Altered cytidine deaminases and methods of use

Abstract

The present disclosure is concerned with altered cytidine deaminases, methods, compositions, and kits for mapping of methylation status of nucleic acids. In one embodiment, altered cytidine deaminases are provided that selectively act on certain modified cytosines of target nucleic acids and converts them to thymidine. Also provided are compositions and kits that include one or more of the proteins and methods for using one or more of the proteins.

Description

ALTERED CYTIDINE DEAMINASES AND METHODS OF USECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 665,656, filed June 28, 2024, which is incorporated by reference herein in its entirety.SEQUENCE LISTING

[0002] This application contains a Sequence Listing electronically submitted to the United States Patent and Trademark Office as an XML file entitled "IP-2811-PCT.xml" having a size of 960,863 bytes and created on June 27, 2025. The information contained in the Sequence Listing is incorporated by reference herein.FIELD

[0003] Embodiments of the present disclosure relate to identifying the methylation status of nucleotides. In particular, embodiments of the proteins, methods, compositions, and kits provided herein relate to mapping of methylation status of nucleotides in a genome. BACKGROUND

[0004] Modified DNA cytosines, including 5-methylcytosine (5mC) and 5 -hydroxymethyl cytosine (5hmC), are a well-studied epigenetic modification that play fundamental roles in human development and disease. Its genome-wide distribution differs between tissue types, and between healthy and diseased states. In recent years, 5mC has also gained prominence as a tool for clinical diagnostics: its distribution in cell-free DNA (cfDNA) - obtained from a liquid biopsy - can be used for the tissue-specific prediction of early-stage cancer or monitoring of cancer recurrence or remission after treatment. As a result, there has been an intense focus on developing methods for mapping modified DNA cytosines at single base resolution, with minimal loss of sample DNA quantity, quality, and complexity. Current methods for mapping modified DNA cytosines, however, exhibit limitations including (i) degradation of sample DNA due to prolonged chemical treatment at non-neutral pH and high temperatures, (ii) loss of sample DNA complexity due to conversion of unmethylated DNA bases to uracil, resulting in low complexity genome mapping, (iii) multi-step conversion, requiring both enzymes and chemical treatment, and (iv) for antibody-based 5mC detection, resolution of detection is limited to ~150bp, precluding the identification of its exact location in the genome.SUMMARY OF THE APPLICATION

[0005] The present disclosure provides altered cytidine deaminases (ACDs) that include 5mC- selective deaminase activity. An ACD includes at least one, in some embodiments at least two, selectivity-enhancing alteration at a position functionally equivalent to amino acid 130, 131, 132, 133, 134, 135, or a combination thereof, in a wild-type APOBEC3A (e.g., SEQ ID NO:3). The selectivity-enhancing alteration at amino acid 130, 131, 132, 133, 134, 135, or a combination thereof can be a substitution mutation to any amino acid, and in some embodiments the ACD includes two or more selectivity-enhancing alterations at a position functionally equivalent to amino acid 130, 131, 132, 133, 134, 135, or a combination thereof. The amino acid sequence of amino acids 130, 131, 132, 133, and 134 can be selected from SEQ ID NO:25-34 of FIG. 4B, SEQ ID NO:35-50 of Table 2, or the amino acids at positions 130, 131, 132, 133, and 134 in the sequences found in Figure 8 or 9.

[0006] In some embodiments, an ACD can further include at least one selectivity-enhancing alteration at a position functionally equivalent to amino acid 102, 103, 104, 105, or a combination thereof in a wild-type APOBEC3A (e.g., SEQ ID NO:3). In some embodiments, the amino acid sequence of amino acids 102, 103, 104, 105, 130, 131, 132, 133, 134, and 135 in an ACD is selected from SEQ ID NO: 100-478 of FIG. 8. In some embodiments, the amino acid sequence of amino acids 130, 131, 132, 133, and 134 is selected from SEQ ID NO: 23, SEQ ID NO:24, or the sequences described in FIG. 8 or FIG. 9 which demonstrate increased 5mC selectivity compared to wild-type (SEQ ID NO:3).

[0007] In some embodiments, an ACD can further include one or more stability-enhancing alterations, two or more stability-enhancing alteration, or three or more stability-enhancing alterations. Examples of stability-enhancing alterations include, but are not limited to, substitution mutations at a position functionally equivalent to Hl IX, L12X, D14X, H16X, H7X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, VI 10X, R11 IX, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X,H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, or N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , or AI26-G27, or combinations thereof, wherein the position number designation is functionally equivalent to the position in a wild-type AP0BEC3A (e.g., SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. For instance, an ACD can include two or more stability mutations selected from I17T, T19Y, G25K, S45W, A59P, K60R, A61-68, R74L, G108A, G108C, C171A, G188P, and A104-105; a combination of stability mutations including T19Y, G25K, S45W, R74L, G108A, Cl 71 A, and G188R; or a combination of stability mutations including I17T, T19Y, G25K, S45W, A59P, K60R, A61-68, R74L, G108C, C171A, and G188R. Specific examples of ACDs provided herein include SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:479-517, 520-605, 607-615, 623, 635-907, and 915-921. BRIEF DESCRIPTION OF THE FIGURES

[0008] The following detailed description of illustrative embodiments of the present disclosure may be best understood when read in conjunction with the following drawings.

[0009] FIG. ID -IE shows the result of treating a DNA sample with a wild-type APOBEC3 A enzyme (FIG. ID), and an example of one-step detection of 5mC using an altered cytidine deaminase described herein (FIG. IE). The top strand of FIG. 1D-E shows C and 5mC bases, and the bottom strand of FIG. 1D-E underlines the changed bases. 5mC nucleobases are marked with CHB, 5 -hydroxymethyl uracil nucleobases are designated with small case "u," and uracil nucleobases are designated with capital "U."

[0010] FIG. 2 is a schematic showing alignment of cytidine deaminase amino acid sequences using the Clustal O algorithm. An (asterisk) indicates positions which have a single, fully conserved residue between some cytidine deaminases. A (colon) indicates conservation between groups of strongly similar properties as below - roughly equivalent to scoring > 0.5 in the Gonnet PAM 250 matrix. A (period) indicates conservation between groups of weakly similar properties as below - roughly equivalent to scoring =< 0.5 and > 0 in the Gonnet PAM 250 matrix. The amino acids marked with "A" show the ZDD motif SEQ ID NO:1 (e.g., above amino acids 70 to 106 of sp|P3194111-199). The amino acids marked with "A" and "#" show the ZDD motif SEQ ID NO:2 (e.g., above amino acids 70 to 153 of sp|P3194111-199). sp|P3194111- 199 is a human APOBEC3A, SEQ ID NO:3; XP_045219544.1 is an APOBEC3A from Macaca fascicularis, SEQ ID NO:4; AER45717.1 is an APOBEC3A from Pongo pygmaeus, SEQ IDNO:5; XP_003264816.1 is an AP0BEC3A from Nomascus leucogenys, SEQ ID NO:6; PNI48846.1 is an APOBEC3A from Pan troglodytes, SEQ ID NO:7; and ADO85886.1 is an APOBEC3 A from Gorilla gorilla, SEQ ID NO:8.

[0011] FIG. 3 shows a bar graph representation of APOBEC3A(Y130X) deaminase activity

[0012] FIG. 4A-4B shows information related to the results of a high-throughput screen to test for mC specific mutants. (FIG. 4A) The library diversity on positions Y130 to Pl 34 before screening and after 2 rounds of enrichment tested by NGS. (FIG. 4B) The top 10 enriched mutants in high throughput assay from NGS analysis.

[0013] FIG. 5A-5B shows selectivity plot for (FIG. 5A) randomly picked mutants after 2 round of sorting, and (FIG. 5B) top enriched mutants based on NGS analysis of the library.

[0014] FIG. 6A-6C shows an exemplary selectivity plot for various mutations on positions S 103 / W104 in a ScF (SEQ ID NO:18) background (FIG. 6A); various mutations at positions S103 / W104 combined with certain AxxxW mutants (FIG. 6B); and various mutations at positions F102 / S103 / W104 / G105 combined with certain AxxxW mutations (FIG. 6C) (see, e.g., SEQ ID NO:955-968).

[0015] FIG. 7A-7C shows the activity of different exemplary ACD mutants on methylation reporting on pUC19 (CG methylated) and Lambda (fully unmethylated). The parent backbone SEQ ID NO: 14 is shown in gray.

[0016] FIG. 8A-8M shows examples of sets of selectivity-enhancing alterations, e.g., substitution mutations, deletions, and / or insertions, of amino acids at positions functionally equivalent to amino acids 102, 103, 104, 105, 130, 131, 132, 133, 134, and / or 135 in SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 18, or SEQ ID NO: 19.

[0017] FIG. 9A-9MM shows amino acid sequences of proteins described herein.

[0018] FIG. 10A-10C demonstrates expression and purification of ACD proteins in fusion with helicases. First step of purification with Ni-NTA column (a) was followed by size exclusion column (b). The purity of the proteins was confirmed by SDS gel (c).

[0019] FIG. 11 Testing ACD deamination activity in fusion constructs using Swal assay, (a) Schematic of restriction enzyme (Swal) -based assay for deamination. In this assay, the oligonucleotide is incubated with a deaminase enzyme (such as ACD). If the enzyme is active on the substrate, it will deaminate methylcytosine (mC) to thymine (T), creating a mismatch with the complementary reverse oligonucleotide. If a mismatch occurs, the restriction enzyme Swalwill cleave the double-stranded DNA oligonucleotide. The cleaved products can be then visualized by UREA-PAGE gel electrophoresis, (b) Swal assay results for ACD fusions with helicases.

[0020] FIG. 12A-12B shows a schematic representation of NGS-based assay to assess ACD activity in helicase fusions. FIG. 12A, Substrate ssDNA oligo contains 17 unmethylated cytosines (C) and 16 methylated C sites (mC). FIG. 12B, Deamination by ACD results in conversion of unmethylated C residues to uracil, and conversion of mC to thymine. These deamination events are read out as C~>T mutations via Illumina sequencing.

[0021] FIG. 13A-13B demonstrates the testing helicase activity in fusion constructs using fluorescent oligos. (FIG. 13A) Schematic of the fluorescent assay for helicase activity on dsDNA. The assay uses a 5'-F AM-labeled oligonucleotide, with the reverse complementary strand containing a quencher to suppress fluorescence. In the presence of helicase activity, the helicase unwinds the double-stranded DNA, replacing the quencher-containing strand with a competitor oligo that lacks the quencher. This replacement removes the quenching effect and results in an increase in FAM fluorescence, which can be detected. (FIG. 13B) Helicase activity results for helicases in fusion with ACD.

[0022] FIG. 14A-14B demonstrates that the ACD in fusion with helicases can deaminate dsDNA. (a) ACD protein deamination with either ds or ssDNA. (b) Deamination of double stranded DNA by ACD-helicases fusion proteins in different buffer conditions.

[0023] FIG. 15 demonstrates that ACD in fusion with helicases can deaminate dsDNA in a complex substrate. ACD protein or ACD-helicase fusions were added to mix of lambda DNA (non- methylated control) with fully methylated pUC19 DNA. DNA was either denatured with heating to 70°C in the presence of DMSO or not denatured at all. Only fusion constructs show activity if the denaturation step is skipped.

[0024] FIG. 16A-16C shows testing direct deamination of 5mC on-flow cell at NextSeq 2000 and NovaSeq X. Comparison of sequencing statistic (A) of 5mC conversion of ACD and Helicase-ACD. (B) Deamination with ACD using denaturation with NaOH without a wash on NextSeq 2000 (B) and NovaSeq X (C).

[0025] FIG. 17A-B shows testing direct deamination of 5mC on-flow cell with the Helicase- ACD fusion using (FIG. 17A) NextSeq 2000 and (FIG. 17B) Novaseq X.

[0026] The schematic drawings are not necessarily to scale. Like numbers used in the figures refer to like components, steps and the like. However, it will be understood that the use of a number to refer to a component in a given figure is not intended to limit the component in another figure labeled with the same number. In addition, the use of different numbers to refer to components is not intended to indicate that the different numbered components cannot be the same or similar to other numbered components.DETAILED DESCRIPTION

[0027] Terms used herein will be understood to take on their ordinary meaning in the relevant art unless specified otherwise. Several terms used herein and their meanings are set forth below.

[0028] As used herein, the term "protein" refers broadly to a polymer of two or more amino acids joined together by peptide bonds. The term "protein" also includes molecules which contain more than one protein joined by disulfide bonds, ionic bonds, or hydrophobic interactions, or complexes of proteins that are joined together, covalently or noncovalently, as multimers (e.g., dimers, tetramers). Thus, the terms peptide, oligopeptide, and polypeptide are all included within the definition of protein and these terms are used interchangeably. It should be understood that these terms do not connote a specific length of a polymer of amino acids, nor are they intended to imply or distinguish whether the protein is produced using recombinant techniques, chemical or enzymatic synthesis, or is naturally occurring.

[0029] An “isolated” protein is one that has been removed from a cell. For instance, an isolated protein is a protein that has been removed from the cytoplasm of a cell, and many of the proteins, nucleic acids, and other cellular material of its natural environment are no longer present. Proteins that are produced outside an organism, e.g., through chemical or recombinant means, are considered to be isolated and purified, since they were never present in a natural environment.

[0030] As used herein, the terms "organism," "subject," are used interchangeably and refer to microbes (e.g., prokaryotic or eukaryotic) animals and plants. An example of an animal is a mammal, such as a human.

[0031] As used herein, the term "target nucleic acid," is intended as a semantic identifier for the nucleic acid in the context of a method or composition or kit set forth herein and does not necessarily limit the structure or function of the nucleic acid beyond what is otherwise explicitly indicated. Reference to a nucleic acid such as a target nucleic acid includes both single-strandedand double-stranded nucleic acids, and both DNA and RNA, unless indicated otherwise. The term library refers to the collection of target nucleic acids containing known common sequences, such as a universal sequence or adapter, at their 3' and 5' ends.

[0032] As used herein, the term "adapter" and its derivatives, e.g., universal adapter, refers generally to any linear oligonucleotide. In one embodiment, a target nucleic acid includes DNA. In one embodiment, a target nucleic acid includes single-stranded DNA. In one embodiment, a target nucleic acid includes double-stranded DNA. In one embodiment, a target nucleic acid includes RNA. In one embodiment, a target nucleic acid includes single-stranded RNA. In one embodiment, a target nucleic acid includes double- stranded RNA. which can be attached to a target nucleic acid. An adapter can be single- stranded or double- stranded DNA, or can include both double-stranded and single-stranded regions. An adapter can include a universal sequence that is substantially identical, or substantially complementary, to at least a portion of a primer, for example a universal primer; an index (also referred to herein as a barcode or tag) to assist with downstream error correction, identification, or sequencing; and / or a unique molecular identifier. In some embodiments, the adapter is substantially non-complementary to the 3' end or the 5' end of any target sequence present in the sample. In some embodiments, suitable adapter lengths are in the range of about 6-100 nucleotides, about 12-60 nucleotides, or about 15-50 nucleotides in length. For instance, the terms "adaptor" and "adapter" are used interchangeably.

[0033] As used herein, the term "universal," when used to describe a nucleotide sequence, refers to a region of sequence that is common to two or more nucleic acid molecules where the molecules also have regions of sequence that differ from each other. A universal sequence that is present in different members of a collection of nucleic acids can be used as, for instance, a "landing pad" in a subsequent step to anneal a nucleotide sequence that can be used as a primer for addition of another nucleotide sequence, such as an index, to a target nucleic acid. A universal sequence that is present in different members of a collection of nucleic acids can allow capture of multiple different nucleic acids using a population of universal capture nucleic acids, e.g., capture oligonucleotides that are complementary to a portion of the universal sequence, e.g., a universal capture sequence. Non-limiting examples of universal capture sequences include sequences that are identical to or complementary to P5 and P7 primers. Similarly, a universal sequence present in different members of a collection of molecules can allow the replication (e.g., sequencing) or amplification of multiple different nucleic acids using a population ofuniversal primers that are complementary to a portion of the universal sequence, e g., a universal anchor sequence. In one embodiment universal anchor sequences are used as a site to which a universal primer (e.g., a sequencing primer for read 1 or read 2) anneals for sequencing. A capture oligonucleotide or a universal primer therefore includes a sequence that can hybridize specifically to a universal sequence.

[0034] The terms "P5" and "P7" may be used when referring to a universal capture sequence or a capture oligonucleotide. The terms "P51" (P5 prime) and "P71" (P7 prime) refer to the complement of P5 and P7, respectively. It will be understood that any suitable universal capture sequence or a capture oligonucleotide can be used in the methods presented herein, and that the use of P5 and P7 are exemplary embodiments only. Uses of capture oligonucleotides such as P5 and P7 or their complements onflow cells are known in the art, as exemplified by the disclosures of WO 2007 / 010251, WO 2006 / 064199, WO 2005 / 065814, WO 2015 / 106941, WO 1998 / 044151, and WO 2000 / 018957, which are incorporated by reference as to P5 and P7 and their uses. For example, any suitable forward amplification primer, whether immobilized or in solution, can be useful in the methods presented herein for hybridization to a complementary sequence and amplification of a sequence. Similarly, any suitable reverse amplification primer, whether immobilized or in solution, can be useful in the methods presented herein for hybridization to a complementary sequence and amplification of a sequence. One of skill in the art will understand how to design and use primer sequences that are suitable for capture and / or amplification of nucleic acids as presented herein.

[0035] As used herein, the term "primer" and its derivatives refer generally to any nucleic acid that can hybridize to a target sequence of interest. Typically, the primer functions as a substrate onto which nucleotides can be polymerized by a polymerase or to which a polynucleotide can be ligated; in some embodiments, however, the primer can become incorporated into the synthesized nucleic acid strand and provide a site to which another primer can hybridize to prime synthesis of a new strand that is complementary to the synthesized nucleic acid molecule. In some embodiments, the primer can be used for hybridization to a predetermined sequence, for instance a predetermined sequence that includes one or more nucleotides that identify the location of a modified cytosine. In one embodiment, a “primer” includes a sequence present in a guide RNA used with a CRISPR-based system to hybridize to a predetermined sequence. Theprimer can include any combination of nucleotides or analogs thereof. In some embodiments, the primer is a single-stranded oligonucleotide or polynucleotide.

[0036] The terms "polynucleotide" and "oligonucleotide" and “nucleic acid” are used interchangeably herein to refer to a polymeric form of nucleotides of any length, and may include ribonucleotides, deoxyribonucleotides, analogs thereof, or mixtures thereof. The terms should be understood to include, as equivalents, analogs of either DNA, RNA, cDNA, or antibody-oligo conjugates made from nucleotide analogs and to be applicable to single stranded (such as sense or antisense) and double stranded polynucleotides. The term as used herein also encompasses cDNA, that is complementary or copy DNA produced from a RNA template, for example by the action of reverse transcriptase.

[0037] As used herein, an "index" (also referred to as an "index region," "index adaptor," "tag," or a "barcode") refers to a unique nucleic acid tag that can be used to identify a sample or source of the nucleic acid material, or a compartment in which a target nucleic acid was present. The index can be present in solution or on a solid-support, or attached to or associated with a solidsupport and released in solution or compartment. When nucleic acid samples are derived from multiple sources, the nucleic acids in each nucleic acid sample can be tagged with different nucleic acid tags such that the source of the sample can be identified. Any suitable index or set of indexes can be used, as known in the art and as exemplified by the disclosures of U.S. Pat. No. 8,053,192, PCT Publication No. WO 05 / 068656, and U.S. Pat. Publication No. 2013 / 0274117. In some embodiments, an index can include a six-base Index 1 (i7) sequence, an eight-base Index 1 (i7) sequence, an eight-base Index 2 (i5e) sequence, a ten-base Index 1 (i7) sequence, or a ten- base Index 2 (i5) sequence from Illumina, Inc. (San Diego, CA).

[0038] As used herein, the term "amplicon," when used in reference to a nucleic acid, means the product of copying the nucleic acid, wherein the product has a nucleotide sequence that is the same as or complementary to at least a portion of the nucleotide sequence of the nucleic acid. An amplicon can be produced by any of a variety of amplification methods that use the nucleic acid, or an amplicon thereof, as a template including, for example, polymerase extension, polymerase chain reaction (PCR), rolling circle amplification (RCA), ligation extension, or ligation chain reaction. An amplicon can be a nucleic acid molecule having a single copy of a particular nucleotide sequence (e.g., a PCR product) or multiple copies of the nucleotide sequence (e.g., a conatemeric product of RCA). A first amplicon of a target nucleic acid is typically acomplementary copy. Subsequent amplicons are copies that are created, after generation of the first amplicon, from the target nucleic acid or from the first amplicon. A subsequent amplicon can have a sequence that is substantially complementary to the target nucleic acid or substantially identical to the target nucleic acid.

[0039] As used herein the term “primer” refers to a single stranded nucleic acid molecule that can hybridize to a target sequence, such as an adapter attached to a fragment. As one example, a flow cell surface bound primer can serve as a starting point for fragment amplification and cluster generation. As another example, a flow cell surface bound primer can serve as a hybridization point for a spatial tag, and thus for targeting attachment of particular transposome complexes and DNA samples. As still another example, a primer (e.g., a sequencing primer) may be introduced that can hybridize to DNA fragments in order to prime synthesis of a new strand that is complementary to the fragments. Any primer can include any combination of nucleotides or analogs thereof. In some examples, the primer is a single-stranded oligonucleotide or polynucleotide. The primer length can be any number of bases long. In an example, each of the flow cell surface bound primer and the sequencing primer is a short strand, ranging from 10 to 60 bases, or from 20 to 40 bases.

[0040] As used herein, "amplify," "amplifying," or "amplification reaction" and their derivatives, refer generally to any action or process whereby at least a portion of a nucleic acid molecule is replicated or copied into at least one additional nucleic acid molecule. The additional nucleic acid molecule optionally includes sequence that is substantially identical or substantially complementary to at least some portion of the template nucleic acid molecule. The template nucleic acid molecule can be single-stranded or double-stranded and the additional nucleic acid molecule can independently be single-stranded or double-stranded. Amplification is typically the exponential replication of a nucleic acid molecule. In some embodiments, such amplification can be performed using isothermal conditions; in other embodiments, such amplification can include thermocycling. In some embodiments, the amplification is a multiplex amplification that includes the simultaneous amplification of a plurality of target sequences in a single amplification reaction. In some embodiments, "amplification" includes amplification of at least some portion of DNA and RNA based nucleic acids alone, or in combination. The amplification reaction can include any of the amplification processes known to one of ordinary skill in the art. In some embodiments, the amplification reaction includes polymerase chain reaction (PCR).

[0041] As used herein, the term "polymerase chain reaction" ("PCR") refers to the method of Mullis U.S. Pat. Nos. 4,683,195 and 4,683,202, which describe a method for increasing the concentration of a segment of a polynucleotide of interest in a mixture of genomic DNA without cloning or purification. This process for amplifying the polynucleotide of interest consists of introducing a large excess of two oligonucleotide primers to the DNA mixture containing the desired polynucleotide of interest, followed by a series of thermal cycling in the presence of a DNA polymerase. The two primers are complementary to their respective strands of the double stranded polynucleotide of interest. The mixture is denatured at a higher temperature first and the primers are then annealed to complementary sequences within the polynucleotide of interest molecule. Following annealing, the primers are extended with a polymerase to form a new pair of complementary strands. The steps of denaturation, primer annealing and polymerase extension can be repeated many times (referred to as thermocycling) to obtain a high concentration of an amplified segment of the desired polynucleotide of interest. The length of the amplified segment of the desired polynucleotide of interest (amplicon) is determined by the relative positions of the primers with respect to each other, and therefore, this length is a controllable parameter. By virtue of repeating the process, the method is referred to as PCR. Because the desired amplified segments of the polynucleotide of interest become the predominant nucleic acid sequences (in terms of concentration) in the mixture, they are said to be "PCR amplified". In a modification to the method discussed above, the target nucleic acid molecules can be PCR amplified using a plurality of different primer pairs, in some cases, one or more primer pairs per target nucleic acid molecule of interest, thereby forming a multiplex PCR reaction.

[0042] As used herein, "amplification conditions" and its derivatives, generally refers to conditions suitable for amplifying one or more nucleic acid sequences. In some embodiments, the amplification conditions can include isothermal conditions or alternatively can include thermocycling conditions, or a combination of isothermal and thermocycling conditions. In some embodiments, the conditions suitable for amplifying one or more nucleic acid sequences include polymerase chain reaction (PCR) conditions. Typically, the amplification conditions refer to a reaction mixture that is sufficient to amplify nucleic acids such as one or more target sequences flanked by a universal sequence, or target specific primers, or to amplify an amplified target sequence flanked by one or more adapters. Generally, the amplification conditions include a catalyst for amplification or for nucleic acid synthesis, for example a polymerase; a primer thatpossesses some degree of complementarity to the nucleic acid to be amplified; and nucleotides, such as deoxyribonucleotide triphosphates (dNTPs) to promote extension of the primer once hybridized to the nucleic acid. The amplification conditions can require hybridization or annealing of a primer to a nucleic acid, extension of the primer and a denaturing step in which the extended primer is separated from the nucleic acid sequence undergoing amplification. Typically, but not necessarily, amplification conditions can include thermocycling; in some embodiments, amplification conditions include a plurality of cycles where the steps of annealing, extending and separating are repeated. Typically, the amplification conditions include cations such as Mg2+or Mn2+and can also include various modifiers of ionic strength.

[0043] As defined herein "multiplex amplification" refers to selective and non-random amplification of two or more target sequences within a sample using at least one target-specific primer. In some embodiments, multiplex amplification is performed such that some or all of the target sequences are amplified within a single reaction vessel. The "plexy" or "plex" of a given multiplex amplification refers generally to the number of different target-specific sequences that are amplified during that single multiplex amplification. In some embodiments, the plexy can be about 12-plex, 24-plex, 48-plex, 96-plex, 192-plex, 384-plex, 768-plex, 1536-plex, 3072-plex, 6144-plex or higher. It is also possible to detect the amplified target sequences by several different methodologies (e.g., gel electrophoresis followed by densitometry, quantitation with a bioanalyzer or quantitative PCR, hybridization with a labeled probe; incorporation of biotinylated primers followed by avidin-enzyme conjugate detection; incorporation of32P- labeled deoxynucleotide triphosphates into the amplified target sequence).

[0044] As used herein, the term "amplification site" refers to a site in or on an array where one or more amplicons can be generated. An amplification site can be further configured to contain, hold or attach at least one amplicon that is generated at the site.

[0045] As used herein, the term "array," "analyte array," and "microarray" are used interchangeably and refer to a population of sites that can be differentiated from each other according to relative location. Different molecules that are at different sites of an array can be differentiated from each other according to the locations of the sites in the array. An individual site of an array can include one or more molecules of a particular type. For example, a site can include a single target nucleic acid molecule having a particular sequence or a site can include several nucleic acid molecules having the same sequence (and / or complementary sequence,thereof). The sites of an array can be different features located on the same substrate. Exemplary features include without limitation, droplets, wells in a substrate, beads (or other particles) in or on a substrate, projections from a substrate, ridges on a substrate or channels in a substrate. The sites of an array can be separate substrates each bearing a different molecule. Different molecules attached to separate substrates can be identified according to the locations of the substrates on a surface to which the substrates are associated or according to the locations of the substrates in a liquid or gel. Exemplary arrays in which separate substrates are located on a surface include, without limitation, those having beads in wells.

[0046] As used herein, the term "compartment" is intended to mean an area or volume that separates or isolates something from other things. Exemplary compartments include, but are not limited to, vials, tubes, wells, droplets, boluses, beads, vessels, surface features, flow cell, or areas or volumes separated by physical forces such as fluid flow, magnetism, electrical current or the like. In one embodiment, a compartment is a well of a multi-well plate, such as a 96- or 384- well plate. As used herein, a droplet may include a hydrogel bead, which is a bead for encapsulating one or more nuclei or cell, and includes a hydrogel composition. In some embodiments, the droplet is a homogeneous droplet of hydrogel material or is a hollow droplet having a polymer hydrogel shell. Whether homogenous or hollow, a droplet may be capable of encapsulating one or more nuclei or cells. In some embodiments, the droplet is a surfactant stabilized droplet. In some embodiments, a single cell or Nuclei is present per compartment. In some embodiments, two or more cells or Nuclei are present per compartment. In some embodiments, each compartment contains a compartment-specific index. In some embodiments, the index is in solution or attached or associated with a solid-phase in each compartment.

[0047] The term "flow cell" as used herein refers to a chamber comprising a solid surface across which one or more fluid reagents can be flowed. A flow cell includes a vessel having an enclosed flow channel where a reaction can be carried out, or a vessel having a channel that is open to a surrounding environment and in which a reaction can be carried out. The vessel with an open flow channel may be referred to herein as an open wafer flow cell. Any example of the flow cell may include an inlet for delivering reagent(s) to the channel, and an outlet for removing reagent(s) from the channel. In some examples, the flow cell enables the detection of the reaction that occurs therein. For example, the flow cell can include one or more transparent surfaces allowing for the optical detection of arrays, optically labeled molecules, or the like.

[0048] Examples of flow cells and related fluidic systems and detection platforms that can be readily used in the methods of the present disclosure are described, for example, in Bentley et al., Nature 456:53-59 (2008), WO 04 / 018497; US 7,057,026; WO 91 / 06678; WO 07 / 123744; US 7,329,492; US 7,211,414; US 7,315,019; US 7,405,281, and US 2008 / 0108082.

[0049] As used herein, the term "clonal population" refers to a population of nucleic acids that is homogeneous with respect to a particular nucleotide sequence. The homogenous sequence is typically at least 10 nucleotides long, but can be even longer including for example, at least 50, 100, 250, 500 or 1000 nucleotides long. A clonal population can be derived from a single target nucleic acid or template nucleic acid. Typically, all of the nucleic acids in a clonal population will have the same nucleotide sequence. It will be understood that a small number of mutations (e.g., due to amplification artifacts) can occur in a clonal population without departing from clonality.

[0050] As used herein, a "pattern of cytosine modification," also referred to as a "methylation profile," refers to the pattern with which both methylation and unmethylation of cysteines is distributed in the genome of a cell or an organism. A “pattern” is inclusive of both modified cytosines and non-modified cytosines. The pattern can be defined in several distribution dimensions: by organ, by tissue, by status of disease or pathological condition (e.g., cancer, neurophysiological), by genome segment (e.g., chromosome or genetic coordinates on a chromosome), by gene, by CpG island, a group of cytosines, or by the site of a modified cytosine. A pattern of cytosine modification can have a known correlation with a disease or pathological condition, or correlation of a pattern of cytosine modification with a disease or pathological condition can be identified using methods described herein. A pattern of cytosine modification can be present at a specific locus (e.g., location) in a genome, and that specific location can be a single modified cytosine or a set of modified cytosines, e.g., a CpG island. A pattern of cytosine modification can be identified by using a predetermined sequence, e.g., a method of using an altered cytidine deaminase can be designed and practiced with the intent of determining a pattern of cytosine modification, for instance, the methylation status of one of more specific cytosines, the methylation status of one or more specific cytosines present at a specific location of a genome, or the combination thereof.

[0051] As used herein, a flow channel is an area that is defined between two bonded or otherwise attached components, or that is defined within a lane so that it is open to thesurrounding environment. The flow channel can selectively receive a liquid sample. In some examples, the flow channel may be defined between two patterned sequencing surfaces or a patterned sequencing surface and a lid, and thus may be in fluid communication with one or more components of the sequencing surface(s).

[0052] As used herein, a fragment is a portion or piece of the DNA sample. A “partially adapted fragment” is a portion or piece of the DNA sample that has been tagmented, and thus includes an adapter ligated to the 5’ end of the DNA fragment. A “fully adapted fragment” is a portion or piece of the DNA sample that has adapters incorporated at both the 3’ and 5’ ends of the DNA fragment.

[0053] As used herein, the term fragmentation is the breaking of nucleic acid into shorter lengths. Fragmentation methods include enzymatic methods, physical methods (including sonication, nebulization, needle shearing, microwave, etc ), and chemical methods (including depurination, hydrolysis, oxidation, etc.). The terms “fragmenting enzymes” or “enzyme-based fragmentation” or “enzyme fragmentation,” as used herein, refer to enzymes that fragment nucleic acids. The enzymes can be a single enzyme or two or more enzymes that work together to fragment the nucleic acid. Some enzymes work on single stranded nucleic acid whereas others work on double stranded nucleic acid and yet others work on one strand of a double stranded nucleic acid. Fragmenting enzymes can cut the nucleic acid randomly or specifically. Examples of fragmenting enzymes include transposase, restriction enzymes, Argonaute, CRISPR -associated nuclease (Cas), endonucleases, exonuclease, topoisomerase, FRAGMENTASE™ (New England Biolabs, Ipswich, MA). Preferred fragmentation examples include methods that fragment while retaining proximity information of the fragments.

[0054] As used herein, the term "each," when used in reference to a collection of items, is intended to identify an individual item in the collection but does not necessarily refer to every item in the collection unless the context clearly dictates otherwise.

[0055] As used in this specification and the appended claims, the term "or" is generally employed in its sense including "and / or" unless the content clearly dictates otherwise. The term "and / or" means one or all of the listed elements or a combination of any two or more of the listed elements. The use of "and / or" in some instances does not imply that the use of "or" in other instances may not mean "and / or."

[0056] Unless otherwise specified, "a," "an," "the," and "at least one" are used interchangeably and mean one or more than one.

[0057] As used in this specification and the appended claims, the term "or" is generally employed in its sense including "and / or" unless the content clearly dictates otherwise. The term "and / or" means one or all of the listed elements or a combination of any two or more of the listed elements. The use of "and / or" in some instances does not imply that the use of "or" in other instances may not mean "and / or."

[0058] The words "preferred" and "preferably" refer to embodiments of the disclosure that may afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the disclosure.

[0059] As used herein, "have," "has," "having," "include," "includes," "including," "comprise," "comprises," "comprising" or the like are used in their open ended inclusive sense, and generally mean "include, but not limited to," "includes, but not limited to," or "including, but not limited to."

[0060] It is understood that wherever embodiments are described herein with the language "have," "has," "having," "include," "includes," "including," "comprise," "comprises," "comprising" and the like, otherwise analogous embodiments described in terms of "consisting of' and / or "consisting essentially of' are also provided. The term "consisting of' means including, and limited to, whatever follows the phrase "consisting of." That is, "consisting of' indicates that the listed elements are required or mandatory, and that no other elements may be present. The term "consisting essentially of' indicates that any elements listed after the phrase are included, and that other elements than those listed may be included provided that those elements do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements.

[0061] Conditions that are "suitable" for an event to occur, such as converting 5 methylcytosine to thymidine by deamination, or "suitable" conditions are conditions that do not prevent such events from occurring. Thus, these conditions permit, enhance, facilitate, and / or are conducive to the event.

[0062] As used herein, "providing" in the context of a protein, sample of DNA or RNA, or composition means making the protein, sample of DNA or RNA, or composition, purchasing the protein, sample of DNA or RNA, or composition, or otherwise obtaining the protein, sample of DNA or RNA, or composition.

[0063] Reference throughout this specification to "one embodiment," "an embodiment," "certain embodiments," or "some embodiments," etc., means that a particular feature, configuration, composition, or characteristic described in connection with the embodiment is included in at least one embodiment of the disclosure. Thus, the appearances of such phrases in various places throughout this specification are not necessarily referring to the same embodiment of the disclosure. Furthermore, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more embodiments.

[0064] While polynucleotide sequences encoding an altered cytidine deaminase are described herein as DNA sequences, it is understood that the complements, reverse sequences, and reverse complements of the DNA sequences can be easily determined by the skilled person. It is also understood that the sequences described herein as DNA sequences can be converted from a DNA sequence to an RNA sequence by replacing each thymidine nucleotide with a uracil nucleotide.

[0065] Polynucleotide and / or polypeptides or protein sequences may include one or more forms of typographical emphasis (e.g., underlined text, bolded text, italicized text). It is understood that the typographical emphasis is non-limiting. Sequences stated with typographical emphasis include the stated sequence without the typographical emphasis. Additionally, polynucleotide sequences may be displayed in capital letters, lower case letters, or a combination thereof. The case of the letters in the polynucleotide sequences is non-limiting. Unless otherwise stated, lower case and upper-case letters simply indicate the identity of the nucleobase.

[0066] Throughout this disclosure, various aspects of the disclosure can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc.,as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 4.5, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0067] In the description herein particular embodiments may be described in isolation for clarity. Unless otherwise expressly specified that the features of a particular embodiment are incompatible with the features of another embodiment, certain embodiments can include a combination of compatible features described herein in connection with one or more embodiments.

[0068] Altered cytidine deaminases (ACDs)

[0069] The present disclosure includes altered cytidine deaminases (ACDs, or the singular form ACD), compositions including ACDs, and methods for using ACDs.

[0070] Wild-type APOBEC3A deaminates cytosine (C), 5 methyl cytosine (5mC), and 5- hydroxymethyl cytosine (5hmC) efficiently in single-stranded DNA (FIG. 1A-C). Treatment of DNA, such as genomic DNA, with wild-type APOBEC3A results in the conversion of C to uracil (U), 5mC to thymidine (T), and 5hmC to 5 -hydroxyuracil cytosine (5hmC) and reduces the complexity of the DNA sequencing (FIG. ID).

[0071] As described herein, mutation of the tyrosine at position 130 in a human APOBEC3A protein to a different amino acid such as alanine resulted in preferential conversion of 5mC to thymidine (FIG. IE). Analysis of the sample DNA after treatment with an altered cytidine deaminase described herein, for example, by sequencing of the sample DNA, and optional comparison to a reference (e g., reference sequence) permits easy identification of C to T point mutations, and these point mutations are inferred as 5mC positions.

[0072] A cytidine deaminase is considered to be an altered cytidine deaminase (ACD) if it has the activity of deaminating 5 methyl cytosine (5mC) and includes at least one of the substitution mutations described herein. An ACD useful in the methods provided herein preferentially deaminates 5mC instead of C (i.e., converts 5mC to T at a greater rate than converting C to U) compared to the equivalent wild-type enzyme and is referred to herein as having “cytosinedefective deaminase activity” and “5mC-selective deaminase activity”, the terms being interchangeable.

[0073] ACDs include apolipoprotein B mRNA editing enzymes, catalytic polypeptide-like (APOBEC) and activation induced cytidine deaminase (AID). Wild-type APOBEC and AID cytidine deaminases have the activity of deaminating cytidine of DNA and / or RNA to formuridine (U). An ACD of the present disclosure has an altered rate of deamination of 5mC when compared to the wild-type enzyme. A cytidine deaminase of the present disclosure can be referred to herein as an "altered cytidine deaminase," "recombinant cytidine deaminase," “ACD,” “recombinant ACD,” “mutant cytidine deaminase,” or “modified cytidine deaminase” and refers to any of the engineered ACDs described herein that include one or more changes from a reference (i.e., wild-type) amino acid sequence that provide one or more of the activities described herein, including but not limited to an altered deamination profile, e.g., alters its ability to preferentially deaminate one form of cytosine over another, enhanced selectivity for 5mC or C, and / or enhanced stability.

[0074] Whether a protein has cytidine deaminase activity may be determined by in vitro assays. One example of an in vitro assay is based on digestion with the restriction enzyme Awal as described in WO 2023 / 196572. A protein that can deaminate 5mC to thymidine has cytidine deaminase activity.

[0075] In certain embodiments, an ACD of the present disclosure is based on a member of the APOBEC protein family. An ACD of the present disclosure that is "based on" a member of the APOBEC protein family means the ACD is an APOBEC protein that includes one or more of the substitution mutations described herein as compared to a reference APOBEC sequence. An ACD of the present disclosure that is "based on" a member of the APOBEC protein family can also include conservative and / or nonconservative mutations as described herein. The positions of the alterations, substitutions or deletions will be at functionally equivalent amino acids from the reference sequence, as described herein.

[0076] The APOBEC protein family includes subfamilies AID, APOBEC 1, APOBEC2, APOBEC3 (including 3 A, 3B, 3C, 3D, 3F, 3G, 3H), and APOBEC4. An ACD of the present disclosure can be based on a member of the AID subfamily, the APOBEC 1 subfamily, the APOBEC2 subfamily, the APOBEC3 subfamily (e.g., the 3A subfamily, the 3B subfamily, the 3C subfamily, the 3D subfamily, the 3F subfamily, the 3G subfamily, or the 3H subfamily), or the APOBEC4 subfamily. An ACD of the present disclosure can be based on a member of the APOBEC protein family from a vertebrate, such as a mammal. Examples of mammals include, but are not limited to, rodents, primates, rabbit, bovine (e.g., cow), porcine (e.g., pig), equine (e.g., horse), elephant, and aardvark. An example of a primate is a human and a chimpanzee.

[0077] The APOBEC protein family is a member of the large cytidine deaminase superfamily that contains a canonical zinc-dependent deaminase (ZDD) signature motif embedded within a core cytidine deaminase fold. This fold includes a five-stranded mixed beta (b)-sheet surrounded by six alpha (a)-helices with the order al-bl-b2-a2-b3-a3-b4-a4-b5-a5-a6 (Salter et al., Trends Biochem Sci. 2016 41(7):578-594. Doi:10.1016 / j.tibs.2016.05.001; Salter et al., Trends Biochem. Sci. 2018, 43(8):606-622 doi.org / 10.1016 / j .tibs.2018.04.013). Each cytidine deaminase domain core structure of APOBEC proteins contains a highly conserved spatial arrangement of the catalytic center residues of a zinc-binding motif H-[P / A / V]-E-X[23-28]-P-C-X[2- 4]-C (SEQ ID NO:1) (referred to herein as the ZDD motif, where X is any amino acid, and the subscript range of numbers after X refers to the number of amino acids) (Salter et al., Trends Biochem Sci. 2016 41(7):578— 594. Doi : 10.1016 / j .tibs.2016.05.001). Without intending to be limited by theory, the H and two C residues coordinate a Zn atom, and the E residue polarizes a water molecule near the Zn-atom for catalysis (Chen et al., 2021, Viruses, 13:497, doi.org / 10.3390 / vl3030497).

[0078] Some members of the APOBEC protein family, e.g., the AID subfamily, the APOBEC 1 subfamily, the APOBEC2 subfamily, the APOBEC3A subfamily, the APOBEC3C subfamily, the APOBEC3H subfamily, and the APOBEC4 subfamily, include one copy of the ZDD motif. Other members of the APOBEC protein family, e.g., the APOBEC3B subfamily, the APOBEC3D subfamily, the APOBEC3F subfamily, and the APOBEC3G subfamily, include two copies of the ZDD motif, but often only the C-terminal copy is active (Salter et al., Trends Biochem Sci. 2016 41(7)578-594. Doi: 10.1016 / j .tibs.2016.05.001). Thus, an altered cytidine deaminase disclosed herein includes one or two ZDD motifs. In one embodiment, an altered cytidine deaminase based on a member of the APOBEC3A subfamily that includes the following ZDD motif: HXEX24SW(S / T)PCX[2-4]CX6FX8LX5R(L / I)YX[8-n]LX2LX[io]M (SEQ ID NO:2) (where X is any amino acid, and the subscript number or range of numbers after X refers to the number of amino acids) (Salter et al., Trends Biochem Sci. 2016 41(7)578-594. Doi: 10.1016 / j. tibs.2016.05.001).

[0079] In one embodiment, an ACD disclosed herein is a member of the APOBEC3 subfamily, e.g., APOBEC3A, APOBEC3B, APOBEC3C, APOBEC3D, APOBEC3F, or APOBEC3G, and can include one or more highly conserved sites that are part of the active site and within the ZDD motif SEQ ID NO: 1. The sites include tryptophan at position 98 and serine or threonine atposition 99 of SEQ ID NO:3 (Kouno et al., 2017, Nat. Comm, 8: 15024, DOI: 10.1038 / ncomms 15024).[000801 In addition to the ZDD motif, a member of the APOBEC protein family also includes other highly conserved residues that are part of the active site but not present as part of the ZDD motif SEQ ID NO:1. A member the APOBEC3A subfamily, APOBEC3B subfamily, APOBEC3C subfamily, APOBEC3D subfamily, APOBEC3F subfamily, and APOBEC3G subfamily typically includes one or more of the following highly conserved sites that are part of the active site: arginine at position 28; histidine, asparagine, or arginine at position 29; serine or threonine, preferably threonine, at position 31; asparagine or aspartic acid at position 57; histidine at position 70; cysteine at position 101; cysteine at position 106; tyrosine or phenylalanine at position 130; asparagine or tyrosine at position 131; asparagine, tyrosine, or phenylalanine, preferably tyrosine, at position 132; and arginine or lysine at position 189 of SEQ ID NO:3 (Kouno et al., 2017, Nat. Comm, 8: 15024, DOI: 10.1038 / ncommsl5024).

[0081] An ACD of the present disclosure includes a substitution mutation, deletion, insertion, or a combination thereof, at one or more residues when compared to a reference cytidine deaminase. A substitution mutation can be at the same position or a functionally equivalent position compared to the reference cytidine deaminase. Reference cytidine deaminases and functionally equivalent positions are described in detail herein. As noted, positions of the altered amino acids described herein and in the tables are in reference to APOBECA3A (SEQ ID NO:3) but one skilled in the art is capable of deriving the functionally equivalent positions in the other referenced cytosine deaminases. The skilled person will readily appreciate that an altered cytidine deaminase described herein is not naturally occurring.

[0082] A reference cytidine deaminase can be a member of the APOBEC protein family. Essentially any known member of the APOBEC protein family can be a reference cytidine deaminase. The skilled person can easily identify members of each of the subfamilies by using a publicly available database such as the Protein database available at the National Center for Biotechnology Information (ncbi.nlm.nih.gov / protein) and searching for APOBEC1, APOBEC2, APOBEC3A, APOBEC3B, APOBEC3C, APOBEC3D, APOBEC3F, APOBEC3G, APOBEC3H, APOBEC4, or, when identifying members of the AID family, Activation-induced cytidine deaminase. A wild-type reference cytidine deaminase has the activity of binding singlestranded DNA (ssDNA) and deaminating a cytosine present on the ssDNA to convert it to uracil.In one embodiment, a wild-type reference cytidine deaminase has the activity of binding singlestranded RNA (ssRNA) and deaminating a cytosine present on the ssRNA to convert it to uracil. Methods for determining whether a protein binds ssDNA or ssRNA and deaminates a cytosine present are known to the skilled person. Other reference cytidine deaminases include, but are not limited to, SEQ ID NO: 13, 14, 15, 16, 17, 18, 19, 20, 21, and 22. Thus, any of the mutations discussed for selectivity (e.g., AxxxW (SEQ ID NO:51) or AxxxWX (SEQ ID NO:52)) may be substituted into the backbone of any one of SEQ ID NO: 13-22 instead of the SEQ ID NO:3 wildtype reference backbone and are contemplated as aspects of the present invention.

[0083] In one embodiment, an ACD has an amino acid sequence that is based on a reference sequence which is a member of the APOBEC protein family includes a ZDD motif H-[P / A / V]-E- X[23-28]-P-C-X[2-4]-C (SEQ ID NO:1) and at least one substitution mutation disclosed herein. Optionally, an altered cytidine deaminase includes a substitution mutation at one or more other active site residues disclosed herein. Non-limiting examples of reference cytidine deaminase proteins for different APOBEC protein family members include UniProt Q9GZX7, UniProt G3QLD2, and UniProt Q9WVE0 (APOBEC protein family member AID); UniProt P41238, NCBI XP 030856728.1, and Uniprot P51908 (APOBEC protein family member APOBEC1); UniProt Q9Y235, Uniprot G3SGN8, and Uniprot Q9WV35 (APOBEC protein family member APOBEC2); UniProt P31941 , GenBank XP 045219544.1, GenBank AER45717.1, GenBank XP 003264816.1, GenBank PNI48846.1, and GenBank ADO85886.1 (APOBEC protein family member APOBEC3A); UniProt Q9UH17, Uniprot G3QV16, and Uniprot F6M3K5 (APOBEC protein family member APOBEC3B); UniProt Q9NRW3, Uniprot Q694B5, and Uniprot B0LW74 (APOBEC protein family member APOBEC3C); UniProt Q96AK3, NCBI NP_001332895.1, and NCBI NP_001332931.1 (APOBEC protein family member APOBEC3D); UniProt Q8IUX4, Uniprot G3RD21, and Uniprot Q1G0Z6 (APOBEC protein family member APOBEC3F); UniProt Q9HC16, Uniprot Q694C1, and Uniprot U5NDB3 (APOBEC protein family member APOBEC3G); UniProt Q6NTF7, Uniprot B7T0U7, and Uniprot Q19Q52 (APOBEC protein family memberAPOBEC3H); and UniProt Q8WW27, NCBIXP 004028087.1, and Uniprot Q497M3 (APOBEC protein family member APOBEC4).

[0084] In one embodiment, an ACD has an amino acid sequence that is based on a reference sequence that is a member of the APOBEC3A subfamily, and includes a ZDD motif HXEX24SW(S / T)PCX[2-4]CX6FX8LX5R(L / I)¥X[8-11]LX2LX[1O]M (SEQ ID NO:2) (where X isany amino acid, and the subscript number or range of numbers after X refers to the number of amino acids) and at least one substitution mutation disclosed herein. In one embodiment, the substitution mutation is a substitution mutation at the underlined tyrosine, such as a substitution mutation to alanine (A). The underlined tyrosine (Y) of SEQ ID NO:2 is the position functionally equivalent to the tyrosine amino acid 130 of the APOBEC3A protein SEQ ID NO:3. Optionally, the altered cytidine deaminase includes other active site residues disclosed herein.

[0085] In one embodiment, the amino acid sequence of an ACD includes the amino acids of a member of the APOBEC3A subfamily: X[i6-26]-GRXXTXLCYXV-Xi5-GXXXN-Xi2-HAEXXF- X14-YXXTWXXSWSPC- X[2-4]-CA-X5-FL-X7-LXIXXXR(L / I)Y-Xs-GLXXLXXXG-X5-M-X4- FXXCWXXFV-X6-FXPW-X13-LXXI- X[2-6] (SEQ ID NO:9) (where X is any amino acid, and the subscript number or range of numbers after X refers to the number of amino acids), or a subset thereof, and at least one substitution mutation disclosed herein. The underlined tyrosine (Y) of SEQ ID NO:9 is the position functionally equivalent to the tyrosine amino acid 130 of the APOBEC3A protein SEQ ID NO :3. In one embodiment, the substitution mutation is a substitution mutation at the underlined tyrosine, such as a substitution mutation to alanine (A). Optionally, the altered cytidine deaminase includes other active site residues disclosed herein.

[0086] In one embodiment, the amino acid sequence of an ACD includes the amino acids of a member of the APOBEC3A subfamily: X26-GRXXTXLCYXV-X15-G-X16-HAEXXF-X14- YXXTWXXSWSPC-X4-CA-X5-FL-X7-LXIFXXR(L / I)Y-X8-GLXXLXXXG-X5-M-X4- FXXCWXXFV-X6-FXPW-X13-LXXI-X6 (SEQ ID NO: 10) (where X is any amino acid, and the subscript number after X refers to the number of amino acids present), or a subset thereof, and at least one substitution mutation disclosed herein. The underlined tyrosine (Y) of SEQ ID NO: 10 is the position functionally equivalent to the tyrosine amino acid 130 of the APOBEC3A protein SEQ ID NO:3. In one embodiment, the substitution mutation is a substitution mutation at the underlined tyrosine (Y), such as a substitution mutation to alanine (A). Optionally, the altered cytidine deaminase includes other active site residues disclosed herein.

[0087] A substitution mutation can be at the same position or a functionally equivalent position compared to a reference cytidine deaminase. By "functionally equivalent" it is meant that the altered cytidine deaminase has the amino acid substitution at the amino acid position in areference cytidine deaminase that has the same functional role in both the reference cytidine deaminase and the altered cytidine deaminase.

[0088] In general, functionally equivalent substitution mutations in two or more different cytidine deaminases occur at homologous amino acid positions in the amino acid sequences of the cytidine deaminases. Hence, use herein of the term "functionally equivalent" also encompasses mutations that are "positionally equivalent" or "homologous" to a given mutation, regardless of whether or not the particular function of the mutated amino acid is known. It is possible to identify the locations of functionally equivalent and positionally equivalent amino acid residues in the amino acid sequences of two or more different cytidine deaminases on the basis of sequence alignment and / or molecular modelling. An example of a sequence alignment to identify positionally equivalent and / or functionally equivalent residues is set forth in FIG. 2. For example, the residues in the members of the APOBEC3A subfamily in FIG. 2 that are vertically aligned are considered positionally equivalent as well as functionally equivalent to the corresponding residue in the human APOBEC3A amino acid sequence. Thus, for example, as shown in FIG. 2, the tyrosine at residue 130 of the APOBEC3A proteins of Homo sapiens, Pongo pygmaeus, Nomascus leucogenys, Pan troglodytes, and Gorilla gorilla and the tyrosine at residue 133 of the APOBEC3A protein from Macaca fascicularis are functionally equivalent and positionally equivalent. The skilled person can easily identify functionally equivalent residues in cytidine deaminases.

[0089] In one embodiment, an altered cytidine deaminase has an amino acid sequence that is structurally similar to a reference cytidine deaminase disclosed herein. In one embodiment, a reference cytidine deaminase is one that includes the amino acid sequence of SEQ ID NO:9 or SEQ ID NO:10. Other examples of reference sequences include, but are not limited to, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:479-517, SEQ ID N0:520-605, SEQ ID NO:607-615, SEQ ID NO:635-954, and SEQ ID NO:962-968

[0090] As used herein, an ACD may be "structurally similar" or have “structural similarity” to a reference cytidine deaminase if the amino acid sequence of the ACD possesses a specified amount of sequence similarity and / or sequence identity compared to the reference cytidine deaminase.

[0091] Structural similarity of two amino acid sequences can be determined by aligning the residues of the two sequences (for example, a candidate ACD and a reference cytidine deaminase described herein) to optimize the number of identical amino acids along the lengths of their sequences; gaps in either or both sequences are permitted in making the alignment in order to optimize the number of identical amino acids, although the amino acids in each sequence must nonetheless remain in their proper order. A candidate altered cytidine deaminase is the cytidine deaminase being compared to the reference cytidine deaminase. A candidate ACD that has structural similarity with a reference cytidine deaminase and cytidine deaminase activity is an altered cytidine deaminase.

[0092] Unless modified as otherwise described herein, a pair-wise comparison analysis of amino acid sequences can be conducted, for instance, by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (see generally Current Protocols in Molecular Biology, Ausubel et al., eds., Current Protocols, a joint venture between Greene Publishing Associates, Inc. and John Wiley & Sons, Inc., supplemented through 2004). One example of an algorithm that is suitable for determining structural similarity is the BLAST® algorithm, which is described in Altschul et al., J. Mol. Biol. 215:403-410 (1990). The BLAST® algorithm can be used to calculate percent sequence identity and percent sequence similarity between two sequences. Software for performing BLAST® analyses is publicly available through the National Center for Biotechnology Information.

[0093] In the comparison of two amino acid sequences, structural similarity may be referred to by percent "identity" or may be referred to by percent "similarity." "Identity" refers to the presence of identical amino acids. "Similarity" refers to the presence of not only identical amino acids but also the presence of conservative substitutions. Thus, in one embodiment the amino acid sequence of an altered cytidine deaminase protein having sequence similarity to a reference sequence may include conservative substitutions of amino acids present in that reference sequence.

[0094] A conservative substitution for an amino acid in a protein may be selected from other members of the class to which the amino acid belongs. For example, it is well-known in the art of protein biochemistry that an amino acid belonging to a grouping of amino acids having a particular size or characteristic (such as charge, hydrophobicity, or hydrophilicity) can be substituted for another amino acid without altering the activity of a protein, particularly in regions of the protein that are not directly associated with biological activity. For example, amino acids having a non-polar side chain include alanine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, tryptophan, and valine; amino acids having a hydrophobic side chain include glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, and tryptophan; amino acids having a polar side chain include arginine, asparagine, aspartic acid, glutamine, glutamic acid, histidine, lysine, serine, cysteine, tyrosine, and threonine; and amino acids having an uncharged side chain include glycine, serine, cysteine, asparagine, glutamine, tyrosine, and threonine.

[0095] Thus, as used herein, reference to a cytidine deaminase as described herein, such as reference to the amino acid sequence of one or more SEQ ID NOs described herein can include a protein having structural similarity to the reference cytidine deaminase, e g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, 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%, or at least 99% amino acid sequence similarity to the reference cytidine deaminase. In one embodiment, a reference protein is SEQ ID NO:3. Examples of other reference proteins are described herein.

[0096] Alternatively, as used herein, reference to a cytidine deaminase as described herein, such as reference to the amino acid sequence of one or more SEQ ID NOs described herein can include a protein having structural similarity to the reference cytidine deaminase, e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, 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%, or at least 99% amino acid sequence identity to the reference cytidine deaminase. In one embodiment, a reference protein is SEQ ID NO:3. Examples of other reference proteins are described herein.

[0097] Substitution mutations conferring increased selectivity or stability

[0098] In one aspect, the present disclosure provides new altered cytidine deaminases (ACDs) that preferentially deaminate 5mC instead of C (i.e., converts 5mC to T at a greater rate than converting C to U) compared to the equivalent wild-type enzyme and first and second generations of ACD that have been identified (International Application Publication NOs. WO 2023 / 196572, WO 2025 / 072793, and WO 2025 / 072800), and include a substitution mutation at a position functionally equivalent to a tyrosine at position 130 (Y130), for instance, Y130A in combination with the mutations described below. An optional substitution mutation is at a position functionally equivalent to a tyrosine at position 132 (Y132), for instance, Y130H. Another optional mutation that increases the selectivity for 5mC is a substitution mutation at a position functionally equivalent to a aspartic acid at position 133 (Y133), for instance, D133W. An example of an ACD with these three substitution mutations is ScA (SEQ ID NO: 13). ACDs of the present disclosure include one or more selectivity-enhancing alterations that result in greater selectivity for 5mC than other ACDs, such as the ACD ScA (SEQ ID NO:13), as well a wild-type APOBEC3A cytidine deaminase (e.g., SEQ ID NO:3).

[0099] A selectivity-enhancing alteration is considered to enhance the selectivity of an ACD for 5mC if it has greater deamination of 5mC when compared to a reference ACD. A suitable reference ACD is one having the same amino acid sequence (also referred to as the same backbone) but without the selectivity-enhancing alteration. Examples of reference ACDs for use in determining whether an alteration is a selectivity-enhancing alteration include, but are not limited to, SEQ ID NO:3, SEQ ZD NO 13, SEQ ID NO: 14, SEQ ID NO:17, or SEQ ID NO 21. In one embodiment, the reference ACD is SEQ ID NO: 14. A selectivity-enhancing alteration is a substitution mutation, a deletion, or an insertion. In one embodiment, an ACD disclosed herein having enhanced selectivity includes one or more selectivity-enhancing alterations that confer increased 5mC-selectivity compared to a reference ACD (an increase in 5mC deamination of at least 5%, at least 10%, at least 15%, least 20%, at least 25%, least 30%, least 40%, least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%). Cytidine deaminase activity of a protein can be determined by in vitro assays. One example of an in vitro assay is based on digestion with the restriction enzyme Swal as described in WO 2023 / 196572.[000100] An ACD of the present disclosure can include a substitution mutation at a position functionally equivalent to tyrosine at position 130 (Y130) in a member of the APOBEC protein family, including a member of the APOBEC3A subfamily (for instance, SEQ ID NO:3). Insome APOBEC family proteins, the wild-type residue at a position functionally equivalent to Y130 is phenylalanine (F). An ACD with a substitution mutation at a position functionally equivalent to Y130 preferentially acts on 5mC compared to cytosine (i.e., has 5mC-selective deaminase activity). The substitution mutation in an ACD is at a position functionally equivalent to position 130 in a member of the APOBEC protein family, including a member of the APOBEC3A subfamily (for instance, SEQ ID NO:3) and can be a mutation to alanine (A), glycine (G), phenylalanine (F), histidine (H), glutamine (Q), methionine (M), asparagine (N), lysine (K), valine (V), aspartic acid (D), glutamic acid I, serine (S), cysteine (C), proline (P), or threonine (T) (FIG. 2). In one embodiment, the substitution mutation at a position functionally equivalent to Y130 is Y130A, Y130S, or Y130H. In one embodiment, the substitution mutation at a position functionally equivalent to Y130 is Y130A. In one embodiment, the substitution mutation at a position functionally equivalent to Y130 is Y130S.[000101] An ACD of the present disclosure can include a second substitution mutation at a position functionally equivalent to the proline at position 134 (Pl 34) in a member of the APOBEC protein family, including a member of the APOBEC3A subfamily (for instance, SEQ ID NO:3). An ACD with a substitution mutation at a position functionally equivalent to Pl 34 preferentially acts on 5mC compared to cytosine (i.e., has 5mC-selective deaminase activity). . In one embodiment, the substitution mutation in an ACD is at a position functionally equivalent to position Pl 34 is a mutation to tryptophan (P134W) or to tyrosine (P134Y). one embodiment, the substitution mutation at a position functionally equivalent to Pl 34 is P134W. In one embodiment, the substitution mutation in an ACD is at a position functionally equivalent to position P134 is a mutation to threonine (P134T).[000102] In one embodiment, an ACD of the present disclosure comprises AxxxW (SEQ ID NO:51) at positions functionally equivalent to 130-134 of SEQ ID NO:3, and where X may be any amino acid (examples demonstrated in Tables 2 and 3 and Figures 8 and 9), and the ACD with AxxxW (SEQ ID NO:51) has an increase in 5mC selectivity as compared to wild-type APOBEC (e.g., SEQ ID NO:3), particularly, for example, has at least 75% increase 5mC specificity as compared to reference APOBEC sequence (e.g., an increase in 5mC deamination of at least 5%, at least 10%, at least 15%, least 20%, at least 25%, least 30%, least 40%, least 50%, at least 75%, at least 78%, at least 80%, at least 82%, at least 85%, at least 90%, at least 92%, or at least 95% as compared to WT APOBEC).[000103] An ACD of the present disclosure can further include a substitution mutation at a position functionally equivalent to the aspartic acid at position 131 (DI 31), the tyrosine at position 132 (Y132), the aspartic acid at position 133 (D133), or any combination thereof. [000104] In one embodiment, when the substitution mutation in an ACD at a position functionally equivalent to position Y130 is Y130A or Y130H, preferably Y130A, and at a position functionally equivalent to position P134 is P134W or P134Y, preferably P134W, then any amino acid can be present at DI 31 (D13 IX), Y132 (Y132X), and / or D133 (D133X). The substitution mutations in an ACD are at positions functionally equivalent to positions 131, 132, and / or 133 in a member of the APOBEC protein family, including a member of the APOBEC3A subfamily (for instance, SEQ ID NO:3). In one embodiment, a substitution mutation at D 131 can be histidine, arginine, lysine, proline, glycine, asparagine, alanine, or valine. In one embodiment, a substitution mutation at Y132 can be alanine, proline, aspartic acid, glutamic acid, glycine, threonine, valine, glutamine, or arginine. In one embodiment, a substitution mutation at D133 can be histidine, tyrosine, phenylalanine, threonine, isoleucine, or valine, [000105] In some embodiments, an ACD of the present disclosure can further include a substitution mutation at a position functionally equivalent to the leucine at position 135 (L135) in a member of the APOBEC protein family, including a member of the APOBEC3A subfamily (for instance, SEQ ID NO:3). The substitution mutation at a position functionally equivalent to L135 preferentially acts on 5mC compared to cytosine (i.e., has 5mC-selective deaminase activity). In one embodiment, the substitution mutation in an ACD at a position functionally equivalent to position L135 is a mutation to tryptophan (L135W). In one embodiment, the substitution mutation in an ACD at a position functionally equivalent to position L 135 is a mutation to histidine (L135H), glutamine (L135Q), tyrosine (L135Y), or cysteine (L135C). In one embodiment, an ACD includes the substitution mutations at positions functionally equivalent to Y130A, Y132H, D133W, P134W, and L135X, where X is tryptophan (L135W), histidine (L135H), glutamine (L135Q), tyrosine (L135Y), or cysteine (L135C).[000106] In some embodiments, an ACD of the present disclosure includes a substitution mutation at positions functionally equivalent to Y130 (such as, but not limited to, Y130A) and Y134 (such as, but not limited to, P134W), and have any amino acid present at positions functionally equivalent to D131, Y132, D133, in a member of the APOBEC protein family, including a member of the APOBEC3A subfamily (for instance, SEQ ID NO:3), or an ACDhaving structural similarity to SEQ ID NO:3. The structural similarity can be, but is not limited to, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO:3. In some embodiments, an ACD of the present disclosure includes a substitution mutation at positions functionally equivalent to Y130 (such as, but not limited to, Y130A) and Y134 (such as, but not limited to, P134W), any amino acid present at positions functionally equivalent to D131, Y132, D133, and a substitution mutation at a position functionally equivalent to L135 in a member of the APOBEC protein family, including a member of the APOBEC3A subfamily (for instance, SEQ ID NO:3)[000107] Examples of substitution mutations at positions functionally equivalent to 130, 131, 132, 133, and 134 that can be present in a wild-type APOBEC3A protein, such as SEQ ID NO:3, or present in an ACD and increase the selectivity for 5mC compared to cytosine include, but are not limited to, those shown in Table 2 (see Example 1). Thus, examples of reference ACDs having these substitution mutations include, but are not limited to, SEQ ID NO: 13, 14, 15, 16, 17, 18, 19, 20, 21, and 22, and those having structural similarity to SEQ ID NO: 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22, where the amino acids at 130, 131, 132, 133 and 134 are those shown in Table 2. The structural similarity can be, but is not limited to, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22. ACDs of SEQ ID NO: 13, 14, 15, 16, 17, 18, 19, 20, 21, and 22 include stability mutations, which are described herein. In some aspects, the ACDs have increased 5mC specificity have mutations at position 103-105 in combination with AxxxW (SEQ ID NO:51) at positions 130- 134, as shown in FIG. 8. Suitable ACD mutations for F102 / S103 / W104 / G105 may include one or more mutations or deletions, two or more, or three or more mutaitons or deletions within F102 / S103 / W104 / G105.[000108] Examples of substitution mutations at positions functionally equivalent to 130, 131, 132, 133, and 134 that can be present in a wild-type APOBEC3A protein, such as SEQ ID NO:3, or present in an ACD and increase the selectivity for 5mC compared to cytosine include, but are not limited to, those shown in Table 2 (see Example 1). Thus, examples of reference ACDs having these substitution mutations include, but are not limited to, SEQ ID NO:13, 14, 15, 16, 17, 18, 19, 20, 21, and 22, and those having structural similarity to SEQ ID NO: 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22, where the amino acids at 130, 131, 132, 133 and 134 are those shown in Table 2. The structural similarity can be, but is not limited to, at least 80%, at least 85%, atleast 90%, or at least 95% sequence identity to SEQ ID NO:13, 14, 15, 16, 17, 18, 19, 20, 21, or 22. ACDs of SEQ ID NO: 13, 14, 15, 16, 17, 18, 19, 20, 21, and 22 include stability mutations, which are described herein. In some aspects, the ACDs have increased 5mC specificity have mutations at position 103-105 in combination with AxxxW (SEQ ID NO:51) at positions 130- 134, as shown in FIG. 8. Suitable ACD mutations for F102 / S103 / W104 / G105 may include one or more mutations or deletions, two or more, or three or more mutations or deletions within F102 / S103 / W104 / G105.[000109] Examples of substitution mutations at positions functionally equivalent to 130, 131, 132, 133, 134, and 135 that can be present in a wild-type APOBEC3A protein, such as SEQ ID NO:3, or present in an ACD and increase the selectivity for 5mC compared to cytosine include, but are not limited to, ADHWWX (SEQ ID NO: 52), where X any amino acid besides L, preferably wherein X is W, H, Q, Y or C. Thus, examples of ACDs that can include these substitution mutations include, but are not limited to, SEQ ID NO:13, 14, 15, 16, 17, 18, 19, 20, 21, and 22, and those having structural similarity to SEQ ID NO: 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22, where the amino acids at 130, 131, 132, 133 134, and 135 is ADHWWX (SEQ ID NO:52), where X is W, H, Q, Y or C. The structural similarity can be, but is not limited to, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22.[000110] Additionally, these ACD may have an additional substitution or deletion at one or more positions functionally equivalent to 102, 103, 104 and 105, for example, one or more substitution mutations, one or more deletions, or one or more insertions, or a combination thereof, of the amino acids at positions functionally equivalent to a phenylalanine at position 102 (Fl 02), a serine at position 103 (SI 03), a tryptophan at position 104 (W104), and / or a glycine at position 105 (G105) in a member of the APOBEC protein family, including a member of the APOBEC3A subfamily (for instance, SEQ ID NO:3). In one embodiment, the substitution mutation at a position functionally equivalent to any one of Fl 02, SI 03, W104, and / or G105 can be any amino acid. In one embodiment, the deletion can be 1, 2, 3, or 4 of the amino acids at a position functionally equivalent to any one of F102, S103, W104, and / or G105. In one embodiment, deletion can be at a position functionally equivalent to W104, G105, or both W104 and G105. Suitable sequences for the region from 102-105 can be selected from, e.g., SEQ ID NO:242-410, FIMA, QVP , YLPA, EMFA, FIIA, ELYA, YLPA, NIP A, VYNA, AFRA, YYIA,FSDD, FQAG, FSAG, AVPG, FVPA, AVPA, YLIA, RYAA, LFWA, TRY A, YLIA, VLYA, RHYA, FMHA, QFPA, RRPA, RIYA, YYIA, RMLA, VLYA, RMLA, AVQA, QVWA, FVPA, FVDA, FSAA, KRAA , RRAA, FPPA, KRRA, VP A A, TDHA, QTDA, YLAA, LPAA, EMAA, MFAA, YVRA, IKLA, YIKA, QTQA, TQYA, KTNA, HLTA, LTGA, HTGA, HLGA, TGAA, HLAA, LTAA, HLTA, LTGA, QTMA, RKTA, KIYA, AYKA, MHAA, NQAA, RKAA, LMAA, LNAA , ACAA, QIAA, IMAA, FCAA, AVAA, QMAA, YDAA, LSAA, CEAA, VLAA, QQAA, RCAA, FCAA, SWAA, AGAA, RWAA, NQAA, QHAA, LAAA, MRAA, FNAA,FNAA, GCAA, SVAA, RMAA, ESAA, LMAA, MCAA, ICAA, GVAA, QHAA, among others.[000111] Additional selectivity-enhancing alterations have been identified at amino acids other than those at positions functionally equivalent to 130-135 of SEQ ID NO:3. In one embodiment, a selectivity-enhancing alteration is one or more substitution mutations, one or more deletions, or one or more insertions, or a combination thereof, of the amino acids at positions functionally equivalent to a phenylalanine at position 102 (F102), a serine at position 103 (S103), a tryptophan at position 104 (W104), and / or a glycine at position 105 (G105) in a member of the APOBEC protein family, including a member of the APOBEC3A subfamily (for instance, SEQ ID NO:3). In one embodiment, the substitution mutation at a position functionally equivalent to any one of Fl 02, SI 03, W104, and / or G105 can be any amino acid. In one embodiment, the deletion can be 1, 2, 3, or 4 of the amino acids at a position functionally equivalent to any one of Fl 02, SI 03, W104, and / or G105. In one embodiment, deletion can be at a position functionally equivalent to W104, G105, or both W104 and G105. In one embodiment, the insertion can be the insertion of 1, 2, 3, or 4 amino acids between two amino acids at a position functionally equivalent to any one of F 102, S103, W104, or G105. In one embodiment, there can be 2 or more separate insertions, e.g., an insertion can be between Fl 02 and SI 03 and an insertion between amino acid SI 03 and W 104. The one or more substitution mutations, one or more deletions, or one or more insertions can be at any combination of positions 102-105, e.g., at one, two, three, or all four positions. Examples of substitution mutations at positions functionally equivalent to SI 03 and W 104 include, but are not limited to, S103D / W104A, S103H / W104P, S103T / W104D, S103T / W104M, S103V / W104E, S103V / W104M, and S103V / W104P.Examples of selectivity-enhancing alterations at positions functionally equivalent to S103, W104, and G105 include, but are not limited to, substitution mutations S103V / W104P and adeletion of G105. In one embodiment, these selectivity-enhancing alterations can be present in SEQ ID NO: 14 (see, for instance, SEQ ID NO:23 and SEQ ID NO:24.[0001121 Examples of selectivity-enhancing alterations at positions functionally equivalent to102, 103, 104, 105, 130, 131, 132, 133, and 134 that can be present in a wild-type APOBEC3A protein, such as SEQ ID NO:3, or present in an ACD and increase the selectivity for 5mC compared to cytosine include, but are not limited to, those shown in Table 3 (see Example 1). Thus, examples of ACDs having these selectivity-enhancing alterations include, but are not limited to, SEQ ID NO: 13, 14, 15, 16, 17, 18, 19, 20, 21, and 22, and those having structural similarity to SEQ ID NO: 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22, where the amino acids at 102,103, 104, 105, 130, 131, 132, 133, and 134 are those shown in Table 3. The structural similarity can be, but is not limited to, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22.[000113] Examples of selectivity-enhancing alterations at positions functionally equivalent to 102, 103, 104, 105, 130, 131, 132, 133, 134, and 135 that can be present in a wild-type APOBEC3A protein, such as SEQ ID NO:3, or present in an ACD and increase the selectivity for 5mC compared to cytosine include, but are not limited to, those shown in FIG. 8. Thus, examples of ACDs having these selectivity-enhancing alterations include, but are not limited to, SEQ ID NO: 13, 14, 15, 16, 17, 18, 19, 20, 21, and 22, and those having structural similarity to SEQ ID NO:13, 14, 15, 16, 17, 18, 19, 20, 21, or 22, where the amino acids at 102, 103, 104, 105, 130, 131, 132, 133, 134, and 135 are those shown in FIG. 8. The structural similarity can be, but is not limited to, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22.[000114] Examples of ACDs with additional mutations that increase selectivity for 5mC are described in International Application Publication Nos. WO 2025 / 072793 and WO 2025 / 072800. [000115] An ACD described herein having enhanced 5mC-selective deaminase activity (e.g., one or more selectivity-enhancing alterations at a position functionally equivalent to F102, 8013, W104, G105, Y130, D131, Y132, D133, P134, L135, or any combination thereof) can optionally include one or more stability-enhancing alterations. A stability-enhancing alteration can be one or more substitution mutations, one or more deletions, one or more insertions, or a combination thereof, at a position functionally equivalent to an amino acid in a member of the APOBEC protein family, including a member of the APOBEC3A subfamily (for instance, SEQ ID NO:3).A stability-enhancing alteration (e.g., substitution mutation, deletion, or insertion) is considered to be stability-enhancing if it can increase the melting temperature of an ACD by at least 1 °C, at least 2 °C, at least 3 °C, at least 4 °C, at least 5 °C, or at least 6 °C compared to the same ACD that does not have the stability-enhancing substitution mutation. A suitable method of determining the melting temperature of an ACD described herein is by fluorimetry. However, it is well within one skilled in the art to determine the melting temperature of the ACDs described herein.[000116] Examples of stability-enhancing alterations include, but are not limited to, substitution mutation at one or more positions functionally equivalent to I17X, T19X, G25X, S45X, A59X, K60X, R74X, G108X, A126X, C171X, G188X, a deletion of amino acids 61-68 (A61-68), a deletion of amino acids 104-105 (A 104- 105), or any combination thereof, in a member of the APOBEC protein family, including a member of the APOBEC3A subfamily (for instance, SEQ ID NO:3). An example of I17X is I17T. An example of T19X is T19Y.Examples of G25X include G25K and G25R. An example of S45X is S45W. An example of A59X is A59P. An example of K60X is K60R. An example of R74X is R74L. An example of A126X is A126C. Examples of G108X include G108C and G108A. An example of C171X is C171A. An example of G188X is G188R. Examples of ACDs having specific combinations of stability-enhancing alterations include, but are not limited to, those shown in Table 1.[000117] Table 1 . Examples of stability mutations in ACDs.[000118] An ACD described herein having enhanced 5mC-selective deaminase activity (e.g., one or more selectivity-enhancing alterations at a position functionally equivalent to F102, S013, W104, G105, Y130, D131, Y132, D133, P134, L135, or any combination thereof) can include one or more stability enhancing alterations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, VI 10X, R11 IX, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, H119X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104- G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3 A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000119] An ACD described herein having enhanced 5mC-selective deaminase activity (e.g., one or more selectivity-enhancing alterations at a position functionally equivalent to Fl 02, SO 13, W104, G105, Y130, D131, Y132, D133, P134, L135, or any combination thereof) can include one or more stability enhancing alterations selected from Hl IL, D14Y, H16D, I17T, T19Y, T19L, T19I, S20F, S20F, S20E, S20Y, S20I, G25R, G25V, G25K, I26R, T31I, T31W, S45W, S45R, K47P, A59P, K60R, K60G, L62P, R74L, L78H, P80R, P80T, P80S, P80G, I89R, I89T, I89H, I89R, S103R, S103Y, S103T, G108C, G108A, G108Y, E109Q, E109L, V110L, Q115K, Q115Y, E116L, T118P, R123H, A126F, A126C, E138R, E138Q, E138A, D145R, C161M, C171A, D180W, D180H, S183W, S183F, S183V, A185I, A185R, G188I, G188, G188Q, G188R, R189K, A192E or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3 A (SEQ ID NO:3).[000120] In one embodiment, an ACD having the one or more selectivity-enhancing alteration described herein (e.g., a selectivity-enhancing alteration at a position functionally equivalent to F102, SO I 3, W104, G105, Y130, D131, Y132, D133, P134, L135, or any combinationthereof) and the stability-enhancing alterations T19Y / R74L / C171A,117T / T 19 Y / G25R / R74L / C 171 A, T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R, 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R, 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R, or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C171A / G188R, can further include one or more stability-enhancing substitution mutations at positions functionally equivalent to those selected from one or more ofH16D, S20F, S20E, S20Y, S20I, K60G, I89R, S103T, E109L, V110L, Q115K, Q115Y, E116L, A126C, E138R, E138Q, E138A, D145R, D180H, S183V, A185R, R189K, and A192E, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3)..[000121] An ACD described herein can include a stability-enhancing alteration that is a deletion. In addition to the AN61-G68 and AW104-G105 deletions described herein, examples of other deletions are at positions functionally equivalent to AM1-L12 (the first 12 amino acids of human APOBECA3A (SEQ ID NO:3), AE36-G53, AN42, AN61-G68, AP86, AW104-G105, API 72, and AS187-N199, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3 A (SEQ ID NO:3).[000122] Some deletions can further include one or more ancillary substitution mutations. An ACD described herein can include the A61-68 deletion and the ancillary substitution mutation at (i) the position functionally equivalent to A59 where the mutation is to proline (A59P) or leucine (A59L), (ii) the position functionally equivalent to K60 where the mutation is to arginine (K60R), glutamic acid ((K60E), glutamine (K60Q), or glycine (K60G), or (iii) the position functionally equivalent to R69 (i.e., the position 69 prior to the deletion of 61-68) where the mutation is to tyrosine (R69Y), asparagine (R69N, histidine (R69H), aspartic acid (R69D), or leucine (R69L). Specific combinations of the A61-68 deletion and ancillary substitution mutations are A61-68 / A59P / K60R, A61-68 / A59L / R69Y, A61- 68 / A59L / K60E / R69N, A61-68 / A59P / K60E / R69H, A61-68 / A59P / K60Q / R69H, A61- 68 / A59L / R69N, A61-68 / R69D, A61-68 / A59L / K60R, and A61-68 / A59P / K60G / R69L. An ACD described herein can include the Al 04- 105 deletion and the ancillary substitution mutation at the position functionally equivalent to Fl 02 where the mutation is to arginine (F102R), the substitution mutation at the position functionally equivalent to SI 03 where the mutation is to asparagine (S103N), or both substitution mutations F102R and S103N. In another embodiment, an ACD described herein can include both the A 104- 105 deletion andthe Al-12 deletion. Additional embodiments include: an ACD having the A104-105 deletion, the Al-12 deletion, and the substitution mutation F102R; an ACD having the A104-105 deletion, the Al-12 deletion, and the substitution mutation S103N; and an ACD having the A104-105 deletion, the Al-12 deletion, and the substitution mutations F102R and S103N. [000123] Without intending to limit the particular combinations of mutations that increase selectivity and stability in an ACD having 5mC-selective deaminase activity, specific combinations encompassed by the present disclosure include, but are not limited to, SEQ ID NO: 11, SEQ ID NO: 12, or SEQ ID NO: 13 that further include (i) selectivity-enhancing substitution mutations Y130A, D131X, Y132X, D133X, and Y134W (e.g., the amino acids at 130, 131, 132, 133 and 134 are those shown in Table 2 (see Example 1), or (ii) selectivityenhancing substitution mutations Y130A, D131X, Y132X, D133X, and Y134W and one or more selectivity-enhancing alterations at positions functionally equivalent to Fl 02, SI 02, W104, and G105, (e.g., the amino acids at 102, 103, 104, 105, 130, 131, 132, 133 and 134 are those shown in Table 3), or (iii) selectivity-enhancing substitution mutations Y130A, D131X, Y132X, D133X, Y134W, and L135X and one or more selectivity-enhancing alterations at positions functionally equivalent to F102, S102, W104, and G105, (e.g., the amino acids at 102, 103, 104, 105, 130, 131, 132, 133, 134 and 135 are those shown in FIG. 8). In some embodiments, an ACD having enhanced 5mC-selective deaminase activity described herein (e.g., a selectivity-enhancing alteration at a position functionally equivalent to F102, SO I 3, W104, G105, Y130, D131, Y132, D133, P134, L135, or any combination thereof) can further include at least one of the following combinations of stabilizing mutations: R74L / C171A; R74L / T19Y; R74L / G25R; R74L / T19I / C171A;R74L / T19L / C171A; R74L / T19Y / C171A / I17T; R74L / T19Y / C171A / G25A; R74L / T19Y / C171A / G25R / I17T; R74L / C171A / G25R / T19F; R74L / T19Y / C171A / G25D; R74L / T19Y / C171A / S45R; R74C / T19Y / C171A; R74L / C171A / T19F; R74L / C171A / T19W; R74L / T19Y / C171A / G108E; R74L / T19Y / C171A / G108D; R74L / T19Y / C171A / G108Q; R74L / T 19 Y / C 171 A / Gl 08 Y; R74L / T 19 Y / C 171 A / Gl 08H; R74L / T 19 Y / C 171 A / Gl 08L; R74L / T 19 Y / C 171 A / Gl 08K; R74L / T 19 Y / C 171 A / Gl 08R; R74L / T 19 Y / C 171 A / Al 26 V; R74L / T19Y / C171I; R74L / T19Y / C171A / G108M; R74L / T19Y / C171A / G108W;R74L / T 19 Y / C 171 A / A 126F ; R74L / T 19 Y / C 171 A / A 1261; R74L / T 19 Y / C 171 A / A 126L; R74L / T19Y / C171A; R74L / T19Y / C171A / S45W; R74L / T19Y / C171A / G25R;R74L / T 19 Y / C 171 A / G25K; R74L / T 19 Y / C 171 A / Gl 88Q; R74L / T 19 Y / C 171 A / Gl 88 A; R74L / T 19 Y / C 171 A / Gl 88R; R74L / T 19 Y / C 171 A / Gl 08 A;R74L / T19Y / C171A / G108A / G188R / G25K / S45W ; R74L / T19Y / C171A / G108C;R74L / T 19 Y / C 171 A / Gl 08 A / Gl 88R / G25K / S45 W / I 17T;R74L / T 19 Y / C 171 A / Gl 08 A / Gl 88R / G25K / S45 W / 117T / A59P / K60R / A61-68;R74L / T 19 Y / C 171 A / Gl 08C / G188R / G25K / S45 W / Il 7T;R74L / T 19 Y / C 171 A / Gl 08C / G188R / G25K / S45 W / 117T / A59P / K60R / A61 -68 / A126C;R74L / T 19 Y / C 171 A / Gl 08C / G188R / G25K / S45 W / 117T / A59P / K60R / A61-68;T 19 Y / R74L / C 171 A; 117T / T 19 Y / G25R / R74L / C 171 A;T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C 171 A / Gl 88R.[000124] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134 a sequence selected from: AVAHW (SEQ ID NO:25), AHIYW (SEQ ID NO:26), AHEYW (SEQ ID NO:27), ARAYW ((SEQ ID NO:28), ANGFW ((SEQ ID NO:29), AKSHW (SEQ ID NO:30), AHLYW (SEQ ID NO:31), AHDFW (SEQ ID NO:32), AKTHW (SEQ ID NO:33), AHMIW (SEQ ID NO:34), AKMVW (SEQ ID NO: 35), AQAFW (SEQ ID NO: 36, ARVKW (SEQ ID NO: 37), AHRVW (SEQ ID NO:38), AKTYW (SEQ ID NO:39), AVAKW (SEQ ID NO:40), AKNFW (SEQ ID NO:41), AHARW (SEQ ID NO:42), AGPYW (SEQ ID NO:43), AKYPW (SEQ ID NO:44), AKPFW (SEQ ID NO:45), AKLIW (SEQ ID NO:46), AHVVW (SEQ ID NO:47), AGRFW (SEQ ID NO:48), AIAHW (SEQ ID NO:49), AKMYW (SEQ ID NO:50), among others in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C171A / G188R In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FIMA (SEQ ID NO:404); HLTG (SEQ ID NO:242); QVPA (SEQ ID NO:405); EFNQ (SEQ ID NO:243); QTDH (SEQ ID NO:244); GLNG (SEQ ID NO:245); YLP (SEQ ID NO:406); EMFA (SEQ ID NO:407); YKQY (SEQ ID NO:246); YVRL (SEQ ID NO:247); YIKL (SEQ ID NO:248); FILA ALAHW (SEQ ID NO:408); QTQY (SEQ ID NO:249); KTNN (SEQ ID NO:250); AYDG (SEQ ID NO:251); HLTG (SEQ ID NO:242); QTMH (SEQ ID NO:252); YVQR (SEQ ID NO:253); ELYA (SEQ ID NO:409):YVEN (SEQ ID NO:254); RMLA (SEQ ID NO:410); QTVG (SEQ ID NO:255); YVQD (SEQ ID NO:256) QTQY (SEQ ID NO:249); QTYG (SEQ ID NO:257_);YYRM AHGYW (SEQ ID NO:258): YLP A; STNN_(SEQ ID NO:259); QTRR (SEQ ID NO:260); AYEY (SEQ ID NO:261); YVND (SEQ ID NO:262); FSWG (SEQ ID NO:263); NIPA;YPFG (SEQ ID NO:264); QTLG_(SEQ ID NO:265); VYNA_; AFRA; ETKH (SEQ ID NO:266); YVEG (SEQ ID NO:267); QTMG_ (SEQ ID NO:268); AQHG_(SEQ ID NO:269); HLRG (SEQ ID NO:270); QTMH (SEQ ID NO:252); YYIA_ (SEQ ID NO:YYIA); HLYG_ (SEQ ID NO:271); YMAG (SEQ ID NO:272); YIWG_ (SEQ ID NO:273); IRQY (SEQ ID NO:274); AQMG (SEQ ID NO:275); FVPG (SEQID NO: 276); and FVPA, FVPG (SEQ ID NO:276), FTDG (SEQ ID NO:277), FVDG (SEQ ID NO: 278), FVPAG (SEQ ID NO:279), FVPLG (SEQ ID NO:280), FVPPG(SEQ ID NO:280), FVPAAG(SEQ ID NO:282), FVPLAG (SEQ ID NO:283), FVPPAG (SEQ ID NO:284), FVPASG (SEQ ID NO:285), FVPLSG (SEQ ID NO:286), FVPPSG (SEQ ID NO:287), FVPAFG (SEQ ID NO:288), FVPLFG (SEQ ID NO:289), FVPPFG (SEQ ID NO:289), FVPAQG (SEQ ID NO:290), FVPLQG (SEQ ID NO:291), FVPPQG (SEQ ID NO:292), FVPADG (SEQ ID NO:293), FVPLDG (SEQ ID NO:294), FVPPDG (SEQ IDNO:295), FVPAKG (SEQ ID NO:296), FVPLKG: (SEQ ID NO:297), FVPPKG(SEQ ID NO:298), among others. Additionally, these ACD may have an additional substitution or deletion at one or more positions functionally equivalent to 102, 103, 104 and 105, for example, one or more substitution mutations, one or more deletions, or one or more insertions, or a combination thereof, of the amino acids at positions functionally equivalent to a phenylalanine at position 102 (Fl 02), a serine at position 103 (SI 03), a tryptophan at position 104 (W104), and / or a glycine at position 105 (G105) in a member of the APOB EC protein family, including a member of the APOBEC3 A subfamily (for instance, SEQ ID NO:3). In one embodiment, the substitution mutation at a position functionally equivalent to any one of F102, S103, W104, and / or G105 can be any amino acid. In one embodiment, the deletion can be 1, 2, 3, or 4 of the amino acids at a position functionally equivalent to any one of F102, S103, W104, and / or G105. In one embodiment, deletion can be at a position functionally equivalent to W104, G105, or both W104 and G105. Suitable sequences for the region from 102-105 can be selected from, e.g., SEQ ID NO:242-410, FIMA, QVPA, YLPA, EMFA, FIIA, ELYA, YLPA, NIP A, VYNA, AFRA, YYIA, FSDD, FQAG, FSAG, AVPG, FVPA, A VP A, YLIA, RYAA, LFWA, IRYA, YLIA, VLYA, RHYA, FMHA, QFPA, RRPA, RIYA, YYIA, RMLA, VLYA, RMLA, AVQA, QVWA, FVPA, FVDA, FSAA, KRAA , RRAA, FPPA, KRRA, VPAA, TDHA, QTDA, YLAA, LPAA, EMAA, MFAA, YVRA, IKLA, YIKA, QTQA, TQYA, KTNA, HLTA, LTGA, HTGA, HLGA, TGAA, HLAA, LTAA, HLTA, LTGA, QTMA, RKTA, KIYA, AYKA, MHAA, NQAA, RKAA, LMAA, LNAA , ACAA, QIAA, IMAA, FCAA, AVAA, QMAA, YDAA, LSAA, CEAA, VLAA, QQAA, RCAA, FCAA, SWAA, AGAA, RWAA, NQAA, QHAA, LAAA, MRAA, FNAA,FNAA, GCAA, SVAA, RMAA, ESAA, LMAA, MCAA, ICAA, GVAA, QHAA, among others.[000125] In some embodiments, an ACD having enhanced 5mC-selective deaminase activity described herein(e.g., a selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104, G105, Y130, D131, Y132, D133, P134, L135, or any combination thereof) can further include at least one of the following combinations of stabilizing mutations: R74L / C171A / T19Y / G25K / S45W;R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C 171 A / Gl 88R.[000126] Specific examples of ACDs of the present disclosure include SEQ ID NO:23, SEQ ID NO:24, and ACDs disclosed in Table 2, Table 3, and FIG 9 (SEQ ID NO:479-517, SEQ ID N0:520-605, SEQ ID NO:607-615, SEQ ID NO:635-954, SEQ ID NO:962-968). [000127] For example, specific examples of ACDs that have increased 5mC selectivity as compared with APOBEC3 A wildtype sequence include, for example, ACD comprising SEQ ID NO: 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509,510, 511, 512, 513, 514, 515, 516, 517, 520, 521, 523, 524, 525, 526, 527, 528,529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 543, 544, 545,546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561,562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577,578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593,594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 607, 608, 609, 610,611, 612, 613, 614, 615, 635, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646,647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662,663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678,679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694,695, 696, 697, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710,711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726,727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742,743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758,759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774,775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790,791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806,807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822,823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838,839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854,855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870,871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886,887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 897, 898, 899, 900, 901, 902,903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918,919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934,935, 936, 937, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 950, 951,952, 953, 954, 955, 956, 957, 958, 959, 960, and 961. Additionally, ACDs that have increased 5mC selectivity as compared to their parental mutant strain (e.g., FIG. 9) include, for example, the ACD comprising SEQ ID NO:479, 493, 497, 498, 501, 504, 506, 507, 527, 529, 530, 533, 536, 539, 543, 545, 546, 547, 548, 549, 557, 558, 565, 566, 571, 572, 579, 580, 588, 602, 604, 605, 623, 633, 641, 643, 646, 649, 650, 652, 653, 655, 660, 661,662, 663, 664, 665 ,666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 677, 680, 681, 682, 683, 684,685, 686, 687, 689, 690, 691, 692, 693, 694, 696, 697, 698, 699, 700, 702, 703, 704, 705,706, 707, 708, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724,725, 726, 727, 728, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 744,745, 746, 747, 748, 749, 750, 752, 753, 754, 755, 756, 759, 760,764, 765, 767, 768, 773, 778, 779, 780, 781, 782, 783, 784, 786, 787, 789, 790, 793, 795, 796, 797, 798, 799, 800, 802,803, 806, 809, 810, 811, 814, 815, 817, 818, 819, 820, 821, 822, 823, 824, 827, 828, 829,830, 831, 832, 834, 835, 836, 837, 838, 844, 851, 870, 878, 879, 881, 882, 888, 890, 896,903, 904, 911, 918, 920, 921, 929, 933, 936, 945, 950, 955, 956, 957, 958, 959, 960, and.961.[000128] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AVAHW (SEQ ID NO:25) in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X,L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S1O3X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000129] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AVAHW (SEQ ID NO:25 in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C171A / G188R. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000130] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AHIYW (SEQ ID NO:26) in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000131] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selectedfrom AHIYW (SEQ ID NO:26) in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C171A / G188R. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000132] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AHEYW (SEQ ID NO:27) in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X,L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S1O3X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000133] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AHEYW (SEQ ID NO:27) in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;IP-281 l-PCT / 531.2811 WO01R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C171A / G188R. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000134] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from ARAYW ((SEQ ID NO:28) in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000135] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selectedfrom: ARAYW ((SEQ ID NO:28) in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C171A / G188R. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000136] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from ANGFW ((SEQ ID NO:29) in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X,L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000137] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: ANGFW ((SEQ ID NO:29) in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C171A / G188R. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000138] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AKSHW (SEQ ID NO: 30) in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000139] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selectedfrom: AKSHW (SEQ ID NO: 30) in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C171A / G188R. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000140] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from AHLYW (SEQ ID NO: 31) in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X,L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S1O3X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000141] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AHLYW (SEQ ID NO:31) in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C171A / G188R. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000142] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AHDFW (SEQ ID NO:32) in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000143] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selectedfrom: AHDFW (SEQ ID NO:32), in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C171A / G188R. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000144] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AKTHW (SEQ ID NO:33), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X,L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S1O3X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000145] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AKTHW (SEQ ID NO:33), in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C171A / G188R In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000146] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AHMIW (SEQ ID NO:34), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000147] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selectedfrom: AHMIW (SEQ ID NO:34), in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C171A / G188R. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000148] In some embodiments, the ACD comprises a backbone sequence relative to AKMVW (SEQ ID NO: 35), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X,S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, A112X, L114X, Q115X, E116X, N117X, T118X, H119X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type AP0BEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, SI 03, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000149] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AKMVW (SEQ ID NO: 35), in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C171A / G188R. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000150] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AQAFW (SEQ ID NO: 36), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000151] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AQAFW (SEQ ID NO: 36), in combination with one or more combinations of stabilityenhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C171A / G188R. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000152] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: ARVKW (SEQ ID NO: 37), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X,C101X, F102X, S1O3X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000153] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: ARVKW (SEQ ID NO: 37), in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C171A / G188R. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000154] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AHRVW (SEQ ID NO: 38), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000155] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AHRVW (SEQ ID NO: 38), in combination with one or more combinations of stabilityenhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C171A / G188R. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000156] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AKTYW (SEQ ID NO: 39), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X,C101X, F102X, S1O3X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000157] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AKTYW (SEQ ID NO: 39), in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C171A / G188R In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000158] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AVAKW (SEQ ID NO:40), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000159] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AVAKW (SEQ ID NO:40), in combination with one or more combinations of stabilityenhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C171A / G188R. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000160] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AKNFW (SEQ ID NO:41), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X,C101X, F102X, S1O3X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000161] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AKNFW (SEQ ID NO:41), in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C171A / G188R. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000162] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AHARW (SEQ ID NO:42), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000163] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AHARW (SEQ ID NO:42), in combination with one or more combinations of stabilityenhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C171A / G188R. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000164] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AGPYW (SEQ ID NO:43), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X,C101X, F102X, S1O3X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000165] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AGPYW (SEQ ID NO:43), in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C171A / G188R. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000166] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AKYPW (SEQ ID NO:44), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000167] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AKYPW (SEQ ID NO:44), in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C171A / G188R In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000168] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AKPFW (SEQ ID NO:45), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X,G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S1O3X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000169] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from AKPFW (SEQ ID NO:45), in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C171A / G188R. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000170] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AKLIW (SEQ ID NO:46), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000171] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AKLIW (SEQ ID NO:46), in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C171A / G188R. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000172] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from AHVVW (SEQ ID NO:47), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X,G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S1O3X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000173] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AHVVW (SEQ ID NO:47), in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C171A / G188R. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000174] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AGRFW (SEQ ID NO:48), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000175] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AGRFW (SEQ ID NO:48), in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C171A / G188R In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000176] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AIAHW (SEQ ID NO:49), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X,G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000177] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AIAHW (SEQ ID NO:49), in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C171A / G188R. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000178] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AKMYW (SEQ ID NO:50), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to F102, S103, W104 and G105, for example, e.g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000179] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 130-134, or functionally equivalent positions, a sequence selected from: AKMYW (SEQ ID NO:50), among others in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C171A / T19Y / G25K / S45W;R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C171A / G188R. In some aspects, the ACD further comprises at least one selectivity-enhancing alteration at a position functionally equivalent to Fl 02, S103, W104 and G105, for example, e g., FVPG, FTDG, FVDG, FVPAG, FVPLG, FVPPG, FVPAAG, FVPLAG, FVPPAG, FVPASG, FVPLSG, FVPPSG, FVPAFG, FVPLFG, FVPPFG, FVPAQG, FVPLQG, FVPPQG, FVPADG, FVPLDG, FVPPDG, FVPAKG, FVPLKG, FVPPKG among others.[000180] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105, or functionally equivalent positions, the sequence FVPG, and from 130-134, or functionally equivalent positions, the sequence AKYPW, in combination with one or more combinations of stability enhancing mutations selected from:at least one of the following combinations of stabilizing mutations:R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C171A / G188R.In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 the sequence FVPG, and from 130-134, or functionally equivalent positions, the sequence AKYPW (SEQ ID NO:44), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, VI 10X, R11 IX, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, H119X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68,AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type AP0BEC3 A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000181] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 the sequence FTDG, and from 130-134, or functionally equivalent positions, the sequence AKYPW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C171A / T19Y / G25K / S45W;R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C 171 A / Gl 88R.[000182] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 the sequence FTDG, and from 130-134, or functionally equivalent positions, the sequence AKYPW (SEQ ID NO:44), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X,R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S1O3X, W104X, G105X, C106X, A107X, G108X, E109X, VI 1OX, R11 IX, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, H119X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104- G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3 A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000183] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 the sequence FVDG, and from 130-134, or functionally equivalent positions, the sequence AKYPW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C171A / T19Y / G25K / S45W;R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C 171 A / Gl 88R.[000184] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 the sequence FVDG, and from 130-134, or functionally equivalent positions, the sequence AKYPW (SEQ ID NO:44), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, VI 10X, R11 IX, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, H119X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104- G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3 A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000185] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 the sequence FVPAG, and from 130-134, or functionally equivalent positions, the sequence AKYPW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C171A / T19Y / G25K / S45W;R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A; 117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R; 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R; 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C 171 A / Gl 88R.[000186] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 the sequence FVPAG, and from 130-134, or functionally equivalent positions, the sequence AKYPW (SEQ ID NO:44), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, VI 10X, R11 IX, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, H119X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104- G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3 A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000187] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 the sequence FVPLG, and from 130-134, or functionally equivalent positions, the sequence AKYPW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C171A / T19Y / G25K / S45W;R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C 171 A / Gl 88R.[000188] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 the sequence FVPLG, and from 130-134, or functionally equivalent positions, the sequence AKYPW (SEQ ID NO:44), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, VI 10X, R11 IX, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, H119X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104- G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3 A (SEQ IDN0:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000189] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 the sequence FVPPG, and from 130-134, or functionally equivalent positions, the sequence AKYPW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C171A / T19Y / G25K / S45W;R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C 171 A / Gl 88R.[000190] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 the sequence FVPPG, and from 130-134, or functionally equivalent positions, the sequence AKYPW (SEQ ID NO:44), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X,R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, VI 10X, R11 IX, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, H119X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104- G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3 A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000191] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 the sequence FVPAAG, and from 130-134, or functionally equivalent positions, the sequence AKYPW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C171A / T19Y / G25K / S45W;R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C 171 A / Gl 88R.[000192] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 the sequence FVPAAG, and from 130-134, or functionally equivalent positions, the sequence AKYPW (SEQ ID NO:44), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, VI 10X, R11 IX, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, H119X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104- G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3 A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000193] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 the sequence FVPLAG, and from 130-134, or functionally equivalent positions, the sequence AKYPW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C171A / T19Y / G25K / S45W;R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A; 117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R; 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R; 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C 171 A / Gl 88R.[000194] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 the sequence FVPLAG, and from 130-134, or functionally equivalent positions, the sequence AKYPW (SEQ ID NO:44), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, VI 10X, R11 IX, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, H119X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104- G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3 A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000195] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 the sequence FVPPAG, and from 130-134, or functionally equivalent positions, the sequence AKYPW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C171A / T19Y / G25K / S45W;R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C 171 A / Gl 88R.[000196] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 the sequence FVPPAG, and from 130-134, or functionally equivalent positions, the sequence AKYPW (SEQ ID NO:44), in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, VI 10X, R11 IX, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, H119X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104- G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3 A (SEQ IDN0:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000197] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 the sequence FVPASG, and from 130-134, or functionally equivalent positions, the sequence AKYPW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C171A / T19Y / G25K / S45W;R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C 171 A / Gl 88R.[000198] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence FIMA AHIYW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C 171 A / Gl 88R.[000199] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence FIMA AHIYW, in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position. In some embodiments,the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102- 105 130-134, or functionally equivalent positions, the sequence HLTG AHEYW , in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations:R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C 171 A / Gl 88R.[000200] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence HLTG AHEYW, in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X,R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type AP0BEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000201] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence QVPA AHDFW , in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C 171 A / Gl 88R.[000202] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, thesequence QVPA AHDFW, in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000203] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence EFNQ ANVHW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C 171 A / Gl 88R.[000204] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence EFNQ ANVHW, in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000205] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence QTDH AAEHW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A; 117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R; 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C 171 A / Gl 88R.[000206] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence QTDH AAEHW, in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000207] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence GLNG AHEYW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C 171 A / Gl 88R.[000208] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence GLNG AHEYW, in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalentto the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000209] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence YLPA ANGFW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C 171 A / Gl 88R.[000210] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence YLPA ANGFW, in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X,C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000211] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence EMFA ANDFW , in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C 171 A / Gl 88R.[000212] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence EMFA ANDFW, in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000213] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence YKQY AGEYW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C 171 A / Gl 88R.[000214] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence YKQY AGEYW, in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000215] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence YVRL AVPFW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A; 117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R; 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C 171 A / Gl 88R.[000216] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence YVRL AVPFW, in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000217] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence YIKL AVAHW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizingmutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C 171 A / Gl 88R.[000218] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence YIKL AVAHW, in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27,or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000219] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence FILA ALAHW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C 171 A / Gl 88R.[000220] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence FILA ALAHW, in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X,L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000221] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence QTQY ARVKW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C 171 A / Gl 88R.[000222] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence QTQY ARVKW, in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000223] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence KTNN ASEHW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A; 117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R; 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C 171 A / Gl 88R.[000224] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence KTNN ASEHW, in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000225] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence AYDG AHEYW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;I l lR74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A; 117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R; 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C 171 A / Gl 88R.[000226] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence AYDG AHEYW, in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000227] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, thesequence HLTG AVAYW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C 171 A / Gl 88R.[000228] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence HLTG AVAYW, in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X,S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type AP0BEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000229] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence QTMH AHQYW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C 171 A / Gl 88R.[000230] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence QTMH AHQYW, in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X,G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S1O3X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000231] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence YVQR ANVYW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C 171 A / Gl 88R.[000232] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence YVQR ANVYW, in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000233] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence ELYA AHIYW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A; 117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R; 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C 171 A / Gl 88R.[000234] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence ELYA AHIYW, in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000235] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence YVEN ANGFW , in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A; 117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R; 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C 171 A / Gl 88R.[000236] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence YVEN ANGFW, in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000237] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence RMLA AAEHW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C 171 A / Gl 88R.[000238] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence RMLA AAEHW, in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X,R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000239] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence QTVG AKSHW , in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104-G105 / G108C / C 171 A / Gl 88R.[000240] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, thesequence QTVG AKSHW, in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000241] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence YVQD AHEYW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188R / G25K / S45 W; T 19 Y / R74L / C 171 A;117T / T 19 Y / G25R / R74L / C 171 A; T 19 Y / G25K / S45 WR74L / G108 A / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / C 171 A / Gl 88R;117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / G108C / A126C / C 171 A / Gl 88R; or 117T / T 19 Y / G25K / S45 W / A59P / K60R / AN61 -G68 / R74L / AW 104- G105 / G108C / C 171 A / Gl 88R.[000242] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence YVQD AHEYW, in combination with one or more combinations of stability enhancing mutations selected from Hl IX, L12X, D14X, H16X, I17X, T19X, S20X, N21X, G25X, I26X, G27X, R28X, H29X, T31X, C34X, E38X, R39X, D41X, N42X, S45X, K47X, M48X, H51X, F54X, H56X, N57X, A59X, K60X, L62X, Y67X, L73X, R74X, D77X, L78X, V79X, P80X, S81X, D85X, A87X, I89X, Y90X, R91X, T93X, W94X, I96X, S97X, C101X, F102X, S103X, W104X, G105X, C106X, A107X, G108X, E109X, V110X, R111X, Al 12X, LI 14X, QI 15X, El 16X, N117X, T118X, Hl 19X, V120X, L122X, R123X, A126X, R128X, L135X, Y136X, E138X, A139X, Q141X, M142X, D145X, A146X, A148X, D156X, E157X, K159X, C161X, D163X, T164X, D167X, Q169X, C171X, D177X, D180X, H182X, S183X, Q184X, A185X, L186X, S187X, G188X, R189X, A192X, N196X a deletion selected from AM1-L12, AE36-G53, AN61-G68, AW104-G105 , AQ195-N199 , AI26-G27, or any combination thereof, where the position number designation is functionally equivalent to the position in a wild-type APOBEC3A (SEQ ID NO:3) and X is an amino acid substitution different from the wild-type amino acid at that position.[000243] In some embodiments, the ACD comprises a backbone sequence relative to SEQ ID NO:3 comprising from 102-105 130-134, or functionally equivalent positions, the sequence QTQY AHEYW, in combination with one or more combinations of stability enhancing mutations selected from: at least one of the following combinations of stabilizing mutations: R74L / C 171 A / T 19 Y / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88Q / G25K / S45W; R74L / C 171 A / T 19 Y / Gl 88 A / S45 W;R74L / C 171 A / T 19 Y / Gl 88 A / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88Q / G25K / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88 A / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / S45 W; R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08 A / Gl 88R / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25R / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G25K / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188Q / S45 W; R74L / C 171 A / T 19 Y / Gl 08C / G188 A / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25R / S45 W;R74L / C 171 A / T 19 Y / Gl 08C / G188 A / G25K / S45 W; R74L / C 171 A / T 19 Y...

Claims

CLAIMS1. An altered cytidine deaminase (ACD) comprising 5mC-selective deaminase activity, the ACD comprising selectivity-enhancing alterations at positions functionally equivalent to amino acid Y130 and P134 in a wild-type AP0BEC3A (SEQ ID NO:3).

2. The ACD of claim 1, wherein the selectivity-enhancing alterations are substitution mutations, wherein the substitution mutation at Y130 is alanine or histidine and the substitution mutation at Pl 34 is tryptophan or tyrosine, optionally wherein the substitution mutation at Y130 is alanine and the substitution mutation at P134 is tryptophan.

3. The ACD of claim 1, further comprising one or more selectivity-enhancing substitution mutations at positions functionally equivalent to amino acid D131, Y132, and D133 in the wild-type AP0BEC3 A (SEQ ID NO:3), wherein the substitution mutations are D13 IX where X is any amino acid except aspartic acid, Y132X where X is any amino acid except tyrosine, and D133X where X is any amino acid except aspartic acid.

4. The ACD of claim 2, wherein the substitution mutation at DI 31 is histidine, arginine, lysine, proline, glycine, asparagine, alanine, or valine.

5. The ACD of claim 2, wherein the substitution mutation at DI 32 is alanine, proline, aspartic acid, glutamic acid, glycine, threonine, valine, glutamine, or arginine.

6. The ACD of claim 2, wherein the substitution mutation at D133 is histidine, tyrosine, phenylalanine, threonine, isoleucine, or valine.

7. The ACD of claim 2, wherein the substitution mutation at D131 is histidine or lysine, wherein the substitution mutation at Y132 is alanine or tyrosine, and the substitution mutation at D133 is arginine or proline.

8. The ACD of claim 1, the ACD further comprising selectivity-enhancing substitution alterations at one or more of positions functionally equivalent to amino acid D131, Y132, and D133 in a wild-type AP0BEC3A (SEQ ID NO:3), wherein the amino acid sequence of Y130, D131, Y132, D133, and P134 is selected from SEQ ID NO: 125, SEQ ID NO: 126, or thesequences described in Table 2, Table 3, FIG. 4B, FIG. 8, or FIG. 9 which demonstrate increased 5mC selectivity compared to wild-type (SEQ ID NO:3).

9. The ACD of claim 7, the ACD further comprising a selectivity-enhancing alteration at L135 in the wild-type AP0BEC3A (SEQ ID NO:3), one or more of positions functionally equivalent to amino acid Y130, D131, Y132, D133, P134, and L135 in a wild-type AP0BEC3A (SEQ ID NO:3), wherein the amino acid sequence of Y130, D131, Y132, D133, P134, and L135 is selected from SEQ ID NO: 125, SEQ ID NO: 126, or the sequences described in FIG. 4B, FIG. 8, or FIG. 9 which demonstrate increased 5mC selectivity compared to wild-type (SEQ ID NO:3).

10. The ACD of claim 1 or 2, wherein the ACD further comprises selectivity-enhancing alterations at positions functionally equivalent to amino acid SI 03 and W 104 in the wild-type APOBEC3A (SEQ ID NO:3), wherein the selectivity-enhancing alterations are substitution mutations, and the substitution mutations are S103X where X is any amino acid except serine and W 104 where X is any amino acid except tryptophan.

11. The ACD of claim 10, wherein the substitution mutation at SI 03 is aspartic acid, histidine, threonine, or valine, and wherein the substitution mutation at amino acid W104 is alanine, aspartic acid, methionine, or glutamic acid.

12. The ACD of claim 10, further comprising a selectivity-enhancing alteration at amino acid G105, wherein the selectivity-enhancing alteration is a deletion of G105.

13. The ACD of claim 10 or 11, the ACD comprising selectivity-enhancing alterations at one or more of positions functionally equivalent to amino acid F102, S103, W104, G105, Y130, D131, Y132, D133, and P134 in a wild-type APOBEC3A (SEQ ID NO:3), wherein the amino acid sequence of F102, S103, W104, G105, Y130, D131, Y132, D133, and P134 is selected from SEQ ID NO: 23, SEQ ID NO:24, or the sequences described in FIG. 8 or FIG.9 which demonstrate increased 5mC selectivity compared to wild-type (SEQ ID NO:3).

14. The ACD of claim 13, the ACD further comprising a selectivity-enhancing alteration at L135 in the wild-type APOBEC3A (SEQ ID NO:3), wherein the amino acid sequence of F102, S103, W104, G105, Y130, D131, Y132, D133, P134, and L135 is selected from SEQID NO: 23, SEQ ID NO:24, or the sequences described in FIG. 8 or FIG. 9 which demonstrate increased 5mC selectivity compared to wild-type (SEQ ID NO:3).

15. The ACD of one of claims 1-9, 11, 12, or 14, further comprising two or more stabilityenhancing alterations.

16. The ACD of claim 15, wherein the two or more stability-enhancing alteration is a substitution mutation, a deletion, an insertion, or a combination thereof.

17. The ACD of claim 16, wherein the ACD comprises two or more stability-enhancing alterations are at a position functionally equivalent to amino acids selected from 117, T 19, G25, S45, A59, K60, N61, L62, L63, C64, G65, F66, Y67, G68, R74, W104, G105, G108, G108, C171, and G188 in the wild-type AP0BEC3A (SEQ ID NO:3).

18. The ACD of claim 17, wherein the at least two stability-enhancing alterations are (i) a substitution mutation, wherein the substitution mutation at 117 is threonine, at T19 is tyrosine, at G25 is lysine or arginine, at S45 is tryptophan, at A59 is proline, at K60 is arginine, at R74 is leucine, at G108 is alanine, at G108 is cytosine or alanine, at C171 is alanine, at G188 is arginine, (ii) a deletion, wherein the deletion is a deletion of W104 and G105R, a deletion of K60-G68, or (iii) any combination thereof.

19. The ACD of claim 18, wherein the ACD comprises stability-enhancing alterations comprising I17T, T19Y, G25K or G25R, S45W, A59P, K60R, deletion of K61-G68, R74L, G108C or G108A, C171A, and G188R.

20. The ACD of claim 19, wherein the ACD comprises (i) stability-enhancing alterations comprising I17T, T19Y, G25K, S45W, A59P, K60R, deletion of K61-G68, R74L, G108C, C171A, and G188R, and (ii) selectivity-enhancing alterations comprising either Y130A, D131H, Y132A, D133R, and P134W, or Y130A, D131K, D133P, and P134W.

21. The ACD of claim 20, wherein the ACD comprises stability-enhancing alterations comprising I17T, T19Y, G25K, S45W, A59P, K60R, deletion of K61-G68, R74L, G108C, C171A, and G188R, and selectivity-enhancing alterations comprising Y130A, D131H,Y132A, D133R, and P134W, and further comprises selectivity-enhancing alterations comprising S103V and W104P.

22. The ACD of claim 20, wherein the ACD comprises SEQ ID NO:23, or an amino acid sequence having at least 80% identity to SEQ ID NO:23.

23. The ACD of claim 20, wherein the ACD comprises stability-enhancing alterations comprising I17T, T19Y, G25K, S45W, A59P, K60R, deletion of K61-G68, R74L, G108C, C171A, and G188R, and selectivity-enhancing alterations comprising Y130A, D131K, D133P, and P134W, and further comprises selectivity-enhancing alterations comprising S103V, W104P, and a deletion of G105.

24. The ACD of claim 23, wherein the ACD comprises SEQ ID NO:24, or an amino acid sequence having at least 80% identity to SEQ ID NO:24.

25. An ACD-helicase complex comprising a helicase attached to an ACD of claim 1.

26. The ACD-helicase complex of claim 25, wherein the ACD and the helicase are a fusion protein.

27. The ACD-helicase complex of claim 26, wherein the fusion protein comprises a linker.

28. The ACD-helicase complex of claim 26, wherein the cytidine deaminase and the helicase are conjugated.

29. A method for deaminating a 5-methyl cytosine, comprising: providing a sample of DNA suspected of comprising single-stranded DNA comprising at least one 5-methyl cytosine (5mC); and contacting the single-stranded DNA with an ACD under conditions suitable for conversion of 5 -methylcytosine (5mC) to thymidine (T) by deamination at a greater rate than conversion of cytosine (C) to uracil (U) by deamination, to result in converted single-stranded DNA, wherein the altered cytidine deaminase is the ACD of claim 1.

30. A method for deaminating a 5-methyl cytosine, comprising: providing a sample of DNA suspected of comprising double-stranded DNA comprising at least one 5-methyl cytosine (5mC); processing the double-stranded DNA to produce a sequencing library; denaturing the sequencing library to result in a single-stranded DNA; contacting the single-stranded DNA with an ACD under conditions suitable for conversion of 5 -methylcytosine (5mC) to thymidine (T) by deamination at a greater rate than conversion of cytosine (C) to uracil (U) by deamination, to result in converted single-stranded DNA, wherein the altered cytidine deaminase is the ACD of claim 1.

31. The method of claim 29 or 30, further comprising converting the converted singlestranded DNA to a converted double-stranded DNA sequencing library.

32. A method for deaminating a 5-methyl cytosine, comprising: providing a sample of DNA suspected of comprising double-stranded DNA comprising at least one 5-methyl cytosine (5mC); contacting the double-stranded DNA with an ACD -helicase complex under conditions suitable for (i) transient conversion of at least a portion of the double-stranded DNA to single-stranded DNA, and (ii) conversion of 5-methylcytosine (5mC) to thymidine (T) by deamination at a greater rate than conversion of cytosine (C) to uracil (U) by deamination, to result in converted double-stranded DNA, wherein the altered cytidine deaminase is the ACD-helicase complex of any one of claims 25- 28; and processing the converted double-stranded DNA to produce a sequencing library.

32. A method of detecting the location of a modified cytosine in a target nucleic acid, the method comprising:(a) contacting target nucleic acids suspected of comprising at least one modified cytosine with the ACD of any one of claims 25-28 to produce converted nucleic acids comprising at least one converted methyl cytosine;(b) detecting the at least one converted methyl cytosine in the converted nucleic acids of (a).

33. A composition comprising the ACD of claim 1 or the ACD-helicase complex of any one of claims 25-28 and a suitable buffer.

34. A polynucleotide encoding the ACD of claim 1 or the ACD-helicase fusion protein of any one of claims 26-28 capable of expressing the ACD or ACD-helicase fusion.

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