editing at the target position 5 at the splice acceptor target site (AG nucleic acid site) achieved by the adenosine base editors (PV variants) with guide 41 assayed versus controls. The Protospacer PAM sequence for the ABE assessed was NGT ABE. FIG. 60B is a table depicting efficiency of target site nucleobase alteration in the target nucleic acid sequence using the base editor systems and methods described herein and following PCR and deep sequencing of DNA. Each nucleobase, A, C, G, T, is listed vertically along the left edge of the table, and the position in the DNA along the target site nucleic acid (in base pairs (bp)) is shown along the bottom of the table. See, also, FIG. 56 supra. FIG. 61 is a bar graph depicting the total percent of A-to-G base editing at the splice acceptor target site (AG nucleic acid site) achieved by the adenosine base editors (PV variants) with guide 24 assayed versus controls. The Protospacer PAM sequence for the ABE assessed was NGA ABE. FIG. 62 shows the SOD1 protein level (left: western blot, right: quantification) in HEK297T cells edited with ABE8.8 or ABE7.10 with guide 20. Beta Actin was used as a control. FIG. 63 is a bar graph depicting the percentage of C-to-T base editing at the target position 8 at the splice acceptor target site (AG nucleic acid site) achieved by the cytidine base editors (PV variants) with guide 19 assayed versus controls. The Protospacer PAM sequence for the ABE assessed was NGC CBE. FIG. 64A is a bar graph (left) depicting the percentage of A-to-G base editing at the target position 5 at the splice acceptor target site (AG nucleic acid site) achieved by the adenosine base editors (PV variants) with guide 41 assayed versus controls. The Protospacer PAM sequence for the ABE assessed was NGT ABE. On the right is a diagramic illustration depicting the numeric genomic DNA locations in the region of exon 3 of the SOD! nucleic acid sequence where guides 41, 20, 40, and 21 are designed to bind. See, also, FIG. 55 supra. FIG. 64B is a table depicting efficiency of target site nucleobase alteration in the target nucleic acid sequence using the base editor systems and methods described herein and following PCR and deep sequencing of DNA. Each nucleobase, A, C, G, T, is listed vertically along the left edge of the table, and the position in the DNA along the target site nucleic acid (in base pairs (bp)) is shown along the bottom of the table. See, also, FIG. 56 supra. FIG. 65 is a bar graph (left) depicting the total percent of A-to-G base editing at the splice acceptor target site (AG nucleic acid site) achieved by the adenosine base editors (ABE variants) with guide 42 assayed versus controls. The Protospacer PAM sequence for the ABE assessed was NGG ABE. On the right is a diagramic illustration depicting the numeric genomic DNA locations in the region of exon 3 of the SOD nucleic acid sequence where guides 42, 24, and 25 are designed to bind. See, also, FIG. 85 supra. FIG. 66A is a bar graph depicting the total percent of C-to-T base editing achieved by the cytidine base editor (BE4 VRQR) with guide 40 assayed versus a control. The Protospacer PAM sequence for the CBE assessed was NGA CBE. FIG. 66B is a table depicting efficiency of target site nucleobase alteration in the target nucleic acid sequence using the base editor systems and methods described herein and following PCR and deep sequencing of DNA. Each nucleobase, A, C, G, T, is listed vertically along the left edge of the table, and the position in the DNA along the target site nucleic acid (in base pairs (bp)) is shown along the bottom of the table. See, also, FIG. 56 supra. FIG. 67 is a bar graph depicting the percentage of A-to-G base editing at the target position 5 at the splice acceptor target site (AG nucleic acid site) achieved by the adenosine base editors (PV variants) with guide 18 assayed versus controls. The Protospacer PAM sequence for the ABE assessed was NGT ABE. FIG. 68 is a table depicting efficiency of target site nucleobase alteration in the target nucleic acid sequence using the base editor systems and methods described herein and following PCR and deep sequencing of DNA. Each nucleobase, A, C, G, T, is listed vertically along the left edge of the table, and the position in the DNA along the target site nucleic acid (in base pairs (bp)) is shown along the bottom of the table. See, also, FIG. 56 supra. FIG. 69 is a bar graph depicting the total percent of C-to-T base editing achieved by the cytidine base editor (BE4 VRQR) with guide 16 assayed versus a control. The Protospacer PAM sequence for the CBE assessed was NGA CBE. FIG. 70 is a bar graph depicting the percentage of C-to-T base editing at the target position 4 achieved by the cytidine base editor (BE4 VRQR) with guide 17 assayed versus a control. The Protospacer PAM sequence for the CBE assessed was NGA CBE. FIG. 71 is a bar graph depicting the percentage of C-to-T base editing at the target position 5 achieved by the cytidine base editor (BE4 VRQR) with guide 21 assayed versus a control. The Protospacer PAM sequence for the CBE assessed was NGA CBE. FIGS. 72A-72L are tables depicting efficiency of target site nucleobase alteration in the target nucleic acid sequence using the base editor systems and methods described herein and following PCR and deep sequencing of DNA. Each nucleobase, A, C, G, T, is listed vertically along the left edge of the table, and the position in the DNA along the target site nucleic acid (in base pairs (bp)) is shown along the bottom of the table. See, also, FIG. 56 supra. FIGS. 73A-73C are tables depicting efficiency of target site nucleobase alteration in the target nucleic acid sequence using the base editor systems and methods described herein and following PCR and deep sequencing of DNA. Each nucleobase, A, C, G, T, is listed vertically along the left edge of the table, and the position in the DNA along the target site nucleic acid (in base pairs (bp)) is shown along the bottom of the table. See, also, FIG. 56 supra. FIGS. 74A-74C are tables depicting efficiency of target site nucleobase alteration in the target nucleic acid sequence using the base editor systems and methods described herein and following PCR and deep sequencing of DNA. Each nucleobase, A, C, G, T, is listed vertically along the left edge of the table, and the position in the DNA along the target site nucleic acid (in base pairs (bp)) is shown along the bottom of the table. See, also, FIG. 56 supra. FIGS. 75A-75D are tables depicting efficiency of target site nucleobase alteration in the target nucleic acid sequence using the base editor systems and methods described herein and following PCR and deep sequencing of DNA. Each nucleobase, A, C, G, T, is listed vertically along the left edge of the table, and the position in the DNA along the target site nucleic acid (in base pairs (bp)) is shown along the bottom of the table. See, also, FIG. 56 supra. FIGS. 76A-76L are tables depicting efficiency of target site nucleobase alteration in the target nucleic acid sequence using the base editor systems and methods described herein and following PCR and deep sequencing of DNA. Each nucleobase, A, C, G, T, is listed vertically along the left edge of the table, and the position in the DNA along the target site nucleic acid (in base pairs (bp)) is shown along the bottom of the table. See, also, FIG. 56 supra. FIGS. 77A-77L are tables depicting efficiency of target site nucleobase alteration in the target nucleic acid sequence using the base editor systems and methods described herein and following PCR and deep sequencing of DNA. Each nucleobase, A, C, G, T, is listed vertically along the left edge of the table, and the position in the DNA along the target site nucleic acid (in base pairs (bp)) is shown along the bottom of the table. See, also, FIG. 56 supra. FIGS. 78A-78D are tables depicting efficiency of target site nucleobase alteration in the target nucleic acid sequence using the base editor systems and methods described herein and following PCR and deep sequencing of DNA. Each nucleobase, A, C, G, T, is listed vertically along the left edge of the table, and the position in the DNA along the target site nucleic acid (in base pairs (bp)) is shown along the bottom of the table. See, also, FIG. 56 supra. FIGS. 79A-79L are tables depicting efficiency of target site nucleobase alteration in the target nucleic acid sequence using the base editor systems and methods described herein and following PCR and deep sequencing of DNA. Each nucleobase, A, C, G, T, is listed vertically along the left edge of the table, and the position in the DNA along the target site nucleic acid (in base pairs (bp)) is shown along the bottom of the table. See, also, FIG. 56 supra. FIG. 80 shows that a stop codon was introduced in exon 1 of the Androgen Receptor when “CAG” was targeted using a cytidine base editor (CBE). FIG. 81 provides two graphs. The graph on the left shows percent C to T editing by the specified cytidine base editor. The graph on the right shows percent indel rate for each of the cytidine base editors. FIGs. 82A-82I are tables depicting the efficiency of percentage of C to T editing in the AR nucleic acid sequence using CBE base editor variants, as detected by deep sequencing (MySeq) following PCR of the genomic DNA in cells in which base editing had occurred. FIGs. 82A-82I depict the percent of C to T base editing at position 6 in the AR nucleic acid target site. Control reactions are shown where water was used in place of the CBE. FIG. 83A provides two graphs. The graph on the left shows the introduction of a premature termination codon in exon 1 resulted in the functional knockout of the androgen receptor in the majority of cells. The graph in the middle shows percent indel rate for each of the cytidine base editors. On the right is a diagramic illustration depicting the numeric genomic DNA locations in the region of exon 1 of the AR nucleic acid sequence where guide 8 are designed to bind. See, also, FIG. 80 supra. FIG. 83B is a table depicting the efficiency of percentage of C to T editing in the AR nucleic acid sequence using CBE base editor variants, as detected by deep sequencing (MySeq) following PCR of the genomic DNA in cells in which base editing had occurred. FIG. 83B depicts the percent of C to T base editing at the target position in the AR nucleic acid target site. Control reactions are shown where water was used in place of the CBE. FIG. 84A is a bar graph (left) depicting the percentage of C-to-T base editing at the target position 6 achieved by the cytidine base editors (BGXS5, BGX27, BGX 29, and BTX448) with guide 10 assayed versus a control and the indel rates in percentage (middle). The Protospacer PAM sequence for the CBE assessed was NGG CBE. On therightisa diagramic illustration depicting the numeric genomic DNA locations in the region of exon 1 of the AR nucleic acid sequence where guides 9 and 10 are designed to bind. See, also, FIG. 80 supra. FIG. 84B is a table depicting the efficiency of percentage of C to T editing in the AR nucleic acid sequence using CBE base editor variants, as detected by deep sequencing (MySeq) following PCR of the genomic DNA in cells in which base editing had occurred. FIG. 83B depicts the percent of C to T base editing at position 6 in the AR nucleic acid target site. Control reactions are shown where water was used in place of the CBE. FIG. 85 is a bar graph depicting the total percent of A-to-G base editing at the splice acceptor target site (AG nucleic acid site) achieved by the adenosine base editors (ABE8 variants) with guide 8 (left) or guide 14 (right) assayed versus controls. The Protospacer PAM sequence for the ABE assessed was NGG ABE. FIG. 86A is a bar graph (top) and a summary table (bottom) depicting the percentage of C-to-T base editing at the target position 8 achieved by the cytidine base editor (BE4 VRQR) with guide 11 assayed versus a control. The Protospacer PAM sequence for the CBE assessed was NGA CBE. FIG. 86B is a table depicting the efficiency of percentage of C to T editing in the AR nucleic acid sequence using CBE base editor variants, as detected by deep sequencing (MySeq) following PCR of the genomic DNA in cells in which base editing had occurred. FIG. 86B depicts the percent of C to T base editing at position 8 in the AR nucleic acid target site. Control reactions are shown where water was used in place of the CBE. FIG. 87A is a bar graph (top) and a summary table (bottom) depicting the percentage of C-to-T base editing at the target position 5 achieved by the cytidine base editor (BE4 VRQR) with guide 12 assayed versus a control. The Protospacer PAM sequence for the CBE assessed was NGA CBE. FIG. 87B is a table depicting the efficiency of percentage of C to T editing in the AR nucleic acid sequence using CBE base editor variants, as detected by deep sequencing (MySeq) following PCR of the genomic DNA in cells in which base editing had occurred. FIG. 87B depicts the percent of C to T base editing at position 5 in the AR nucleic acid target site. Control reactions are shown where water was used in place of the CBE. FIG. 88 is a bar graph depicting the total percent of C-to-T base editing achieved by the cytidine base editor (BE4 VRQR) with guide 15 assayed versus a control. The Protospacer PAM sequence for the CBE assessed was NGA CBE. Each nucleobase, A, C, G, T, is listed vertically along the left edge of the table, and the position in the DNA along the target site nucleic acid (in base pairs (bp)) is shown along the bottom of the table. FIGS. 89A-89D are tables depicting efficiency of target site nucleobase alteration in the target nucleic acid sequence using the base editor systems and methods described herein and following PCR and deep sequencing of DNA. Shown is percentage efficiency of precise C-to-T or A-to-G nucleotide change (alteration) in the target nucleic acid sequence of exon 1 of the AR genomic nucleic acid sequence, as detected by deep sequencing (MySeq) following PCR of the genomic DNA in cells in which base editing by had occurred. Each nucleobase, A, C, G, T, is listed vertically along the left edge of the table, and the position in the DNA along the target site nucleic acid (in base pairs (bp)) is shown along the bottom of the table. FIGS. 90A-90C are tables depicting efficiency of target site nucleobase alteration in the target nucleic acid sequence using the base editor systems and methods described herein and following PCR and deep sequencing of DNA. Shown is percentage efficiency of precise C-to-T or A-to-G nucleotide change (alteration) in the target nucleic acid sequence of exon 1 of the AR genomic nucleic acid sequence, as detected by deep sequencing (MySeq) following PCR of the genomic DNA in cells in which base editing by had occurred. Each nucleobase, A, C, G, T, is listed vertically along the left edge of the table, and the position in the DNA along the target site nucleic acid (in base pairs (bp)) is shown along the bottom of the table. FIGS. 91A-91C are tables depicting efficiency of target site nucleobase alteration in the target nucleic acid sequence using the base editor systems and methods described herein and following PCR and deep sequencing of DNA. Shown is percentage efficiency of precise C-to-T or A-to-G nucleotide change (alteration) in the target nucleic acid sequence of exon 1 of the AR genomic nucleic acid sequence, as detected by deep sequencing (MySeq) following PCR of the genomic DNA in cells in which base editing by had occurred. Each nucleobase, A, C, G, T, is listed vertically along the left edge of the table, and the position in the DNA along the target site nucleic acid (in base pairs (bp)) is shown along the bottom of the table. FIGS. 92A and 92B are tables depicting efficiency of target site nucleobase alteration in the target nucleic acid sequence using the base editor systems and methods described herein and following PCR and deep sequencing of DNA. Shown is percentage efficiency of precise C-to-T or A-to-G nucleotide change (alteration) in the target nucleic acid sequence of exon 1 of the AR genomic nucleic acid sequence, as detected by deep sequencing (My Seq) following PCR of the genomic DNA in cells in which base editing by had occurred. Each nucleobase, A, C, G, T, is listed vertically along the left edge of the table, and the position in the DNA along the target site nucleic acid (in base pairs (bp)) is shown along the bottom of the table. FIGS. 93A-93X are tables depicting efficiency of target site nucleobase alteration in the target nucleic acid sequence using the base editor systems and methods described herein and following PCR and deep sequencing of DNA. Shown is percentage efficiency of precise C-to-T or A-to-G nucleotide change (alteration) in the target nucleic acid sequence of exon 1 of the AR genomic nucleic acid sequence, as detected by deep sequencing (MySeq) following PCR of the genomic DNA in cells in which base editing by had occurred. Each nucleobase, A, C, G, T, is listed vertically along the left edge of the table, and the position in the DNA along the target site nucleic acid (in base pairs (bp)) is shown along the bottom of the table. DETAILED DESCRIPTION OF THE INVENTION The invention provides compositions comprising novel adenine base editors (e.g., ABES) that have increased efficiency and methods of using them to generate modifications in target nucleobase sequences. NUCLEOBASE EDITOR Disclosed herein is a base editor or a nucleobase editor for editing, modifying or altering a target nucleotide sequence of a polynucleotide. In particular embodiments, a base editor of the invention modifies an SOD polynucleotide. In particular embodiments, a base editor of the invention introduces a stop codon or disrupts a splice site in an AR polynucleotide. Described herein is a nucleobase editor or a base editor comprising a polynucleotide programmable nucleotide binding domain (e.g, Cas9) and a nucleobase editing domain (e.g., adenosine deaminase). A polynucleotide programmable nucleotide binding domain (e.g., Cas9), when in conjunction with a bound guide polynucleotide (e.g., gRNA), can specifically bind to a target polynucleotide sequence (i.e., via complementary base pairing between bases of the bound guide nucleic acid and bases of the target polynucleotide sequence) and thereby localize the base editor to the target nucleic acid sequence desired to be edited. In some embodiments, the target polynucleotide sequence comprises single-stranded DNA or double-stranded DNA. In some embodiments, the target polynucleotide sequence comprises RNA. In some embodiments, the target polynucleotide sequence comprises a DNA-RNA hybrid. Polynucleotide Programmable Nucleotide Binding Domain It should be appreciated that polynucleotide programmable nucleotide binding domains can also include nucleic acid programmable proteins that bind RNA. For example, the polynucleotide programmable nucleotide binding domain can be associated with a nucleic acid that guides the polynucleotide programmable nucleotide binding domain to an RNA. Other nucleic acid programmable DNA binding proteins are also within the scope of this disclosure, though they are not specifically listed in this disclosure. A polynucleotide programmable nucleotide binding domain of a base editor can itself comprise one or more domains. For example, a polynucleotide programmable nucleotide binding domain can comprise one or more nuclease domains. In some embodiments, the nuclease domain of a polynucleotide programmable nucleotide binding domain can comprise an endonuclease or an exonuclease. Herein the term “exonuclease” refers to a protein or polypeptide capable of digesting a nucleic acid (e.g., RNA or DNA) from free ends, and the term “endonuclease” refers to a protein or polypeptide capable of catalyzing (e.g., cleaving) internal regions in a nucleic acid (e.g., DNA or RNA), In some embodiments, an endonuclease can cleave a single strand of a double-stranded nucleic acid. In some embodiments, an endonuclease can cleave both strands of a double-stranded nucleic acid molecule. In some embodiments a polynucleotide programmable nucleotide binding domain can be a deoxyribonuclease. In some embodiments a polynucleotide programmable nucleotide binding domain can be a ribonuclease. In some embodiments, a nuclease domain of a polynucleotide programmable nucleotide binding domain can cut zero, one, or two strands of a target polynucleotide. In some embodiments, the polynucleotide programmable nucleotide binding domain can comprise a nickase domain. Herein the term “nickase” refers to a polynucleotide programmable nucleotide binding domain comprising a nuclease domain that is capable of cleaving only one strand of the two strands in a duplexed nucleic acid molecule (e.g., DNA). In some embodiments, a nickase can be derived from a fully catalytically active (e.g., natural) form of a polynucleotide programmable nucleotide binding domain by introducing one or more mutations into the active polynucleotide programmable nucleotide binding domain. For example, where a polynucleotide programmable nucleotide binding domain comprises a nickase domain derived from Cas9, the Cas9-derived nickase domain can include a D10A mutation and a histidine at position 840. In such embodiments, the residue H840 retains catalytic activity and can thereby cleave a single strand of the nucleic acid duplex. In another example, a Cas9-derived nickase domain can comprise an H340A mutation, while the amino acid residue at position 10 remains a D. In some embodiments, a nickase can be derived from a fully catalytically active (e.g., natural) form of a polynucleotide programmable nucleotide binding domain by removing all or a portion of a nuclease domain that is not required for the nickase activity. For example, where a polynucleotide programmable nucleotide binding domain comprises a nickase domain derived from Cas9, the Cas9-derived nickase domain can comprise a deletion of all or a portion of the RuvC domain or the HNH domain. The amino acid sequence of an exemplary catalytically active Cas9 is as follows: MDKKYSIGLDIGTINSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAEAT RLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVD EVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFI QLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGL TPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNT EITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEF YKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLK DNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMT NFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRK VIVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIV LTLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDF LKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVV DELVKVMGRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQL QNEKLYLYYLONGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDS IDNKVLTRSDKNRGKSD NVPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKH VAQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVRE INNYHHAHDAYLNAV VGTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLAN GEIRKRPLIETNGETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNS DKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNP IDFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLAS HYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPI REQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQ Leech. A base editor comprising a polynucleotide programmable nucleotide binding domain comprising a nickase domain is thus able to generate a single-strand DNA break (nick) at a specific polynucleotide target sequence (e.g., determined by the complementary sequence of a bound guide nucleic acid). In some embodiments, the strand of a nucleic acid duplex target polynucleotide sequence that is cleaved by a base editor comprising a nickase domain (e.g., Cas9-derived nickase domain) is the strand that is not edited by the base editor (7.e., the strand that is cleaved by the base editor is opposite to a strand comprising a base to be edited). In other embodiments, a base editor comprising a nickase domain (e.g., Cas9- derived nickase domain) can cleave the strand of a DNA molecule which is being targeted for editing. In such embodiments, the non-targeted strand is not cleaved. Also provided herein are base editors comprising a polynucleotide programmable nucleotide binding domain which is catalytically dead (i.e., incapable of cleaving a target polynucleotide sequence). Herein the terms “catalytically dead” and “nuclease dead” are used interchangeably to refer to a polynucleotide programmable nucleotide binding domain which has one or more mutations and / or deletions resulting in its inability to cleave a strand of a nucleic acid. In some embodiments, a catalytically dead polynucleotide programmable nucleotide binding domain base editor can lack nuclease activity as a result of specific point mutations in one or more nuclease domains. For example, in the case of a base editor comprising a Cas9 domain, the Cas9 can comprise both a D10A mutation and an H840A mutation. Such mutations inactivate both nuclease domains, thereby resulting in the loss of nuclease activity. In other embodiments, a catalytically dead polynucleotide programmable nucleotide binding domain can comprise one or more deletions of all or a portion of a catalytic domain (e.g., RuvC1 and / or HNH domains). In further embodiments, a catalytically dead polynucleotide programmable nucleotide binding domain comprises a point mutation (e.g., D10A or H840A) as well as a deletion of all or a portion of a nuclease domain. Also contemplated herein are mutations capable of generating a catalytically dead polynucleotide programmable nucleotide binding domain from a previously functional version of the polynucleotide programmable nucleotide binding domain. For example, in the case of catalytically dead Cas9 (“dCas9”), variants having mutations other than D10A and H840A are provided, which result in nuclease inactivated Cas9. Such mutations, by way of example, include other amino acid substitutions at D10 and H840, or other substitutions within the nuclease domains of Cas9 (e.g., substitutions in the HNH nuclease subdomain and / or the RuvC1 subdomain). Additional suitable nuclease-inactive dCas9 domains can be apparent to those of skill in the art based on this disclosure and knowledge in the field, and are within the scope of this disclosure. Such additional exemplary suitable nuclease-inactive Cas9 domains include, but are not limited to, D10A / H840A, D10A / D839A / H840A, and D10A / D839A / H840A / N863 A mutant domains (See, e.g., Prashant et al., CAS9 transcriptional activators for target specificity screening and paired nickases for cooperative genome engineering. Nature Biotechnology. 2013; 31(9): 833-838, the entire contents of which are incorporated herein by reference). Non-limiting examples of a polynucleotide programmable nucleotide binding domain which can be incorporated into a base editor include a CRISPR protein-derived domain, a restriction nuclease, a meganuclease, TAL nuclease (TALEN), and a zinc finger nuclease (ZFN). In some embodiments, a base editor comprises a polynucleotide programmable nucleotide binding domain comprising a natural or modified protein or portion thereof which via a bound guide nucleic acid is capable of binding to a nucleic acid sequence during CRISPR (i.e., Clustered Regularly Interspaced Short Palindromic Repeats)-mediated modification of a nucleic acid. Such a protein is referred to herein as a “CRISPR protein.” Accordingly, disclosed herein is a base editor comprising a polynucleotide programmable nucleotide binding domain comprising all or a portion of a CRISPR protein (i.e. a base editor comprising as a domain all or a portion of a CRISPR protein, also referred to as a “CRISPR protein-derived domain” of the base editor). A CRISPR protein-derived domain incorporated into a base editor can be modified compared to a wild-type or natural version of the CRISPR protein. For example, as described below a CRISPR protein-derived domain can comprise one or more mutations, insertions, deletions, rearrangements and / or recombinations relative to a wild-type or natural version of the CRISPR protein. CRISPR is an adaptive immune system that provides protection against mobile genetic elements (viruses, transposable elements and conjugative plasmids). CRISPR clusters contain spacers, sequences complementary to antecedent mobile elements, and target invading nucleic acids. CRISPR clusters are transcribed and processed into CRISPR RNA (crRNA). In type II CRISPR systems, correct processing of pre-crRNA requires a trans- encoded small RNA (tracrRNA), endogenous ribonuclease 3 (rnc) and a Cas9 protein. The tractRNA serves as a guide for ribonuclease 3-aided processing of pre-crRNA. Subsequently, Cas9 / crRNA / tractRNA endonucleolytically cleaves linear or circular dsDNA target complementary to the spacer. The target strand not complementary to ctRNA is first cut endonucleolytically, and then trimmed 3-5’ exonucleolytically. In nature, DNA-binding and cleavage typically requires protein and both RNAs. However, single guide RNAs (“sgRNA,” or simply “gNRA”) can be engineered so as to incorporate aspects of both the crRNA and tracrRNA into a single RNA species. See, e.g., Jinek M,, et al., Science 337:816- 821(2012), the entire contents of which is hereby incorporated by reference. Cas9 recognizes a short motif in the CRISPR repeat sequences (the PAM or protospacer adjacent motif) to help distinguish self versus non-self. In some embodiments, the methods described herein can utilize an engineered Cas protein. A guide RNA (gRNA) is a short synthetic RNA composed of a scaffold sequence necessary for Cas-binding and a user-defined ~20 nucleotide spacer that defines the genomic target to be modified. Thus, a skilled artisan can change the genomic target of the Cas protein specificity is partially determined by how specific the gRNA targeting sequence is for the genomic target compared to the rest of the genome, In some embodiments, the gRNA scaffold sequence is as follows: GUUUUAGAGC UAGAAAUAGC AAGUUAAAAU AAGGCUAGUC CGUUAUCAAC UUGAAAAAGU GGCACCGAGU CGGUGCUUUU. In some embodiments, a CRISPR protein-derived domain incorporated into a base editor is an endonuclease (e.g., deoxyribonuclease or ribonuclease) capable of binding a target polynucleotide when in conjunction with a bound guide nucleic acid. In some embodiments, a CRISPR protein-derived domain incorporated into a base editor is a nickase capable of binding a target polynucleotide when in conjunction with a bound guide nucleic acid. In some embodiments, a CRISPR protein-derived domain incorporated into a base editor is a catalytically dead domain capable of binding a target polynucleotide when in conjunction with a bound guide nucleic acid. In some embodiments, a target polynucleotide bound by a CRISPR protein derived domain of a base editor is DNA. In some embodiments, a target polynucleotide bound by a CRISPR protein-derived domain of a base editor is RNA. Cas proteins that can be used herein include class 1 and class 2. Non-limiting examples of Cas proteins include Casl, Cas1B, Cas2, Cas3, Cas4, Cas5, Cas5d, Cas5t, Cas5h, Cas5a, Cas6, Cas7, Cas8, Cas9 (also known as Csnl or Csx12), Cas10, Csyl, Csy2, Csy3, Csy4, Csel, Cse2, Cse3, Cse4, CseSe, Cscl, Csc2, Csa5, Csnl, Csn2, Csm1, Csm2, Csm3, Csm4, Csm5, Csm6, Cmrl, Cmr3, Cmr4, CmrS, Cmr6, Csb1, Csb2, Csb3, Csx17, Csx14, Csx10, Csx16, CsaX, Csx3, Csx1, Csx1S, Csfl, Csf2, CsO, Csf4, Csdl, Csd2, Cstl, Cst2, Cshl, Csh2, Csal, Csa2, Csa3, Csa4, Csa5, Cas12a / Cpfl, Cas12b / C2cl, Cas12¢ / C2c3, Casl2d / CasY, Casl2e / CasX, Casl2g, Cas12h, and Cas12i, CARF, DinG, homologues thereof, or modified versions thereof. An unmodified CRISPR enzyme can have DNA cleavage activity, such as Cas9, which has two functional endonuclease domains: RuvC and HNH. A CRISPR enzyme can direct cleavage of one or both strands at a target sequence, such as within a target sequence and / or within a complement of a target sequence. For example, a CRISPR enzyme can direct cleavage of one or both strands within about 1, 2, 3, 4, 5,6,7,8,9,10, 15, 20, 25, 50, 100, 200, 500, or more base pairs from the first or last nucleotide of a target sequence. A vector that encodes a CRISPR enzyme that is mutated to with respect, to a corresponding wild-type enzyme such that the mutated CRISPR enzyme lacks the ability to cleave one or both strands of a target polynucleotide containing a target sequence can be used. Cas9 can refer to a polypeptide with at least or at least about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity and / or sequence homology to a wild-type exemplary Cas9 polypeptide (e.g., Cas9 from S. pyogenes). Cas9 can refer to a polypeptide with at most or at most about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity and / or sequence homology to a wild-type exemplary Cas9 polypeptide (e.g., from S. pyogenes). Cas9 can refer to the wild-type or a modified form of the Cas9 protein that can comprise an amino acid change such as a deletion, insertion, substitution, variant, mutation, fusion, chimera, or any combination thereof, In some embodiments, a CRISPR protein-derived domain of a base editor can include all or a portion of Cas9 from Corynebacterium ulcerans (NCBI Refs: NC_015683.1, NC_017317.1); Corynebacterium diphtheria (NCBI Refs: NC_016782.1, NC_016786.1); Spiroplasma syrphidicola (NCBI Ref: NC_021284.1); Prevotella intermedia (NCBI Ref: NC _017861.1); Spiroplasma taiwanense (NCBI Ref: NC_021846.1); Streptococcus iniae (NCBI Ref: NC_021314.1); Belliella baltica (NCBI Ref: NC_018010.1); Psychroflexus torquis (NCBI Ref: NC_018721.1); Streptococcus thermophilus (NCBI Ref: YP_820832.1); Listeria innocua (NCBI Ref: NP_472073.1); Campylobacter jejuni (NCBI Ref: YP_002344900.1); Neisseria meningitidis (NCBI Ref: YP_002342100.1), Streptococcus pyogenes, or Staphylococcus aureus. Cas9 domains of Nucleobase Editors Cas9 nuclease sequences and structures are well known to those of skill in the art (See, e.g., “Complete genome sequence of an MI strain of Streptococcus pyogenes.” Ferretti etal., Proc. Natl. Acad. Sci. U.S.A. 98:4658-4663(2001); “CRISPR RNA maturation by trans-encoded small RNA and host factor RNase IIL.” Deltcheva E., et al., Nature 471:602- 607(2011); and “A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity.” Jinek M., et al., Science 337:816-821(2012), the entire contents of each of which are incorporated herein by reference). Cas9 orthologs have been described in various species, including, but not limited to, S. pyogenes and S. thermophilus. Additional suitable Cas9 nucleases and sequences will be apparent to those of skill in the art based on this disclosure, and such Cas9 nucleases and sequences include Cas9 sequences from the organisms and loci disclosed in Chylinski, Rhun, and Charpentier, “The tractRNA and Cas9 families of type II CRISPR-Cas immunity systems” (2013) RNA Biology 10:5, 726-737; the entire contents of which are incorporated herein by reference. In some embodiments, a nucleic acid programmable DNA binding protein (napDNADp) is a Cas9 domain. Non-limiting, exemplary Cas9 domains are provided herein. The Cas9 domain may be a nuclease active Cas9 domain, a nuclease inactive Cas9 domain (dCas9), or a Cas9 nickase (nCas9). In some embodiments, the Cas9 domain is a nuclease active domain. For example, the Cas9 domain may be a Cas9 domain that cuts both strands of a duplexed nucleic acid (e.g., both strands of a duplexed DNA molecule). In some embodiments, the Cas9 domain comprises any one of the amino acid sequences as set forth herein. In some embodiments the Cas9 domain comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to any one of the amino acid sequences set forth herein. In some embodiments, the Cas9 domain comprises an amino acid sequence that has 1, 2, 3,4, 5,6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more or more mutations compared to any one of the amino acid sequences set forth herein. In some embodiments, the Cas9 domain comprises an amino acid sequence that has at least 10, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, at least 500, at least 600, at least 700, at least 800, at least 900, at least 1000, at least 1100, or at least 1200 identical contiguous amino acid residues as compared to any one of the amino acid sequences set forth herein. In some embodiments, proteins comprising fragments of Cas9 are provided. For example, in some embodiments, a protein comprises one of two Cas9 domains: (1) the gRNA binding domain of Cas9; or (2) the DNA cleavage domain of Cas9. In some embodiments, proteins comprising Cas9 or fragments thereof are referred to as “Cas9 variants.” A Cas9 variant shares homology to Cas9, or a fragment thereof. For example, a Cas9 variant is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% identical to wild-type Cas9. In some embodiments, the Cas9 variant may have 1, 2, 3, 4,5,6,7,8,9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 21, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more amino acid changes compared to wild-type Cas9. In some embodiments, the Cas9 variant comprises a fragment of Cas9 (e.g, a gRNA binding domain or a DNA-cleavage domain), such that the fragment is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% identical to the corresponding fragment of wild-type Cas9. In some embodiments, the fragment is at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% identical, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% of the amino acid length of a corresponding wild-type Cas9. In some embodiments, the fragment is at least 100 amino acids in length. In some embodiments, the fragment is at least 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, or at least 1300 amino acids in length. In some embodiments, Cas9 fusion proteins as provided herein comprise the full- length amino acid sequence of a Cas9 protein, e.g., one of the Cas9 sequences provided herein. In other embodiments, however, fusion proteins as provided herein do not comprise a full-length Cas9 sequence, but only one or more fragments thereof. Exemplary amino acid sequences of suitable Cas9 domains and Cas9 fragments are provided herein, and additional suitable sequences of Cas9 domains and fragments will be apparent to those of skill in the art. A Cas9 protein can associate with a guide RNA that guides the Cas9 protein to a specific DNA sequence that has complementary to the guide RNA. In some embodiments, the polynucleotide programmable nucleotide binding domain is a Cas9 domain, for example a nuclease active Cas9, a Cas9 nickase (nCas9), or a nuclease inactive Cas9 (dCas9). Examples of nucleic acid programmable DNA binding proteins include, without limitation, Cas9 (e.g., dCas9 and nCas9), CasX, CasY, Cpfl, Cas12b / C2C1, and Cas12¢ / C2C3. In some embodiments, wild-type Cas9 corresponds to Cas9 from Streptococcus pyogenes (NCBI Reference Sequence: NC_017053.1, nucleotide and amino acid sequences as follows). ATGGATAAGAAATACTCAATAGGCTTAGATATCGGCACARATAGCGTCGGATGGGCGGTGAT CACTGATGATTATAAGGTTCCGTCTARRAAGTTCAAGGTTCTGGGAAATACAGACCGCCACA GTATCAAAAAAAATCTTATAGGGGCTCTTTTATTTGGCAGTGGAGAGACAGCGGAAGCGACT CGTCTCAAACGGACAGCTCGTAGAAGGTATACACGTCGGAAGAATCGTATTTGTTATCTACA GGAGATTTTTTCAAATGAGATGGCGARAGTAGATGATAGTTTCTTTCATCGACTTGAAGAGT CTTTTTTGGTGGAAGAAGACAAGAAGCATGAACGTCATCCTATTTTTGGAAATATAGTAGAT GAAGTTGCTTATCATGAGAAATATCCAACTATCTATCATCTGCGARARAAAATTGGCAGATTC TACTGATAAAGCGGATTTGCGCTTAATCTATTTGGCCTTAGCGCATATGATTAAGTTTCGTG GTCATTTTTTGATTGAGGGAGATTTARATCCTGATAATAGTGATGTGGACAAACTATTITATC CAGTTGGTACAAATCTACAATCAATTATTTGAAGAAAACCCTATTAACGCAAGTAGAGTAGA TGCTAAAGCGATTCTTTCTGCACGATTGAGTARATCAAGACGATTAGAARATCTCATTGCTC AGCTCCCCGGTGAGAAGAGAAATGGCTTGTTTGGGAATCTCATTGCTTTGTCATTGGGATTG ACCCCTAATTTTARATCARATTTTGATTTGGCAGAAGATGCTAAATTACAGCTTTCAAAAGA TACTTACGATGATGATTTAGATAATTTATTGGCGCAAATTGGAGATCAATATGCTGATTTGT TTTTGGCAGCTAAGAATTTATCAGATGCTATTTTACTTTCAGATATCCTAAGAGTARATAGT GAAATAACTAAGGCTCCCCTATCAGCTTCAATGATTAAGCGCTACGATGAACATCATCAAGA CTTGACTCTTTTARAAGCTTTAGTTCGACAACAACTTCCAGAAAAGTATAAAGAAATCTTTT TTGATCAATCAAARAACGGATATGCAGGTTATATTGATGGGGGAGCTAGCCAAGAAGAATTT TATAAATTTATCAAACCAATTTTAGAAARAAATGGATGGTACTGAGGAATTATTGGTGAAACT AAATCGTGAAGATTTGCTGCGCAAGCAACGGACCTTTGACAACGGCTCTATTCCCCATCAAA TTCACTTGGGTGAGCTGCATGCTATTTTGAGAAGACAAGAAGACTTTTATCCATTTTTARAA GACAATCGTGAGAAGATTGAAAAAATCTTGACTTTTCGAATTCCTTATTATGTTGGTCCATT GEC GOGTIGCCAR TACTIC TT ITC CATGGATGA CC TCG ARC TCTCABRCARACAATTIACCCCAT GGAATTTTGAAGAAGTTGTCGATAAAGGTGCTTCAGCTCAATCATTTATTGAACGCATGACA AACTTTGATAAARATCTTCCAAATGARAARAGTACTACCAAARACATAGTTTGCTTTATGAGTA TTTTACGGTTTATAACGAATTGACARAGGTCAAATATGTTACTGAGGGAATGCGARAACCAG CATTTCTTTCAGGTGAACAGARGAAAGCCATTGTTGATTTACTCTTCAAAACAAATCGAARA GTAACCGTTAAGCAATTAAAAGAAGATTATTTCAAAAARATAGAATGTTTTGATAGTGTTGA AATTTCAGGAGTTGAAGATAGATTTAATGCTTCATTAGGCGCCTACCATGATTTGCTAARAA TTATTAAAGATAAAGATTTTTTGGATAATGAAGAAAATGAAGATATCTTAGAGGATATTGTT TTAACATTGACCTTATTTGAAGATAGGGGGATGATTGAGGAAAGACTTARAACATATGCTCA CCTCTTTGATGATAAGGTGATGARACAGCTTAAACGTCGCCGTTATACTGGTTGGGGACGTT TGTCTCGARAATTGATTAATGGTATTAGGGATAAGCAATCTGGCAAAACAATATTAGATTTT TTGAAATCAGATGGTTTTGCCAATCGCAATTTTATGCAGCTGATCCATGATGATAGTTTGAC ATTTAAAGAAGATATTCAAAAAGCACAGGTGTCTGGACAAGGCCATAGTTTACATGAACAGA TTGCTAACTTAGCTGGCAGTCCTGCTATTARAAAAGGTATTTTACAGACTGTAAARATTGTT GATGAACTGGTCAAAGTAATGGGGCATAAGCCAGAAAATATCGTTATTGAAATGGCACGTGA AAATCAGACAACTCAAAAGGGCCAGAARRATTCGCGAGAGCGTATGAAACGAATCGAAGAAG GTATCARAGAATTAGGAAGTCAGATTCTTAAAGAGCATCCTGTTGAARATACTCAATTGCAA AATGAAAAGCTCTATCTCTATTATCTACAAAATGGAAGAGACATGTATGTGGACCAAGAATT AGATATTAATCGTTTAAGTGATTATGATGTCGATCACATTGTTCCACARAGTTTCATTAAAG ACGATTCAATAGACAATAAGGTACTAACGCGTTCTGATARAAATCGTGGTAAATCGGATAAC GTTCCAAGTGAAGAAGTAGTCAAAAAGATGARARACTATTGGAGACAACTTCTAAACGCCAA GTTAATCACTCAACGTAAGTTTGATAATTTAACGAAAGCTGAACGTGGAGGTTTGAGTGAAC TTGATAAAGCTGGTTTTATCAAACGCCAATTGGTTGAAACTCGCCAARATCACTAAGCATGTG GCACAAATTTTGGATAGTCGCATGAATACTARATACGATGAARATGATAAACTTATTCGAGA GGTTAAAGTGATTACCTTAAAATCTARATTAGTTTCTGACTTCCGAAAAGATTTCCAATTCT ATAAAGTACGTGAGATTAACAATTACCATCATGCCCATGATGCGTATCTARATGCCGTCGTT GGAACTGCTTTGATTARGAAATATCCAARACTTGAATCGGAGTTTGTCTATGGTGATTATAA AGTTTATGATGTTCGTAAAATGATTGCTAAGTCTGAGCAAGARATAGGCAAAGCAACCGCAA AATATTTCTTTTACTCTAATATCATGAACTTCTTCAAAACAGAAATTACACTTGCAAATGGA GAGATTCGCAAACGCCCTCTAATCGARACTAATGGGGAAACTGGAGARATTGTCTGGGATAA AGGGCGAGATTTTGCCACAGTGCGCARAGTATTGTCCATGCCCCAAGTCAATATTGTCAAGA AARACAGAAGTACAGACAGGCGGATTCTCCAAGGAGTCAATTTTACCAAAAAGARATTCGGAC AAGCTTATTGCTCGTAARARAGACTGGGATCCAAAAAAATATGGTGGTTTTGATAGTCCAAC GGTAGCTTATTCAGTCCTAGTGGTTGCTAAGGTGGAAAAAGGGAAATCGAAGAAGTTAAAAT CCGTTAAAGAGTTACTAGGGATCACAATTATGGARAAGAAGTTCCTTTGAAAAAAATCCGATT GACTTTTTAGAAGCTAAAGGATATAAGGAAGTTAAAAAAGACTTAATCATTAAACTACCTAA ATATAGTCTTTTTGAGTTAGAARACGGTCGTAAACGGATGCTGGCTAGTGCCGGAGAATTAC AAAAAGGAAATGAGCTGGCTCTGCCAAGCAAATATGTGAATTTTTTATATTTAGCTAGTCAT TATGAAAAGTTGARGGGTAGTCCAGAAGATAACGAACAARAACAATTGTTTGTGGAGCAGCA TAAGCATTATTTAGATGAGATTATTGAGCARATCAGTGAATTTTCTAAGCGTGTTATTTTAG CAGATGCCAATTTAGATAARAGTTCTTAGTGCATATAACAAACATAGAGACAAACCAATACGT GAACAAGCAGAAAATATTATTCATTTATTTACGTTGACGAATCTTGGAGCTCCCGCTGCTTT TAAATATTTTGATACAACAATTGATCGTAAACGATATACGTCTACAAAAGAAGTTTTAGATG CCACTCTTATCCATCAATCCATCACTGGTCTTTATGAAACACGCATTGATTTGAGTCAGCTA GCGAGGCTGAC TGA: MDKKYSIGLDIGTNSVGWAVITDDYKVPSKKFKVLGNTDRHS IKKNLIGALLFGSGETAEAT RLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVD EVAYHEKYPTIYHLRKKLADSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLEL QLVQIYNQLFEENPINASRVDAKAILSARLSKSRRLENLIAQLPGEKRNGLFGNLIALSLGL TPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNS EITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDOSKNGYAGYIDGGASQEEF YKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLK DNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMT NFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRK VIVKQLKEDYFKKIECFDSVEISGVEDRFNASLGAYHDLLKI IKDKDFLDNEENEDILEDIV LTLTLFEDRGMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDF LKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGHSLHEQIANLAGSPATIKKGILQTVKIV DELVKVMGHKPENTVIEMARENQTTQKGOKNSRERMKRIEEGIKELGSQILKEHPVENTQLO NEKLYLYYLONGRDMYVDQELDINRLSDYDVDHIVPQSFIKDDS I DNKVLTRSDKNRGKSDN VPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVETRQI TKHV AQILDSRMNTKYDENDKLIREVKVITLKSKILVSDFRKDFQFYKVRE INNYHHAHDAYLNAVV GTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQRIGKATAKYFFYSNIMNFFKTEITLANG EIRKRPLIETNGETGEIVWDKGRDFATVRKVLSMPOVNIVKKTEVQTGGFSKES ILPKRNSD KLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPI DFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASH ...

Claims

CLAIMS ‘What is claimed is: L A method of treating a neurological disorder in a subject in need thereof, the method comprising: administering to the subject (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase modification at a splice site of a target gene associated with the neurological disorder in the subject, thereby treating the neurological disorder in the subject. 2 The method of claim 1, wherein the adenosine deaminase comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding substitution thereof.

3. The method of claim 1 or 2, wherein the single nucleobase modification results in alternative splicing of a transcript encoded by the target gene. 4, The method of any one of claims 1-3, wherein the alternative splicing generates a truncated or nonfunctional protein encoded by the target gene.

5. The method of any one of claims 1-4, wherein the single nucleobase modification results in reduced expression of the target gene in the subject.

6. The method of any one of claims 1-5, wherein the target gene is a superoxide dismutase 1 (SOD) gene and wherein the neurological disease is Amyotrophic Lateral Sclerosis (ALS). 7 A method of treating Amyotrophic Lateral Sclerosis (ALS) in a subject in need thereof, the method comprising; administering to the subject (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the base editor comprises a programmable DNA binding domain and a deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase modification at a splice site of a superoxide dismutase 1 (SODI) gene in the subject, thereby treating ALS in the subject.

8. A method of treating Amyotrophic Lateral Sclerosis (ALS) in a subject in need thereof, the method comprising: administering to the subject (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the base editor comprises a programmable DNA binding domain and a deaminase domain, wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase modification in a superoxide dismutase 1 (SOD) gene in the subject and wherein the single nucleobase modification results in a premature stop codon in the SOD gene, thereby treating ALS in the subject.

9. The method of claim 7 or 8, wherein the deaminase is an adenosine deaminase comprising an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding substitution thereof.

10. The method of any one of claims 7-9, wherein the single nucleobase modification is an A-to-G modification.

11. The method of any one of claims 7-10, wherein the single nucleobase modification is at a splice acceptor site of the SOD gene.

12. The method of any one of claims 7-11, wherein the splice site is a splice acceptor site 5’ of an exon of the SOD gene.

13. The method of any one of claims 7-12, wherein the exon of the SOD! gene is exon 3 corresponding to SEQ ID NO: 3, or a variant thereof.

14. The method of any one of claims 7-13, wherein the exon 3 of the SOD! gene is adjacent to the splice acceptor AG at nucleotide position 6828 of the SOD polynucleotide sequence as numbered in SEQ ID NO: 3, or a variant thereof.

15. The method of any one of claims 7-12, wherein the exon of the SOD! gene is exon 4 corresponding to SEQ ID NO: 3, or a variant thereof.

16. The method of any one of claims 7-15, wherein the single nucleobase modification generates a transcription product lacking exons 3-5 of the human SOD! gene corresponding to SEQ ID NO: 3, or a variant thereof.

17. The method of any one of claims 7-16, wherein expression of the SODI gene is reduced by at least 40% in the subject after the administration.

18. The method of any one of claims 7-17, wherein guide polynucleotide comprises a nucleic acid sequence complementary to a splice acceptor nucleic acid sequence or a splice donor nucleic acid sequence of the SOD gene.

19. The method of any one of claims 7-18, wherein the guide polynucleotide comprises any one of the nucleic acid sequences selected from Table 19 or Table 23.

20. The method of any one of claims 7-19, wherein the guide polynucleotide comprises a nucleic acid sequence selected from the group consisting of 5'- UUAAAGGAAAGUAAUGGACCAGU-3', 5'- UAAAUAGGCUGUACCAGUGCAGG-3', 5'- UUCAUUAUUAGGCAUGUUGGAGA-3', 5'- AAAUAGGCUGUACCAGUGCAGGU-3’, 5'- VUAUUAGGCAUGUUGGAGACUUGG-3".

21. The method of any one of claims 1-5, wherein the target gene is an androgen receptor (AR) gene and wherein the neurological disease is spinal and bulbar muscular atrophy (SBMA).

22. A method of treating spinal and bulbar muscular atrophy (SBMA) in a subject, the method comprising: administering to the subject (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the base editor comprises a programmable DNA binding domain and a deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase modification at a splice site of an androgen receptor (4R) gene in the subject, thereby treating SBMA in the subject.

23. A method of treating spinal and bulbar muscular atrophy (SBMA) in a subject, the method comprising: administering to the subject (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and a deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase modification in an androgen receptor (4R) gene in the subject and wherein the single nucleobase modification results in a premature stop codon in the AR gene, thereby treating SBMA in the subject.

24. The method of claim 22 or 23, wherein the nucleobase modification results in a CAG- TAG codon change in the AR gene.

25. The method of any one of claims 22-24, wherein the codon change is in exon 1 or exon 2 in the AR gene.

26. The method of any one of claims 22-25, wherein the deaminase is an adenosine deaminase comprising an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO:

2.

27. The method of any one of claims 22-26, wherein the single nucleobase modification is an A-to-G modification.

28. The method of any one of claims 22-27, wherein the A-to-G nucleobase modification is at a splice acceptor site of the AR gene.

29. The method of any one of claims 22-28, wherein the splice site is a splice acceptor site 5’ of an exon of the AR gene.

30. The method of any one of claims 22-29, wherein the exon of the AR gene is exon 2 corresponding to SEQ ID NO: 4, or a variant thereof.

31. The method of any one of claims 22-28, wherein the splice site is a splice donor site 3’ of an exon of the AR gene.

32. The method of any one of claims 22-28 and 31, wherein the exon of the AR gene is exon 1 corresponding to SEQ ID NO: 4, or a variant thereof.

33. The method of any one of claims 22-32, wherein the expression of the AR gene is reduced by at least 40% in the subject after the administration. 34, The method of any one of claims 22-33, wherein guide polynucleotide comprises a nucleic acid sequence complementary to a splice acceptor nucleic acid sequence or a splice donor nucleic acid sequence of the AR gene.

35. The method of any one of claims 22-34, wherein the guide polynucleotide comprises a nucleic acid sequence selected from Table 41A or 41B.

36. The method of any one of claims 22-35, wherein the guide polynucleotide comprises a nucleic acid sequence selected from the group consisting of 5'- ACUUACCGCAUGUCCCCGUAAGG-3', 5'- AGUGCAGUUAGGGCUGGGAAGGG-3', 5'- AAGUGCAGUUAGGGCUGGGAAGG-3".

37. The method of any one of claims 1-36, wherein the subject is a mammal or a human.

38. The method of any one of claims 1-37, wherein the administering is performed through delivery to a cell of the central nervous system (CNS) of the subject.

39. The method of any one of claims 1-38, wherein the cell is a motor neuron.

40. A method of modifying a target gene or a regulatory element thereof associated with a neurological disorder, the method comprising: contacting the target gene or regulatory element thereof with (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase alteration at a splice site of the target gene.

41. The method of claim 40, wherein the adenosine deaminase comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO:

2.

42. The method of claim 40 or 41, wherein the single nucleobase alteration results in alternative splicing of a transcript encoded by the target gene, a truncated and / or nonfunctional protein encoded by the target gene, and / or reduced expression of the target gene when expressed in a cell.

43. The method of any one of claims 40-42, wherein the target gene is a superoxide dismutase 1 (SOD) gene and wherein the neurological disease is Amyotrophic Lateral Sclerosis (ALS). 44, A method of modulating expression of a superoxide dismutase (SOD / ) gene, the method comprising: contacting a SOD! gene or a regulatory element thereof with (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the base editor comprises a programmable DNA binding domain and a deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase alteration at a splice site of a superoxide dismutase 1 (SODI) gene.

45. A method of modifying a superoxide dismutase (SOD!) gene, the method comprising: contacting the SOD gene or a regulatory element thereof with (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase alteration in a superoxide dismutase 1 (SOD) gene in the subject and wherein the single nucleobase alteration results in a premature stop codon in the SOD! gene.

46. The method of claim 44 or 45, wherein the single nucleobase alteration is an A-to-G alteration.

47. The method of any one of claims 44-46, wherein the nucleobase alteration is at a splice acceptor site of the SOD gene.

48. The method of any one of claims 44-47, wherein the splice site is a splice acceptor site 5’ of an exon of the SOD gene.

49. The method of any one of claims 44-48, wherein the exon of the SOD! gene is exon 3 corresponding to SEQ ID NO: 3, or a variant thereof.

50. The method of any one of claims 44-49, wherein the exon 3 of the SODI gene is adjacent to the splice acceptor at nucleotide position 6828 of the SOD! polynucleotide sequence as numbered in SEQ ID NO: 3, or a variant thereof.

51. The method of any one of claims 44-48, wherein the exon of the SOD gene is exon 4 corresponding to SEQ ID NO: 3, or a variant thereof.

52. The method of any one of claims 44-51, wherein the single nucleobase alteration generates a transcription product lacking exons 3-5 of the SOD! gene corresponding to SEQ ID NO: 3, or a variant thereof.

53. The method of any one of claims 44-52, wherein guide polynucleotide comprises a nucleic acid sequence complementary to a splice acceptor nucleic acid sequence or a splice donor nucleic acid sequence of the SOD gene.

54. The method of any one of claims 44-53, wherein the guide polynucleotide comprises a nucleic acid sequence selected from Table 19 or Table 23.

55. The method of any one of claims 44-54, wherein the guide polynucleotide comprises a nucleic acid sequence selected form the group consisting of 5'- UUAAAGGAAAGUAAUGGACCAGU-3', 5'- UAAAUAGGCUGUACCAGUGCAGG-3', 5'- UUCAUUAUUAGGCAUGUUGGAGA-3', 5'- AAAUAGGCUGUACCAGUGCAGGU-3 / , 5'- UAUUAGGCAUGUUGGAGACUUGG-3".

56. The method of any one of claims 40-42, wherein the target gene is a androgen receptor (AR) gene and wherein the neurological disease is spinal and bulbar muscular atrophy (SBMA).

57. A method of modulating expression of an androgen receptor (AR) gene, the method comprising: contacting the AR gene or a regulatory element thereof with (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the base editor comprises a programmable DNA binding domain and a deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase alteration at a splice site of a androgen receptor (AR) gene.

58. A method of modifying an androgen receptor (AR) gene, the method comprising: contacting the AR gene or a regulatory element thereof with (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the base editor comprises a programmable DNA binding domain and a deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase alteration in a androgen receptor (AR) gene in the subject and wherein the single nucleobase alteration results in a premature stop codon in the AR gene.

59. The method of claim 57 or 58, wherein the deaminase is an adenosine deaminase comprising an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO:

2.

60. The method of any one of claims 57-59, wherein the deaminase is a cytidine deaminase.

61. The method of any one of claims 57-60, wherein the single nucleobase alteration is a C-to-T alteration.

62. The method of any one of claims 57-61, wherein the nucleobase alteration results in a CAG-TAG codon change in the AR gene.

63. The method of any one of claims 57-62, wherein the codon change is in exon 1 or exon 2 in the AR gene.

64. The method of any one of claims 57-63, wherein the single nucleobase alteration is an A-to-G alteration.

65. The method of any one of claims 57-64, wherein the A-to-G nucleobase alteration is at a splice acceptor site of the AR gene.

66. The method of any one of claims 57-65, wherein the splice site is a splice acceptor site 5’ of an exon of the AR gene.

67. The method of any one of claims 57-66, wherein the exon of the AR gene is exon 2 corresponding to SEQ ID NO: 4, or a variant thereof.

68. The method of any one of claims 57-65, wherein the splice site is a splice donor site 3” of an exon of the AR gene.

69. The method of any one of claims 57-65 and 68, wherein the exon of the AR gene is exon 1 corresponding to SEQ ID NO: 4, or a variant thereof.

70. The method of any one of claims 57-69, wherein the guide polynucleotide comprises a nucleic acid sequence selected from Table 41A or 41B.

71. The method of any one of claims 57-70, wherein guide polynucleotide comprises a nucleic acid sequence complementary to a splice acceptor nucleic acid sequence or a splice donor nucleic acid sequence of the AR gene.

72. The method of any one of claims 57-71, wherein the guide polynucleotide comprises a nucleic acid sequence selected from Table 41A or 41B.

73. The method of any one of claims 57-72, wherein the guide polynucleotide comprises a nucleic acid sequence selected from the group consisting of 5'- ACUUACCGCAUGUCCCCGUAAGG-3', 5'- AGUGCAGUUAGGGCUGGGAAGGG-3', 5'- AAGUGCAGUUAGGGCUGGGAAGG-3' and a complement thereof.

74. The method of any one of claims 57-73, wherein the contacting is in a cell.

78. The method of any one of claims 57-74, wherein the single nucleobase modification results in less than 15% indels in a genome of the cell.

76. The method of any one of claims 57-75, wherein the single nucleobase modification results in less than 5% indels in a genome of the cell. ir The method of any one of claims 57-76, wherein the single nucleobase modification results in less than 2% indels in a genome of the cell.

78. The method of any one of claims 57-77, wherein the cell is a mammalian cell or a human cell.

79. The method of any one of claims 57-78, wherein the cell is a central nervous system cell.

80. The method of any one of claims 57-79, wherein the cell is a motor neuron.

81. The method of any one of claims 57-80, wherein the contacting is in a population of cells.

82. The method of any one of claims 57-81, wherein at least 40% of the population of cells comprise the single nucleobase modification after the contacting.

83. The method of any one of claims 57-82, wherein at least 50% of the population of cells comprise the single nucleobase modification after the contacting.

84. The method of any one of claims 57-83, wherein at least 60% of the population of cells comprise the single nucleobase modification after the contacting.

85. The method of any one of claims 57-84, wherein at least 85% of the population of cells are viable after the contacting.

86. The method of any one of claims 57-85, wherein the population of cells are mammalian cells or human cells.

87. The method of any one of claims 57-86, wherein the population of cells are central nervous system cells.

88. The method of any one of claims 57-87, wherein the population of cells are motor neurons.

89. The method of any one of claims 1-88, wherein the adenosine deaminase comprises a TadA deaminase.

90. The method of claim 89, wherein the adenosine deaminase is TadA7.

10.

91. The method of claim 89 or 90, wherein the adenosine deaminase is a TadA comprising comprises a V28S mutation or a T166R mutation as numbered in SEQ ID NO: 2 or a corresponding mutation thereof, 92. The method of any one of claims 89-91, wherein the adenosine deaminase comprises one or more of the following mutations: Y147T, Y147R, Q154S, Y123H, and Q154R as numbered in SEQ ID NO: 2 or a corresponding mutation thereof.

93. The method of any one of claims 89-92, wherein the adenosine deaminase comprises a combination of mutations selected from the group consisting of: Y147T + Q154R; Y147T + Q154S; Y147R + Q154S; V82S + Q154S; V82S + Y147R; V82S + Q154R; V82S + Y123H; I76Y + V82S; V82S + Y123H + Y147T; V82S + Y123H + Y147R; V82S + Y123H + Q154R; Y147R + Q154R +Y123H; Y147R + Q154R + I76Y; Y147R + Q154R + T166R; Y123H + Y147R + Q154R + 176Y; V82S + Y123H + Y147R + Q154R; and I76Y + V82S + Y123H + Y147R + Q154R as numbered in SEQ ID NO: 2 or corresponding mutations thereof.

94. The method of any one of claims 89-93, wherein the adenosine deaminase comprises a deletion of the C terminus beginning at a residue selected from the group consisting of 149, 150, 151, 152, 153, 154, 155, 156, and 157.

95. The method of any one of claims 89-94, wherein the adenosine deaminase comprises a TadA dimer.

96. The method of any one of claims 89-95, wherein the adenosine deaminase comprises an adenosine deaminase monomer.

97. The method of any one of claims 1-96, wherein the polynucleotide programmable DNA binding domain is a Cas9 domain.

98. The method of claim 97, wherein the Cas9 domain is a Cas9 nickase domain.

99. The method of claim 97 or 98, wherein the Cas domain comprises a SpCas9 domain.

100. The method of any one of claims 97-99, wherein the SpCas9 domain comprises a DI10A and / or a H840A amino acid substitution as numbered in SEQ ID NO: 1 or corresponding amino acid substitutions thereof, 101. The method of any one of claims 97-100, wherein the Cas9 domain comprises a SaCas9 domain.

102. The method of any one of claims 97-101, wherein the Cas9 domain has specificity for an altered PAM.

103. The method of any one of claims 97-102, wherein the Cas9 domain has specificity for a PAM sequence selected from the group consisting of NGG, NGA, NGCG, NGN, NNGRRT, NNNRRT, NGCG, NGCN, NGTN, and NGC, wherein Nis A, G, C,or T and wherein Ris Aor G.

104. A population of cells produced by any one of claims 1-103.

105. A base editor system that comprises (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the base editor comprises a programmable DNA binding domain and a deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase modification at a splice site of a superoxide dismutase 1 (SODJ).

106. A base editor system that comprises (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the base editor comprises a programmable DNA binding domain and a deaminase domain, wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase modification in a superoxide dismutase 1 (SOD) gene and wherein the single nucleobase modification results in a premature stop codon in the SOD! gene.

107. The base editor system of claim 105 or 106, wherein the deaminase is an adenosine deaminase comprising an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO:

2.

108. The base editor system of any one of claims 105-107, wherein the deaminase is a cytidine deaminase.

109. The base editor system of any one of claims 105-108, wherein the single nucleobase modification is an A-to-G modification.

110. The base editor system of any one of claims 105-109, wherein the A-to-G nucleobase modification is at a splice acceptor site of the SOD gene.

111. The base editor system of any one of claims 105-110, wherein the splice site is a splice acceptor site 5’ of an exon of the SODI gene.

112. The base editor system of any one of claims 105-111, wherein the exon of the SOD1 gene is exon 3 corresponding to SEQ ID NO: 3, or a variant thereof.

113. The base editor system of any one of claims 105-112, wherein the exon 3 of the SOD / gene is adjacent to the splice acceptor AG at nucleotide position 6828 of the SOD / polynucleotide sequence as numbered in SEQ ID NO: 3, or a variant thereof.

114. The base editor system of any one of claims 105-113, wherein the alternative splicing of the SOD] transcript generates a transcription product lacking exons 3-5 of the SOD1 gene corresponding to SEQ ID NO: 3, or a variant thereof.

115. The base editor system of any one of claims 105-111, wherein the exon of the SOD1 gene is exon 4 corresponding to SEQ ID NO: 3, or a variant thereof.

116. The base editor system of any one of claims 105-115, wherein guide polynucleotide comprises a nucleic acid sequence complementary to a splice acceptor nucleic acid sequence or a splice donor nucleic acid sequence of the SOD gene.

117. The base editor system of any one of claims 105-116, wherein the guide polynucleotide comprises a nucleic acid sequence selected from Table 19 or Table 23.

118. The base editor system of any one of claims 105-117, wherein the guide polynucleotide comprises a nucleic acid sequence selected form the group consisting of 5'-UUAAAGGAAAGUAAUGGACCAGU-3 / , 5'- UAAAUAGGCUGUACCAGUGCAGG-3', 5'- UUCAUUAUUAGGCAUGUUGGAGA-3', 5'- AAAUAGGCUGUACCAGUGCAGGU-3’, 5'- UAUUAGGCAUGUUGGAGACUUGG-3', and a complementary sequence thereof.

119. A base editor system that comprises (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the base editor comprises a programmable DNA binding domain and a deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase modification at a splice site of a androgen receptor (AR) gene.

120. A base editor system that comprises (i) a base editor or a nucleic acid sequence encoding the base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and a deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect a single nucleobase modification in a androgen receptor (AR) gene in the subject and wherein the single nucleobase modification results in a premature stop codon in the AR gene.

121. The base editor system of claim 119 or 120, wherein the deaminase is an adenosine deaminase comprising an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO:

2.

122. The base editor system of any one of claims 119-121, wherein the deaminase is a cytidine deaminase.

123. The base editor system of any one of claims 119-122, wherein the single nucleobase modification is a C-to-T modification.

124. The base editor system of any one of claims 119-123, wherein the single nucleobase modification results in a CAG-TAG codon change in the AR gene.

125. The base editor system of any one of claims 119-124, wherein the codon change is in exon 1 or exon 2 in the AR gene corresponding to SEQ ID NO: 4, or a variant thereof.

126. The base editor system of any one of claims 119-125, wherein the single nucleobase modification is an A-to-G modification.

127. The base editor system of any one of claims 119-126, wherein the A-to-G nucleobase modification is at a splice acceptor site of the AR gene.

128. The base editor system of any one of claims 119-127, wherein the splice site is a splice acceptor site 5' of an exon of the AR gene.

129. The base editor system of any one of claims 119-128, wherein the exon of the AR gene is exon 2 corresponding to SEQ ID NO: 4, or a variant thereof.

130. The base editor system of any one of claims 119-127, wherein the splice site is a splice donor site 3° of an exon of the AR gene.

131. The base editor system of any one of claims 119-127 and 130, wherein the exon of the AR gene is exon 1 corresponding to SEQ ID NO: 4, or a variant thereof.

132. The base editor system of any one of claims 119-131, wherein guide polynucleotide comprises a nucleic acid sequence complementary to a splice acceptor nucleic acid sequence or a splice donor nucleic acid sequence of the AR gene.

133. The base editor system of any one of claims 119-132, wherein the guide polynucleotide comprises a nucleic acid sequence selected from Table 41A or 41B.

134. The base editor system of any one of claims 119-133, wherein the guide polynucleotide comprises a nucleic acid sequence selected from the group consisting of 5-ACUUACCGCAUGUCCCCGUAAGG-3, 5'- AGUGCAGUUAGGGCUGGGAAGGG-3', 5'- AAGUGCAGUUAGGGCUGGGAAGG-3' and a complement thereof.

135. The base editor system of any one of claims 105-134, wherein the adenosine deaminase comprises a TadA deaminase.

136. The base editor system of claim 135, wherein the adenosine deaminase is TadA7.

10.

137. The base editor system of claim 135 or 136, wherein the adenosine deaminase is a TadA comprising comprises a V28S mutation or a T166R mutation as numbered in SEQ ID NO: 2 or a corresponding mutation thereof.

138. The base editor system of any one of claims 135-137, wherein the adenosine deaminase comprises one or more of the following mutations: Y147T, Y147R, Q154S, Y123H, and Q154R as numbered in SEQ ID NO: 2 or a corresponding mutation thereof.

139. The base editor system of any one of claims 135-138, wherein the adenosine deaminase comprises a combination of mutations selected from the group consisting of: Y147T + Q154R; Y147T + Q154S; Y147R + Q154S; V82S + Q154S; V82S + Y147R; V82S + Q154R; V82S + Y123H; I76Y + V82S; V82S + Y123H + Y147T; V82S + Y123H + Y147R; V82S + Y123H + Q154R; Y147R + Q154R +Y123H; Y147R + Q154R + 176Y; Y147R + Q154R + T166R; Y123H + Y147R + Q154R + 176Y; V82S + Y123H + Y147R + Q154R; and I176Y + V82S + Y123H + Y147R + Q154R as numbered in SEQ ID NO: 2 or corresponding mutations thereof.

140. The base editor system of any one of claims 135-139, wherein the adenosine deaminase comprises a deletion of the C terminus beginning at a residue selected from the group consisting of 149, 150, 151, 152, 153, 154, 155, 156, and 157.

141. The base editor system of any one of claims 135-140, wherein the adenosine deaminase comprises a TadA dimer.

142. The base editor system of any one of claims 135-141, wherein the adenosine deaminase comprises an adenosine deaminase monomer, 143. The base editor system of any one of claims 105-142, wherein the polynucleotide programmable DNA binding domain is a Cas domain.

144. The base editor system of claim 143, wherein the Cas9 domain is a Cas9 nickase domain.

145. The base editor system of claim 143 or 144, wherein the Cas9 domain comprises a SpCas9 domain.

146. The base editor system of any one of claims 143-145, wherein the SpCas9 domain comprises a D10A and / or a H840A amino acid substitution as numbered in SEQ ID NO: lor corresponding amino acid substitutions thereof, 147. The base editor system of any one of claims 143-146, wherein the Cas9 domain comprises a SaCas9 domain.

148. The base editor system of any one of claims 105-147, wherein the Cas9 domain has specificity for an altered PAM.

149. The base editor system of any one of claims 143-148, wherein the Cas domain has specificity for a PAM sequence selected from the group consisting of NGG, NGA, NGCG, NGN, NNGRRT, NNNRRT, NGCG, NGCN, NGTN, and NGC, wherein N is A, G, C, or T and wherein R is A or G.

150. A vector comprising the nucleic acid sequence encoding the polynucleotide programmable DNA binding domain and the nucleic acid sequence encoding the adenosine deaminase domain in the base editor system of any one of claims 105-149.

151. The vector of claim 150, further comprising the nucleic acid sequence encoding the guide polynucleotide.

152. The vector of claim 150 or 151, wherein the vector is a viral vector.

153. A cell comprising the base editor system of any one of claims 105-149 or the vector of any one of claims 150-152.

154. The cell of claim 153, wherein the cell is a mammalian cell, a human cell, or a motor neuron.

155. The cell of claim 153 or 154, wherein the cell is in vivo, ex vivo, or in vitro.

156. The cell of any one of claims 153-155, wherein the cell is an autologous cell isolated from a subject.

157. The cell of any one of claims 153-156, wherein the cell is an allogeneic cell.

158. A population of cells comprising the base editor system of any one of claims 105-149 or the vector of any one of claims 150-152.

159. The population of cells of claim 158, wherein the population of cells is mammalian cells, human cells, or motor neurons.

160. The population of cells of claim 158 or 159, wherein the population of cells is in vivo, ex vivo, or in vitro.

161. The population of cells of any one of claims 158-160, wherein the cell is an autologous cell isolated from a subject.

162. A pharmaceutical composition comprising the base editor system of any one of claims 105-149, the vector of any one of claims 150-152, or the cells of any one of claims 153-157, the population of cells of any one of claims 158-161, and a pharmaceutically acceptable carrier.

163. The pharmaceutical composition of claim 162, further comprising a lipid.

164. The pharmaceutical composition of claim 162, further comprising a virus.

165. A kit comprising the base editor system of any one of claims 105-149, or the vector of any one of claims 150-152, 166. The method of any one of the preceding claims wherein at least one nucleotide of the guide polynucleotide comprises a non-naturally occurring modification.

167. The method of any one of claims 20, 36, 55, or 73 wherein at least one nucleotide of the nucleic acid sequence comprises a non-naturally occurring modification.

168. The base editor system of any one of claims 118, or 134 wherein at least one nucleotide of the nucleic acid sequence comprises a non-naturally occurring modification.

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