NOVEL MUTATIONS THAT ENHANCE THE DNA CLESTING ACTIVITY OF ACIDAMINOCOCCUS SP CPF1.

Abstract

This description relates to polynucleotides and amino acids from Acidaminococcus sp. Cas12a (Cpf1) and methods for their use for genome editing in eukaryotic cells.

Description

NOVEL MUTATIONS THAT IMPROVE THE DNA-CLEAVING ACTIVITY OF ACIDAMINOCOCCUS SP. CPF1. FIELD OF THE INVENTION This invention relates to the ability to cleave double-stranded DNA from living organisms at precise positions with the clustered regularly interspaced short palindromic repeats ("CRISPR") nuclease / CRISPR-associated proteins 12a ("CRISPR") system. Cas12a”, (CRISPR from Prevotellay Francisella 1 (“Cpf1”)). In particular, a series of recombinant Casi2a proteins are described that are useful in a eukaryotic cell context. BACKGROUND OF THE INVENTION Cas12a is an RNA-guided endonuclease found in bacterial species, including Acidaminococcus sp., and is part of the clustered regularly interspaced short palindromic repeats (CRISPR) adaptive immune system. Cas12a is guided to a 21-24 nt DNA target sequence, or commonly referred to as a protospacer, by a 21-24 nt complementary RNA specific to the target site. The Cas12a-gRNA ribonucleoprotein (RNP) complex mediates DNA double-strand breaks (“DSBs”), which are then repaired by non-homologous end-joining (“NHEJ”). which typically introduces mutations or indels at the cleavage site) or homology directed repair (HDR) for precise editing if a suitable template nucleic acid is present. For recognition of the correct DNA target for Casi2a both the CRISPR RNA (“crRNA”) and the canonical “TTTV” protospacer adjacent motif (“PAM”) are included, which it is a 4 bp sequence immediately upstream of the protospacer. Compared to the 2-bp NGG PAM from Streptococcus pyogenes Cas9, Casi 2a expanded targetable loci in genome editing, particularly over AT-rich sites that are inaccessible to the CRISPR-associated protein 9 system (“Cas9”) , for its acronym in English). However, due to its relatively low enzymatic activity, the probability that efficient genome editing can be achieved for a given site is much lower than that of the Cas9 system, restricting its wider application. As a consequence, the Cas12a system is often considered as an alternative method only when Cas9 cannot target the genomic site. Protein modification by mutagenesis can alter the PAM sequence preference of the CRISPR system. Through a structurally guided mutagenic screen of residues in the vicinity of the PAM sequence, a previous study has identified two variants of Cpf1 from Acidaminococcus sp. (“AsCpfl ”, for its abbreviation in English) that are compatible with TYCV and TATV PAMs, respectively. Although these variants collectively expanded the targeting sites of the Cpf1 system over the coding region of the human genome by 3-fold, the utility of each individual variant is still limited, due to their mutually exclusive requirement for PAM sequences (TYCV vs. TATV vs. TTTV). ) . It is highly desirable to identify Cpf1 variants with shorter PAM and greater sequence flexibility without sacrificing activity at canonical PAM sites. Therefore, there is a need to improve the utility of Cas12a. One aspect of the present application is to improve the utility of Cpf1 by extending its compatibility with PAM. In this regard, certain novel variants of the Cas12a nuclease of Acidaminococcus sp. (“AsCas12a”) with enhanced activity. Another desired goal is to maximize delivery of the bacterial protein to the eukaryotic nucleus while avoiding disruption of basic Cas12a function. Since Cas12a is a bacterial protein, certain molecular genetic hurdles must first be overcome before successful delivery of the protein to eukaryotic cells can be achieved. This invention provides unique solutions to achieve these objectives. BRIEF DESCRIPTION OF THE INVENTION In a first aspect, there is provided a CRISPR-associated protein comprising a polypeptide encoding a variant of AsCpfl. The AsCpfl variant is selected from the group consisting of M537R (SEQ ID NO.: 472), F870L (SEQ ID NO.: 473), and M537R / F870L (SEQ ID NO.: 465). In a second aspect, a CRISPR ribonucleoprotein complex is provided. The CRISPR ribonucleoprotein complex includes a guide RNA and a CRISPR-associated protein. CRISPR-associated protein including a polypeptide encoding a variant of AsCpfl. The AsCpfl variant is selected from the group consisting of M537R (SEQ ID NO.: 472), F870L (SEQ ID NO.: 473), and M537R / F870L (SEQ ID NO.: 465). In a third aspect, a method is provided for increasing the efficiency of gene editing at TTTN PAM sites in a cell with a CRISPR ribonucleoprotein complex. The method includes the step of contacting a cell with the CRISPR ribonucleoprotein complex. The CRISPR ribonucleoprotein complex includes a guide RNA and a CRISPR-associated protein. CRISPR-associated protein including a polypeptide encoding a variant of AsCpfl. The AsCpfl variant is selected from the group consisting of M537R (SEQ ID NO.: 472), F870L (SEQ ID NO.: 473), and M537R / F870L (SEQ ID NO.: 465). In a fourth aspect, a kit is provided comprising a guide RNA and a CRISPR-associated protein. The CRISPR-associated protein includes a polypeptide encoding a variant of AsCpfl. In a fifth aspect, the CRISPR-associated protein comprising a polypeptide encoding an AsCas12a variant, wherein the AsCas12a variant is selected from the group consisting of at least one amino acid variant selected from cpQ / bn / Lznza positions / YiAi amino acids 499-640 and 840-913, provided that the AsCas12a variant provides enhancement in CRISPR / AsCas12a-associated nuclease activity at non-canonical RAM TTTT sites. In a sixth aspect, a CRISPR ribonucleoprotein complex is provided. The CRISPR ribonucleoprotein complex includes a guide RNA and a CRISPR-associated protein. The CRISPR-associated protein includes a polypeptide encoding an AsCas12a variant, wherein the AsCas12a variant is selected from the group consisting of at least one amino acid variant selected from amino acid positions 499-640 and 840-913, provided that the AsCas12a variant provides an enhancement in CRISPR / AsCas12a-associated nuclease activity at non-canonical TTTT PAM sites. In a seventh aspect, a method is provided for increasing the efficiency of gene editing at non-canonical TTTT PAM sites in a cell with a CRISPR ribonucleoprotein complex. The method includes a step of contacting a cell with the CRISPR ribonucleoprotein complex that includes a guide RNA and a CRISPR-associated protein. The CRISPR-associated protein includes a polypeptide encoding an AsCas12a variant, wherein the AsCas12a variant is selected from the group consisting of at least one amino acid variant selected from amino acid positions 499-640 and 840-913, provided that the AsCas12a variant provides an enhancement in CRISPR / AsCas12a-associated nuclease activity at non-canonical TTTT PAM sites. In an eighth aspect, a kit is provided that includes a guide RNA and a CRISPR-associated protein comprising a polypeptide encoding a variant of AsCas12a. The AsCas12a variant is selected from the group consisting of at least one amino acid variant selected from amino acid positions 499-640 and 840-913, provided that the AsCas12a variant provides enhancement in CRISPR / AsCas12a-associated nuclease activity at sites TTTT PAM non-canonical. In a ninth aspect, there is provided a nucleic acid encoding a CRISPR-associated protein comprising a polypeptide encoding a variant of AsCas12a. The AsCas12a variant is selected from the group consisting of at least one amino acid variant selected from amino acid positions 499-640 and 840-913, provided that the AsCas12a variant provides enhancement in CRISPR / AsCas12a-associated nuclease activity at sites TTTT PAM non-canonical. In a tenth aspect, a polynucleotide sequence encoding a Casi2a polypeptide is provided. The polynucleotide sequence includes a member selected from the group consisting of SEQ ID NOs.: 5-17. In an eleventh aspect, an amino acid sequence encoding a Cas12a polypeptide is provided. The amino acid sequence includes a member selected from the group consisting of SEQ ID NOs.: 18-30. cMQ / bn / Lznza / YiAi In a twelfth aspect, there is provided a CRISPR-associated endonuclease ("CAS") system comprising an expression cassette encoding a polynucleotide sequence encoding a Cas12a polypeptide. Includes a member selected from the group consisting of SEQ ID NOs.: 5-17. In a thirteenth aspect, a CAS endonuclease system is provided comprising an amino acid sequence encoding a Cas12a polypeptide. The amino acid sequence includes a member selected from the group consisting of SEQ ID NOs.: 1830. In a fourteenth aspect, a method for performing genome editing in eukaryotic cells is provided. The method includes the step of introducing a CAS endonuclease system into the eukaryotic cell, said CAS endonuclease system comprising an expression cassette encoding a polynucleotide sequence encoding a Cas12a polypeptide, comprising a member selected from the group consisting of SEQ ID Nos.: 517. In a fifteenth aspect, a method for performing genome editing in a eukaryotic cell is provided. The method includes the step of introducing a CAS endonuclease system into the eukaryotic cell, said CAS endonuclease system comprising an amino acid sequence encoding a Casi 2a polypeptide comprising a member selected from the group consisting of SEQ ID NOs.: 18- 30. In a sixteenth aspect, there is provided a CRISPR-associated protein comprising a fusion polypeptide. The fusion polypeptide includes an AsCas12a open reading frame, a nuclear localization signal, optionally an amino acid linker, and optionally an affinity tag. In a seventeenth aspect, a method for performing genome editing in a eukaryotic cell is provided. The method includes the step of introducing a CAS endonuclease system into the eukaryotic cell, said CAS endonuclease system comprising a CRISPR-associated protein according to the sixteenth aspect. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 depicts multiple recombinant forms of Casi2a that produce a spectrum of editing efficiencies. A series of recombinant Cas12a proteins with different composition and arrangement of nuclear localization signal sequences ("NLS"), purification tags and linkers (A-M; corresponding to SEQ ID NOs) were cloned and purified to homogeneity. .: 18-30). The resulting purified Cas12a derivatives were delivered into HEK293 cells by complexed electroporation with RNA guides targeting the HPR7--38186 (SEQ ID NO.:1) and HPRT38228 (SEQ ID NO.:2) loci. DNA was isolated from genome editing experiments 48 hours later, and editing efficiencies were determined by reaction amplification in Q / Q / frOI 707 -1 / ΥΙΛΙ polymerase chain ("PCR") of edited loci using HPRT-FWD (SEQ ID NO.: 3) and HPRT-REM (SEQ ID NO. .: 4) and the Alt-R Genome Editing Detection Kit (Integrated DNA Technologies). The following abbreviations apply to the illustrated constructs: V5 refers to the V5 epitope tag (SEQ ID NO.: 485); SV40 refers to a nuclear localization signal of the simian virus SV40 large tumor antigen (SEQ ID NO.: 475); Casi2a refers to a Casi2a coding sequence; HIS refers to a hexahistidine tag (SEQ ID NO.: 487); OpT refers to an optimized nuclear localization signal (SEQ ID NO.: 477); aNLS refers to alternative nuclear localization signal (SEQ ID NO.: 479); BIP1 refers to a first bipartite nuclear localization signal (SEQ ID NO.: 481); and BIP2 refers to a second bipartite nuclear localization signal (SEQ ID NO.: 483). The arrows provided in the constructs represent the transcriptional start sites for mRNA transcripts originating from DNA. Figure 2 shows exemplary results of M537R and F870L mutations with enhanced Cpf1 cleavage activity in a bacterial-based activity assay. Screening E. coli strains were transformed with Cpf1 expression vectors and crRNA targeted to the HPRT-38346 site on the toxin expression plasmid. The apparent activity of Cpf1 for TTTT or TTTC PAM can be estimated by the number of surviving colonies under arabinose selection when an equivalent amount of plasmids is administered. Clearly, both mutations increased the survival rate at the TTTC and TTTT PAM sites, indicating enhanced cleavage activity relative to wild-type Cpf 1 ("WT-Cpf1"). Figure 3A shows an exemplary sodium dodecyl sulfate-polyacrylamide gel electrophoresis ("SDS-PAGE") analysis of AsCpfl variants used in the in vitro cleavage assay and subsequent genome editing in human cell lines. . The indicated amount of protein was loaded and no difference was observed compared to WT-Cpf1. These results demonstrate that the M537R and F870L mutations can increase the in vitro cleavage activity of Cpf1 at the non-tapered TTTT PAM site while maintaining high activity at the canonical TTTV site. Figure 3B shows exemplary DNA cleavage activities of Cpf1 variants at the HPRT-38346 site with TTTC or TTTT PAM. Both variants resulted in a higher percentage of DNA cleavage at the TTTT PAM site than WT-Cpf1. These results demonstrate that the M537R and F870L mutations can increase the in vitro cleavage activity of Cpf1 at the non-tapered TTTT PAM site while maintaining high activity at the canonical TTTV site. Figure 4 shows a summary of results showing exemplary results from M537R and F870L mutations that have greatly improved targeting efficiency. Genomic Qyq / bn / Lznza / YiAi of AsCpfl at TTTN PAM sites in the human cell line. Genomic targeting efficiencies of Cpf1 variants were tested in a human cell line model using the T7 endonuclease I ("T7EI") assay. Twenty-four crRNAs targeting the CTNNB1 gene were synthesized with TTTN PAMs, assembled with Cpf1 variants as RNP complex, and delivered by nucleofection (Lonza). Genomic DNA was collected 48 hours after administration to assess indel formation by Τ7ΕΙ. Not only did it allow DNA cleavage at all TTTT PAM sites, many of which could not be targeted by WT-Cpf1, the reported variants, particularly the double mutant (M537R / F870L), greatly improved the targeting efficiency of Cpf1 in 22 of 24 sites tested independently of the PAM sequence. Figure 5A shows an exemplary correlation of the relative survival rate of M537R / F870L-AsCas12a in condition 1 (X axis) versus the relative survival rate of M537R / F870L-AsCas72a condition 2 (Y axis). A consistent phenotype measurement (p ~ 0.7) was obtained. Figure 5B shows an exemplary correlation of the relative survival rate of M537R / F870L-AsCas12a in condition 1 (X-axis) versus the relative survival rate of WT-AsCas12a in condition 3 (Y-axis). A consistent phenotype measurement (p ~ 0.7) was obtained. Figure 5C shows an exemplary correlation of the relative survival rate of M537R / F870L-AsCas12a in condition 2 (X-axis) versus the relative survival rate of WT-AsCas12a in condition 2 (Y-axis). A consistent phenotype measurement (p ~ 0.7) was obtained. Figure 5D shows phenotype exemplary variant scores (relative survival rate) of single point mutations of a selected number of AsCas12a at positions 537 and 870 under conditions 1 and 2. Figure 5E shows exemplary phenotype variant scores (relative survival rate) of single point mutations of a selected number of AsCas12a at positions 537 and 870 under conditions 1 and 2. Figure 5D and Figure 5E show that M537R and F870L are the optimal substitutions at the respective positions, which is consistent with the result of our screening and characterization of previous mutants. Figure 5F shows phenotype exemplary variant scores (relative survival rate) of single point mutations of a selected number of AsCas12a at positions 505, 510, 569 and 599 under conditions 1, 2 and 3. Figure 6A shows the survival rate of E. coli resulting from the DNA cleavage activity of WT-AsCas12a in TTTT PAM. The cleavage activity of the AsCas12a variants at the TTTT PAM site was measured by a bacteria-based activity assay. Q / Q / frOI 707 -1 / ΥΙΛΙ The Petri dish with the initial bacterial plate is shown on the left, while the Petri dish with the surviving bacterial colonies is shown on the right. Survival of E. coli under selection depends on successful cleavage of a toxin-expressing plasmid containing a TTTT PAM site. Figure 6B shows the survival rate of E. coli resulting from the DNA cleavage activity of the L505K-AsCas12a variant in TTTT PAM. The presentation of the Petri dishes and the experimental details are as shown in Figure 6A. Figure 6C shows the survival rate of E. coli resulting from the DNA cleavage activity of the S510L-AsCas12a variant in TTTT PAM. The presentation of the Petri dishes and the experimental details are as shown in Figure 6A. Figure 6D shows the survival rate of E. coli resulting from the DNA cleavage activity of the M537R-AsCas12a variant in TTTT PAM. The presentation of the Petri dishes and the experimental details are as shown in Figure 6A. Figure 6E shows the E. coli survival rate resulting from the DNA cleavage activity of the P569D-AsCas12a variant in TTTT PAM. The presentation of the Petri dishes and the experimental details are as shown in Figure 6A. Figure 6F shows the survival rate of E. coli resulting from the DNA cleavage activity of the P599G-AsCas12a variant in TTTT PAM. The presentation of the Petri dishes and the experimental details are as shown in Figure 6A. Figure 7A shows the survival rate of E. coli resulting from M537R / F870L-AsCas12a DNA cleavage activity in TTTT PAM. The cleavage activity of the M537R / F870L-AsCas12a variants at the TTTT PAM site was measured by a bacteria-based activity assay. The Petri dish with the initial bacterial plate is shown on the left, while the Petri dish with the surviving bacterial colonies is shown on the right. Survival of E. coli under selection depends on successful cleavage of a toxin-expressing plasmid containing a TTTT PAM site. Figure 7B shows the survival rate of E. coli resulting from the DNA cleavage activity of the L505K / M537R / F870L-AsCas12a variant in TTTT PAM. The presentation of the Petri dishes and the experimental details are as shown in Figure 7A. Figure 70 shows the survival rate of E. coli resulting from the DNA cleavage activity of the M537R / F870L-AsCas12a variant in TTTT PAM. The presentation of the Petri dishes and the experimental details are as shown in Figure 7A. Figure 7D shows the survival rate of E. coli resulting from the DNA cleavage activity of the P569D / M537R / F870L-AsCas12a variant in TTTT PAM. The presentation of the Petri dishes and the experimental details are as shown in Figure 7A. Q / Q / bn / Lznza / YiAi Figure 7E shows the survival rate of E. coli resulting from the DNA cleavage activity of the P599G / M537R / F870L-AsCas12a variant in TTTT PAM. The presentation of the Petri dishes and the experimental details are as shown in Figure 7A. Figure 7F shows the survival rate of E. coli resulting from the DNA cleavage activity of the S510L / M537R / F870L-AsCas12a variant in TTTT PAM. The presentation of the Petri dishes and the experimental details are as shown in Figure 7A. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to Cas12a variant compositions and methods for improving the utility of Cas12a and variants thereof for expression in eukaryotic cells. Definitions When elements of aspects of the description or particular modalities are introduced, the articles "a", "a", "the", "the" and "said" are intended to signify that there is one or more of the elements. The terms "comprising", "including" and "having" are intended to be inclusive and mean that there may be additional items other than the items listed. The term "or" means any member of a particular list and also includes any combination of members of that list, unless otherwise specified. As intended herein, the terms "substantially," "approximately," and "about," as well as similar terms, are intended to have a broad meaning consistent with common and accepted usage in the art to which the subject matter of this article pertains. description. Those skilled in the art reviewing this description should understand that these terms are intended to permit a description of certain described and claimed features without restricting the scope of these features to precise numerical ranges provided. Accordingly, these terms are to be construed as indicating that insubstantial or inconsequential modifications or alterations to the described and claimed subject matter are considered to be within the scope of the invention as set forth in the appended claims. Definitions relating to certain terms and phrases applicable herein can be found in related US patents and publications, such as US patent applications Serial Numbers 14 / 975,709, 15 / 299,549, 15 / 299,590, 15 / 299,593, 15 / 881,684, 15 / 729,491, 15 / 821,736, 15 / 964,041, 15 / 839,817, 15 / 839,820, 62 / 716,138, and US Patent No. 9,840 .702. The term "substantially purified," as applied to a composition, refers to a composition that is at least 90% pure or greater, including 90% pure, 95% pure, 99% pure, and greater than 99% pure. of purity. Qyg / bn / Lznza / YiAi The adjective "isolated" when modifying a composition, such as a polynucleotide, polypeptide, or ribonucleoprotein complex, refers to a substantially purified composition, or in the case of a ribonucleoprotein complex, where at least one component is a substantially purified component. With respect to an isolated ribonucleoprotein complex, preferably all components are substantially purified. The terms "nucleic acid" and "polynucleotide" are interchangeable and have the same meaning. The terms "amino acid sequence", "polypeptide" and "protein" are interchangeable and have the same meaning. The term "affinity tag" refers to a ligand that allows detection and / or selection of an oligonucleotide sequence to which the ligand binds. For the purposes of this description, a bait may include an affinity tag. In particular, the affinity tag is typically placed at one or both of the N' and / or C' termini of a polypeptide using conventional chemical coupling technology or recombinant DNA technology. Exemplary affinity tags include biotin, digoxigenin, streptavidin, polyhistine (eg, (His6)), glutathione-S-transferase (GST), HaloTag®, AviTag, calmodulin tag, polyglutamate tag, FLAG tag, HA tag, Myc-tag, S-tag, SBP-tag, Softag 3, V5 tag, Xpresstag, a hapten, among others. The term "eukaryotic cell" includes those cells of or derived from a particular organism, such as a plant or mammal, including, but not limited to, human or non-human eukaryotic cells, or human animal or mammalian cells, as described herein, for example, mouse, rat, rabbit, dog, cattle, or non-human mammal or primate. In some embodiments, processes to modify the genetic identity of the germ line of humans and / or processes to modify the genetic identity of animals that are likely to cause them suffering without any substantial medical benefit to man or animal, and also the animals resulting from said processes can be excluded. Preferred human cells include cells derived from somatic cells and germ line cells. Exemplary somatic cells include cells from all major organ and tissue systems, including the immune system and the hematopoietic system. As set forth herein, Conditions 1, 2, and 3 refer to different combinations of background strain and the amounts of gRNA introduced into the background strain prior to selection of variants. Condition 1 is a background of M537R / F870L including an introduced amount of gRNA (100 pmol per 10 microliter transformation / overlay experiment) in which variants were selected. Condition 2 is a background of M537R / F870L including an introduced amount of gRNA (50 pmol per 10 microliter transformation / overlay experiment) in which variants were selected. The Q / Q / frOI 707 -1 / ΥΙΛΙ condition 3 is a background of wild-type AsCpfl including an introduced amount of gRNA (200 pmol per 10 microliter transformation / overlay experiment) in which variants were selected. Casi2a polypeptides with eukaryotic nuclear localization signals Since Casi 2a is a bacterial protein, it does not have a native targeting mechanism to reach the eukaryotic nucleus, where the target DNA resides. To more efficiently direct proteins to the eukaryotic nucleus, short protein sequences called nuclear localization signals (NLS) are commonly added to the amino or carboxy termini of a given open reading frame. NLSs are recognized by imported proteins in the eukaryotic nuclear envelope that first bind to the nuclear membrane and subsequently allow translocation of the pores into the nucleus by an energy-dependent process. While recombinant protein tags such as an NLS can greatly improve localization, any addition of exogenous amino acid sequences has a reasonable chance of perturbing protein function. As such, the discovery of a recombinant Casi2a protein sequence that facilitates the greatest amount of nuclear delivery without adversely affecting its activity will ultimately result in the most powerful Casi2a genome editing solution, which is non-trivial and highly desirable. To improve the nuclear delivery of Cas12a without perturbing its function, several different recombinant versions of Casi2a were constructed in which the identity, location, and number of protein tags (NLS, hexahistidine tag (an exemplary affinity tag)) were varied. While hexahistidine and V5 tags were added to the Cas12a constructs to aid in protein purification and / or detection, NLS tags were added to aid in delivery to the eukaryotic nucleus. The domain-breaking linker sequences were also varied in composition and location to empirically determine the best arrangement and context of the tagged sequences. All constructs were first expressed in E. coli, and recombinant Casi2a proteins were purified with immobilized metal affinity chromatography ("IMAC") followed by ion exchange chromatography as previously described. AsCpfl polypeptide variants with novel cleavage activities Amino acid substitutions in AsCpfl that enhance cleavage activity at canonical (TTTV) and non-canonical (TTTT) PAM sites are described using a bacterial screening approach. This screen contained two components: i) a toxin plasmid encoding an arabinose-inducible cell proliferation toxin and a cleavage site in the CRISPR / Cpf1 target (HPRT-38346) with TTTT PAM, and ii) a resistance plasmid to arabinose. chloramphenicol containing a region within the AsCpfl sequence (~5 mutations per kb). Screening was performed as follows: E. coli BW25141 (ADE3) was transformed with the cMQ / bn / Lznza / YiAi toxin plasmid containing the HPRT-38346 target site in the absence of arabinose, where no arabinose occurs. the toxin and cell survival is allowed. Cells with the stably replicating toxin plasmid are subsequently transformed with the AsCpfl expression plasmid and crRNA targeting HPRT-38346, and cells are subsequently plated with media containing both chloramphenicol and arabinose. Bacteria that grew were those that i) were successfully transformed with the AsCpfl expression plasmid, i¡) expressed enough AsCpfl variant to cleave the plasmid from the toxin at the HPRT-38346 site using TTTT PAM. AsCpfl expression plasmids within surviving cells were recovered and used in the next round of selection. After multiple rounds of selection, the identities of the enriched AsCpfl variants were determined by DNA sequencing and carried forward for analysis in mammalian cells. The disclosure provides the following two novel point mutations and combination in the AsCpfl gene that improve cleavage activity: M537R and F870L. The cleavage activity of an individual mutant was first tested in a bacterial-based activity assay. The purified proteins were then further tested in vitro and in human cell lines. In summary, both substitutions significantly enhanced Cpf1 DNA cleavage activity at TTTT PAM sites in all assays. Furthermore, the combination of M537R and F870L greatly improved the targeting efficiency of AsCpfl in the human cell line. In general, the present invention identifies novel amino acid positions in the AsCpfl gene that can be mutated to enhance its cleavage activity at all TTTN (N = A / G / C / T) PAM sites. As explained in the Background section, the prior art consists of using wild-type Cpf1 protein or two variants that are compatible with TYCV and TATV PAMs. As noted above, these variants have limited utility due to the complex and mutually exclusive requirement for the PAM sequence. Furthermore, none of the variants showed enhanced cleavage activity at TTTT PAM, which unfortunately is more frequent than other TTTV PAM sites (V = G / A / C) throughout the human genome. In contrast, the mutations reported in this invention (M537R and F870L) not only allow efficient cleavage in TTTT PAM, they also greatly enhance Cpf1 cleavage activity at the canonical TTTV sites analyzed in the human cell line. Taken together, the enhanced activity and expanded PAM flexibility (TTTN) of this invention make it a superior CRISPR enzyme, which could directly replace the current wild-type Cpf1 in application genomic editing. High-throughput generation of AsCas12a variants that have cleavage activity towards a TTTT PAM-containing target site. Q / a / frn / Lznza / YiAi The phenotype of all point mutations in the following regions of AsCas12a are described: 499-640 and 840-913 in the bacterial screen measuring DNA cleavage activity in non-canonical TTTT PAM. Three sets of screening were performed to measure the phenotype of each point mutation, in the context of WT-AsCas12a and M537R / F870L-AsCas12a. Cross-comparison of three data sets revealed consistent phenotype measurements, allowing us to isolate novel AsCas12a variants with enhanced activity beyond M537R and F870L. High-throughput characterization of Casi2a activity at a TTTT PAM site provided the functional consequence of each possible amino acid change within the target region. The unbiased approach of the present invention allows the identification of a large collection of mutants to further improve AsCas12a cleavage activity over our previous invention (M537R / F870L). To improve the coverage and efficiency of screening, we generated an AsCas12a deep-scanning mutagenesis library containing all possible point mutations at the protein level in the target regions (490-640 and 840-913), and most of them. clones contain only one mutation. This type of library allowed us to directly assess the phenotype of each point mutation, measuring their relative survival rates over the reference protein in the bacterial screen. Briefly, the screening strain harboring the toxin plasmid was transformed with the AsCas12a library with the TTTT PAM-containing target site on the toxin plasmid. After transformation, cells were plated with selective medium. The AsCas12a expression plasmids carried by the surviving E. coli cells were extracted and purified. Both the input and selected plasmid libraries were amplified by PCR and sequenced on the lllumina MiSeq with 1~2 million reads per library. The frequencies of each AsCas12a variant in both libraries were determined using Enrich 2 and normalized to the reference protein (WT or M537R / F870L). The relative survival rate of each point mutation over the control was calculated as the normalized frequency ratio between the selected library and the input library. Since the degree of cell survival is indicative of the DNA cleavage activity of each AsCas12a variant, any variant with a higher survival rate than the reference protein would be the one with enhanced activity in TTTT PAM. As presented herein, codon-optimized Casi2a polypeptides are provided, including codon-optimized Casi2a polypeptides for CRISPR ribonucleoprotein complexes. An example of a codon-optimized sequence is in this case a sequence optimized for expression in eukaryotes, eg, humans (i.e., optimized for expression in humans), or for another eukaryote, animal or mammal as described. described herein. While this is preferred, it will be understood that other examples are possible cMQ / bn / Lznza / YiAi and codon optimization for a host species other than human, or for codon optimization for specific organs is known. In some embodiments, an enzyme-coding sequence encoding a CRISPR Cas12a polypeptide is codon-optimized for expression in particular cells, such as eukaryotic cells. Eukaryotic cells may be cells of or derived from a particular organism, such as a plant or mammal, including, but not limited to, human or non-human, or animal or mammalian eukaryotic cells, as described herein. eg, mouse, rat, rabbit, dog, cattle, or non-human mammal or primate. In some embodiments, processes to modify the genetic identity of the germ line of humans and / or processes to modify the genetic identity of animals that are likely to cause them suffering without any substantial medical benefit to man or animal, and also the animals resulting from said processes can be excluded. Preferred human cells include cells derived from somatic cells and germ line cells. Exemplary somatic cells include cells from all major organ and tissue systems, including the immune system and the hematopoietic system. In general, codon optimization refers to a process of modifying a nucleic acid sequence for improved expression in the host cells of interest by replacing at least one codon (for example, about or more than about 1, 2, 3 , 4, 5, 10, 15, 20, 25, 50 or more codons) of the native sequence with the codons that are most frequently used or most frequently used in the genes of that host cell while maintaining the native amino acid sequence. Various species display a particular bias for certain codons of a particular amino acid. Codon bias (differences in codon usage between organisms) is often correlated with the efficiency of messenger RNA (mRNA) translation, which in turn is thought to depend on, among other things, the properties of codons. that are translated and the availability of particular transfer RNA (tRNA) molecules. The dominance of selected tRNAs in a cell is generally a reflection of the most frequently used codons in peptide synthesis. Accordingly, genes can be tailored for optimal gene expression in a given organism based on codon optimization. Codon usage tables are available. See Nakamura, Y., et al. “Codon usage tabulated from the International DNA sequence databases: status for the year 2000” Nucí. Acids Res. 28:292 (2000). Computer algorithms for codon optimization of a particular sequence for expression in a particular host cell are also available, such as Gene Forge (Aptagen; Jacobus, Pa). In some embodiments, one or more codons (eg, 1, 2, 3, 4, 5, 10, 15, 20, 25, 50 or more, or all codons) in a 2a-encoding sequence correspond to the codon most frequently used, for a particular amino acid. Q;Q / frOI 707 -1 / ΥΙΛΙ In addition, codon-optimized Cas12a polypeptides are provided, including codon-optimized Cas12a polypeptides for CRISPR ribonucleoprotein complexes, wherein the Casi 2a polypeptide sequence is optimized for expression in prokaryotes, such as bacteria (eg, E. coli). . Applications This invention is useful for basic research or therapeutic fields for any CRISPR / Cas12a gene editing and / or DNA cleavage experiments or treatments. The superior activity of these recombinant variants could apply to Cas12a from any species or potentially any CRISPR enzyme. In a first aspect, there is provided a CRISPR-associated protein comprising a polypeptide encoding a variant of AsCpfl. The AsCpfl variant is selected from the group consisting of M537R (SEQ ID NO.: 472), F870L (SEQ ID NO.: 473), and M537R / F870L (SEQ ID NO.: 465). In a first aspect, the CRISPR-associated protein corresponding to an AsCpfl variant is M537R. In a second aspect, the CRISPR-associated protein corresponding to an AsCpfl variant is F870L (SEQ ID NO.: 473). In a third aspect, the CRISPR-associated protein corresponding to an AsCpfl variant is M537R / F870L (SEQ ID NO.: 465). In a second aspect, a CRISPR ribonucleoprotein complex is provided. The CRISPR ribonucleoprotein complex includes a guide RNA and a CRISPR-associated protein. CRISPR-associated protein including a polypeptide encoding a variant of AsCpfl. The AsCpfl variant is selected from the group consisting of M537R (SEQ ID NO.: 472), F870L (SEQ ID NO.: 473), and M537R / F870L (SEQ ID NO.: 465). In a first aspect, the CRISPR ribonucleoprotein complex includes the variant of AsCpfl which is M537R. In a second aspect, the CRISPR ribonucleoprotein complex includes the AsCpfl variant which is F870L (SEQ ID NO.: 473). In a third aspect, the CRISPR ribonucleoprotein complex includes the AsCpfl variant which is M537R / F870L (SEQ ID NO.: 465). In a third aspect, a method is provided for increasing the efficiency of gene editing at TTTN PAM sites in a cell with a CRISPR ribonucleoprotein complex. The method includes the step of contacting a cell with the CRISPR ribonucleoprotein complex. The CRISPR ribonucleoprotein complex includes a guide RNA and a CRISPR-associated protein. CRISPR-associated protein including a polypeptide encoding a variant of AsCpfl. The AsCpfl variant is selected from the group consisting of M537R (SEQ ID NO.: 472), F870L (SEQ ID NO.: 473), and M537R / F870L (SEQ ID NO.: 465). In a first aspect, the TTTN PAM sites consist of one selected from the group of TTTA, TTTT and TTTC PAM sites. In a fourth aspect, a kit includes a guide RNA and a CRISPR-associated protein is provided. The CRISPR-associated protein includes a polypeptide encoding a variant of ayq / bn / Lznza / YiAi AsCpfl. The AsCpfl variant is selected from the group consisting of M537R (SEQ ID NO.: 472), F870L (SEQ ID NO.: 473), and M537R / F870L (SEQ ID NO.: 465). In a first aspect, the AsCpfl variant is M537R. In a second aspect, the AsCpfl variant is F870L (SEQ ID NO.: 473). In a third aspect, the AsCpfl variant is M537R / F870L (SEQ ID NO.: 465). In a fifth aspect, a CRISPR-associated protein comprising a polypeptide encoding an AsCas12a variant, wherein the AsCas12a variant is selected from the group consisting of at least one amino acid variant selected from amino acid positions 499-640 and 840-913, provided that the AsCas12a variant provides an enhancement in CRISPR / AsCas12a-associated nuclease activity at non-canonical TTTT PAM sites. In a first aspect, the AsCas12a variant is selected from the group consisting of SEQ ID NOs.: 59-245. In a second aspect, the AsCas12a variant, as described in the first aspect or in the first aspect above the first aspect, further comprises M537R / F870L mutations (SEQ ID NO.: 465). In a sixth aspect, a CRISPR ribonucleoprotein complex is provided. The CRISPR ribonucleoprotein complex includes a guide RNA and a CRISPR-associated protein. The CRISPR-associated protein includes a polypeptide encoding an AsCas12a variant, wherein the AsCas12a variant is selected from the group consisting of at least one amino acid variant selected from amino acid positions 499-640 and 840-913, provided that the AsCas12a variant provides an enhancement in CRISPR / AsCas12a-associated nuclease activity at non-canonical TTTT PAM sites. In a first aspect, the AsCas12a variant is selected from the group consisting of SEQ ID NOs.: 59-245. In a second aspect, the AsCas12a variant, as described in the second aspect or in the first aspect above of the second aspect, further comprises M537R / F870L mutations (SEQ ID NO.: 465). In a seventh aspect, a method is provided for increasing the efficiency of gene editing at non-canonical TTTT PAM sites in a cell with a CRISPR ribonucleoprotein complex. The method includes a step of contacting a cell with the CRISPR ribonucleoprotein complex that includes a guide RNA and a CRISPR-associated protein. The CRISPR-associated protein includes a polypeptide encoding an AsCas12a variant, wherein the AsCas12a variant is selected from the group consisting of at least one amino acid variant selected from amino acid positions 499-640 and 840-913, provided that the AsCas12a variant provides an enhancement in CRISPR / AsCas12a-associated nuclease activity at non-canonical TTTT PAM sites. In a first aspect, the AsCas12a variant is selected from the group consisting of SEQ ID NOs.: 59-245. In a second aspect, the AsCas12a variant, as described in the third aspect or in the first aspect above of the third aspect, further comprises M537R / F870L mutations (SEQ ID NO.: 465). a / Q / bn / Lznza / YiAi 1β In an eighth aspect, a kit is provided that includes a guide RNA and a CRISPR-associated protein comprising a polypeptide encoding a variant of AsCas12a. The AsCas12a variant is selected from the group consisting of at least one amino acid variant selected from amino acid positions 499-640 and 840-913, provided that the AsCas12a variant provides enhancement in CRISPR / AsCas12a-associated nuclease activity at sites TTTT PAM non-canonical. In a first aspect, the AsCas12a variant is selected from the group consisting of SEQ ID NOs.: 59-245. In a second aspect, the AsCas12a variant, as described in the third aspect or in the first aspect above of the third aspect, further comprises M537R / F870L mutations (SEQ ID NO.: 465). In a ninth aspect, there is provided a nucleic acid encoding a CRISPR-associated protein comprising a polypeptide encoding a variant of AsCas12a. The AsCas12a variant is selected from the group consisting of at least one amino acid variant selected from amino acid positions 499-640 and 840-913, provided that the AsCas12a variant provides enhancement in CRISPR / AsCas12a-associated nuclease activity at sites TTTT PAM non-canonical. Highly preferred nucleic acids encoding a CRISPR-associated protein include isolated nucleic acids encoding a CRISPR-associated protein. In a first aspect, the AsCas12a variant is selected from the group consisting of SEQ ID NOs.: 59-245. In a second aspect, the AsCas12a variant further includes M537R / F870L mutations (SEQ ID NO.: 465). In a second aspect, the AsCas12a variant further includes M537R / F870L mutations (SEQ ID NO.: In a fourth aspect, the nucleic acid is DNA or RNA. In a tenth aspect, a polynucleotide sequence encoding a Casi2a polypeptide is provided. The polynucleotide sequence includes a member selected from the group consisting of SEQ ID NOs.: 5-17. In an eleventh aspect, an amino acid sequence encoding a Cas12a polypeptide is provided. The amino acid sequence includes a member selected from the group consisting of SEQ ID NOs.: 18-30. In a twelfth aspect, there is provided a CAS endonuclease system comprising an expression cassette encoding a polynucleotide sequence encoding a Casi2a polypeptide. Includes a member selected from the group consisting of SEQ ID NOs.: 5-17. In a thirteenth aspect, a CAS endonuclease system is provided comprising an amino acid sequence encoding a Cas12a polypeptide. The amino acid sequence includes a member selected from the group consisting of SEQ ID NOs.: 1830. cMQ / bn / Lznza / YiAi In a fourteenth aspect, a method for performing genome editing in eukaryotic cells is provided. The method includes the step of introducing a CAS endonuclease system into the eukaryotic cell, said CAS endonuclease system comprising an expression cassette encoding a polynucleotide sequence encoding a Cas12a polypeptide, comprising a member selected from the group consisting of SEQ ID Nos.: 517. In a fifteenth aspect, a method for performing genome editing in a eukaryotic cell is provided. The method includes the step of introducing a CAS endonuclease system into the eukaryotic cell, said CAS endonuclease system comprising an amino acid sequence encoding a Casi2a polypeptide comprising a member selected from the group consisting of SEQ ID NOs.: 18-30 . In a sixteenth aspect, there is provided a CRISPR-associated protein comprising a fusion polypeptide. The fusion polypeptide includes an AsCas12a open reading frame, a nuclear localization signal, optionally an amino acid linker, and optionally an affinity tag. Highly preferred CRISPR-associated proteins include isolated CRISPR-associated proteins. In a first aspect, the AsCas12a open reading frame is selected from the group consisting of SEQ ID NOs.: 59-245. In a first aspect, the AsCas12a open reading frame is selected from the group consisting of SEQ ID NOs: 475, 477, 479, 481 and 483. In a third aspect, the CRISPR-associated protein is encoded by SEQ ID NOs .: 488-491. In a fourth aspect, the CRISPR-associated protein is selected from SEQ ID NOs.: 492 and 493. In a seventeenth aspect, a method for performing genome editing in a eukaryotic cell is provided. The method includes the step of introducing a CAS endonuclease system into the eukaryotic cell, said CAS endonuclease system comprising a CRISPR-associated protein according to the sixteenth aspect. Highly preferred CRISPR-associated proteins include isolated CRISPR-associated proteins. EXAMPLES Example 1. Recombinant Cas12a proteins with different tags / linker sequences produce a spectrum of editing efficiencies The following example demonstrates that recombinant Cas 12a proteins with only modest changes in the amino- and carboxy-terminal tag sequences result in proteins that demonstrate a wide range of editing efficiencies in human cells (Figure 1). Briefly, the site-directed mutagenesis ("SDM") method was employed to create the expression constructs having As Cas12a coding sequences with different nuclear localization signals (NLS). Site-directed mutagenesis was performed by designing complementary primers spanning the base changes. Qyq / bn / Lznza / YiAi of desired nucleotides, together with the flanking plasmid vector sequence, wherein each flanking region has a melting temperature ("Tm") of at least 60°C. A polymerase chain reaction (PCR) test was then performed using standard cycling conditions for a total of 16 cycles. The restriction enzyme, DPN I, was added to digest the starting plasmid vector material so that only the new product containing the base changes remained. Following DPN I treatment, a small amount of the PCR product was transformed into competent E. coli cells, recovered in super optimal catabolite repressed ("SOC") broth medium and placed on Luria broth (“LB”) agar plates with kanamycin resistance. Colonies were screened using the Sanger sequencing method to verify correct base changes in selected clones. The results indicate that the ideal sequence and location of the NLS sequences in Cas12a is not obvious, and that a highly efficient Cas12a genome editing solution should be empirically determined as done in this study. Proteins were analyzed using guides that target the HPRT-38186 (SEQ ID NO.:1) and HPRT-38228 (SEQ ID NO.:2) loci in human cells. SEQ ID NOs.: 1-4 are shown in Table 1. Table 1. Sequence of oligonucleotides used as crRNAs or cMQ / bn / Lznza / YiAi primers. PCR. Sequence Name SEQ ID NO. HPRT-38186-S rUrArArUrUrUrCrUrArCrUrCrUrUrGrUrArGrArUrUrArArArUr GrCrCrCrUrGrUrArGrUrCrUrCrUrCrUrG SEQ ID NO. 1 HPRT-38228-S rUrArArUrUrUrCrUrArCrUrCrUrUrGrUrArGrArUrUrUrArArArUr urArArCrArGrCrUrUrGrCrUrGrGrUrGrA SEQ ID NO. 2 HPRT-F\ND AAGAATGTTGTGATAAAAGGTGATGCT SEQ ID NO. 3 HPRT-REV GAGGCAGAAGTCCCATGGATGTGT SEQ ID NO. 4 The following nucleotide sequences encoding the preferred Casi2a polypeptides of this example are shown below: SEQ ID NO.: 5 ATGGGCAGCAGCAGCAGCGGCCTGGTGCCGCGCGGCAGCCATATGGCTAGCAT GACTGGTGGACAGCAAATGGGTCGGGATCCAGGTAAACCGATTCCGAATCCGCTGCTGG GTCTGGATAGCACCGCACCGAAAAAAAACGTAAAGTTGGTATTCATGGTGTTCCGGCAG CAACCCAGTTTGAAGGTT TCACCAATCTGTATCAGGTTAGCAAAACCCTGCGTTTTGAACT GATTCCGCAGGGTAAAACCCTGAAACATATTCAAGAACAGGGCTTCATCGAAGAGGATAA AGCACGTAACGATCACTACAAAGAACTGAAACCGATTATCGACCGCATCTATAAAACCTAT GCAGATCAGTGTCTGCAGCTGGTTCAGCTGGATTGGGAAAATCTGAGCGCAGCA ATTGAT AGTTATCGCAAAGAAAAAACCGAAGAAACCCGTAATGCACTGATTGAAGAACAGGCAACC TATCGTAATGCCATCCATGATTATTCATTGGTCGTACCGATAATCTGACCGATGCAATTAA CAAACGTCACGCCGAAATCTATAAAGGCCTGTTTAAAGCCGAACTGTTTAATGGCAAAGTT CTGAAACAGCTGGGCACCGTTACCACCCACCGAACATGAAAATGCACTGCTGCGTAGCTTT GATAAATTCACCACCCTATTTCAGCGGCTTT TATGAGAATCGCAAAAACGTGTTTAGCGCAG AAGATATTAGCACCGCAATTCCGCATCGTATTGTGCAGGATAATTTCCCGAAATTCAAAGA GAACTGCCACATTTTACCCGTCTGATTACCGCAGTTCCGAGCCTGCGTGAACATTTTGAA AACGTTAAAAAAAGCCATCGGCATCTTTGTTAGCACCAGCATTGAAGAAGTTTTTAGCTTCC CGTTTTACAATCAGCTGCTGACCCAGACCCAGATTGATCTGTATAACCAACTGCTGGGTG GTATTAGCCGTGAAGCAGGCACCGAAAAAATCAAAGGTCTGAATGAAGTGCTGAATCTGG CCATTCAGAAAAATGATGAAACCGCACATATTATTGCAAGCCTGCCGCATCGTTTTATTCC GCTGTTCAAACAAATTCTGAGCGATCGTAATA CCCTGAGCTTTATTCTGGAAGAATTCAAA TCCGATGAAGAGGTGATTCAGAGCTTTGCAAATACAAAACGCTGCTGCGCAATGAAAAT GTTCTGGAAACTGCCGAAGCACTGTTTAACGAACTGAATAGCATTGATCTGACCCACATCT TTATCAGCCACAAAAAAACTGGAAACCATTTCAAGCGCACTGTGTGATCATTGGGATACCCT GCGTAAT GCCCTGTATGAACGTCGTATTAGCGAACTGACCGGTAAAATTACCAAAAGCGC GAAAGAAAAAAGTTCAGCGCAGTCTGAAACATGAGGATATTAATCTGCAAGAGATTATTAGC GCAGCCGGTAAAGAACTGTCAGAAGCATTTAAACAGAAAACCAGCGAAATTCTGTCACAT GCACATGCAGCACTGGATCAGCCGCTGCCGACCACCCT GAAAAAACAAGAAAAAAAGA AATCCTGAAAAGCCAGCTGGATAGCCTGCTGGGTCTGTATCATCTGCTGGACTGGTTTGC AGTTGATGAAAGCAATGAAGTTGATCCGGAATTTAGCGCACGTCTGACCGGCATTAAACT GGAAATGGAACCGAGCCTGAGCTTTTATAACAAAGCCCGTAATTATGCCACCAAAAAACC GTATAGCGTCGA AAAATTCAAACTGAACTTTCAGATGCCGACCCTGGCAAGCGGTTGGGA TGTTAATAAAGAAAAAAACAACGGTGCCATCCTGTTCGTGAAAAATGGCCTGTATTATCTG GGTATTATGCCGAAACAGAAAGGTCGTTATAAAGCGCTGAGCTTTGAACCGACGGAAAAA ACCAGTGAAGGTTTTGATAAAATGTACTACGACTATTTTTCCGG ATGCAGCCAAAATGATTC CGAAATGTAGCACCCAGCTGAAAGCAGTTACCGCACATTTTCAGACCCATACCACCCCCGA TTCTGCTGAGCAATAACTTTATTGAACCGCTGGAAATCACCAAAGAGATCTACGATCTGAA TAACCCGGAAAAAGAGCCGAAAAAATTCCAGACCGCATATGCAAAAAAAACCGGTGATCA GAAAGGTTATCGTGAAGCG CTGTGTAAATGGATTGATTTCACCCGTGATTTTCTGAGCAAA TACACCAAAACCACCAGTATCGATCTGAGCAGCCTGCGTCCGAGCAGCCAGTATAAAGAT CTGGGCGAATATTATGCAGAACTGAATCCGCTGCTGTATCATATTAGCTTTCAGCGTATTG CCGAGAAAGAAATCATGGACGCAGTTGAAACCGGTAAACTGTACCTGTTC CAGATCTACA ATAAAGATTTTGCCAAAGGCCATCATGGCAAACCGAATCTGCATACCCTGTATTGGACCG GTCTGTTTAGCCCTGAAAATCTGGCAAAAACCTCGATTAAACTGAATGGTCAGGCGGAAC TGTTTTATCGTCCGAAAAGCCGTATGAAACGTATGGCACATCGTCTGGGTGAAAAAATGCT GAACAAAAACTGAAAGACCAGA AAACCCCGATCCCGGATACACTGTATCAAGAACTGTA TGATTATGTGAACCATCGTCTGAGCCATGATCTGAGTGATGAAGCACGTGCCCTGCTGCC GAATGTTATTACCAAAGAAGTTAGCCACGAGATCATTAAGATCGTCGTTTTACCAGCGAC AAATTCTTTTTTCATGTGCCGATTACCCTGAATTATCAGGCAGCAAATAGCCCGAGCAAAT TTAACCAGCGTGTTAATGCATATCTGAAAGAACATCCAGAAACGCCGATTATTGGTATTGA TCGTGGTGAACGTAACCTGATTTATATC ACCGTTATTGATAGCACCGGCAAAATCCTGGAA CAGCGTAGCCTGAATACCATTCAGCAGTTTGATTACCAGAAAAAACTGGATAATCGCGAG AAAGAACGTGTTGCAGCACGTCAGGCATGGTCAGTTGTTGGTACAATTAAAGACCTGAAA CAGGGTTATCTGAGCCAGGTTATTCATGAAATTGTGGATCTGATGATTCACTATCAG GCCG TTGTTGTGCTGGAAAACCTGAATTTTGGCTTTAAAGCAAACGTACCGGCATTGCAGAAAA AGCAGTTTATCAGCAGTTCGAGAAAATGCTGATTGACAAACTGAATTGCCTGGTGCTGAAA GATTATCCGGCTGAAAAAGTTGGTGGTGTTCTGAATCCGTATCAGCTGACCGATCAGTTTA CCAGCTTTGCAAAAAT GGGCACCCAGAGCGGATTTCTGTTTTATGTTCCGGCACCGTATA CGAGCAAAATTGATCCGCTGACCGGTTTTGTTGATCCGTTTGTTTGGAAAACCATCAAAAAA CCATGAAAGCCGCAAACATTTTCTGGAAGGTTTCGATTTTCTGCATTACGACGTTAAAACGGGTGATTTCATCCTGCACTTTAAAATGAATCGCAATCTGAGTTTTCA GCGTGGCCTGCCTG GTTTTATGCCTGCATGGGATATTGTGTTTGAGAAAACGAAACACAGTTCGATGCAAAAGG CACCCCGTTTATTGCAGGTAAACGTATTGTTCCGGTGATTGAAAATCATCGTTTCACCGGT CGTTATCGCGATCTGTATCCGGCAAATGAACTGATCGCACTGCTGGAAGAGAAAGGTATT GTTTTTCGT GATGGCTCAAACATTCTGCCGAAACTGCTGGAAAATGATGATAGCCATGCAA TTGATACCATGGTTGCACTGATTCGTAGCGTTCTGCAGATGCGTAATAGCAATGCAGCAA CCGGTGAAGATTACATTAATAGTCCGGTTCGTGATCTGAATGGTGTTTGTTTTGATAGCCG TTTTCAGAATCCGGAATGGCCGATGGATG CAGATGCAAATGGTGCATATCATATTGCACT GAAAGGACAGCTGCTGCTGAACCACCTGAAAGAAAGCAAAAGATCTGAAACTGCAAAACGG CATTAGCAATCAGGATTGGCTGGCATATATCCAAGAACTGCGTAACCCTAAAAAAAAACGC AAAGTGAAGCTTGCGGCCGCACTCGAGCACCACCACCACCACCACTGA SEQ ID NO.: 6 ATGGGCAGCAGCAGCAGCGGCCTGGTGCCGCGCGGCAGCCATATGGCTAGCAT GACTGGTGGACAGCAAATGGGTCGGGATCCAGCACCGAAAAAAAACGTAAAGTTGGTAT TCATGGTGTTCCGGCAGCAACCCAGTTTGAAGGTTTCACCAATCTGTATCAGGTTAGCAAA ACCCTGCGTTTTGAACTGA TTCCGCAGGGTAAAACCCTGAAACATATTCAAGAACAGGGC TTCATCGAAGAGGATAAAGCACGTAACGATCACTACAAAGAACTGAAACCGATTATCGACC GCATCTATAAAACCTATGCAGATCAGTGTCTGCAGCTGGTTCAGCTGGATTGGGAAAATCT GAGCGCAGCAATTGATAGTTATCGCAAAGAAAAAACCGAAAGAAACCCGTAATG CACTGAT TGAAGAACAGGCAACCTATCGTAATGCCATCCATGATTATTCATTGGTCGTACCGATAAT CTGACCGATGCAATTAACAAACGTCACGCCGAAATCTATAAAGGCCTGTTTAAAGCCGAA CTGTTTAATGGCAAAGTTCTGAAACAGCTGGGCACCGTTACCACCACCGAACATGAAAAT GCACTGCTGCGTAGCTTTGATA AATTCACCACCTATTTCAGCGGCTTTTATGAGAATCGCA AAAACGTGTTTAGCGCAGAAGATATTAGCACCGCAATTCCGCATCGTATTGTGCAGGATAA O / d / Ml / LΖΠΖ / 3 / ΥΙΛΙ TTTCCCGAAATTCAAAGAGAACTGCCACATTTTTACCCGTCTGATTACCGCAGTTCCGAGC CTGCGTGAACATTTTGAAAACGTTAAAAAAAGCCATCGGCATCTTTGTTAGCACCAGCATTG AAGAAGTTTTTAGCTTCCCGTTTTACAATCAGCTGCTGACCCAGACCCAGATTGATCTGTA TAACCAACTGCTGGGTGGTATTAGCCG TGAAGCAGGCACCGAAAAAATCAAAGGTCTGAA TGAAGTGCTGAATCTGGCCATTCAGAAAAATGATGAAACCGCACATATTATTGCAAGCCTG CCGCATCGTTTTATTCCGCTGTTCAAACAAATTCTGAGCGATCGTAATACCCTGAGCTTTA TTCTGGAAGAATTCAAATCCGATGAAGAGGTGATTCAGAGCTTTTGCAAATACAAAACG CT GCTGCGCAATGAAAATGTTCTGGAAACTGCCGAAGCACTGTTTAACGAACTGAATAGCATT GATCTGACCCACATCTTTTATCAGCCACAAAAAACTGGAAACCATTTCAAGCGCACTGTGTG ATCATTGGGATACCCTGCGTAATGCCCTGTATGAACGTCGTATTAGCGAACTGACCGGTA AAATTACCAAAAGCGCGAAAGAAAAAAGTTCAGCGCA GTCTGAAACATGAGGATATTAATCT GCAAGAGATTATTAGCGCAGCCGGTAAAGAACTGTCAGAAGCATTTAAACAGAAAACCAG CGAAATTCTGTCACATGCACATGCAGCACTGGATCAGCCGCTGCCGACCACCCTGAAAAA ACAAGAAGAAAAAGAAATCCTGAAAAGCCAGCTGGATAGCCTGCTGGGTCTGTATCATCT GCTGGACT GGTTTGCAGTTGATGAAAGCAATGAAGTTGATCCGGAATTTAGCGCACGTCT GACCGGCATTAAACTGGAAATGGAACCGAGCCTGAGCTTTTATAACAAAGCCCGTAATTAT GCCACCAAAAAACCGTATAGCGTCGAAAAATTCAAACTGAACTTTCAGATGCCGACCCTG GCAAGCGGTTGGGATGTTAATAAAGAAAAAAAACAACGGTGCCA TCCTGTTCGTGAAAAAT GGCCTGTATTATCTGGGTATTATGCCGAAACAGAAAGGTCGTTATAAAGCGCTGAGCTTT GAACCGACGGAAAAAACCAGTGAAGGTTTTGATAAAATGTACTACGACTATTTTTCCGGATG CAGCCAAAATGATTCCGAAATGTAGCACCCAGCTGAAAGCAGTTACCGCACATTTTCAGA CCCATACCACCCCCGATT CTGCTGAGCAATAACTTTATTGAACCGCTGGAAATCACCAAAGA GATCTACGATCTGAATAACCCGGAAAAAGAGCCGAAAAAATTCCAGACCGCATATGCAAAAAAAACCGGTGATCAGAAAGGTTATCGTGAAGCGCTGTGTAAATGGATTGATTTCACCCG TGATTTTCTGAGCAAATACACCAAAACCACCAGTATCGATCTGAGCAGCCTGCG TCCGAG CAGCCAGTATAAAGATCTGGGCGAATATTATGCAGAACTGAATCCGCTGCTGTATCATATT AGCTTTCAGCGTATTGCCGAGAAAGAAATCATGGACGCAGTTGAAACCGGTAAACTGTAC CTGTTCCGATCTACAATAAAGATTTTGCCAAAGGCCATCATGGCAAACCGAATCTGCATA CCCTGTATTGGACCGGTCTGTTTAG CCCTGAAAATCTGGCAAAAACCTCGATTAAACTGAA TGGTCAGGCGGAACTGTTTTATCGTCCGAAAAGCCGTATGAAACGTATGGCACATCGTCT GGGTGAAAAAATGCTGAACAAAAAACTGAAAGACCAGAAAACCCCGATCCCGGATACACT GTATCAAGAACTGTATGATTATGTGAACCATCGTCTGAGCCATGATCTGAGTGATGAAG CA CGTGCCCTGCTGCCGAATGTTATTACCAAAGAAGTTAGCCACGAGATCATTAAGATCGT CGTTTTACCAGCGACAAATTCTTTTTTCATGTGCCGATTACCCTGAATTATCAGGCAGCAA ATAGCCCGAGCAAATTTAACCAGCGTGTTAATGCATATCTGAAAGAACATCCAGAAACGCCGATTATTGGTATTGATCGTGGTGA ACGTAACCTGATTTATATCACCGTTATTGATAGCACC GGCAAAATCCTGGAACAGCGTAGCCTGAATACCATTCAGCAGTTTGATTACCAGAAAAAA cMQ / bn / Lznza / YiAi CTGGATAATCGCGAGAAAAGAACGTGTTGCAGCACGTCAGGCATGGTCAGTTGTTGGTACA ATTAAAGACCTGAAACAGGGTTATCTGAGCCAGGTTATTCATGAAATTGTGGATCTGATGA TTCACTATCAGGCCGTTGTTGTGCTGGAAAACCTGAATTTTGGCTTTAAAGCAAACGTAC CGGCATTGCAGAAAAAAGCA GTTTATCAGCAGTTCGAGAAAATGCTGATTGACAAACTGAAT TGCCTGGTGCTGAAAGATTATCCGGCTGAAAAAGTTGGTGGTGTTCTGAATCCGTATCAG CTGACCGATCAGTTTACCAGCTTTGCAAAAATGGGCACCCAGAGCGGATTTCTGTTTTATG TTCCGGCACCGTATACGAGCAAAATTGATCCGCTGACCGGTTTT GTTGATCCGTTTGTTTG GAAAACCATCCAAAAACCATGAAAGCCGCAAACATTTTCTGGAAGGTTTCGATTTTCTGCAT TACGACGTTAAAACGGGTGATTTCATCCTGCACTTTAAAATGAATCGCAATCTGAGTTTTC AGCGTGGCCTGCCTGGTTTTATGCCTGCATGGGATATTGTGTTTGAGAAAACGAAACAC AGTT CGATGCAAAAGGCACCCCGTTTATTGCAGGTAAACGTATTGTTCCGGTGATTGAAAA TCATCGTTTCACCGGTCGTTATCGCGATCTGTATCCGGCAAATGAACTGATCGCACTGCT GGAAGAGAAAGGTATTGTTTTTCGTGATGGCTCAAACATTCTGCCGAAACTGCTGGAAAAT GATGATAGCCATGCAATTGATACCATGGTTG CACTGATTCGTAGCGTTCTGCAGATGCGT AATAGCAATGCAGCAACCGGTGAAGATTACATTAATAGTCCGGTTCGTGATCTGAATGGT GTTTGTTTTGATAGCCGTTTTCAGAATCCGGAATGGCCGATGGATGCAGATGCAAATGGT GCATATCATATTGCACTGAAAGGACAGCTGCTGCTGAACCACCTGAAAGAAAAGCAA AGAT CTGAAACTGCAAAACGGCATTAGCAATCAGGATTGGCTGGCATATATCCAAGAACTGCGT AACCCTAAAAAAAACGCAAAGTGAAGCTTGCGGCCGCACTCGAGCACCACCACCACCAC CACTGA SEQ ID NO.: 7 ATGCCGAAAAAAAAAACGCAAAGTGGGTATTCATGGTGTTCCGGCAGCAACCCAGT TTGAAGGTTTCACCAATCTGTATCAGGTTAGCAAAACCCTGCGTTTTGAACTGATTCCGCA GGGTAAAACCCTGAAACATATTCAAGAACAGGGCTTCATCGAAGAGGATAAAGCACGTAA CGATCACTACAAGAACTGAAACCGATTATCGAC CGCATCTATAAAACCTATGCAGATCAG TGTCTGCAGCTGGTTCAGCTGGATTGGGAAAATCTGAGCGCAGCAATTGATAGTTATCGC AAAGAAAAAACCGAAAGAAACCCGTAATGCACTGATTGAAGAACAGGCAACCTATCGTAAT GCCATCCATGATTATTCATTGGTCGTACCGATAATCTGACCGATGCAATTAACAAACGTC ACGCCGAA ATCTATAAAGGCCTGTTTAAAGCCGAACTGTTTAATGGCAAAGTTCTGAAACA GCTGGGCACCGTTACCACCCACCGAACATGAAAATGCACTGCTGCGTAGCTTTGATAAATT CACCACCTATTTCAGCGGCTTTTATGAGAATCGCAAAAACGTGTTTAGCGCAGAAGATATT AGCACCGCAATTCCGCATCGTATTGTGCAGGATAATTTCCC GAAATTCAAAGAGAACTGC CACATTTTTACCCGTCTGATTACCGCAGTTCCGAGCCTGCGTGAACATTTTGAAAACGTTA AAAAAGCCATCGGCATCTTTGTTAGCACCAGCATTGAAGAAGTTTTTAGCTTCCCGTTTTA CAATCAGCTGCTGACCCAGACCCAGATTGATCTGTATAACCAACTGCTGGGTGGTATTAG CCGTGAAGCAGG CACCGAAAAAATCAAAGGTCTGAATGAAGTGCTGAATCTGGCCATTCAGAAAAATGATGAAACCGCACATATTATTGCAAGCCTGCCGCATCGTTTTATTCCGCTGTTC AAACAAATTCTGAGCGATCGTAATACCCTGAGCTTTATTCTGGAAGAATTCAAATCCGATG AAGAGGTGATTCAGAGCTTTTGCAAATACAAAACGCTGCTGCGCAATGAAAATGTTCTGGA AACTGCCGAAGCACTGTTTAACGAACTGAATAGCATTGATCTGACCCATCCTTTTATCAGC CACAAAAAACTGGAAACCATTTCAAGCGCACTGTGTGA TCATTGGGATACCCTGCGTAAT GCCCTGTATGAACGTCGTATTAGCGAACTGACCGGTAAAATTACCAAAAGCGCGAAAAGAA AAAGTTCAGCGCAGTCTGAAACATGAGGATATTAATCTGCAAGAGATTATTAGCGCAGCC GGTAAAGAACTGTCAGAAGCATTTAAACAGAAAACCAGCGAAATTCTGTCACATGCACATG CAGCACTGGA TCAGCCGCTGCCGACCACCCTGAAAAAACAAGAAAAAAAGAAATCCTGA AAAGCCAGCTGGATAGCCTGCTGGGTCTGTATCATCTGCTGGACTGGTTTGCAGTTGATG AAAGCAATGAAGTTGATCCGGAATTTAGCGCACGTCTGACCGGCATTAAACTGGAAATGG AACCGAGCCTGAGCTTTTATAACAAAGCCCGTAATTATG CCACCAAAAAACCGTATAGCGT CGAAAAATTCAAACTGAACTTTCAGATGCCGACCCTGGCAAGCGGTTGGGATGTTAATAA AGAAAAAAACAACGGTGCCATCCTGTTCGTGAAAAATGGCCTGTATTATCTGGGTATTATG CCGAAACAGAAAGGTCGTTATAAAGCGCTGAGCTTTGAACCGACGGAAAAAACCAGTGAA GGTT TTGATAAAATGTACTACGACTATTTTTCCGGATGCAGCCAAAATGATTCCGAAATGTA GCACCCAGCTGAAAGCAGTTACCGCACATTTTCAGACCCATACCACCCCCGATTCTGCTGA GCAATAACTTTATTGAACCGCTGGAAATCACCAAAGAGATCTACGATCTGAATAACCCGGA AAAAGAGCCGAAAAAATTCCAGACCGCATATGCAAAAAAAACCGGTGA TCAGAAAGGTTA TCGTGAAGCGCTGTGTAAATGGATTGATTTCACCCGTGATTTTCTGAGCAAATACACCAAA ACCACCAGTATCGATCTGAGCAGCCTGCGTCCGAGCAGCCAGTATAAAGATCTGGGCGA ATATTATGCAGAACTGAATCCGCTGCTGTATCATATTAGCTTTCAGCGTATTGCCGAGAAA GAAATCATGGACGCAGTTGA AACCGGTAAACTGTACCTGTTCCGATCTACAATAAAGATT TTGCCAAAGGCCATCATGGCAAACCGAATCTGCATACCCTGTATTGGACCGGTCTGTTTA GCCCTGAAAATCTGGCAAAAACCTCGATTAAACTGAATGGTCAGGCGGAACTGTTTTATC GTCCGAAAAGCCGTATGAAACGTATGGCACATCGTCTGGGTGAAAAAAT GCTGAACAAAAAACTGAAAGACCAGAAAACCCGATCCCGGATACACTGTATCAAGAACTGTATGATTATGT GAACCATCGTCTGAGCCATGATCTGAGTGATGAAGCACGTGCCCTGCTGCCGAATGTTAT TACCAAAGAAGTTAGCCACGAGATCATTAAGATCGTCGTTTTACCAGCGACAAATTCTTT TTTCATGTGCCGATTACCCTGAAT TATCAGGCAGCAAATAGCCCGAGCAAATTTAACCAGC GTGTTAATGCATATCTGAAAGAACATCCAGAAACGCCGATTATTGGTATTGATCGTGGTGA ACGTAACCTGATTTATATCACCGTTATTGATAGCACCGGCAAAATCCTGGAACAGCGTAGC CTGAATACCATTCAGCAGTTTGATTACCAGAAAAAACTGGATAATCGCGAGAAAGAA CGTG TTGCAGCACGTCAGGCATGGTCAGTTGTTGGTACAATTAAAGACCTGAAACAGGGTTATC TGAGCCAGGTTATTCATGAAATTGTGGATCTGATGATTCACTATCAGGCCGTTGTTGTGCT GGAAAACCTGAATTTTGGCTTTAAAAAGCAAACGTACCGGCATTGCAGAAAAAGCAGTTTAT CAGCAGTTCGAGA AAATGCTGATTGACAAACTGAATTGCCTGGTGCTGAAAGATTATCCG GCTGAAAAAGTTGGTGGTGTTCTGAATCCGTATCAGCTGACCGATCAGTTTACCAGCTTTG CAAAAATGGGCACCCAGAGCGGATTTCTGTTTTATGTTCCGGCACCGTATACGAGCAAAA TTGATCCGCTGACCGGTTTTGTTGATCCGTTTGTTTGGAAAACCATCAAAAACCATGAAAG CCGCAAACATTTTCTGGAAGGTTTCGATTTTCTGCATTACGACGTTAAAACGGGTGATTTC ATCCTGCACTTTAAATGAATCGCAATCT GAGTTTTCAGCGTGGCCTGCCTGGTTTTATGC CTGCATGGGATATTGTGTTTGAGAAAAACGAAACACAGTTCGATGCAAAAGGCACCCCGT TTATTGCAGGTAAACGTATTGTTCCGGTGATTGAAAATCATCGTTTCACCGGTCGTTATCG CGATCTGTATCCGGCAAATGAACTGATCGCACTGCTGGAAGAGAAAGG TATTGTTTTTCGT GATGGCTCAAACATTCTGCCGAAACTGCTGGAAAATGATGATAGCCATGCAATTGATACCA TGGTTGCACTGATTCGTAGCGTTCTGCAGATGCGTAATAGCAATGCAGCAACCGGTGAAG ATTACATTAATAGTCCGGTTCGTGATCTGAATGGTGTTTGTTTTGATAGCCGTTTTCAGAAT CCGGAATGG CCGATGGATGCAGATGCAAATGGTGCATATCATATTGCACTGAAAGGACAG CTGCTGCTGAACCACCTGAAAGAAAGCAAAGATCTGAAACTGCAAAACGGCATTAGCAAT CAGGATTGGCTGGCATATATCCAAGAACTGCGTAACCCGAAAAAAAACGCAAAGTGCTC GAGCACCACCACCACCACCACTGA SEQ ID NO.: 8 ATGACCCAGTTTGAAGGTTTCACCAATCTGTATCAGGTTAGCAAAACCCTGCGTTT TGAACTGATTCCGCAGGGTAAAACCCTGAAACATATTCAAGAACAGGGCTTCATCGAAGA GGATAAAGCACGTAACGATCACTACAAAGAACTGAAACCGATTATCGACCGCATCTATAAA ACCTATGCAGATCAGTGTCTGCAGCTGGTTCAGCTGGA TTGGGAAAATCTGAGCGCAGCA ATTGATAGTTATCGCAAAGAAAAAACCGAAAGAAACCCCGTAATGCACTGATTGAAGAACAGG CAACCTATCGTAATGCCATCCATGATTATTCATTGGTCGTACCGATAATCTGACCGATGC AATTAACAAACGTCACGCCGAAATCTATAAAGGCCTGTTTAAAGCCGAACTGTTTAATGGC AAAGTTCTGAA ACAGCTGGGCACCGTTACCACCCACCGAACATGAAAATGCACTGCTGCGT AGCTTTGATAAATTCACCACCCTATTTCAGCGGCTTTTATGAGAATCGCAAAAACGTGTTTA GCGCAGAAGATATTAGCACCGCAATTCCGCATCGTATTGTGCAGGATAATTTCCCGAAATT CAAAGAGAACTGCCACATTTTTACCCGTCTGATTACCGCAGTTCCGAG CCTGCGTGAACA TTTTGAAAACGTTAAAAAAAGCCATCGGCATCTTTGTTAGCACCAGCATTGAAGAAGTTTTTA GCTTCCCGTTTTACAATCAGCTGCTGACCCAGACCCAGATTGATCTGTATAACCAACTGCT GGGTGGTATTAGCCGTGAAGCAGGCACCGAAAAAATCAAAGGTCTGAATGAAGTGCTGAA TCTGGCCATTCAGAA AAATGATGAAACCGCACATATTATTGCAAGCCTGCCGCATCGTTTT ATTCCGCTGTTCAAACAAATTCTGAGCGATCGTAATACCCTGAGCTTTATTCTGGAAGAATTCAAATCCGATGAAGAGGTGATTCAGAGCTTTTGCAAATACAAAACGCTGCTGCGCAATG AAAATGTTCTGGAAACTGCCGAAGCACTGTTTAACGAACTGAATAGCATT GATCTGACCCA CATCTTTATCAGCCACAAAAAACTGGAAACCATTTCAAGCGCACTGTGTGATCATTGGGAT ACCCTGCGTAATGCCCTGTATGAACGTCGTATTAGCGAACTGACCGGTAAAATTACCAAAA GCGCGAAAAAAAAGTTCAGCGCAGTCTGAAACATGAGGATATTAATCTGCAAGAGATTA TTAGCGCAGCCGGTAAAGAACT GTCAGAAGCATTTAAACAGAAAACCAGCGAAATTCTGT Q / Q / bn / Lznza / YiAi CACATGCACATGCAGCACTGGATCAGCCGCTGCCGACCACCCTGAAAAAACAAGAAAGAAAAAGAAATCCTGAAAAGCCAGCTGGATAGCCTGCTGGGTCTGTATCATCTGCTGGACTGGT TTGCAGTTGATGAAAGCAATGAAGTTGATCCGGAATTTAGCGCACGTCTGACCGGCATTA AACTGGAAATGGAACCGAGCCTGA GCTTTTATAACAAAGCCCGTAATTATGCCACCAAAAA ACCGTATAGCGTCGAAAAATTCAAACTGAACTTTCAGATGCCGACCCTGGCAAGCGGTTG GGATGTTAATAAAGAAAAAAACAACGGTGCCATCCTGTTCGTGAAAAATGGCCTGTATTAT CTGGGTATTATGCCGAAACAGAAAGGTCGTTATAAAGCGCTGAGCTTTGAACC GACGGAA AAAACCAGTGAAGGTTTTGATAAAATGTACTACGACTATTTTCCGGATGCAGCCAAAATGA TTCCGAAATGTAGCACCCAGCTGAAAGCAGTTACCGCACATTTTCAGACCCATACCACCC CGATTCTGCTGAGCAATAACTTTATTGAACCGCTGGAAATCACCAAAGAGATCTACGATCT GAATAACCCGGAAAAAGAGCCGAAAAAATTCCAGA CCGCATATGCAAAAAAAACCGGTGA TCAGAAAGGTTATCGTGAAGCGCTGTGTAAATGGATTGATTTCACCCGTGATTTTCTGAGC AAATACACCAAAACCACCAGTATCGATCTGAGCAGCCTGCGTCCGAGCAGCCAGTATAAA GATCTGGGCGAATATTATGCAGAACTGAATCCGCTGCTGTATCATATTAGCTTTCAGCGTA TTG CCGAGAAAGAAATCATGGACGCAGTTGAAACCGGTAAACTGTACCTGTTCCAGATCT ACAATAAAGATTTTGCCAAAGGCCATCATGGCAAACCGAATCTGCATACCCTGTATTGGAC CGGTCTGTTTAGCCCTGAAAATCTGGCAAAAACCTCGATTAAACTGAATGGTCAGGCGGA ACTGTTTTATCGTCCGAAAAGCCGTATGAAACGTAT GGCACATCGTCTGGGTGAAAAAATG CTGAACAAAAAACTGAAAGACCAGAAAACCCCGATCCCGGATACACTGTATCAAGAACTG TATGATTATGTGAACCATCGTCTGAGCCATGATCTGAGTGATGAAGCACGTGCCCTGCTG CCGAATGTTATTACCAAAGAAGTTAGCCACGAGATCATTAAGATCGTCGTTTTACCAGCG ACAAATT CTTTTTTCATGTGCCGATTACCCTGAATTATCAGGCAGCAAATAGCCCGAGCAA ATTTAACCAGCGTGTTAATGCATATCTGAAAGAACATCCAGAAACGCCGATTATTGGTATT GATCGTGGTGAACGTAACCTGATTTATATCACCGTTATTGATAGCACCGGCAAAATCCTGG AACAGCGTAGCCTGAATACCATTCAGCAGTTTGA TTACCAGAAAAAACTGGATAATCGCGA GAAAGAACGTGTTGCAGCACGTCAGGCATGGTCAGTTGTTGGTACAATTAAAGACCTGAA ACAGGGTTATCTGAGCCAGGTTATTCATGAAATTGTGGATCTGATGATTCACTATCAGGCC GTTGTTGTGCTGGAAAACCTGAATTTTGGCTTTAAAAGCAAACGTACCGGCATTGCAGA AA AAGCAGTTTATCAGCAGTTCGAGAAAATGCTGATTGACAAACTGAATTGCCTGGTGCTGAA AGATTATCCGGCTGAAAAAGTTGGTGGTGTTCTGAATCCGTATCAGCTGACCGATCAGTTT ACCAGCTTTGCAAAAATGGGCACCCAGAGCGGATTTCTGTTTTATGTTCCGGCACCGTAT ACGAGCAAAATTGATCCGCT GACCGGTTTTGTTGATCCGTTTGTTTGGAAAACCATCAAAA ACCATGAAAGCCGCAAACATTTTCTGGAAGGTTTCGATTTTCTGCATTACGACGTTAAAAC GGGTGATTTCATCCTGCACTTTTAAAATGAATCGCAATCTGAGTTTTCAGCGTGGCCTGCCT GGTTTTATGCCTGCATGGGATATTGTGTTTGAGAAAAAACGAA ACACAGTTCGATGCAAAAG GCACCCCGTTTATTGCAGGTAAACGTATTGTTCCGGTGATTGAAAATCATCGTTTCACCGG TCGTTATCGCGATCTGTATCCGGCAAATGAACTGATCGCACTGCTGGAAGAGAAAGGTAT Q / Q / bn / LΖηΖ-1 / ΥΙΛΙ TGTTTTTCGTGATGGCTCAAACATTCTGCCGAAACTGCTGGAAAATGATGATAGCCATGCA ATTGATACCATGGTTGCACTGATTCGTAGCGTTCTGCAGATGCGTAATAGCAATGCAGCAA CCGGTGAAGATTACATTAATAGTCCGGTTCGTGATCTGAATGGTGTTTGTTTTGATAGCCG TTTTCAGAATCCGGAATGG CCGATGGATGCAGATGCAAATGGTGCATATCATATTGCACT GAAAGGACAGCTGCTGCTGAACCACCTGAAAGAAAGCAAAGATCTGAAACTGCAAAACGG CATTAGCAATCAGGATTGGCTGGCATATATCCAAGAACTGCGTAACCCGAAAAAAAACGCAAAGTGCTCGAGCACCACCACCACCACCACTGA SEQ ID NO.: 9 ATGGGCAGCAGCCATCATCATCATCATCACAGCAGCGGCCTGGTGCCGCGCGGC AGCCATATGGCTAGCATGACTGGTGGACAGCAAATGGGTCGGGATCCAACCCAGTTTGAA GGTTTCACCAATCTGTATCAGGTTAGCAAAACCCTGCGTTTTGAACTGATTCCGCAGGGTA AAACCCTGAAACATATTCAAGA ACAGGGCTTCATCGAAGAGGATAAAGCACGTAACGATC ACTACAAAGAACTGAAACCGATTATCGACCGCATCTATAAAACCTATGCAGATCAGTGTCT GCAGCTGGTTCAGCTGGATTGGGAAAATCTGAGCGCAGCAATTGATAGTTATCGCAAAGA AAAAACCGAAGAAACCCGTAATGCACTGATTGAAGAACAGGCAACCTATCGTAATGCCAT CC ATGATTATTTCATTGGTCGTACCGATAATCTGACCGATGCAATTAACAAACGTCACGCC GAAATCTATAAAGGCCTGTTTAAAGCCGAACTGTTTAATGGCAAAGTTCTGAAACAGCTGGGCACCGTTACCACCGAACATGAAAATGCACTGCTGCGTAGCTTTGATAAATTCACCA CCTATTTCAGCGGCTTTTATGAGAATCGCAAAAACGT GTTTAGCGCAGAAGATATTAGCAC CGCAATTCCGCATCGTATTGTGCAGGATAATTTCCCGAAATTCAAAGAGAACTGCCACATT TTTACCCGTCTGATTACCGCAGTTCCGAGCCTGCGTGAACATTTTGAAAACGTTAAAAAAAGCCATCGGCATCTTTGTTAGCACCAGCATTGAAGAAGTTTTTAGCTTCCCGTTTTACAATCA GCTGCTGA CCCAGACCCAGATTGATCTGTATAACCAACTGCTGGGTGGTATTAGCCGTGA AGCAGGCACCGAAAAAATCAAAGGTCTGAATGAAGTGCTGAATCTGGCCATTCAGAAAAA TGATGAAACCGCACATATTATTGCAAGCCTGCCGCATCGTTTTATTCCGCTGTTCAAAACAA ATTCTGAGCGATCGTAATACCCTGAGCTTTATTCTG GAAGAATTCAAATCCGATGAAGAGG TGATTCAGAGCTTTGCAAATACAAAACGCTGCTGCGCAATGAAAATGTTCTGGAAACTGC CGAAGCACTGTTTAACGAACTGAATAGCATTGATCTGACCCACATCTTTATCAGCCACAAA AAACTGGAAACCATTTCAAGCGCACTGTGTGATCATTGGGATACCCTGCGTAATGCCCTG TATGAACGTC GTATTAGCGAACTGACCGGTAAAATTACCAAAAGCGCGAAAAAAAAGTTC AGCGCAGTCTGAAACATGAGGATATTAATCTGCAAGAGATTATTAGCGCAGCCGGTAAAG AACTGTCAGAAGCATTTAAACAGAAAACCAGCGAAATTCTGTCACATGCACATGCAGCACT GGATCAGCCGCTGCCGACCACCCTGAAAAAACAAGAAAAAAA GAAATCCTGAAAAGCCA GCTGGATAGCCTGCTGGGTCTGTATCATCTGCTGGACTGGTTTGCAGTTGATGAAAGCAA TGAAGTTGATCCGGAATTTAGCGCACGTCTGACCGGCATTAAACTGGAAATGGAACCGAG CCTGAGCTTTTATAACAAAGCCCGTAATTATGCCACCAAAAAACCGTATAGCGTCGAAAAA TTCAAACTGAACTTTCA GATGCCGACCCTGGCAAGCGGTTGGGATGTTAATAAAGAAAAAA a / a / bn / Lznza / YiAi ACAACGGTGCCATCCTGTTCGTGAAAAATGGCCTGTATTATCTGGGTATTATGCCGAAACA GAAAGGTCGTTATAAAGCGCTGAGCTTTGAACCGACGGAAAAAACCAGTGAAGGTTTTGA TAAAATGTACTACGACTATTTTTCGGATGCAGCCAAAATGATTCCGAAATGTAGCACCCAG CTGAAAGCAGTTACCGCACATTTT CAGACCCATACCACCCGATTCTGCTGAGCAATAACT TTATTGAACCGCTGGAAATCACCAAAGAGATCTACGATCTGAATAACCCGGAAAAAGAGC CGAAAAAATTCCAGACCGCATATGCAAAAAAAACCGGTGATCAGAAAGGTTATCGTGAAG CGCTGTGTAAATGGATTGATTTCACCCGTGATTTTCTGAGCAAATACACCAAAACCACCAG TAT CGATCTGAGCAGCCTGCGTCCGAGCAGCCAGTATAAAGATCTGGGCGAATATTATGC AGAACTGAATCCGCTGCTGTATCATATTAGCTTTCAGCGTATTGCCGAGAAAGAAATCATGGACGCAGTTGAAACCGGTAAACTGTACCTGTTCCAGATCTACAATAAAGATTTTGCCAAAG GCCATCATGGCAAACCGAATCTGCATACCCTGTATT GGACCGGTCTGTTTAGCCCTGAAA ATCTGGCAAAAACCTCGATTAAACTGAATGGTCAGGCGGAACTGTTTTATCGTCCGAAAAG CCGTATGAAACGTATGGCACATCGTCTGGGTGAAAAAATGCTGAACAAAAACTGAAAGA CCAGAAAACCCCGATCCCGGATACACTGTATCAAGAACTGTATGATTATGTGAACCATCGT CTGAG CCATGATCTGAGTGATGAAGCACGTGCCCTGCTGCCGAATGTTATTACCAAAGAA GTTAGCCACGAGATCATTAAGATCGTCGTTTTACCAGCGACAAATTCTTTTTTCATGTGC CGATTACCCTGAATTATCAGGCAGCAAATAGCCCGAGCAAATTTAACCAGCGTGTTAATGC ATATCTGAAAGAACATCCAGAAACGCCGATTATTG GTATTGATCGTGGTGAACGTAACCTG ATTTATATCACCGTTATTGATAGCACCGGCAAAATCCTGGAACAGCGTAGCCTGAATACCA TTCAGCAGTTTGATTACCAGAAAAAACTGGATAATCGCGAGAAAGAACGTGTTGCAGCAC GTCAGGCATGGTCAGTTGTTGGTACAATTAAAGACCTGAAACAGGGTTATCTGAGCCAGG TTATTCATGAAATTGTGGATCTGATGATTCACTATCAGGCCGTTGTTGTGCTGGAAAACCT GAATTTTGGCTTTAAAGCAAACGTACCGGCATTGCAGAAAAAGCAGTTTATCAGCAGTTC GAGAAAATGCTGATTGACAAACTGAATTGCCTGGTGCTGAAAGATTATCCGGCTGAAAAA GTTGGTGGTGTTCTGAAT CCGTATCAGCTGACCGATCAGTTTACCAGCTTTGCAAAAATGG GCACCCAGAGCGGATTTCTGTTTTATGTTCCGGCACCGTATACGAGCAAAATTGATCCGC TGACCGGTTTTGTTGATCCGTTTGTTTGGAAAACCATCCAAAAACCATGAAAGCCGCAAACA TTTTCTGGAAGGTTTCGATTTTCTGCATTACGACGTTAAAACGGGTGA TTTCATCCTGCAC TTTAAAATGAATCGCAATCTGAGTTTTCAGCGTGGCCTGCCTGGTTTTATGCCTGCATGGG ATATTGTGTTTGAGAAAAACGAAACACAGTTCGATGCAAAAGGCACCCCGTTTATTGCAGG TAAACGTATTGTTCCGGTGATTGAAAATCATCGTTTCACCGGTCGTTATCGCGATCTGTAT CCGG CAAATGAACTGATCGCACTGCTGGAAGAGAAAGGTATTGTTTTTCGTGATGGCTCA AACATTCTGCCGAAACTGCTGGAAAATGATGATAGCCATGCAATTGATACCATGGTTGCAC TGATTCGTAGCGTTCTGCAGATGCGTAATAGCAATGCAGCAACCGGTGAAGATTACATTAA TAGTCCGGTTCGTGATCTGAATGGTGT TTGTTTTGATAGCCGTTTTCAGAATCCGGAATGG CCGATGGATGCAGATGCAAATGGTGCATATCATATTGCACTGAAAGGACAGCTGCTGCTG AACCACCTGAAAGAAAGCAAAGATCTGAAACTGCAAAACGGCATTAGCAATCAGGATTGG a / a / bn / Lznza / YiAi CTGGCATATATCCAAGAACTGCGTAACGGTCGTAGCAGTGATGATGAAGCAACCGCAGAT AGCCAGCATGCAGCACCGCCTAAAAAGAAACGTAAAGTTGGTGGTAGCGGTGGTTCAGG TGGTAGTGGCGGTAGTGGTGGCTCAGGGGGTTCTGGTGGCTCTGGTGGTAGCCTCGAG CA CCACCCACCACCACTGA SEQ ID NO.: 10 ATGACCCAGTTTGAAGGTTTCACCAATCTGTATCAGGTTAGCAAAACCCTGCGTTT TGAACTGATTCCGCAGGGTAAAACCCTGAAACATATTCAAGAACAGGGCTTCATCGAAGA GGATAAAGCACGTAACGATCACTACAAAGAACTGAAACCGATTATCGACCGCATCTATAAA ACCTATGCAGATCAGTGTCTGCAGCTGGTTCAGCTGGA TTGGGAAAATCTGAGCGCAGCA ATTGATAGTTATCGCAAAGAAAAAACCGAAAGAAACCCCGTAATGCACTGATTGAAGAACAGG CAACCTATCGTAATGCCATCCATGATTATTCATTGGTCGTACCGATAATCTGACCGATGC AATTAACAAACGTCACGCCGAAATCTATAAAGGCCTGTTTAAAGCCGAACTGTTTAATGGC AAAGTTCTGAA ACAGCTGGGCACCGTTACCACCCACCGAACATGAAAATGCACTGCTGCGT AGCTTTGATAAATTCACCACCCTATTTCAGCGGCTTTTATGAGAATCGCAAAAACGTGTTTA GCGCAGAAGATATTAGCACCGCAATTCCGCATCGTATTGTGCAGGATAATTTCCCGAAATT CAAAGAGAACTGCCACATTTTTACCCGTCTGATTACCGCAGTTCCGAG CCTGCGTGAACA TTTTGAAAACGTTAAAAAAAGCCATCGGCATCTTTGTTAGCACCAGCATTGAAGAAGTTTTTA GCTTCCCGTTTTACAATCAGCTGCTGACCCAGACCCAGATTGATCTGTATAACCAACTGCT GGGTGGTATTAGCCGTGAAGCAGGCACCGAAAAAATCAAAGGTCTGAATGAAGTGCTGAA TCTGGCCATTCAGAA AAATGATGAAACCGCACATATTATTGCAAGCCTGCCGCATCGTTTT ATTCCGCTGTTCAAACAAATTCTGAGCGATCGTAATACCCTGAGCTTTATTCTGGAAGAATTCAAATCCGATGAAGAGGTGATTCAGAGCTTTTGCAAATACAAAACGCTGCTGCGCAATG AAAATGTTCTGGAAACTGCCGAAGCACTGTTTAACGAACTGAATAGCATT GATCTGACCCA CATCTTTATCAGCCACAAAAAACTGGAAACCATTTCAAGCGCACTGTGTGATCATTGGGAT ACCCTGCGTAATGCCCTGTATGAACGTCGTATTAGCGAACTGACCGGTAAAATTACCAAAA GCGCGAAAAAAAAGTTCAGCGCAGTCTGAAACATGAGGATATTAATCTGCAAGAGATTA TTAGCGCAGCCGGTAAAGAACT GTCAGAAGCATTTAAACAGAAAACCAGCGAAATTCTGT CACATGCACATGCAGCACTGGATCAGCCGCTGCCGACCACCCTGAAAAAACAAGAAGAAAAAGAAATCCTGAAAAGCCAGCTGGATAGCCTGCTGGGTCTGTATCATCTGCTGGACTGGT TTGCAGTTGATGAAAGCAATGAAGTTGATCCGGAATTTAGCACGCACGTCT GACCGGCATTA AACTGGAAATGGAACCGAGCCTGAGCTTTTATAACAAAGCCCGTAATTATGCCACCAAAAA ACCGTATAGCGTCGAAAAATTCAAACTGAACTTTCAGATGCCGACCCTGGCAAGCGGTTG GGATGTTAATAAAGAAAAAAACAACGGTGCCATCCTGTTCGTGAAAAATGGCCTGTATTAT CTGGGTATTATGCCGA AACAGAAAGGTCGTTATAAAGCGCTGAGCTTTGAACCGACGGAA AAAACCAGTGAAGGTTTTGATAAAATGTACTACGACTATTTTTCCGGATGCAGCCAAAATGA TTCCGAAATGTAGCACCCAGCTGAAAGCAGTTACCGCACATTTTCAGACCCATACCACCC CGATTCTGCTGAGCAATAACTTTATTGAACCGCTGGAAATCACCAAAGAGATCTACG ATCT Q / Q / frOI 707 -1 / ΥΙΛΙ GAATAACCCGGAAAAAGAGCCGAAAAAATTCCAGACCGCATATGCAAAAAAAACCGGTGA TCAGAAAGGTTATCGTGAAGCGCTGTGTAAATGGATTGATTTCACCCGTGATTTTCTGAGC AAATACACCAAAACCACCAGTATCGATCTGAGCAGCCTGCGTCCGAGCAGCCAGTATAAA GATCTGGGCGAATATTATGCAGAACTGAAT CCGCTGCTGTATCATATTAGCTTTCAGCGTA TTGCCGAGAAAGAAATCATGGACGCAGTTGAAACCGGTAAACTGTACCTGTTCCAGATCT ACAATAAAGATTTTGCCAAAGGCCATCATGGCAAACCGAATCTGCATACCCTGTATTGGAC CGGTCTGTTTAGCCCTGAAAATCTGCAAAAACCTCGATTAAACTGAATGGTCAGGCGGA ACTGTTTTATCGTCCGAAAAGCCGTATGAAACGTATGGCACATCGTCTGGGTGAAAAAATG CTGAACAAAAAACTGAAAGACCAGAAAACCCCGATACCCGGATACACTGTATCAAGAACTG TATGATTATGTGAACCATCGTCTGAGCCATGATCTGAGTGATGAAGCACGTGCCCTGCTG CCGAATGTTATTACCAAAGAAGTTAGCCACGA GATCATTAAAGATCGTCGTTTTACCAGCG ACAAATTCTTTTTTCATGTGCCGATTACCCTGAATTATCAGGCAGCAAATAGCCCGAGCAA ATTTAACCAGCGTGTTAATGCATATCTGAAAGAACATCCAGAAACGCCGATTATTGGTATT GATCGTGGTGAACGTAACCTGATTTATATCACCGTTATTGATAGCACCGGCAAAATCCTG G AACAGCGTAGCCTGAATACCATTCAGCAGTTTGATTACCAGAAAAAACTGGATAATCGCGA GAAAGAACGTGTTGCAGCACGTCAGGCATGGTCAGTTGTTGGTACAATTAAAGACCTGAA ACAGGGTTATCTGAGCCAGGTTATTCATGAAATTGTGGATCTGATGATTCACTATCAGGCC GTTGTTGTGCTGGAAAACCTGAATT TTGGCTTTAAAAAGCAAACGTACCGGCATTGCAGAAA AAGCAGTTTATCAGCAGTTCGAGAAAATGCTGATTGACAAACTGAATTGCCTGGTGCTGAA AGATTATCCGGCTGAAAAAGTTGGTGGTGTTCTGAATCCGTATCAGCTGACCGATCAGTTT ACCAGCTTTGCAAAAATGGGCACCCAGAGCGGATTCTGTTTTATG TTCCGGCACCGTAT ACGAGCAAAATTGATCCGCTGACCGGTTTTGTTGATCCGTTTGTTTGGAAAACCATCAAAA ACCATGAAAGCCGCAAACATTTTCTGGAAGGTTTCGATTTTCTGCATTACGACGTTAAAC GGGTGATTTCATCCTGCACTTTAAAATGAATCGCAATCTGAGTTTTCAGCGTGGCCTGCCT GGTTTTATGC CTGCATGGGATATTGTGTTTGAGAAAAACGAAACACAGTTCGATGCAAAAG GCACCCCGTTTATTGCAGGTAAACGTATTGTTCCGGTGATTGAAAATCATCGTTTCACCGG TCGTTATACGCGATCTGTATCCGGCAAATGAACTGATCGCACTGCTGGAAGAGAAAGGTAT TGTTTTTCGTGATGGCTCAAACATTCTGCCGAAACTG CTGGAAAATGATGATAGCCATGCA ATTGATACCATGGTTGCACTGATTCGTAGCGTTCTGCAGATGCGTAATAGCAATGCAGCAA CCGGTGAAGATTACATTAATAGTCCGGTTCGTGATCTGAATGGTGTTTGTTTTGATAGCCG TTTTCAGAATCCGGAATGGCCGATGGATGCAGATGCAAATGGTGCATATCATATTG CACT GAAAGGACAGCTGCTGCTGAACCACCTGAAAGAAAGCAAAGATCTGAAACTGCAAAACGG CATTAGCAATCAGGATTGGCTGGCATATATCCAAGAACTGCGTAACGGTCGTAGCAGTGA TGATGAAGCAACCGCAGATAGCCAGCATGCAGCACCGCCTAAAAAGAAACGTAAAGTTGG TGGTAGCGGTGGTTCAGGT GGTAGTGGCGGTAGTGGTGGCTCAGGGGGTTCTGGTGGC TCTGGTGGTAGCCTCGAGCACCACCACCACCACCACTGA SEQ ID NO.: 11 cMQ / bn / Lznza / YiAi ATGGGCAGCAGCAGCAGCGGCCTGGTGCCGCGCGGCAGCCATATGGCTAGCAT GACTGGTGGACAGCAAATGGGTCGGGATCCAACCCAGTTTGAAGGTTTCACCAATCTGTA TCAGGTTAGCAAAACCCTGCGTTTTGAACTGATTCCGCAGGGTAAAACCCTGAAACATATT CAAGAACAGGGCTTCATCGAAG AGGATAAAGCACGTAACGATCACTACAAAGAACTGAAA CCGATTATCGACCGCATCTATAAAACCTATGCAGATCAGTGTCTGCAGCTGGTTCAGCTG GATTGGGAAAATCTGAGCGCAGCAATTGATAGTTATCGCAAAGAAAAAACCGAAAGAAACC CGTAATGCACTGATTGAAGAACAGGCAACCTATCGTAATGCCATCCATGATTATTTCATTG GT CGTACCGATAATCTGACCGATGCAATTAACAAACGTCACGCCGAAATCTATAAAGGCCT GTTTAAAGCCGAACTGTTTAATGGCAAAGTTCTGAAACAGCTGGGCACCGTTACCACCAC CGAACATGAAAATGCACTGCTGCGTAGCTTTGATAAATTCACCACCCTATTTCAGCGGCTTT TATGAGAATCGCAAAAACGTGTTTAGCGCAGAAGATATTAG CACCGCAATTCCGCATCGTA TTGTGCAGGATAATTTCCCGAAATTCAAAGAGAACTGCCACATTTTTACCCGTCTGATTAC CGCAGTTCCGAGCCTGCGTGAACATTTTGAAAACGTTAAAAAAAGCCATCGGCATCTTTGTT AGCACCAGCATTGAAGAAGTTTTTAGCTTCCCGTTTTACAATCAGCTGCTGACCCAGACCC AGATTGATCT GTATAACCAACTGCTGGGTGGTATTAGCCGTGAAGCAGGCACCGAAAAAA TCAAAGGTCTGAATGAAGTGCTGAATCTGGCCATTCAGAAAAAATGATGAAACCGCACATAT TATTGCAAGCCTGCCGCATCGTTTTATTCCGCTGTTCAAACAAATTCTGAGCGATCGTAAT ACCCTGAGCTTTATTCTGGAAGAATTCAAATCCGATGA AGAGGTGATTCAGAGCTTTTGCA AATACAAAACGCTGCTGCGCAATGAAAATGTTCTGGAAACTGCCGAAGCACTGTTTAACG AACTGAATAGCATTGATCTGACCCACATCTTTATCAGCCACAAAAAAACTGGAAACCATTTC AAGCGCACTGTGTGATCATTGGGATACCCTGCGTAATGCCCTGTATGAACGTCGTATTAG CGAACTGACCG GTAAAATTACCAAAAGCGCGAAAAAAAAAGTTCAGCGCAGTCTGAAACA TGAGGATATTAATCTGCAAGAGATTATTAGCGCAGCCGGTAAAGAACTGTCAGAAGCATTT AAACAGAAAACCAGCGAAATTCTGTCACATGCACATGCAGCACTGGATCAGCCGCTGCCG ACCACCCTGAAAAAACAAGAAGAAAAAGAAATCCTGAAAAGCCAGCTG GATAGCCTGCTG GGTCTGTATCATCTGCTGGACTGGTTTGCAGTTGATGAAAGCAATGAAGTTGATCCGGAA TTTAGCGCACGTCTGACCGGCATTAAACTGGAAATGGAACCGAGCCTGAGCTTTTATAAC AAAGCCCGTAATTATGCCACCAAAAAACCGTATAGCGTCGAAAAATTCAAACTGAACTTTC AGATGCCGACCCTGGCA AGCGGTTGGGATGTTAATAAAGAAAAAAACAACGGTGCCATCC TGTTCGTGAAAAATGGCCTGTATTATCTGGGTATTATGCCGAAACAGAAAGGTCGTTATAA AGCGCTGAGCTTTGAACCGACGGAAAAAACCAGTGAAGGTTTTGATAAAATGTACTACGA CTATTTTCCGGATGCAGCCAAAATGATTCCGAAATGTAGCA CCCAGCTGAAAGCAGTTAC CGCACATTTTCAGACCCATACCACCCCCGATTCTGCTGAGCAATAACTTTATTGAACCGCTG GAAATCACCAAAGAGATCTACGATCTGAATAACCCGGAAAAAGAGCCGAAAAAATTCCAG ACCGCATATGCAAAAAAAACCGGTGATCAGAAAGGTTATCGTGAAGCGCTGTGTAAATGG ATTGATTTCACCCGTGATT TTCTGAGCAAATACACCAAAACCACCAGTATCGATCTGAGCA GCCTGCGTCCGAGCAGCCAGTATAAAGATCTGGGCGAATATTATGCAGAACTGAATCCGC TGCTGTATCATATTAGCTTTCAGCGTATTGCCGAGAAAGAAATCATGGACGCAGTTGAAAC CGGTAAACTGTACCTGTTCCAGATCTACAATAAAGATTTTGCCAAAGGCCATCATGGCAAA CCGAATCTGCATACCCTGTATTGGACCGGTCTGTTTAGCCCTGAAAATCTGGCAAAAACCT CGATTAAACTGAATGGTCAGGCGGAACTG TTTTATCGTCCGAAAAGCCGTATGAAACGTAT GGCACATCGTCTGGGTGAAAAAATGCTGAACAAAAAACTGAAAGACCAGAAAACCCCGAT CCCGGATACACTGTATCAAGAACTGTATGATTATGTGAACCATCGTCTGAGCCATGATCTG AGTGATGAAGCACGTGCCCTGCTGCCGAATGTTATTACCAAAGAAGTTAGCCACGAGATC ATTAAAGATCGTCGTTTTACCAGCGACAAATTCTTTTTTCATGTGCCGATTACCCTGAATTA TCAGGCAGCAAATAGCCCGAGCAAATTTAACCAGCGTGTTAATGCATATCTGAAAGAACAT CCAGAAACGCCGATTATTGGTATTGATCGTGGTGAACGTAACCTGATTTATATCACCGTTA TTGATAGCACCGGCAAAATCCTGGA ACAGCGTAGCCTGAATACCATTCAGCAGTTTGATTA CCAGAAAAAACTGGATAATCGCGAGAAAAGAACGTGTTGCAGCACGTCAGGCATGGTCAGT TGTTGGTACAATTAAAGACCTGAAACAGGGTTATCTGAGCCAGGTTATTCATGAAATTGTG GATCTGATGATTCACTATCAGGCCGTTGTTGTGCTGGAAAACCTGAATTTT GGCTTTAAAA GCAAACGTACCGGCATTGCAGAAAAAGCAGTTTATCAGCAGTTCGAGAAAATGCTGATTG ACAAACTGAATTGCCTGGTGCTGAAAGATTATCCGGCTGAAAAAGTTGGTGGTGTTCTGA ATCCGTATCAGCTGACCGATCAGTTTACCAGCTTTGCAAAAATGGGCACCCAGAGCGGAT TTCTGTTTTATGTTCC GGCACCGTATACGAGCAAAATTGATCCGCTGACCGGTTTTGTTGA TCCGTTTGTTTGGAAAACCATCAAAAAC CATG AAAG CCGCAAACATTTTCTG G AAG GTTTC GATTTTCTGCATTACGACGTTAAAACGGGTGATTTCATCCTGCACTTTAAATGAATCGCA ATCTGAGTTTTCAGCGTGGCCTGCCTGGTTTTATG CCTGCATGGGATATTGTGTTTGAGAA AAACGAAACACAGTTCGATGCAAAAGGCACCCCGTTTATTGCAGGTAAACGTATTGTTCC GGTGATTGAAAATCATCGTTTCACCGGTCGTTATCGCGATCTGTATCCGGCAAATGAACTG ATCGCACTGCTGGAAGAGAAAGGTATTGTTTTTCGTGATGGCTCAAACATTCTGCCGAA AC TGCTGGAAAATGATGATAGCCATGCAATTGATACCATGGTTGCACTGATTCGTAGCGTTCT GCAGATGCGTAATAGCAATGCAGCAACCGGTGAAGATTACATTAATAGTCCGGTTCGTGA TCTGAATGGTGTTTGTTTTGATAGCCGTTTTCAGAATCCGGAATGGCCGATGGATGCAGAT GCAAATGGTGCATATCATA TTGCACTGAAAGGACAGCTGCTGCTGAACCACCTGAAAGAA AGCAAAGATCTGAAACTGCAAAACGGCATTAGCAATCAGGATTGGCTGGCATATATCCAA GAACTGCGTAACGGTCGTAGCAGTGATGATGAAGCAACCGCAGATAGCCAGCATGCAGC ACCGCCTAAAAAGAAACGTAAAGTTGGTGGTAGCGGTGGTT CAGGTGGTAGTGGCGGTA GTGGTGGCTCAGGGGGTTCTGGTGGCTCTGGTGGTAGCCTCGAGCACCACCACCACCAC CACTGA SEQ ID NO.: 12 ATGCCGCCTCCGAAACGTCCGCGTCTGGATGGTATCCACGGAGTCCCAGCAGCC ACCCAGTTTGAAGGTTTCACCAATCTGTATCAGGTTAGCAAAACCCTGCGTTTTGAACTGA TTCCGCAGGGTAAAACCCTGAAACATATTCAAGAACAGGGCTTCATCGAAGAGGATAAAG CACGTAACGATCACTACAAAGAACTGAAACCGATTATCGACCGCATCTATAAAACCTATGC AGATCAGTGTCTGCAGCTGGTTCAGCTGGATTGGGAAAATCTGAGCGCAGCAATTGATAG TTATCGCAAAGAAAAAACCGAAAGAAACCCGTAATGCACTGATTGAAGAACAGGCAACCTAT CGTAATGCCATCCATGATTTCATTGGTCGTA CCGATAATCTGACCGATGCAATTAACA AACGTCACGCCGAAATCTATAAAGGCCTGTTTAAAGCCGAACTGTTTAATGGCAAAGTTCT GAAACAGCTGGGCACCGTTACCACCCACCGAACATGAAAATGCACTGCTGCGTAGCTTTGA TAAATTCACCACCCTATTTCAGCGGCTTTTATGAGAATCGCAAAAACGTGTTTAGCGCAGAA GATATT AGCACCGCAATTCCGCATCGTATTGTGCAGGATAATTTCCCGAAATTCAAAGAGA ACTGCCACATTTTTACCCGTCTGATTACCGCAGTTCCGAGCCTGCGTGAACATTTTGAAAA CGTTAAAAAAAGCCATCGGCATCTTTGTTAGCACCAGCATTGAAGAAGTTTTTAGCTTCCCG TTTTACAATCAGCTGCTGACCCAGACCCAGATTGATCT GTATAACCAACTGCTGGGTGGTA TTAGCCGTGAAGCAGGCACCGAAAAAATCAAAGGTCTGAATGAAGTGCTGAATCTGGCCA TTCAGAAAAATGATGAAACCGCACATATTATTGCAAGCCTGCCGCATCGTTTTATTCCGCTGTTCAAACAAATTCTGAGCGATCGTAATACCCTGAGCTTTATTCTGGAAGAATTCAAATCC GATGA AGAGGTGATTCAGAGCTTTGCAAATACAAAACGCTGCTGCGCAATGAAAATGTTC TGGAAACTGCCGAAGCACTGTTTAACGAACTGAATAGCATTGATCTGACCCACATCTTTAT CAGCCACAAAAACTGGAAACCATTTCAAGCGCACTGTGTGATCATTGGGATACCCTGCG TAATGCCCTGTATGAACGTCGTATTAGCGAACTGACC GGTAAAATTACCAAAAGCGCGAA AGAAAAAGTTCAGCGCAGTCTGAAACATGAGGATATTAATCTGCAAGAGATTATTAGCGCA GCCGGTAAAGAACTGTCAGAAGCATTTAAACAGAAAACCAGCGAAATTCTGTCACATGCA CATGCAGCACTGGATCAGCCGCTGCCGACCACCCTGAAAAAACAAGAAGAAAAAGAAATC CTGAAAAGCCAG CTGGATAGCCTGCTGGGTCTGTATCATCTGCTGGACTGGTTTGCAGTT GATGAAAGCAATGAAGTTGATCCGGAATTTAGCGCACGTCTGACCGGCATTAAACTGGAA ATGGAACCGAGCCTGAGCTTTTATAACAAAGCCCGTAATTATGCCACCAAAAAACCGTATA GCGTCGAAAAATTCAAACTGAACTTTCAGATGCCGACCCTGGCA AGCGGTTGGGATGTTA ATAAAGAAAAAAACAACGGTGCCATCCTGTTCGTGAAAAATGGCCTGTATTATCTGGGTAT TATGCCGAAACAGAAAGGTCGTTATAAAGCGCTGAGCTTTGAACCGACGGAAAAAACCAG TGAAGGTTTTGATAAAATGTACTACGACTATTTTTCCGGATGCAGCCAAAATGATTCCGAAA TGTAGCA CCCAGCTGAAAGCAGTTACCGCACATTTTCAGACCCATACCACCCGATTCTG CTGAGCAATAACTTTATTGAACCGCTGGAAATCACCAAAGAGATCTACGATCTGAATAACC CGGAAAAAGAGCCGAAAAAATTCCAGACCGCATATGCAAAAAAAACCGGTGATCAGAAAG GTTATCGTGAAGCGCTGTGTAAATGGATTGATTTCACCCGTGATTTT CTGAGCAAATACAC CAAAACCACCAGTATCGATCTGAGCAGCCTGCGTCCGAGCAGCCAGTATAAAGATCTGGG CGAATATTATGCAGAACTGAATCCGCTGCTGTATCATATTAGCTTTCAGCGTATTGCCGAG AAAGAAATCATGGACGCAGTTGAAACCGGTAAACTGTACCTGTTCCAGATCTACAATAAAG ATTTTGCCAAAGGCCATCAT GGCAAACCGAATCTGCATACCCTGTATTGGACCGGTCTGTT TAGCCCTGAAAATCTGGCAAAAACCTCGATTAAACTGAATGGTCAGGCGGAACTGTTTTAT Q / Q / bn / Lznza / YiAi CGTCCGAAAAGCCGTATGAAACGTATGGCACATCGTCTGGGTGAAAAAATGCTGAACAAA AAACTGAAAGACCAGAAAACCCCGATCCCGGATACACTGTATCAAGAACTGTATGATTATG TGAACCATCGTCTGAGCCATGATCTGAGTGATGAAGCACGTGCCCTGCTGCCGAATGTTA TTACCAAAGAAGTTAGCCACGAGATC ATTAAAGATCGTCGTTTTACCAGCGACAAATTCTT TTTTCATGTGCCGATTACCCTGAATTATCAGGCAGCAAATAGCCCGAGCAAATTTAACCAG CGTGTTAATGCATATCTGAAAGAACATCCAGAAACGCCGATTATTGGTATTGATCGTGGTG AACGTAACCTGATTTATATCACCGTTATTGATAGCACCGGCAAAATCCTGGA ACAGCGTAG CCTGAATACCATTCAGCAGTTTGATTACCAGAAAAAACTGGATAATCGCGAGAAAAGAACGT GTTGCAGCACGTCAGGCATGGTCAGTTGTTGGTACAATTAAAGACCTGAAACAGGGTTAT CTGAGCCAGGTTATTCATGAAATTGTGGATCTGATGATTCACTATCAGGCCGTTGTTGTGC TGGAAAACCTGAATTTT GGCTTTAAAAGCAAACGTACCGGCATTGCAGAAAAAGCAGTTTA TCAGCAGTTCGAGAAAATGCTGATTGACAAACTGAATTGCCTGGTGCTGAAAGATTATTCCG GCTGAAAAAGTTGGTGGTGTTCTGAATCCGTATCAGCTGACCGATCAGTTTACCAGCTTTG CAAAAATGGGCACCCAGAGCGGATTCTGTTTTATGTTCC GGCACCGTATACGAGCAAAA TTGATCCGCTGACCGGTTTTGTTGATCCGTTTGTTTGGAAAACCATCAAAAACCATGAAAG CCGCAAACATTTTCTGGAAGGTTTCGATTTTCTGCATTACGACGTTAAACGGTGATTTC ATCCTGCACTTTAAATGAATCGCAATCTGAGTTTTCAGCGTGGCCTGCCTGGTTTTATGC CTG CATGGGATATTGTGTTTGAGAAAAACGAAACACAGTTCGATGCAAAAGGCACCCCGT TTATTGCAGGTAAACGTATTGTTCCGGTGATTGAAAATCATCGTTTCACCGGTCGTTATCGCGATCTGTATCCGGCAAATGAACTGATCGCACTGCTGGAAGAGAAAGGTATTGTTTTTCGT GATGGCTCAAACATTCTGCCGAAACTGCT GGAAAATGATGATAGCCATGCAATTGATACCA TGGTTGCACTGATTCGTAGCGTTCTGCAGATGCGTAATAGCAATGCAGCAACCGGTGAAG ATTACATTAATAGTCCGGTTCGTGATCTGAATGGTGTTTGTTTTGATAGCCGTTTTCAGAAT CCGGAATGGCCGATGGATGCAGATGCAAATGGTGCATATCATATTGC ACTGAAAGGACAG CTGCTGCTGAACCACCTGAAAGAAAGCAAAGATCTGAAACTGCAAAACGGCATTAGCAAT CAGGATTGGCTGGCATATATCCAAGAACTGCGTAACGGTCGTAGCAGTGATGATGAAGCA ACCGCAGATAGCCAGCATGCAGCACCGCCTAAAAAGAAACGTAAAGTTGGTGGTAGCGGTGGTTCAGGT GGTAGTGGCGGTAGTGGTGGCTCAGGGGGTTCTGGTGGCTCTGGTGGTA GCCTCGAGCACCACCACCACCACCACTGA SEQ ID NO.: 13 ATGAGCAGTGATGATGAAGCAACCGCAGATAGCCAGCATGCAGCACCGCCTAAAA AGAAACGTAAAGTTGGTATCCACGGAGTCCCAGCAGCCACCCAGTTTGAAGGTTTCACCA ATCTGTATCAGGTTAGCAAAACCCTGCGTTTTGAACTGATTCCGCAGGGTAAAACCCTGAA ACATATTCAAGAACAGGGCTTCATCGAAGAGG ATAAAGCACGTAACGATCACTACAAAGA ACTGAAACCGATTATCGACCGCATCTATAAAACCTATGCAGATCAGTGTCTGCAGCTGGTT CAGCTGGATTGGGAAAATCTGAGCGCAGCAATTGATAGTTATCGCAAAGAAAAAACCGAA GAAACCCGTAATGCACTGATTGAAGAACAGGCAACCTATCGTAATGCCATCCATGATTATT Q / Q / bn / LΖΠΖ / 3 / ΥΙΛΙ TCATTGGTCGTACCGATAATCTGACCGATGCAATTAACAAACGTCACGCCGAAATCTATAA AGGCCTGTTTAAAGCCGAACTGTTTAATGGCAAAGTTCTGAAACAGCTGGGCACCGTTAC CACCACCGAACATGAAAATGCACTGCTGCGTAGCTTTGATAAATTCACCACCCTATTTCAGC GGCTTTTATGAGAATCGCAAAAACGTG TTTAGCGCAGAAGATATTAGCACCGCAATTCCG CATCGTATTGTGCAGGATAATTTCCCGAAATTCAAAGAGAACTGCCACATTTTTACCCGTC TGATTACCGCAGTTCCGAGCCTGCGTGAACATTTTGAAAACGTTAAAAAAAGCCATCGGCAT CTTTGTTAGCACCAGCATTGAAGAAGTTTTTAGCTTCCCGTTTTACAATCAGCTGCTGACC CAGA CCCAGATTGATCTGTATAACCAACTGCTGGGTGGTATTAGCCGTGAAGCAGGCACC GAAAAAATCAAAGGTCTGAATGAAGTGCTGAATCTGGCCATTCAGAAAAAATGATGAAACCG CACATATTATTGCAAGCCTGCCGCATCGTTTTATTCGCTGTTCAAACAAATTCTGAGCGA TCGTAATACCCTGAGCTTTATTCTGGAAGAATTCA AATCCGATGAAGAGGTGATTCAGAGC TTTTGCAAATACAAAACGCTGCTGCGCAATGAAAATGTTCTGGAAACTGCCGAAGCACTGT TTAACGAACTGAATAGCATTGATCTGACCCACATCTTTATCAGCCACAAAAAACTGGAAAC CATTTCAAGCGCACTGTGTGATCATTGGGATACCCTGCGTAATGCCCTGTATGAACGTCG TATT AGCGAACTGACCGGTAAAATTACCAAAAGCGCGAAAAAAAAAGTTCAGCGCAGTCT GAAACATGAGGATATTAATCTGCAAGAGATTATTAGCGCAGCCGGTAAAGAACTGTCAGA AGCATTTAAACAGAAAACCAGCGAAATTCTGTCACATGCACATGCAGCACTGGATCAGCC GCTGCCGACCACCCTGAAAAAACAAGAAGAAAAAGAATCCT GAAAAGCCAGCTGGATAG CCTGCTGGGTCTGTATCATCTGCTGGACTGGTTTGCAGTTGATGAAAGCAATGAAGTTGA TCCGGAATTTAGCCACGTCTGACCGGCATTAAACTGGAAATGGAACCGAGCCTGAGCTT TTATAACAAAGCCCGTAATTATGCCACCAAAAAACCGTATAGCGTCGAAAAATTCAAACTG AACTTTCAGATG CCGACCCTGGCAAGCGGTTGGGATGTTAATAAAGAAAAAAACAACGGT GCCATCCTGTTCGTGAAAAATGGCCTGTATTATCTGGGTATTATGCCGAAACAGAAAGGTC GTTATAAAGCGCTGAGCTTTGAACCGACGGAAAAAACCAGTGAAGGTTTTGATAAAATGTA CTACGACTATTTTTCCGGATGCAGCCAAAATGATTCCGAA ATGTAGCACCCAGCTGAAAGC AGTTACCGCACATTTTCAGACCCATACCACCCGATTCTGCTGAGCAATAACTTTATTGAA CCGCTGGAAATCACCAAAGAGATCTACGATCTGAATAACCCGGAAAAAGAGCCGAAAAAA TTCCAGACCGCATATGCAAAAAAAACCGGTGATCAGAAAGGTTATCGTGAAGCGCTGTGT AAATGGATTGATTTC ACCCGTGATTTTCTGAGCAAATACACCAAAACCACCAGTATCGATC TGAGCAGCCTGCGTCCGAGCAGCCAGTATAAAGATCTGGGCGAATATTATGCAGAACTGA ATCCGCTGCTGTATCATATTAGCTTTCAGCGTATTGCCGAGAAAGAAATCATGGACGCAGT TGAAACCGGTAAACTGTACCTGTTCCAGATCTACAATAAAGATTTTGCCAA AGGCCATCAT GGCAAACCGAATCTGCATACCCTGTATTGGACCGGTCTGTTTAGCCCTGAAAATCTGGCA AAAACCTCGATTAAACTGAATGGTCAGGCGGAACTGTTTTATCGTCCGAAAAGCCGTATGA AACGTATGGCACATCGTCTGGGTGAAAAAATGCTGAACAAAAACTGAAAGACCAGAAAA CCCCGATCCCGGATACACTG TATCAAGAACTGTATGATTATGTGAACCATCGTCTGAGCC ATGATCTGAGTGATGAAGCACGTGCCCTGCTGCCGAATGTTATTACCAAAGAAGTTAGCC O / d / Ml / LΖΠΖ / 3 / ΥΙΛΙ ACGAGATCATTAAAGATCGTCGTTTTACCAGCGACAAATTCTTTTTTCATGTGCCGATTACC CTGAATTATCAGGCAGCAAATAGCCCGAGCAAATTTAACCAGCGTGTTAATGCATATCTGA AAGAACATCCAGAAACGCCGATTATTGGTATTGATCGTGGTGAACGTAACCTGATTTATAT CACCGTTATTGATAGCACCGGCAAA ATCCTGGAACAGCGTAGCCTGAATACCATTCAGCA GTTTGATTACCAGAAAAAACTGGATAATCGCGAGAAAGAACGTGTTGCAGCACGTCAGGC ATGGTCAGTTGTTGGTACAATTAAAGACCTGAAACAGGGTTATCTGAGCCAGGTTATTCAT GAAATTGTGGATCTGATGATTCACTATCAGGCCGTTGTTGTGCTGGAAAACCT GAATTTTG GCTTTAAAGCAAACGTACCGGCATTGCAGAAAAAGCAGTTTATCAGCAGTTCGAGAAAAT GCTGATTGACAAACTGAATTGCCTGGTGCTGAAAGATTATCCGGCTGAAAAAGTTGGTGG TGTTCTGAATCCGTATCAGCTGACCGATCAGTTTACCAGCTTTGCAAAAATGGGCACCCA GAGCGGATTCTGTTTTAT GTTCCGGCACCGTATACGAGCAAAATTGATCCGCTGACCGG TTTTGTTGATCCGTTTGTTTGGAAAACCATCAAAACCATGAAAGCCGCAAACATTTTCTG GAAGGTTTCGATTTTCTGCATTACGACGTTAAAACGGGTGATTTCATCCTGCACTTTAAAAT GAATCGCAATCTGAGTTTTCAGCGTGGCCTGCCTGGTTTTAT GCCTGCATGGGATATTGT GTTTGAGAAAAACGAAACACAGTTCGATGCAAAAGGCACCCCGTTTATTGCAGGTAAACG TATTGTTCCGGTGATTGAAAATCATCGTTTCACCGGTCGTTATCGCGATCTGTATCCGGCA AATGAACTGATCGCACTGCTGGAAGAGAAAGGTATTGTTTTTCGTGATGGCTCAAACATTC TGCCGAA ACTGCTGGAAAATGATGATAGCCATGCAATTGATACCATGGTTGCACTGATTC GTAGCGTTCTGCAGATGCGTAATAGCAATGCAGCAACCGGTGAAGATTACATTAATAGTC CGGTTCGTGATCTGAATGGTGTTTGTTTTGATAGCCGTTTTCAGAATCCGGAATGGCCGAT GGATGCAGATGCAAATGGTGCATATCATA TTGCACTGAAAGGACAGCTGCTGCTGAACCA CCTGAAAGAAAGCAAAGATCTGAAACTGCAAAACGGCATTAGCAATCAGGATTGGCTGGC ATATATCCAAGAACTGCGTAACGGTCGTAGCAGTGATGATGAAGCAACCGCAGATAGCCA GCATGCAGCACCGCCTAAAAAGAAACGTAAAGTTGGTGGTAGCGGTGGTT CAGGTGGTA GTGGCGGTAGTGGTGGCTCAGGGGGTTCTGGTGGCTCTGGTGGTAGCCTCGAGCACCA CCACCACCACCACTGA SEQ ID NO.: 14 ATGACCCAGTTTGAAGGTTTCACCAATCTGTATCAGGTTAGCAAAACCCTGCGTTT TGAACTGATTCCGCAGGGTAAAACCCTGAAACATATTCAAGAACAGGGCTTCATCGAAGA GGATAAAGCACGTAACGATCACTACAAAGAACTGAAACCGATTATCGACCGCATCTATAAA ACCTATGCAGATCAGTGTCTGCAGCTGGTTCAGCTGGA TTGGGAAAATCTGAGCGCAGCA ATTGATAGTTATCGCAAAGAAAAAACCGAAAGAAACCCCGTAATGCACTGATTGAAGAACAGG CAACCTATCGTAATGCCATCCATGATTATTCATTGGTCGTACCGATAATCTGACCGATGC AATTAACAAACGTCACGCCGAAATCTATAAAGGCCTGTTTAAAGCCGAACTGTTTAATGGC AAAGTTCTGAA ACAGCTGGGCACCGTTACCACCCACCGAACATGAAAATGCACTGCTGCGT AGCTTTGATAAATTCACCCACCTATTTCAGCGGCTTTTATGAGAATCGCAAAAACGTGTTTA GCGCAGAAGATATTAGCACCGCAATTCCGCATCGTATTGTGCAGGATAATTTCCCGAAATT CAAAGAGAACTGCCACATTTTTACCCGTCTGATTACCGCAGTTCCGAGCCTGCGTGAACA TTTTGAAAACGTTAAAAAAAGCCATCGGCATCTTTGTTAGCACCAGCATTGAAGAAGTTTTTA GCTTCCCGTTTTACAATCAGCTGCTGACCCAGACCCAGATTGATCTGTATAACCAACTGCT GGGTGGTATTAGCCGTGAAGCAGGCACCGA AAAAATCAAAGGTCTGAATGAAGTGCTGAA TCTGGCCATTCAGAAAAATGATGAAACCGCACATATTATTGCAAGCCTGCCGCATCGTTTT ATTCCGCTGTTCAAACAAATTCTGAGCGATCGTAATACCCTGAGCTTTATTCTGGAAGAATTCAAATCCGATGAAGAGGTGATTCAGAGCTTTTGCAAATACAAAACGCTGCTGCGCAATG AAAATGTTCTGGAAACTGCCGAAGCACTGTTTAACGAACTGAATAGCATTGATCTGACCCA CATCTTTATCAGCCACAAAAAACTGGAAACCATTTCAAGCGCACTGTGTGATCATTGGGAT ACCCTGCGTAATGCCCTGTATGAACGTCGTATTAGCGAACTGACCGGTAAAATTACCAAAA GCGCGAAAAAAAAGTTCAGCGCAGTCTGAAACAT GAGGATATTAATCTGCAAGAGATTA TTAGCGCAGCCGGTAAAGAACTGTCAGAAGCATTTAAACAGAAAACCAGCGAAATTCTGT CACATGCACATGCAGCACTGGATCAGCCGCTGCCGACCACCCTGAAAAAACAAGAAGAAA AAGAAATCCTGAAAAGCCAGCTGGATAGCCTGCTGGGTCTGTATCATCTGCTGGACTGGT TTGCAGTTGATGAAAGCAATGAAGTTGATCCGGAATTTAGCGCACGTCTGACCGGCATTA AACTGGAAATGGAACCGAGCCTGAGCTTTTATAACAAAGCCCGTAATTATGCCACCAAAAA ACCGTATAGCGTCGAAAAATTCAAACTGAACTTTCAGATGCCGACCCTGGCAAGCGGTTG GGATGTTAATAAAGAAAAAAACAACGGTGCCATCCT GTTCGTGAAAAATGGCCTGTATTAT CTGGGTATTATGCCGAAACAGAAAGGTCGTTATAAAGCGCTGAGCTTTGAACCGACGGAA AAAACCAGTGAAGGTTTTGATAAAATGTACTACGACTATTTTTCGATGCAGCCAAAATGA TTCCGAAATGTAGCACCCAGCTGAAAGCAGTTACCGCACATTTTCAGACCCATACCACCC CGATT CTGCTGAGCAATAACTTTATTGAACCGCTGGAAATCACCAAAGAGATCTACGATCT GAATAACCCGGAAAAAGAGCCGAAAAAATTCCAGACCGCATATGCAAAAAAAACCGGTGA TCAGAAAGGTTATCGTGAAGCGCTGTGTAAATGGATTGATTTCACCCGTGATTTTCTGAGC AAATACACCAAAACCACCAGTATCGATCTGAGCAGCCTG CGTCCGAGCAGCCAGTATAAA GATCTGGGCGAATATTATGCAGAACTGAATCCGCTGCTGTATCATATTAGCTTTCAGCGTA TTGCCGAGAAAGAAATCATGGACGCAGTTGAAACCGGTAAACTGTACCTGTTCCAGATCT ACAATAAAGATTTTGCCAAAGGCCATCATGGCAAACCGAATCTGCATACCCTGTATTGGAC CGGTCTGTTTA GCCCTGAAAATCTGGCAAAAACCTCGATTAAACTGAATGGTCAGGCGGA ACTGTTTTATCGTCCGAAAAGCCGTATGAAACGTATGGCACATCGTCTGGGTGAAAAAATG CTGAACAAAAAACTGAAAGACCAGAAAACCCCGATCCCGGATACACTGTATCAAGAACTG TATGATTATGTGAACCATCGTCTGAGCCATGATCTGAGTGAT GAAGCACGTGCCCTGCTG CCGAATGTTATTACCAAAGAAGTTAGCCACGAGATCATTAAGATCGTCGTTTTACCAGCG ACAAATTCTTTTTTCATGTGCCGATTACCCTGAATTATCAGGCAGCAAATAGCCCGAGCAA ATTTAACCAGCGTGTTAATGCATATCTGAAAGAACATCCGAAACGCCGATTATTGGTATT GATCGTGGTGA ACGTAACCTGATTTATATCACCGTTATTGATAGCACCGGCAAAATCCTGG AACAGCGTAGCCTGAATACCATTCAGCAGTTTGATTACCAGAAAAAACTGGATAATCGCGA GAAAGAACGTGTTGCAGCACGTCAGGCATGGTCAGTTGTTGGTACAATTAAAGACCTGAA ACAGGGTTATCTGAGCCAGGTTATTCATGAAATTGTGGATCTGATGATTCACTATCAGGCC GTTGTTGTGCTGGAAAACCTGAATTTTGGCTTTAAAAAGCAAACGTACCGGCATTGCAGAAA AAGCAGTTTATCAGCAGTTC GAGAAAATGCTGATTGACAAACTGAATTGCCTGGTGCTGAA AGATTATCCGGCTGAAAAAGTTGGTGGTGTTCTGAATCCGTATCAGCTGACCGATCAGTTT ACCAGCTTTGCAAAAATGGGCACCCAGAGCGGATTTCTGTTTTATGTTCCGGCACCGTAT ACGAGCAAAATTGATCCGCTGACCGGTTTTGTTGATCCGTTT GTTTGGAAAACCATCAAAA ACCATGAAAGCCGCAAACATTTTCTGGAAGGTTTCGATTTTCTGCATTACGACGTTAAAAC GGGTGATTTCATCCTGCACTTTAAAATGAATCGCAATCTGAGTTTTCAGCGTGGCCTGCCTGGTTTTATGCCTGCATGGGATATTGTGTTTGAGAAAACGAAACACAGTTCGATGCAAAAG GCACC CCGTTTATTGCAGGTAAACGTATTGTTCCGGTGATTGAAAATCATCGTTTCACCGG TCGTTATCGCGATCTGTATCCGGCAAATGAACTGATCGCACTGCTGGAAGAGAAAGGTAT TGTTTTTCGTGATGGCTCAAACATTCTGCCGAAACTGCTGGAAAATGATGATAGCCATGCA ATTGATACCATGGTTGCACTGATTCGTAGCGTT CTGCAGATGCGTAATAGCAATGCAGCAA CCGGTGAAGATTACATTAATAGTCCGGTTCGTGATCTGAATGGTGTTTGTTTTGATAGCCG TTTTCAGAATCCGGAATGGCCGATGGATGCAGATGCAAATGGTGCATATCATATTGCACT GAAAGGACAGCTGCTGCTGAACCACCTGAAAGAAAGCAAAGATCTGAAACTGCA AAACGG CATTAGCAATCAGGATTGGCTGGCATATATCCAAGAACTGCGTAACGGTCGTAAACGTCC GGCAGCAACCAAAAAAGCAGGTCAGGCAAAAAAAGAAAAAAGGTGGTAGCGGTGGTTCAG GTGGTAGTGGCGGTAGTGGTGGCTCAGGGGGTTCTGGTGGCTCTGGTGGTAGCCTCGA GCA CCACCCACCACCACTGA SEQ ID NO.: 15 ATGACCCAGTTTGAAGGTTTCACCAATCTGTATCAGGTTAGCAAAACCCTGCGTTT TGAACTGATTCCGCAGGGTAAAACCCTGAAACATATTCAAGAACAGGGCTTCATCGAAGA GGATAAAGCACGTAACGATCACTACAAAGAACTGAAACCGATTATCGACCGCATCTATAAA ACCTATGCAGATCAGTGTCTGCAGCTGGTTCAGCTGGA TTGGGAAAATCTGAGCGCAGCA ATTGATAGTTATCGCAAAGAAAAAACCGAAAGAAACCCCGTAATGCACTGATTGAAGAACAGG CAACCTATCGTAATGCCATCCATGATTATTCATTGGTCGTACCGATAATCTGACCGATGC AATTAACAAACGTCACGCCGAAATCTATAAAGGCCTGTTTAAAGCCGAACTGTTTAATGGC AAAGTTCTGAA ACAGCTGGGCACCGTTACCACCCACCGAACATGAAAATGCACTGCTGCGT AGCTTTGATAAATTCACCACCCTATTTCAGCGGCTTTTATGAGAATCGCAAAAACGTGTTTA GCGCAGAAGATATTAGCACCGCAATTCCGCATCGTATTGTGCAGGATAATTTCCCGAAATT CAAAGAGAACTGCCACATTTTTACCCGTCTGATTACCGCAGTTCCGAG CCTGCGTGAACA TTTTGAAAACGTTAAAAAAAGCCATCGGCATCTTTGTTAGCACCAGCATTGAAGAAGTTTTTA GCTTCCCGTTTTACAATCAGCTGCTGACCCAGACCCAGATTGATCTGTATAACCAACTGCT GGGTGGTATTAGCCGTGAAGCAGGCACCGAAAAAATCAAAGGTCTGAATGAAGTGCTGAA TCTGGCCATTCAGAA AAATGATGAAACCGCACATATTATTGCAAGCCTGCCGCATCGTTTT QjQ / bn / Lznza / YiAi ATTCCGCTGTTCAAACAAATTCTGAGCGATCGTAATACCCTGAGCTTTATTCTGGAAGAATTCAAATCCGATGAAGAGGTGATTCAGAGCTTTTGCAAATACAAAACGCTGCTGCTGCGCAATG AAAATGTTCTGGAAACTGCCGAAGCACTGTTTAACGAACTGAATAGCATTGATCTGACCCA CATCTTTATCAGCCACAAAAAACTGGAAACCATTTCAAG CGCACTGTGTGATCATTGGGAT ACCCTGCGTAATGCCCTGTATGAACGTCGTATTAGCGAACTGACCGGTAAAATTACCAAAA GCGCGAAAAAAAAGTTCAGCGCGCAGTCTGAAACATGAGGATATTAATCTGCAAGAGATTA TTAGCGCAGCCGGTAAAGAACTGTCAGAAGCATTTAAACAGAAAACCAGCGAAATTCTGT CACATG CACATGCAGCACTGGATCAGCCGCTGCCGACCACCCTGAAAAAACAAGAAGAAA AAGAAATCCTGAAAAGCCAGCTGGATAGCCTGCTGGGTCTGTATCATCTGCTGGACTGGT TTGCAGTTGATGAAAGCAATGAAGTTGATCCGGAATTTAGCCACGTCTGACCGGCATTA AACTGGAAATGGAACCGAGCCTGAGCTTTTATA ACAAAGCCCGTAATTATGCCACCAAAAA ACCGTATAGCGTCGAAAAATTCAAACTGAACTTTCAGATGCCGACCCTGGCAAGCGGTTG GGATGTTAATAAAGAAAAAAACAACGGTGCCATCCTGTTCGTGAAAAATGGCCTGTATTAT CTGGGTATTATGCCGAAACAGAAAGGTCGTTATAAAGCGCTGAGCTTTGAACCGACGGAA A AAACCAGTGAAGGTTTTGATAAAATGTACTACGACTATTTTCCGGATGCAGCCAAAATGA TTCCGAAATGTAGCACCCAGCTGAAAGCAGTTACCGCACATTTTCAGACCCATACCACCC CGATTCTGCTGAGCAATAACTTTATTGAACCGCTGGAAATCACCAAAGAGATCTACGATCT GAATAACCCGGAAAAAGAGCCGAAAAAATTCCAGACCGCATAT GCAAAAAAAACCGGTGA TCAGAAAGGTTATCGTGAAGCGCTGTGTAAATGGATTGATTTCACCCGTGATTTTCTGAGC AAATACACCAAAACCACCAGTATCGATCTGAGCAGCCTGCGTCCGAGCAGCCAGTATAAA GATCTGGGCGAATATTATGCAGAACTGAATCCGCTGCTGTATCATATTAGCTTTCAGCGTA TTGCCGAGAAAGA AATCATGGACGCAGTTGAAACCGGTAAACTGTACCTGTTCCAGATCT ACAATAAAGATTTTGCCAAAGGCCATCATGGCAAACCGAATCTGCATACCCTGTATTGGAC CGGTCTGTTTAGCCCTGAAAATCTGGCAAAAACCTCGATTAAACTGAATGGTCAGGCGGA ACTGTTTTATCGTCCGAAAAGCCGTATGAAACGTATGGCACATC GTCTGGGTGAAAAAATG CTGAACAAAAACTGAAAGACCAGAAAACCCCGATACCCGGATACACTGTATCAAGAACTG TATGATTATGTGAACCATCGTCTGAGCCATGATCTGAGTGATGAAGCACGTGCCCTGCTG CCGAATGTTATTACCAAAGAAGTTAGCCACGAGATCATTAAGATCGTCGTTTTACCAGCG ACAAATTCTTTTTTCAT GTGCCGATTACCCTGAATTATCAGGCAGCAAATAGCCCGAGCAA ATTTAACCAGCGTGTTAATGCATATCTGAAAGAACATCCAGAAACGCCGATTATTGGTATT GATCGTGGTGAACGTAACCTGATTTATATCACCGTTATTGATAGCACCGGCAAAATCCTGG AACAGCGTAGCCTGAATACCATTCAGCAGTTTGATTACCAGAAA AAACTGGATAATCGCGA GAAAGAACGTGTTGCAGCACGTCAGGCATGGTCAGTTGTTGGTACAATTAAAGACCTGAA ACAGGGTTATCTGAGCCAGGTTATTCATGAAATTGTGGATCTGATGATTCACTATCAGGCC GTTGTTGTGCTGGAAAACCTGAATTTTGGCTTTAAAGCAAACGTACCGGCATTGCAGAAA AAGCAG TTTATCAGCAGTTCGAGAAAATGCTGATTGACAAACTGAATTGCCTGGTGCTGAA AGATTATCCGGCTGAAAAAGTTGGTGGTGTTCTGAATCCGTATCAGCTGACCGATCAGTTT Q / Q / bn / LΖηΖ-1 / ΥΙΛΙ ACCAGCTTTGCAAAAATGGGCACCCAGAGCGGATTTCTGTTTTATGTTCCGGCACCGTAT ACGAGCAAAATTGATCCGCTGACCGGTTTTGTTGATCCGTTTGTTTGGAAAACCATCAAAA ACCATGAAAGCCGCAAACATTTTCTGGAAGGTTTCGATTTTCTGCATTACGACGTTAAAAC GGGTGATTTCATCCTGCACTTTAAA ATGAATCGCAATCTGAGTTTTCAGCGTGGCCTGCCT GGTTTTATGCCTGCATGGGATATTGTGTTTGAGAAAAACGAAACACAGTTCGATGCAAAAG GCACCCCGTTTATTGCAGGTAAACGTATTGTTCCGGTGATTGAAAATCATCGTTTCACCGG TCGTTATCGCGATCTGTATCCGGCAAATGAACTGATCGCACTGCTGGAAG AGAAAGGTAT TGTTTTTCGTGATGGCTCAAACATTCTGCCGAAACTGCTGGAAAATGATGATAGCCATGCA ATTGATACCATGGTTGCACTGATTCGTAGCGTTCTGCAGATGCGTAATAGCAATGCAGCAA CCGGTGAAGATTACATTAATAGTCCGGTTCGTGATCTGAATGGTGTTTGTTTTGATAGCCG TTTTCAGAATC CGGAATGGCCGATGGATGCAGATGCAAATGGTGCATATCATATTGCACT GAAAGGACAGCTGCTGCTGAACCACCTGAAAGAAAGCAAAGATCTGAAACTGCAAAACGG CATTAGCAATCAGGATTGGCTGGCATATATCCAAGAACTGCGTAACGGTCGTAAACGTAC CGCAGATGGTAGCGAATTTGAAAGCCCGAAAAAA AGCGTAAGGTGGAAGGTGGTAGCG GTGGTTCAGGTGGTAGTGGCGGTAGTGGTGGCTCAGGGGGTTCTGGTGGCTCTGGTGGT AGCCTCGAGCACCACCACCACCACCACTGA SEQ ID NO.: 16 ATGACCCAGTTTGAAGGTTTCACCAATCTGTATCAGGTTAGCAAAACCCTGCGTTT TGAACTGATTCCGCAGGGTAAAACCCTGAAACATATTCAAGAACAGGGCTTCATCGAAGA GGATAAAGCACGTAACGATCACTACAAAGAACTGAAACCGATTATCGACCGCATCTATAAA ACCTATGCAGATCAGTGTCTGCAGCTGGTTCAGCTGGA TTGGGAAAATCTGAGCGCAGCA ATTGATAGTTATCGCAAAGAAAAAACCGAAAGAAACCCCGTAATGCACTGATTGAAGAACAGG CAACCTATCGTAATGCCATCCATGATTATTCATTGGTCGTACCGATAATCTGACCGATGC AATTAACAAACGTCACGCCGAAATCTATAAAGGCCTGTTTAAAGCCGAACTGTTTAATGGC AAAGTTCTGAA ACAGCTGGGCACCGTTACCACCCACCGAACATGAAAATGCACTGCTGCGT AGCTTTGATAAATTCACCACCCTATTTCAGCGGCTTTTATGAGAATCGCAAAAACGTGTTTA GCGCAGAAGATATTAGCACCGCAATTCCGCATCGTATTGTGCAGGATAATTTCCCGAAATT CAAAGAGAACTGCCACATTTTTACCCGTCTGATTACCGCAGTTCCGAG CCTGCGTGAACA TTTTGAAAACGTTAAAAAAAGCCATCGGCATCTTTGTTAGCACCAGCATTGAAGAAGTTTTTA GCTTCCCGTTTTACAATCAGCTGCTGACCCAGACCCAGATTGATCTGTATAACCAACTGCT GGGTGGTATTAGCCGTGAAGCAGGCACCGAAAAAATCAAAGGTCTGAATGAAGTGCTGAA TCTGGCCATTCAGAA AAATGATGAAACCGCACATATTATTGCAAGCCTGCCGCATCGTTTT ATTCCGCTGTTCAAACAAATTCTGAGCGATCGTAATACCCTGAGCTTTATTCTGGAAGAATTCAAATCCGATGAAGAGGTGATTCAGAGCTTTTGCAAATACAAAACGCTGCTGCGCAATG AAAATGTTCTGGAAACTGCCGAAGCACTGTTTAACGAACTGAATAGCATT GATCTGACCCA CATCTTTATCAGCCACAAAAAACTGGAAACCATTTCAAGCGCACTGTGTGATCATTGGGAT ACCCTGCGTAATGCCCTGTATGAACGTCGTATTAGCGAACTGACCGGTAAAATTACCAAAA Q / Q / Wl / LΖΠΖ / 3 / ΥΙΛΙ GCGCGAAAAAAAAGTTCAGCGCAGTCTGAAACATGAGGATATTAATCTGCAAGAGATTA TTAGCGCAGCCGGTAAAGAACTGTCAGAAGCATTTAAACAGAAAACCAGCGAAATTCTGT CACATGCACATGCAGCACTGGATCAGCCGCTGCCGACCACCCTGAAAAAACAAGAAGAAAAAGAAATCCTGAAAAGCCAGCTGGATAGCCT GCTGGGTCTGTATCATCTGCTGGACTGGT TTGCAGTTGATGAAAGCAATGAAGTTGATCCGGAATTTAGCGCACGTCTGACCGGCATTA AACTGGAAATGGAACCGAGCCTGAGCTTTTATAACAAAGCCCGTAATTATGCCACCAAAAA ACCGTATAGCGTCGAAAAATTCAAACTGAACTTTCAGATGCCGACCCTGGCAAGCGGTTG G GATGTTAATAAAGAAAAAAACAACGGTGCCATCCTGTTCGTGAAAAATGGCCTGTATTAT CTGGGTATTATGCCGAAACAGAAAGGTCGTTATAAAGCGCTGAGCTTTGAACCGACGGAA AAAACCAGTGAAGGTTTTGATAAAATGTACTACGACTATTTTTCCGGATGCAGCCAAAATGA TTCCGAAATGTAGCACCCAGCTGAA AGCAGTTACCGCACATTTTCAGACCCATACCACCC CGATTCTGCTGAGCAATAACTTTATTGAACCGCTGGAAATCACCAAAGAGATCTACGATCT GAATAACCCGGAAAAAGAGCCGAAAAAATTCCAGACCGCATATGCAAAAAAAACCGGTGATCAGAAAGGTTATCGTGAAGCGCTGTGTAAATGGATTGATTTCACCCGTGATTTTCTGAGC AA ATACACCAAAACCACCAGTATCGATCTGAGCAGCCTGCGTCCGAGCAGCCAGTATAAA GATCTGGGCGAATATTATGCAGAACTGAATCCGCTGCTGTATCATATTAGCTTTCAGCGTA TTGCCGAGAAAGAAATCATGGACGCAGTTGAAACCGGTAAACTGTACCTGTTCCAGATCT ACAATAAAGATTTTGCCAAAGGCCATCATGGCAAACCGA ATCTGCATACCCTGTATTGGAC CGGTCTGTTTAGCCCTGAAAATCTGGCAAAAACCTCGATTAAACTGAATGGTCAGGCGGA ACTGTTTTATCGTCCGAAAAGCCGTATGAAACGTATGGCACATCGTCTGGGTGAAAAAATG CTGAACAAAAACTGAAAGACCCAGAAAACCCCGATCCCGGATACACTGTATCAAGAACTG TATGATTAT GTGAACCATCGTCTGAGCCATGATCTGAGTGATGAAGCACGTGCCCTGCTG CCGAATGTTATTACCAAAGAAGTTAGCCACGAGATCATTAAGATCGTCGTTTTACCAGCG ACAAATTCTTTTTTCATGTGCCGATTACCCTGAATTATCAGGCAGCAAATAGCCCGAGCAA ATTTAACCAGCGTGTTAATGCATATCTGAAAGAACATC CAGAAACGCCGATTATTGGTATT GATCGTGGTGAACGTAACCTGATTTATATCACCGTTATTGATAGCACCGGCAAAATCCTGG AACAGCGTAGCCTGAATACCATTCAGCAGTTTGATTACCAGAAAAAACTGGATAATCGCGA GAAAGAACGTGTTGCAGCACGTCAGGCATGGTCAGTTGTTGGTACAATTAAAGACCTGAA ACAGG GTTATCTGAGCCAGGTTATTCATGAAATTGTGGATCTGATGATTCACTATCAGGCC GTTGTTGTGCTGGAAAACCTGAATTTTGGCTTTTAAAAGCAAACGTACCGGCATTGCAGAAAAAGCAGTTTATCAGCAGTTCGAGAAAATGCTGATTGACAAACTGAATTGCCTGGTGCTGAA AGATTATCCGGCTGAAAAAGTTGGT GGTGTTCTGAATCCGTATCAGCTGACCGATCAGTTT ACCAGCTTTGCAAAAATGGGCACCCAGAGCGGATTTCTGTTTTATGTTCCGGCACCGTAT ACGAGCAAAATTGATCCGCTGACCGGTTTTGTTGATCCGTTTGTTTGGAAAACCATCAAAA ACCATGAAAGCCGCAAACATTTTCTGGAAGGTTTCGATTTTCTGCATTACGACG TTAAAAC GGGTGATTTCATCCTGCACTTTAAAATGAATCGCAATCTGAGTTTTCAGCGTGGCCTGCCT GGTTTTATGCCTGCATGGGATATTGTGTTTGAGAAAAACGAAACACAGTTCGATGCAAAAG Q / Q / bn / Lznza / YiAi GCACCCCGTTTATTGCAGGTAAACGTATTGTTCCGGTGATTGAAAATCATCGTTTCACCGG TCGTTATCGCGATCTGTATCCGGCAAATGAACTGATCGCACTGCTGGAAGAGAAAGGTAT TGTTTTTCGTGATGGCTCAAACATTCTGCCGAAACTGCTGGAAAATGATGATAGCCATGCA ATTGATACCATGGTTGCACTGATTCG TAGCGTTCTGCAGATGCGTAATAGCAATGCAGCAA CCGGTGAAGATTACATTAATAGTCCGGTTCGTGATCTGAATGGTGTTTGTTTTGATAGCCG TTTTCAGAATCCGGAATGGCCGATGGATGCAGATGCAAATGGTGCATATCATATTGCACT GAAAGGACAGCTGCTGCTGAACCACCTGAAAGAAAGCAAAGATCTGA AACTGCAAAACGG CATTAGCAATCAGGATTGGCTGGCATATATCCAAGAACTGCGTAACGGTCGTAGCAGTGA TGATGAAGCAACCGCAGATAGCCAGCATGCAGCACCGCCTAAAAAGAAACGTAAAGTTGG TGGTAGCGGCGGTAGTAAACGTACCGCAGATGGTAGCGAATTTGAAAGCCCGAAAAAAAA GCGTAAGGTG GAAGGTGGTAGCGGTGGTTCAGGTGGTAGTGGCGGTAGTGGTGGCTCA GGGGGTTCTGGTGGCTCTGGTGGTAGCCTCGAGCACCACCACCACCACCACTGA SEQ ID NO.: 17 ATGACCCAGTTTGAAGGTTTCACCAATCTGTATCAGGTTAGCAAAACCCTGCGTTT TGAACTGATTCCGCAGGGTAAAACCCTGAAACATATTCAAGAACAGGGCTTCATCGAAGA GGATAAAGCACGTAACGATCACTACAAAGAACTGAAACCGATTATCGACCGCATCTATAAA ACCTATGCAGATCAGTGTCTGCAGCTGGTTCAGCTGGA TTGGGAAAATCTGAGCGCAGCA ATTGATAGTTATCGCAAAGAAAAAACCGAAAGAAACCCCGTAATGCACTGATTGAAGAACAGG CAACCTATCGTAATGCCATCCATGATTATTCATTGGTCGTACCGATAATCTGACCGATGC AATTAACAAACGTCACGCCGAAATCTATAAAGGCCTGTTTAAAGCCGAACTGTTTAATGGC AAAGTTCTGAA ACAGCTGGGCACCGTTACCACCCACCGAACATGAAAATGCACTGCTGCGT AGCTTTGATAAATTCACCACCCTATTTCAGCGGCTTTTATGAGAATCGCAAAAACGTGTTTA GCGCAGAAGATATTAGCACCGCAATTCCGCATCGTATTGTGCAGGATAATTTCCCGAAATT CAAAGAGAACTGCCACATTTTTACCCGTCTGATTACCGCAGTTCCGAG CCTGCGTGAACA TTTTGAAAACGTTAAAAAAAGCCATCGGCATCTTTGTTAGCACCAGCATTGAAGAAGTTTTTA GCTTCCCGTTTTACAATCAGCTGCTGACCCAGACCCAGATTGATCTGTATAACCAACTGCT GGGTGGTATTAGCCGTGAAGCAGGCACCGAAAAAATCAAAGGTCTGAATGAAGTGCTGAA TCTGGCCATTCAGAA AAATGATGAAACCGCACATATTATTGCAAGCCTGCCGCATCGTTTT ATTCCGCTGTTCAAACAAATTCTGAGCGATCGTAATACCCTGAGCTTTATTCTGGAAGAATTCAAATCCGATGAAGAGGTGATTCAGAGCTTTTGCAAATACAAAACGCTGCTGCGCAATG AAAATGTTCTGGAAACTGCCGAAGCACTGTTTAACGAACTGAATAGCATT GATCTGACCCA CATCTTTATCAGCCACAAAAAACTGGAAACCATTTCAAGCGCACTGTGTGATCATTGGGAT ACCCTGCGTAATGCCCTGTATGAACGTCGTATTAGCGAACTGACCGGTAAAATTACCAAAA GCGCGAAAAAAAAGTTCAGCGCAGTCTGAAACATGAGGATATTAATCTGCAAGAGATTA TTAGCGCAGCCGGTAAAGAACT GTCAGAAGCATTTAAACAGAAAACCAGCGAAATTCTGT CACATGCACATGCAGCACTGGATCAGCCGCTGCCGACCACCCTGAAAAAACAAGAAGAAAAAGAAATCCTGAAAAGCCAGCTGGATAGCCTGCTGGGTCTGTATCATCTGCTGGACTGGT a / a / bn / Lznza / YiAi TTGCAGTTGATGAAAGCAATGAAGTTGATCCGGAATTTAGCGCACGTCTGACCGGCATTA AACTGGAAATGGAACCGAGCCTGAGCTTTTATAACAAAGCCCGTAATTATGCCACCAAAAA ACCGTATAGCGTCGAAAAATTCAAACTGAACTTTCAGATGCCGACCCTGGCAAGCGGTTG GGATGTTAATAAAGAAAAAAACAACGGTGCCA TCCTGTTCGTGAAAAATGGCCTGTATTAT CTGGGTATTATGCCGAAACAGAAAGGTCGTTATAAAGCGCTGAGCTTTGAACCGACGGAA AAAACCAGTGAAGGTTTTGATAAAATGTACTACGACTATTTTCCGGATGCAGCCAAAATGA TTCCGAAATGTAGCACCCAGCTGAAAGCAGTTACCGCACATTTTCAGACCCATACCACCC C GATTCTGCTGAGCAATAACTTTATTGAACCGCTGGAAATCACCAAAGAGATCTACGATCT GAATAACCCGGAAAAAGAGCCGAAAAAATTCCAGACCGCATATGCAAAAAAAACCGGTGA TCAGAAAGGTTATCGTGAAGCGCTGTGTAAATGGATTGATTTCACCCGTGATTTTCTGAGC AAATACACCAAAACCACCAGTATCGATCTGAGCAGC CTGCGTCCGAGCAGCCAGTATAAA GATCTGGGCGAATATTATGCAGAACTGAATCCGCTGCTGTATCATATTAGCTTTCAGCGTA TTGCCGAGAAAGAAATCATGGACGCAGTTGAAACCGGTAAACTGTACCTGTTCCAGATCT ACAATAAAGATTTTGCCAAAGGCCATCATGGCAAACCGAATCTGCATACCCTGTATTGGAC CGGTCTG TTTAGCCCTGAAAATCTGGCAAAAACCTCGATTAAACTGAATGGTCAGGCGGA ACTGTTTTATCGTCCGAAAAGCCGTATGAAACGTATGGCACATCGTCTGGGTGAAAAAATG CTGAACAAAAAACTGAAAGACCAGAAAACCCCGATCCCGGATACACTGTATCAAGAACTG TATGATTATGTGAACCATCGTCTGAGCCATGATCTGAGT GATGAAGCACGTGCCCTGCTG CCGAATGTTATTACCAAAGAAGTTAGCCACGAGATCATTAAGATCGTCGTTTTACCAGCG ACAAATTCTTTTTTCATGTGCCGATTACCCTGAATTATCAGGCAGCAAATAGCCCGAGCAA ATTTAACCAGCGTGTTAATGCATATCTGAAAGAACATCCGAAACGCCGATTATTGGTATT GATCGTGG TGAACGTAACCTGATTTATATCACCGTTATTGATAGCACCGGCAAAATCCTGG AACAGCGTAGCCTGAATACCATTCAGCAGTTTGATTACCAGAAAAAACTGGATAATCGCGA GAAAGAACGTGTTGCAGCACGTCAGGCATGGTCAGTTGTTGGTACAATTAAAGACCTGAA ACAGGGTTATCTGAGCCAGGTTATTCATGAAATTGTG GATCTGATGATTCACTATCAGGCC GTTGTTGTGCTGGAAAACCTGAATTTTGGCTTTAAAGCAAACGTACCGGCATTGCAGAAA AAGCAGTTTATCAGCAGTTCGAGAAAATGCTGATTGACAAACTGAATTGCCTGGTGCTGAA AGATTATCCGGCTGAAAAAGTTGGTGGTGTTCTGAATCCGTATCAGCTGACCGATCAG TTT ACCAGCTTTGCAAAAATGGGCACCCAGAGCGGATTTCTGTTTTATGTTCCGGCACCGTAT ACGAGCAAAATTGATCCGCTGACCGGTTTTGTTGATCCGTTTGTTTGGAAAACCATCAAAA ACCATGAAAGCCGCAAACATTTTCTGGAAGGTTTCGATTTTCTGCATTACGACGTTAAAAC GGGTGATTTCATCCTGCACTTTA AAATGAATCGCAATCTGAGTTTTCAGCGTGGCCTGCCT GGTTTTATGCCTGCATGGGATATTGTGTTTGAGAAAAACGAAACACAGTTCGATGCAAAAG GCACCCCGTTTATTGCAGGTAAACGTATTGTTCCGGTGATTGAAAATCATCGTTTCACCGG TCGTTATCGCGATCTGTATCCGGCAAATGAACTGATCGCACTGCTGGA AGAGAAAGGTAT TGTTTTTCGTGATGGCTCAAACATTCTGCCGAAACTGCTGGAAAATGATGATAGCCATGCA ATTGATACCATGGTTGCACTGATTCGTAGCGTTCTGCAGATGCGTAATAGCAATGCAGCAA a / a / bn / Lznza / YiAi CCGGTGAAGATTACATTAATAGTCCGGTTCGTGATCTGAATGGTGTTTGTTTTGATAGCCG TTTTCAGAATCCGGAATGGCCGATGGATGCAGATGCAAATGGTGCATATCATATTGCACT GAAAGGACAGCTGCTGCTGAACCACCTGAAAGAAAGCAAAGATCTGAAACTGCAAAACGG CATTAGCAATCAGGATTGGCT GGCATATATCCAAGAACTGCGTAACGGTCGTAAACGTCC GGCAGCAACCAAAAAAGCAGGTCAGGCAAAAAAGAAAAAAGGTGGTAGCGGCGGTAGTA AACGTACCGCAGATGGTAGCGAATTTGAAAGCCCGAAAAAAAAGCGTAAGGTGGAAGGT GGTAGCGGTGGTTCAGGTGGTAGTGGCGGTAGT GGTGGCTCAGGGGGTTCTGGTGGCT CTGGTGGTAGCCTCGAGCACCACCACCACCACCACTGA The following preferred Casi2a polypeptide amino acid sequences are depicted below. SEQ ID NO.:18 MGSSSSGLVPRGSHMASMTGGQQMGRDPGKPIPNPLLGLDSTAPKKKRKVGIHGVP AATQFEGFTNLYQVSKTLRFELIPQGKTLKHIQEQGFIEEDKARNDHYKELKPIIDRIYKTYADQ CLQLVQLDWENLSAAIDSYRKEKTEETRNALIEEQATYRNAIHDYFIGRTDNLTDAIN KRHAEIY KGLFKAELFNGKVLKQLGTVTTTEHENALLRSFDKFTTYFSGFYENRKNVFSAEDISTAIPHRIV QDNFPKFKENCHIFTRLITAVPSLREHFENVKKAIGIFVSTSIEEVFSFPFYNQLLTQTQIDLYNQ LLGGISREAGTEKIKGLNEVLNLAIQKNDETAHIIASLPHRFIPLFKQ ILSDRNTLSFILEEFKSDEE VIQSFCKYKTLLRNENVLETAEALFNELNSIDLTHIFISHKKLETISSALCDHWDTLRNALYERRI SELTGKITKSAKEKVQRSLKHEDINLQEIISAAGKELSEAFKQKTSEILSHAHAALDQPLPTTLKK QEEKEILKSQLDSLLGLYHLLDWFAVDESNEVDPEFSARLTGIKLEME PSLSFYNKARNYATKK PYSVEKFKLNFQMPTLASGWDVNKEKNNGAILFVKNGLYYLGIMPKQKGRYKALSFEPTEKTS EGFDKMYYDYFPDAAKMIPKCSTQLKAVTAHFQTHTTPILLSNNFIEPLEITKEIYDLNNPEKEP KKFQTAYAKKTGDQKGYREALCKWI DFTRDFLSKYTKTTSIDLSSLRPSSQYKDLGEYYAELN PLLYHISFQRIAEKEIMDAVETGKLYLFQIYNKDFAKGHHGKPNLHTLYWTGLFSPENLAKTSIK LNGQAELFYRPKSRMKRMAHRLGEKMLNKKLKDQKTPIPDTLYQELYDYVNHRLSHDLSDEA RALL PNVITKEVSHEIIKDRRFTSDKFFFHVPITLNYQAANSPSKFNQRVNAYLKEHPETPIIGID RGERNLIYITVIDSTGKILEQRSLNTIQQFDYQKKLDNREKERVAARQAWSWGTIKDLKQGYL SQVIHEIVDLMIHYQAWVLENLNFGFKSKRTGIAEKAVYQQFEKMLIDKLNC LVLKDYPAEKVG GVLNPYQLTDQFTSFAKMGTQSGFLFYVPAPYTSKIDPLTGFVDPFVWKTIKNHESRKHFLEG FDFLHYDVKTGDFILHFKMNRNLSFQRGLPGFMPAWDIVFEKNETQFDAKGTPFIAGKRIVPVI ENHRFTGRYRDLYPANELIALLEEKGIVFRDGSNI LPKLLENDDSHAIDTMVALIRSVLQMRNSN AATGEDYINSPVRDLNGVCFDSRFQNPEWPMDADANGAYHIALKGQLLLNHLKESKDLKLQN GISNQDWLAYIQELRNPKKKRKVKLAAALEHHHHHH SEQ ID NO.:19 MGSSSSGLVPRGSHMASMTGGQQMGRDPAPKKKRKVGIHGVPAATQFEGFTNLYQ VSKTLRFELIPQGKTLKHIQEQGFIEEDKARNDHYKELKPIIDRIYKTYADQCLQLVQLDWENLS AAIDSYRKEKTEETRNALIEEQATYRNAIHDYFIGRTDNLTDAINKRHAEIYKGLFKAEL FNGKVL KQLGTVTTTEHENALLRSFDKFTTYFSGFYENRKNVFSAEDISTAIPHRIVQDNFPKFKENCHIF TRLITAVPSLREHFENVKKAIGIFVSTSIEEVFSFPFYNQLLTQTQIDLYNQLLGGISREAGTEKIK GLNEVLNLAIQKNDETAHIIASLPHRFIPLFKQILSDRNTLSFILEEFKSDEEVIQSFCK YKTLLRN ENVLETAEALFNELNSIDLTHIFISHKKLETISSALCDHWDTLRNALYERRISELTGKITKSAKEKV QRSLKHEDINLQEIISAAGKELSEAFKQKTSEILSHAHAALDQPLPTTLKKQEEKEILKSQLDSLL GLYHLLDWFAVDESNEVDPEFSARLTGIKLEMEPSLSFYNKARNYATKKPYSVE KFKLNFQMP TLASGWDVNKEKNNGAILFVKNGLYYLGIMPKQKGRYKALSFEPTEKTSEGFDKMYYDYFPD AAKMIPKCSTQLKAVTAHFQTHTTPILLSNNFIEPLEITKEIYDLNNPEKEPKKFQTAYAKKTGD QKGYREALCKWIDFTRDFLSKYTKTTSIDLSSLRPSS QYKDLGEYYAELNPLLYHISFQRIAEKE IMDAVETGKLYLFQIYNKDFAKGHHGKPNLHTLYWTGLFSPENLAKTSIKLNGQAELFYRPKSR MKRMAHRLGEKMLNKKLKDQKTPIPDTLYQELYDYVNHRLSHDLSDEARALLPNVITKEVSHEI IKDRRFTSDKFFF HVPITLNYQAANSPSKFNQRVNAYLKEHPETPIIGIDRGERNLIYITVIDSTG KILEQRSLNTIQQFDYQKKLDNREKERVAARQAWSWGTIKDLKQGYLSQVIHEIVDLMIHYQA WVLENLNFGFKSKRTGIAEKAVYQQFEKMLIDKLNCLVLKDYPAEKVGGVLNPY QLTDQFTS FAKMGTQSGFLFYVPAPYTSKIDPLTGFVDPFVWKTIKNHESRKHFLEGFDFLHYDVKTGDFIL HFKMNRNLSFQRGLPGFMPAWDIVFEKNETQFDAKGTPFIAGKRIVPVIENHRFTGRYRDLYP ANELIALLEEKGIVFRDGSNILPKLLENDDSHAIDTMVALIRSVLQMR NSNAATGEDYINSPVRD LNGVCFDSRFQNPEWPMDADANGAYHIALKGQLLLNHLKESKDLKLQNGISNQDWLAYIQEL RNPKKKRKVKLAAALEHHHHHH SEQ ID NO.:20 MPKKKRKVGIHGVPAATQFEGFTNLYQVSKTLRFELIPQGKTLKHIQEQGFIEEDKARN DHYKELKPIIDRIYKTYADQCLQLVQLDWENLSAAIDSYRKEKTEETRNALIEEQATYRNAIHDY FIGRTDNLTDAINKRHAEIYKGLFKAELFNGKVLKQLGTVTTTEHENALLRSFDK FTTYFSGFYE NRKNVFSAEDISTAIPHRIVQDNFPKFKENCHIFTRLITAVPSLREHFENVKKAIGIFVSTSIEEVF SFPFYNQLLTQTQIDLYNQLLGGISREAGTEKIKGLNEVLNLAIQKNDETAHIIASLPHRFIPLFK QILSDRNTLSFILEEFKSDEEVIQSFCKYKTLLRNENVLETAEALFN ELNSIDLTHIFISHKKLETIS SALCDHWDTLRNALYERRISELTGKITKSAKEKVQRSLKHEDINLQEIISAAGKELSEAFKQKTS EILSHAHAALDQPLPTTLKKQEEKEILKSQLDSLLGLYHLLDWFAVDESNEVDPEFSARLTGIKL EMEPLSFYNKARNYATKKPYSVEKFKLNFQMPTLASG WDVNKEKNNGAILFVKNGLYYLGIM PKQKGRYKALSFEPTEKTSEGFDKMYYDYFPDAAKMIPKCSTQLKAVTAHFQTHTTPILLSNN FIEPLEITKEIYDLNNPEKEPKKFQTAYAKKTGDQKGYREALCKWIDFTRDFLSKYTKTTSIDLS SLRPSSQYKDLGEYYAELNPLL YHISFQRIAEKEIMDAVETGKLYLFQIYNKDFAKGHHGKPNL HTLYWTGLFSPENLAKTSIKLNGQAELFYRPKSRMKRMAHRLGEKMLNKKLKDQKTPIPDTLY QELYDYVNHRLSHDLSDEARALLPNVITKEVSHEIIKDRRFTSDKFFFHVPITLNYQAANSPSKF N QRVNAYLKEHPETPIIGIDRGERNLIYITVIDSTGKILEQRSLNTIQQFDYQKKLDNREKERVAA RQAWSWGTIKDLKQGYLSQVIHEIVDLMIHYQAVWLENLNFGFKSKRTGIAEKAVYQQFEKM LIDKLNCLVLKDYPAEKVGGVLNPYQLTDQFTSFAKMGTQ SGFLFYVPAPYTSKIDPLTGFVDP FVWKTIKNHESRKHFLEGFDFLHYDVKTGDFILHFKMNRNLSFQRGLPGFMPAWDIVFEKNET QFDAKGTPFIAGKRIVPVIENHRFTGRYRDLYPANELIALLEEKGIVFRDGSNILPKLLENDDSH AIDTMVALIRSVLQMRNSNAATGEDYINSPVRDLNGVCFDSRFQNPEWPMDADANGAYHI AL KGQLLLNHLKESKDLKLQNGISNQDWLAYIQELRNPKKKRKVLEHHHHHH SEQ ID NO.:21 MTQFEGFTNLYQVSKTLRFELIPQGKTLKHIQEQGFIEEDKARNDHYKELKPIIDRIYKT YADQCLQLVQLDWENLSAIDSYRKEKTEETRNALIEEQATYRNAIHDYFIGRTDNLTDAINKR HAEIYKGLFKAELFNGKVLKQLGTVTTTEHENALLRSFDKFTTYFSGFYENRKNV FSAEDISTAI PHRIVQDNFPKFKENCHIFTRLITAVPSLREHFENVKKAIGIFVSTSIEEVFSFPFYNQLLTQTQID LYNQLLGGISREAGTEKIKGLNEVLNLAIQKNDETAHIIASLPHRFIPLFKQILSDRNTLSFILEEFK SDEEVIQSFCKYKTLLRNENVLETAEALFNELNSIDLTHIFISHKKLETISS ALCDHWDTLRNALY ERRISELTGKITKSAKEKVQRSLKHEDINLQEIISAAGKELSEAFKQKTSEILSHAHAALDQPLPT TLKKQEEKEILKSQLDSLLGLYHLLDWFAVDESNEVDPEFSARLTGIKLEMEPSLSFYNKARNY ATKKPYSVEKFKLNFQMPTLASGWDVNKEKNNGAILFV KNGLYYLGIMPKQKGRYKALSFEPT EKTSEGFDKMYYDYFPDAAKMIPKCSTQLKAVTAHFQTHTTPILLSNNFIEPLEITKEIYDLNNP EKEPKKFQTAYAKKTGDQKGYREALCKWIDFTRDFLSKYTKTTSIDLSSLRPSSQYKDLGEYY AELNPLLYHISFQRIAEKEIMDA VETGKLYLFQIYNKDFAKGHHGKPNLHTLYWTGLFSPENLA KTSIKLNGQAELFYRPKSRMKRMAHRLGEKMLNKKLKDQKTPIPDTLYQELYDYVNHRLSHDL SDEARALLPNVITKEVSHEIIKDRRFTSDKFFFHVPITLNYQAANSPSKFNQRVNAYLKEHPETP IIGIDRGERNLIYITVIDSTGKILEQRSLNTIQQFDYQKKLDNREKERVAARQAWSWGTIKDLKQ GYLSQVIHEIVDLMIHYQAWVLENLNFGFKSKRTGIAEKAVYQQFEKMLIDKLNCLVLKDYPAE KVGGVLNPYQLTDQFTSFAKMGTQSGFLFYVPAPYTSKIDP LTGFVDPFVWKTIKNHESRKHF LEGFDFLHYDVKTGDFILHFKMNRNLSFQRGLPGFMPAWDIVFEKNETQFDAKGTPFIAGKRI VPVIENHRFTGRYRDLYPANELIALLEEKGIVFRDGSNILPKLLENDDSHAIDTMVALIRSVLQM RNSNAATGEDYINSPVRDLNGVCFDSRFQNPEWPMDA DANGAYHIALKGQLLLNHLKESKDL KLQNGISNQDWLAYIQELRNPKKKRKVLEHHHHHH SEQ ID NO.:22 MGSSHHHHHHSSGLVPRGSHMASMTGGQQMGRDPTQFEGFTNLYQVSKTLRFELIP QGKTLKHIQEQGFIEEDKARNDHYKELKPIIDRIYKTYADQCLQLVQLDWENLSAAIDSYRKEKT EETRNALIEEQATYRNAIHDYFIGRTDNLTDAINKRHAEIYKGLFKAELFNGKVLKQ LGTVTTTE HENALLRSFDKFTTYFSGFYENRKNVFSAEDISTAIPHRIVQDNFPKFKENCHIFTRLITAVPSLR EHFENVKKAIGIFVSTSIEEVFSFPFYNQLLTQTQIDLYNQLLGGISREAGTEKIKGLNEVLNLAI QKNDETAHIIASLPHRFIPLFKQILSDRNTLSFILEEFKSDEEVIQSFCKYKT LLRNENVLETAEAL FNELNSIDLTHIFISHKKLETISSALCDHWDTLRNALYERRISELTGKITKSAKEKVQRSLKHEDI NLQEIISAAGKELSEAFKQKTSEILSHAHAALDQPLPTTLKKQEEKEILKSQLDSLLGLYHLLDW FAVDESNEVDPEFSARLTGIKLEMEPSLSFYNKARNYATKKPYSVEKFK LNFQMPTLASGWDV NKEKNNGAILFVKNGLYYLGIMPKQKGRYKALSFEPTEKTSEGFDKMYYDYFPDAAKMIPKCS Q / Q / frni 7Π7 -1 / ΥΙΛΙ TQLKAVTAHFQTHTTPILLSNNFIEPLEITKEIYDLNNPEKEPKKFQTAYAKKTGDQKGYREALC KWIDFTRDFLSKYTKTTSIDLSSLRPSSQYKDLGEYYAELNPLLYHISFQRIAEKEIMDAVETGK LYLFQIYNKDFAKGHHGKPNLHTLYWTGLFSPENLAKTSI KLNGQAELFYRPKSRMKRMAHRL GEKMLNKKLKDQKTPIPDTLYQELYDYVNHRLSHDLSDEARALLPNVITKEVSHEIIKDRRFTSD KFFFHVPITLNYQAANSPSKFNQRVNAYLKEHPETPIIGIDRGERNLIYITVIDSTGKILEQRSLNT IQQFDYQKKLDNREKERVAARQAWSW GTIKDLKQGYLSQVIHEIVDLMIHYQAWVLENLNF GFKSKRTGIAEKAVYQQFEKMLIDKLNCLVLKDYPAEKVGGVLNPYQLTDQFTSFAKMGTQSG FLFYVPAPYTSKIDPLTGFVDPFVWKTIKNHESRKHFLEGFDFLHYDVKTGDFILHFKMNRN LS FQRGLPGFMPAWDIVFEKNETQFDAKGTPFIAGKRIVPVIENHRFTGRYRDLYPANELIALLEE KGIVFRDGSNILPKLLENDDSHAIDTMVALIRSVLQMRNSNAATGEDYINSPVRDLNGVCFDSR FQNPEWPMDADANGAYHIALKGQLLLNHLKESKDLKLQNGISNQDWLAYIQELRNGRSSDDE ATADSQHAAPPKKKRKVGGSGGSGGSGGSGGSGGSGGSGGSLEHHHHHH SEQ ID NO.:23 MTQFEGFTNLYQVSKTLRFELIPQGKTLKHIQEQGFIEEDKARNDHYKELKPIIDRIYKT YADQCLQLVQLDWENLSAIDSYRKEKTEETRNALIEEQATYRNAIHDYFIGRTDNLTDAINKR HAEIYKGLFKAELFNGKVLKQLGTVTTTEHENALLRSFDKFTTYFSGFYENRKNV FSAEDISTAI PHRIVQDNFPKFKENCHIFTRLITAVPSLREHFENVKKAIGIFVSTSIEEVFSFPFYNQLLTQTQID LYNQLLGGISREAGTEKIKGLNEVLNLAIQKNDETAHIIASLPHRFIPLFKQILSDRNTLSFILEEFK SDEEVIQSFCKYKTLLRNENVLETAEALFNELNSIDLTHIFISHKKLETISS ALCDHWDTLRNALY ERRISELTGKITKSAKEKVQRSLKHEDINLQEIISAAGKELSEAFKQKTSEILSHAHAALDQPLPT TLKKQEEKEILKSQLDSLLGLYHLLDWFAVDESNEVDPEFSARLTGIKLEMEPSLSFYNKARNY ATKKPYSVEKFKLNFQMPTLASGWDVNKEKNNGAILFV KNGLYYLGIMPKQKGRYKALSFEPT EKTSEGFDKMYYDYFPDAAKMIPKCSTQLKAVTAHFQTHTTPILLSNNFIEPLEITKEIYDLNNP EKEPKKFQTAYAKKTGDQKGYREALCKWIDFTRDFLSKYTKTTSIDLSSLRPSSQYKDLGEYY AELNPLLYHISFQRIAEKEIMDA VETGKLYLFQIYNKDFAKGHHGKPNLHTLYWTGLFSPENLA KTSIKLNGQAELFYRPKSRMKRMAHRLGEKMLNKKLKDQKTPIPDTLYQELYDYVNHRLSHDL SDEARALLPNVITKEVSHEIIKDRRFTSDKFFFHVPITLNYQAANSPSKFNQRVNAYLKEHPETP IIGIDRGERNLIYITVIDSTGKILEQRSLNTIQQFDYQKKLDNREKERVAARQAWSWGTIKDLKQ GYLSQVIHEIVDLMIHYQAVWLENLNFGFKSKRTGIAEKAVYQQFEKMLIDKLNCLVLKDYPAE KVGGVLNPYQLTDQFTSFAKMGTQSGFLFYVPAPYTSKIDP LTGFVDPFVWKTIKNHESRKHF LEGFDFLHYDVKTGDFILHFKMNRNLSFQRGLPGFMPAWDIVFEKNETQFDAKGTPFIAGKRI VPVIENHRFTGRYRDLYPANELIALLEEKGIVFRDGSNILPKLLENDDSHAIDTMVALIRSVLQM RNSNAATGEDYINSPVRDLNGVCFDSRFQNPEWPMDA DANGAYHIALKGQLLLNHLKESKDL KLQNGISNQDWLAYIQELRNGRSSDDEATADSQHAAPPKKKRKVGGSGGSGGSGGSGGSG GSGGSGGSLEHHHHHH SEQ ID NO.:24 MGSSSSGLVPRGSHMASMTGGQQMGRDPTQFEGFTNLYQVSKTLRFELIPQGKTLK HIQEQGFIEEDKARNDHYKELKPIIDRIYKTYADQCLQLVQLDWENLSAIDSYRKEKTEETRNA LIEEQATYRNAIHDYFIGRTDNLTDAINKRHAEIYKGLFKAELFNGKVLKQLGTVTT TEHENALL RSFDKFTTYFSGFYENRKNVFSAEDISTAIPHRIVQDNFPKFKENCHIFTRLITAVPSLREHFEN VKKAIGIFVSTSIEEVFSFPFYNQLLTQTQIDLYNQLLGGISREAGTEKIKGLNEVLNLAIQKNDE TAHUAS LPHRFIPLFKQILSDRNTLSFILEEFKSDEEVIQSFCKYKTLLRN ENVLETAEALFNELN SIDLTHIFISHKKLETISSALCDHWDTLRNALYERRISELTGKITKSAKEKVQRSLKHEDINLQEIIS AAGKELSEAFKQKTSEILSHAHAALDQPLPTTLKKQEEKEILKSQLDSLLGLYHLLDWFAVDES NEVDPEFSARLTGIKLEMEPSLSFYNKARNYATKKPYSVEKFK LNFQMPTLASGWDVNKEKN NGAILFVKNGLYYLGIMPKQKGRYKALSFEPTEKTSEGFDKMYYDYFPDAAKMIPKCSTQLKA VTAHFQTHTTPILLSNNFIEPLEITKEIYDLNNPEKEPKKFQTAYAKKTGDQKGYREALCKWIDF TRDFLSKYTKTTSIDLSSLRPSSQY KDLGEYYAELNPLLYHISFQRIAEKEIMDAVETGKLYLFQI YNKDFAKGHHGKPNLHTLYWTGLFSPENLAKTSIKLNGQAELFYRPKSRMKRMAHRLGEKML NKKLKDQKTPIPDTLYQELYDYVNHRLSHDLSDEARALLPNVITKEVSHEIIKDRRFTSDKFFFH VPI TLNYQAANSPSKFNQRVNAYLKEHPETPIIGIDRGERNLIYITVIDSTGKILEQRSLNTIQQFD YQKKLDNREKERVAARQAWSWGTIKDLKQGYLSQVIHEIVDLMIHYQAWVLENLNFGFKSK RTGIAEKAVYQQFEKMLIDKLNCLVLKDYPAEKVGGVLNPYQLTD QFTSFAKMGTQSGFLFYV PAPYTSKIDPLTGFVDPFVWKTIKNHESRKHFLEGFDFLHYDVKTGDFILHFKMNRNLSFQRGL PGFMPAWDIVFEKNETQFDAKGTPFIAGKRIVPVIENHRFTGRYRDLYPANELIALLEEKGIVFR DGSNILPKLLENDDSHAIDTMVALIRSVLQMRNSNAAT GEDYINSPVRDLNGVCFDSRFQNPE WPMDADANGAYHIALKGQLLLNHLKESKDLKLQNGISNQDWLAYIQELRNGRSSDDEATADS QHAAPPKKKRKVGGSGGSGGSGGSGGSGGSGGSGGSLEHHHHHH SEQ ID NO.:25 MPPPKRPRLDGIHGVPAATQFEGFTNLYQVSKTLRFELIPQGKTLKHIQEQGFIEEDKA RNDHYKELKPIIDRIYKTYADQCLQLVQLDWENLSAIDSYRKEKTEETRNALIEEQATYRNAIH DYFIGRTDNLTDAINKRHAEIYKGLFKAELFNGKVLKQLGTVTTTEHENALLRSFDK FTTYFSGF YENRKNVFSAEDISTAIPHRIVQDNFPKFKENCHIFTRLITAVPSLREHFENVKKAIGIFVSTSIEE VFSFFPFYNQLLTQTQIDLYNQLLGGISREAGTEKIKGLNEVLNLAIQKNDETAHIIASLPHRFIPLF KQILSDRNTLSFILEEFKSDEEVIQSFCKYKTLLRNENVLETAEALFNELNS IDLTHIFISHKKLETI SSALCDHWDTLRNALYERRISELTGKITKSAKEKVQRSLKHEDINLQEIISAAGKELSEAFKQKT SEILSHAHAALDQPLPTTLKKQEEKEILKSQLDSLLGLYHLLDWFAVDESNEVDPEFSARLTGIK LEMEPSLSFYNKARNYATKKPYSVEKFKLNFQMPTLASGWDVN KEKNNGAILFVKNGLYYLGI MPKQKGRYKALSFEPTEKTSEGFDKMYYDYFPDAAKMIPKCSTQLKAVTAHFQTHTTPILLSN NFIEPLEITKEIYDLNNPEKEPKKFQTAYAKKTGDQKGYREALCKWIDFTRDFLSKYTKTTSIDL SSLRPSSQYKDLGEYYAELNPLLYHISFQ RIAEKEIMDAVETGKLYLFQIYNKDFAKGHHGKPN LHTLYWTGLFSPENLAKTSIKLNGQAELFYRPKSRMKRMAHRLGEKMLNKKLKDQKTPIPDTL YQELYDYVNHRLSHDLSDEARALLPNVITKEVSHEIIKDRRFTSDKFFFHVPITLNYQAANSPSK FNQRVNAYLKEHPETPIIGIDRGERNLIYITVIDSTGKILEQRSLNTIQQFDYQKKLDNREKERVA ARQAWSWGTIKDLKQGYLSQVIHEIVDLMIHYQAVWLENLNFGFKSKRTGIAEKAVYQQFEK MLIDKLNCLVLKDYPAEKVGGVLNPYQLTDQFTSFAKMG TQSGFLFYVPAPYTSKIDPLTGFV DPFVWKTIKNHESRKHFLEGFDFLHYDVKTGDFILHFKMNRNLSFQRGLPGFMPAWDIVFEKN ETQFDAKGTPFIAGKRIVPVIENHRFTGRYRDLYPANELIALLEEKGIVFRDGSNILPKLLENDDS HAIDTMVALIRSVLQMRNSNAATGEDYINSP VRDLNGVCFDSRFQNPEWPMDADANGAYHIA LKGQLLLNHLKESKDLKLQNGISNQDWLAYIQELRNGRSSDDEATADSQHAAPPKKKRKVGG SGGSGGSGGSGGSGGSGGSGGSLEHHHHHH SEQ ID NO.:26 MSSDDEATADSQHAAPPKKKRKVGIHGVPAATQFEGFTNLYQVSKTLRFELIPQGKTL KHIQEQGFIEEDKARNDHYKELKPIIDRIYKTYADQCLQLVQLDWENLSAAIDSYRKEKTEETRN ALIEEQATYRNAIHDYFIGRTDNLTDAINKRHAEIYKGLFKAELFNGKVLKQLG TVTTTEHENALL RSFDKFTTYFSGFYENRKNVFSAEDISTAIPHRIVQDNFPKFKENCHIFTRLITAVPSLREHFEN VKKAIGIFVSTSIEEVFSFPFYNQLLTQTQIDLYNQLLGGISREAGTEKIKGLNEVLNLAIQKNDE TAHUAS LPHRFIPLFKQILSDRNTLSFILEEFKSDEEVIQSFCKYKT LLRNENVLETAEALFNELN SIDLTHIFISHKKLETISSALCDHWDTLRNALYERRISELTGKITKSAKEKVQRSLKHEDINLQEIIS AAGKELSEAFKQKTSEILSHAHAALDQPLPTTLKKQEEKEILKSQLDSLLGLYHLLDWFAVDES NEVDPEFSARLTGIKLEMEPSLSFYNKARNYATKKPYSVEK FKLNFQMPTLASGWDVNKEKN NGAILFVKNGLYYLGIMPKQKGRYKALSFEPTEKTSEGFDKMYYDYFPDAAKMIPKCSTQLKA VTAHFQTHTTPILLSNNFIEPLEITKEIYDLNNPEKEPKKFQTAYAKKTGDQKGYREALCKWIDF TRDFLSKYTKTTSIDLSSLRPSS QYKDLGEYYAELNPLLYHISFQRIAEKEIMDAVETGKLYLFQI YNKDFAKGHHGKPNLHTLYWTGLFSPENLAKTSIKLNGQAELFYRPKSRMKRMAHRLGEKML NKKLKDQKTPIPDTLYQELYDYVNHRLSHDLSDEARALLPNVITKEVSHEIIKDRRFTSDKFFFH VPITLNYQAANSPSKFNQRVNAYLKEHPETPIIGIDRGERNLIYITVIDSTGKILEQRSLNTIQQFD YQKKLDNREKERVAARQAWSWGTIKDLKQGYLSQVIHEIVDLMIHYQAWVLENLNFGFKSK RTGIAEKAVYQQFEKMLIDKLNCLVLKDYPAEKVGGVLNPYQ LTDQFTSFAKMGTQSGFLFYV PAPYTSKIDPLTGFVDPFVWKTIKNHESRKHFLEGFDFLHYDVKTGDFILHFKMNRNLSFQRGL PGFMPAWDIVFEKNETQFDAKGTPFIAGKRIVPVIENHRFTGRYRDLYPANELIALLEEKGIVFR DGSNILPKLLENDDSHAIDTMVALIRSVLQMRNS NAATGEDYINSPVRDLNGVCFDSRFQNPE WPMDADANGAYHIALKGQLLLNHLKESKDLKLQNGISNQDWLAYIQELRNGRSSDDEATADS QHAAPPKKKRKVGGSGGSGGSGGSGGSGGSGGSGGSLEHHHHHH SEQ ID NO.:27 MTQFEGFTNLYQVSKTLRFELIPQGKTLKHIQEQGFIEEDKARNDHYKELKPIIDRIYKT YADQCLQLVQLDWENLSAIDSYRKEKTEETRNALIEEQATYRNAIHDYFIGRTDNLTDAINKR HAEIYKGLFKAELFNGKVLKQLGTVTTTEHENALLRSFDKFTTYFSGFYENRKNV FSAEDISTAI PHRIVQDNFPKFKENCHIFTRLITAVPSLREHFENVKKAIGIFVSTSIEEVFSFPFYNQLLTQTQID LYNQLLGGISREAGTEKIKGLNEVLNLAIQKNDETAHIIASLPHRFIPLFKQILSDRNTLSFILEEFK Q / Q / bn / Lznza / YiAi SDEEVIQSFCKYKTLLRNENVLETAEALFNELNSIDLTHIFISHKKLETISSALCDHWDTLRNALY ERRISELTGKITKSAKEKVQRSLKHEDINLQEIISAAGKELSEAFKQKTSEILSHAHAALDQPLPT TLKKQEEKEILKSQLDSLLGLYHLLDWFAVDESNEVDPEFSARLTGIKLEMEPSLSFYNK ARNY ATKKPYSVEKFKLNFQMPTLASGWDVNKEKNNGAILFVKNGLYYLGIMPKQKGRYKALSFEPT EKTSEGFDKMYYDYFPDAAKMIPKCSTQLKAVTAHFQTHTTPILLSNNFIEPLEITKEIYDLNNP EKEPKKFQTAYAKKTGDQKGYREALCKWIDFTRDFLSK YTKTTSIDLSSLRPSSQYKDLGEYY AELNPLLYHISFQRIAEKEIMDAVETGKLYLFQIYNKDFAKGHHGKPNLHTLYWTGLFSPENLA KTSIKLNGQAELFYRPKSRMKRMAHRLGEKMLNKKLKDQKTPIPDTLYQELYDYVNHRLSHDL SDEARALLPNVITKEVS HEIIKDRRFTSDKFFFHVPITLNYQAANSPSKFNQRVNAYLKEHPETP IIGIDRGERNLIYITVIDSTGKILEQRSLNTIQQFDYQKKLDNREKERVAARQAWSWGTIKDLKQ GYLSQVIHEIVDLMIHYQAWVLENLNFGFKSKRTGIAEKAVYQQFEKMLIDKLNCLVLKDYPA E KVGGVLNPYQLTDQFTSFAKMGTQSGFLFYVPAPYTSKIDPLTGFVDPFVWKTIKNHESRKHF LEGFDFLHYDVKTGDFILHFKMNRNLSFQRGLPGFMPAWDIVFEKNETQFDAKGTPFIAGKRI VPVIENHRFTGRYRDLYPANELIALLEEKGIVFRDGSNILPKLLENDDSHA IDTMVALIRSVLQM RNSNAATGEDYINSPVRDLNGVCFDSRFQNPEWPMDADANGAYHIALKGQLLLNHLKESKDL KLQNGISNQDWLAYIQELRNGRKRPAATKKAGQAKKKKGGSGGSGGSGGSGGSGGSGGSG GSLEHHHHHH SEQ ID NO.:28 MTQFEGFTNLYQVSKTLRFELIPQGKTLKHIQEQGFIEEDKARNDHYKELKPIIDRIYKT YADQCLQLVQLDWENLSAIDSYRKEKTEETRNALIEEQATYRNAIHDYFIGRTDNLTDAINKR HAEIYKGLFKAELFNGKVLKQLGTVTTTEHENALLRSFDKFTTYFSGFYENRKNV FSAEDISTAI PHRIVQDNFPKFKENCHIFTRLITAVPSLREHFENVKKAIGIFVSTSIEEVFSFPFYNQLLTQTQID LYNQLLGGISREAGTEKIKGLNEVLNLAIQKNDETAHIIASLPHRFIPLFKQILSDRNTLSFILEEFK SDEEVIQSFCKYKTLLRNENVLETAEALFNELNSIDLTHIFISHKKLETISS ALCDHWDTLRNALY ERRISELTGKITKSAKEKVQRSLKHEDINLQEIISAAGKELSEAFKQKTSEILSHAHAALDQPLPT TLKKQEEKEILKSQLDSLLGLYHLLDWFAVDESNEVDPEFSARLTGIKLEMEPSLSFYNKARNY ATKKPYSVEKFKLNFQMPTLASGWDVNKEKNNGAILFV KNGLYYLGIMPKQKGRYKALSFEPT EKTSEGFDKMYYDYFPDAAKMIPKCSTQLKAVTAHFQTHTTPILLSNNFIEPLEITKEIYDLNNP EKEPKKFQTAYAKKTGDQKGYREALCKWIDFTRDFLSKYTKTTSIDLSSLRPSSQYKDLGEYY AELNPLLYHISFQRIAEKEIMDA VETGKLYLFQIYNKDFAKGHHGKPNLHTLYWTGLFSPENLA KTSIKLNGQAELFYRPKSRMKRMAHRLGEKMLNKKLKDQKTPIPDTLYQELYDYVNHRLSHDL SDEARALLPNVITKEVSHEIIKDRRFTSDKFFFHVPITLNYQAANSPSKFNQRVNAYLKEHPETP IIGIDRGERNLIYITVIDSTGKILEQRSLNTIQQFDYQKKLDNREKERVAARQAWSWGTIKDLKQ GYLSQVIHEIVDLMIHYQAVWLENLNFGFKSKRTGIAEKAVYQQFEKMLIDKLNCLVLKDYPAE KVGGVLNPYQLTDQFTSFAKMGTQSGFLFYVPAPYTSKIDP LTGFVDPFVWKTIKNHESRKHF LEGFDFLHYDVKTGDFILHFKMNRNLSFQRGLPGFMPAWDIVFEKNETQFDAKGTPFIAGKRI VPVIENHRFTGRYRDLYPANELIALLEEKGIVFRDGSNILPKLLENDDSHAIDTMVALIRSVLQM Q / Q / WVLZnZ-1 / ΥΙΛΙ RNSNAATGEDYINSPVRDLNGVCFDSRFQNPEWPMDADANGAYHIALKGQLLLNHLKESKDL KLQNGISNQDWLAYIQELRNGRKRTADGSEFESPKKKRKVEGGSGGSGGSGGSGGSGGSG GSGGSLEHHHHHH SEQ ID NO.:29 MTQFEGFTNLYQVSKTLRFELIPQGKTLKHIQEQGFIEEDKARNDHYKELKPIIDRIYKT YADQCLQLVQLDWENLSAIDSYRKEKTEETRNALIEEQATYRNAIHDYFIGRTDNLTDAINKR HAEIYKGLFKAELFNGKVLKQLGTVTTTEHENALLRSFDKFTTYFSGFYENRKNV FSAEDISTAI PHRIVQDNFPKFKENCHIFTRLITAVPSLREHFENVKKAIGIFVSTSIEEVFSFPFYNQLLTQTQID LYNQLLGGISREAGTEKIKGLNEVLNLAIQKNDETAHIIASLPHRFIPLFKQILSDRNTLSFILEEFK SDEEVIQSFCKYKTLLRNENVLETAEALFNELNSIDLTHIFISHKKLETISS ALCDHWDTLRNALY ERRISELTGKITKSAKEKVQRSLKHEDINLQEIISAAGKELSEAFKQKTSEILSHAHAALDQPLPT TLKKQEEKEILKSQLDSLLGLYHLLDWFAVDESNEVDPEFSARLTGIKLEMEPSLSFYNKARNY ATKKPYSVEKFKLNFQMPTLASGWDVNKEKNNGAILFV KNGLYYLGIMPKQKGRYKALSFEPT EKTSEGFDKMYYDYFPDAAKMIPKCSTQLKAVTAHFQTHTTPILLSNNFIEPLEITKEIYDLNNP EKEPKKFQTAYAKKTGDQKGYREALCKWIDFTRDFLSKYTKTTSIDLSSLRPSSQYKDLGEYY AELNPLLYHISFQRIAEKEIMDA VETGKLYLFQIYNKDFAKGHHGKPNLHTLYWTGLFSPENLA KTSIKLNGQAELFYRPKSRMKRMAHRLGEKMLNKKLKDQKTPIPDTLYQELYDYVNHRLSHDL SDEARALLPNVITKEVSHEIIKDRRFTSDKFFFHVPITLNYQAANSPSKFNQRVNAYLKEHPETP IIGIDRGERNLIYITVIDSTGKILEQRSLNTIQQFDYQKKLDNREKERVAARQAWSWGTIKDLKQ GYLSQVIHEIVDLMIHYQAWVLENLNFGFKSKRTGIAEKAVYQQFEKMLIDKLNCLVLKDYPAE KVGGVLNPYQLTDQFTSFAKMGTQSGFLFYVPAPYTSKIDP LTGFVDPFVWKTIKNHESRKHF LEGFDFLHYDVKTGDFILHFKMNRNLSFQRGLPGFMPAWDIVFEKNETQFDAKGTPFIAGKRI VPVIENHRFTGRYRDLYPANELIALLEEKGIVFRDGSNILPKLLENDDSHAIDTMVALIRSVLQM RNSNAATGEDYINSPVRDLNGVCFDSRFQNPEWPMDA DANGAYHIALKGQLLLNHLKESKDL KLQNGISNQDWLAYIQELRNGRSSDDEATADSQHAAPPKKKRKVGGSGGSKRTADGSEFES PKKKRKVEGGSGGSGGSGGSGGSGGSGGSGGSLEHHHHHH SEQ ID NO.:30 MTQFEGFTNLYQVSKTLRFELIPQGKTLKHIQEQGFIEEDKARNDHYKELKPIIDRIYKT YADQCLQLVQLDWENLSAIDSYRKEKTEETRNALIEEQATYRNAIHDYFIGRTDNLTDAINKR HAEIYKGLFKAELFNGKVLKQLGTVTTTEHENALLRSFDKFTTYFSGFYENRKNV FSAEDISTAI PHRIVQDNFPKFKENCHIFTRLITAVPSLREHFENVKKAIGIFVSTSIEEVFSFPFYNQLLTQTQID LYNQLLGGISREAGTEKIKGLNEVLNLAIQKNDETAHIIASLPHRFIPLFKQILSDRNTLSFILEEFK SDEEVIQSFCKYKTLLRNENVLETAEALFNELNSIDLTHIFISHKKLETISS ALCDHWDTLRNALY ERRISELTGKITKSAKEKVQRSLKHEDINLQEIISAAGKELSEAFKQKTSEILSHAHAALDQPLPT TLKKQEEKEILKSQLDSLLGLYHLLDWFAVDESNEVDPEFSARLTGIKLEMEPSLSFYNKARNY ATKKPYSVEKFKLNFQMPTLASGWDVNKEKNNGAILFV KNGLYYLGIMPKQKGRYKALSFEPT EKTSEGFDKMYYDYFPDAAKMIPKCSTQLKAVTAHFQTHTTPILLSNNFIEPLEITKEIYDLNNP Q / Q / bn / LΖηΖ-1 / ΥΙΛΙ EKEPKKFQTAYAKKTGDQKGYREALCKWIDFTRDFLSKYTKTTSIDLSSLRPSSQYKDLGEYY AELNPLLYHISFQRIAEKEIMDAVETGKLYLFQIYNKDFAKGHHGKPNLHTLYWTGLFSPENLA KTSIKLNGQAELFYRPKSRMKRMAHRLGEKMLNKKLK DQKTPIPDTLYQELYDYVNHRLSHDL SDEARALLPNVITKEVSHEIIKDRRFTSDKFFFHVPITLNYQAANSPSKFNQRVNAYLKEHPETP IIGIDRGERNLIYITVIDSTGKILEQRSLNTIQQFDYQKKLDNREKERVAARQAWSWGTIKDLKQ GYLSQVIHEIVDLMIHYQAVWLENLN FGFKSKRTGIAEKAVYQQFEKMLIDKLNCLVLKDYPAE KVGGVLNPYQLTDQFTSFAKMGTQSGFLFYVPAPYTSKIDPLTGFVDPFVWKTIKNHESRKHF LEGFDFLHYDVKTGDFILHFKMNRNLSFQRGLPGFMPAWDIVFEKNETQFDAKGTPFIAGKRI V PVIENHRFTGRYRDLYPANELIALLEEKGIVFRDGSNILPKLLENDDSHAIDTMVALIRSVLQM RNSNAATGEDYINSPVRDLNGVCFDSRFQNPEWPMDADANGAYHIALKGQLLLNHLKESKDL KLQNGISNQDWLAYIQELRNGRKRPAATKKAGQAKKKKGGSGGSKRTADGSEFESPKK RK VEGGSGGSGGSGGSGGSGGSGGSGGSLEHHHHHH Example 2. Novel Cpf1 mutants enhance DNA cleavage activity at the TTTT PAM site in the bacterial-based activity assay. The following example demonstrates the improved activity of the invention at the TTTT and TTTC PAM sites in a bacteria-based activity assay (Figure 2). Screening strains harboring the toxin plasmid were transformed with the AsCpfl WT, M537R or F870L expression plasmid. After recovery and isopropyl-p-D-1thiogalactopyranoside (IPTG) induction, cells were plated with LB-Chloramphenicol medium with or without arabinose. The degree of cell survival under arabinose selection compared to the transformation entry control (without arabinose) is indicative of the cleavage activity of Cpf1 variants at the HPRT-38346 protospacer on the toxin plasmid, in the context of TTTT or TTTC PAM. For WT-Cpf1, the survival rate of TTTC-transformed E. coli is significantly higher than the TTTT PAM, consistent with previous knowledge that TTTT is a low-activity PAM site. 61 In contrast, both M537R such as F870L increased the survival rate in TTTT PAM, indicating that these mutants extended the PAM compatibility of AsCpfl at this alternative PAM site. More importantly, the survival rate of both mutants in the canonical TTTC PAM is even higher than that of WT-Cpf1, suggesting that these mutants generally enhanced the performance of the AsCpfl protein at other TTTV sites as well. Given these positive results, the single AsCpfl variant and the double mutant (M537R / F870L) were expressed and purified to determine their intrinsic cleavage activities in vitro. Example 3. Novel Cpf1 mutants enhance intrinsic DNA cleavage activity at TTTT PAM sites in vitro The intrinsic DNA cleavage activities of the AsCpfl variants (M537R, F870L and M537R / F870L) were compared to the wild-type protein using an in vitro cMQ / bn / Lznza / YiAi cleavage assay. Briefly, the Cpf1-crRNA ribonucleoprotein (RNP) complex was first assembled by incubating the purified proteins (Figure 3A) with HPRT-38346 crRNA in 1X cleavage buffer (20 mM HEPES, pH 7.5, 150 mM KCI, 25 mM MgCI, 10% glycerol and 1 mM DTT) for 15 minutes at 37°C. Cleavage reactions were initiated by titrating the RNP complex (8-500 nM) in 10 nM dsDNA substrate containing the HPRT-38346 protospacer, in the context of TTTC or TTTT PAM. Samples of cleavage reactions were taken at various time points and quenched with 50 mM ethylenediaminetetraacetic acid ("EDTA"). After removal of AsCpfl protein by proteinase K treatment (56°C, 30 min), reactions were resolved by capillary electrophoresis (Fragment Analyzer, AATI). The relative concentration of cleavage products and uncleaved dsDNA were quantified to calculate percent DNA cleavage. The intrinsic DNA cleavage activities of the WT and Cpf1 variants at the TTTT and TTTC PAM sites were compared in Figure 3B. For simplicity, only a single concentration of RNP (31 nM) was shown at 20 seconds. As expected, the single nucleotide change of the PAM sequence from TTTC to TTTT reduced the cleavage activity of WT-Cpf1 from -95% to -40%. Consistent with observations in the bacteria-based activity assay, both mutants significantly increased DNA cleavage in TTTT PAM, while maintaining high activity in TTTC PAM (Figure 3B). The double mutant (M537R / F870L) has similar activities to M537R in this assay. However, it is worth noting that this is likely due to the limited resolution of this particular assay, in resolving further differences between those high activity variants. Overall, these results demonstrated that the reported mutations enhanced Cpf1 activity by enhancing intrinsic DNA cleavage. Therefore, we anticipate that the observed benefits of these mutants will be broadly applicable and independent of the delivery methods and / or cellular contexts of the specific experiment. Example 4. The new mutants greatly improve the targeting efficiency of the TTTN PAM sites in the human cell line. The following example demonstrates the ability of the invention to increase the efficiency of gene editing at TTTN PAM sites when the Cpf1-crRNA complex is delivered to cells as an RNP. CRISPR / Cpf1 cell editing experiments were performed by first forming a 4 μΜ RNP complex with purified Cpf1 protein and the Alt-RTM crRNAs in Opti-MEM for 5 min at 25°C. Table 2 shows the targeted protospacers and PAM sequences at the CTNNB1 loci. The RNP complexes were then transfected into HEK293 cells by Lonza nucleofection. Experiments were performed in biological triplicate. After 48 h at 37°C with 5% CO2, adherent cells were washed cMQ / bn / Lznza / YiAi with 0.1 ml PBS and used with 0.05 ml QuickExtract™ DNA extraction solution. Cell lysates were incubated at 65°C for 15 min followed by heat inactivation at 98°C for 3 min. The crude DNA samples were then diluted 3-fold with 0.1 ml ddH2O and used as PCR templates. PCR primers are listed in Table 2. PCR was used to amplify 1 kb fragments of the CTNNB1 loci using ΚΑΡΑ HiFi DNA polymerase and the following cycle parameters: 955:0°, (980:2°, 64015, 720:3°) repeated 29 times, 722 00. Heteroduplexes were formed using the following cycle parameters: 9510:0° cooled to 85 in 1 min, 851:0° cooled to 75 in 1 min, 751:0° cooled to 65 in 1 min, 651:0° cooled to 55 in 1 min, 551:0° cooled to 45 in 1 min, 451 00 cooled to 35 for 1 min, 35100 cooled to 25 for 1 min, 251:0°. The heteroduplexes were cleaved by the addition of Endonuclease 2U T7 I (New England Biolabs) for 1 hour at 37°C, and the cleaved products were analyzed by capillary electrophoresis (Fragment Analyzer, Advanced Analytical). Q / Q / frni 7Π7 -1 / ΥΙΛΙ Table 2. Sequence of DNA target sites and primer used for PCR amplification (SEQ ID NOs.: 31-58). Sequence Name (5'-3') SEQ ID NO.: HPRT38346 TTTT PAM TTTTACATAAAACTCTTTTAGGTTA SEQ ID NO.: 31 HPRT38346 TTTC PAM TTTCACATAAAACTCTTTTAGGTTA SEQ ID NO.: 32 CTNNB1 111-S TTTTCCCCTCCCTGGCTTTTATTAT SEQ ID NO.: 33 CTNNB1 112-S TTTCCCCTCCCTGGCTTTTATTATT SEQ ID NO.: 34 CTNNB1 127-S TTTTATTATTACAACTCTGTGCTTT SEQ ID NO.: 35 CTNNB1 128-S TTTATTATTACAACTCTGTGCTTTT SEQ ID NO.: 36 CTNNB1 149-S TTTTTCATCACCATCCTGAATATCT SEQ ID NO.: 37 CTNNB1 150-S TTTTCACTCACCATCCTGAATATCTA SEQ ID NO.: 38 CTNNB1 151-S TTTCATCACCATCCTGAATATC TAT SEQ ID NO.: 39 CTNNB1 184-S TTTATACTATTAATAAAAAGACATT SEQ ID NO.: 40 CTNNB1 193-AS TTTATTAATAGTATAAATATTAATT SEQ ID NO.: 41 CTNNB1 194-AS I I I IATTAATAGTATAAATAT TAAT SEQ ID NO.: 42 CTNNB1 195-AS lili IATTAATAGTATAAATATTAA SEQ ID NO.: 43 CTNNB1 207-S lili IGGTAAGGAGGAG I I I ICACT SEQ ID NO.: 44 CTNNB1 208-S lili GGTAAGGAGGAG lili CACTG SEQ ID NO.: 45 CTNNB1 209-S TTTGGTAAGGAGGAG lili CACTGA SEQ ID NO.: 46CTNNB1 224-S I I I I CACTGAAGTTCAGCAGTGATG SEQ ID NO.: 47 CTNNB1 225-S TTTCACTGAAGTTCAGCAGTGATGG SEQ ID NO.: 48 CTNNB1 291-S TTTCACTAACCTGGTAAAAGAGGAT SEQ ID NO.: 49 CTNNB1 301-AS TTTACCAGGTTAG TGAAACGCAGAC SEQ ID NO.: 50 CTNNB1 302-AS I I I IACCAGGTTAGTGAAACGCAGA SEQ ID NO.: 51 CTNNB1 321-S HUI I I IG IGGGTGTAATAGTGAC SEQ ID NO.: 52 CTNNB1 322-S I I I I I I IGIGGGTGTAATAGTGACA SEQ ID NO.: 53 CTNNB1 323-S I I I I I IGTGGGTGTAATAGTGACAT SEQ ID NO.: 54 CTNNB1 324-S TTTTTGTGGGTGTAATAGTGACATT SEQ ID NO.: 55 CTNNB1 325-S TTTTGTGGGTGTAATAGTGACATTT SEQ ID NO.: 56 CTNNB1_FWD TCCCACTGTACCTCTGTTATCCA SEQ ID NO.: 57 CTNNB1_REV TGGTCCTCGTCAT TTAGCAGTTT SEQ ID NO.: 58 cMQ / bn / Lznza / YiAi Referring to Figure 4, the T7EI assay revealed a significant improvement in targeting efficiency by M537R and F870L mutations. First, M537R, F870L or the double mutant (M537R / F870L) allowed efficient cleavage at all 15 sites with TTTT PAM, where 11 out of 15 had no cleavage detectable by WT-Cpf1. For other canonical TTTV PAM sites, these variants maintained or improved targeting efficiency. The benefit is particularly significant at low activity sites, such as CTNNB1 111-s (3-fold improvement over WT). Among these variants, the double mutant (M537R / F870) has the most consistent improvement in targeting efficiency across all sites tested, where single mutants exhibited more site-dependent variations, such as F870L at 323-S (no activity). , same as WT). In general, the described invention exhibits much higher target power than WT-Cpf1. Example 5. High-throughput measurement of DNA cleavage activity of AsCas12a variants at the TTTT PAM site in E. cali. The following example demonstrates the robustness of our new high-throughput screening strategy to directly measure the cleavage activity of thousands of AsCas12a variants at the TTTT PAM site in the bacteria-based activity assay (Figure 5). Figure 5A, Figure 5B, Figure 5C, Figure 5D, Figure 5E and Figure 5F show an exemplary high throughput phenotypic measurement of AsCas12a point mutations by deep scanning mutagenesis. A library encompassing all possible AsCas12a point mutations in the target region (499-640 and 840-913) was generated in the context of WTAsCas12a or M537R / F870L-AsCas12a. The relative survival rate of each variant over the reference protein in an E. coli-based activity assay was determined by deep sequencing. The phenotype of individual point mutations was measured under multiple selection stringencies in the context of M537R / F870L (condition 1 and 2), and a third condition in the background of WT-AsCas12a (condition 3). As shown in Figure 5A, Figure 5B, and Figure 5C, the phenotype scores (i.e., the natural log of the relative survival rate) of the variants are positively correlated under different conditions (p ~ 0.7), demonstrating consistency and reproducibility of this method. As a positive control, only M537R and F870L / I, but no other substitutions at these positions, survived longer than WT-AsCas12a (Figure 5D). In contrast, the R537 or L870 mutation in the M537R / F870L-AsCas72a ubiquitously reduced the survival rate (Figure 5E). These results demonstrated that the phenotype score measured by the bacterial screen reflects the DNA cleavage activity of previously characterized AsCas12a variants in TTTT. PAM. To further validate the result of our bacterial detection, we studied four AsCas12a point mutations with a higher survival rate than control under all three conditions (L505K, S510L, P569D and P599G, Figure 5F). Of note, P599G has been shown to enhance AsCas12a cleavage activity in TTCC PAM. The other three point mutations have not been characterized by any study published so far. Therefore, we measured the survival rate of E. coii cells transformed with plasmids expressing the individual AsCas12a variant under selection. Compared to WT-AsCas12a, all selected point mutations increased survival rate when targeting a TTTT-ΡΑΜ site (Figure 6). Unexpectedly, the benefits of these point mutations were maintained even in the context of M537R / F870L-AsCas72a, where the survival rate was further elevated (Figure 7). Taken together, these results demonstrated that our high-throughput screen can accurately predict the phenotype of uncharacterized AsCas12a variants. The phenotype scores of 3194 AsCas12a variants with a single point mutation covered by the screen with sufficient sequencing count are listed in Table 3. Overall, ~60% showed some benefit (ie, phenotype score > 0) in one of the three conditions. Table 3. Summary of selected variants under different background conditions.1 Mutant Calif. from enriqu. (D Std. error (1) Enrichment qual. (2) Std. error (2) Enrichment qual. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? R499C 0.14 0.08 0.60 0.07 0.06 0.10 Yes Yes R499L 0.08 0.05 0.05 0.06 0.09 0.15 Yes Yes R499K 0.54 0.06 0.23 0.06 0.38 0.10 Yes Yes R499A -0.29 0.05 0.27 0.04 0.22 0.07 Yes No R499N 0.39 0.11 -0.49 0.15 -0.13 0.29 Yes No R499D 0.03 0.09 -1.01 0.12 -0.51 0.44 Yes No R499Q -0.10 0.08 0.42 0.07 0.19 0.20 Yes No R499E -0.23 0.06 0.50 0.05 -0.10 0.10 Yes No R499G -0.11 0.03 0.12 0.03 0.14 0.06 Yes No R499H -0.45 0.11 0.50 0.09 NA NA Yes No R499I -0.14 0.10 0.09 0.09 -0.18 0.13 Yes No R499M -0.44 0.09 0.50 0.07 0.27 0.21 Yes No R499F 0.01 0.15 -0.31 0.17 NA NA Yes No R499P -0.56 0.08 -0.06 0.07 -0 .70 0.26 No No R499S -0.14 0.05 0.02 0.05 -0.04 0.06 Yes No Matante Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? R499* -0.76 0.10 -0.61 0.10 -1.06 0.18 No No R499T -0.01 0.07 0.56 0.06 0.23 0.16 Yes No R499W -0.27 0.05 0.11 0.05 -0.53 0.11 Yes No R499V 0.09 0.05 0.09 0.05 -0.10 0.14 Yes No L500M 0.01 0.05 0.30 0.05 0.28 0.12 Yes Yes L500A -0.27 0.04 0.21 0.03 -0.15 0.07 Yes No L500R -0.35 0.03 -0.40 0.03 -0.47 0.05 No No L500N -1.11 0.14 -0.60 0.12 -0.50 0.16 No No L500 D -1.03 0.08 -1.98 0.13 -1.26 0.19 No No L500C -0.19 0.05 0.26 0.05 0.00 0.10 Yes No L500Q -0.67 0.06 -0.63 0.06 -0.13 0.07 No No L500E -1.00 0.06 -1.22 0.07 -1.29 0.07 No No L500G -0.72 0.03 -0.79 0.03 -0.84 0.03 No No L500H -0.30 0.09 0.01 0.08 0.01 0.22 Yes No L500I -0.31 0.09 0.07 0.08 0.26 0.15 Yes No L500K -1.21 0.09 -0.32 0.07 -0.28 0.07 No No L500F -0.19 0.08 -0.33 0.09 0.09 0.21 Yes No L500P -0.79 0.05 -0.80 0.05 -0.91 0.07 No No L500S -0.84 0.04 -0.43 0.04 -0.37 0.07 No No L500* -1.39 0.09 -1.60 0.11 -1.66 0.16 No No L500T -0.19 0.05 -0.37 0.06 -0.17 0.06 No No L500W -0.25 0.04 -0.29 0.04 0.01 0.11 Yes No L500Y -0.01 0.09 0.04 0.09 0.05 0.22 Yes No L500V -0.13 0.03 0.11 0.03 -0.03 0.06 Yes No T501L 0.18 0.04 0.32 0.04 0.12 0.07 Yes Yes T501M 0.32 0.07 0.35 0.07 0.17 0.29 Yes Yes T501V 0.22 0.06 0.29 0.06 0.13 0.20 Yes Yes T501A -0.06 0.03 -0.13 0.03 -0.07 0.10 No No T501R 0.01 0.03 -0.16 0.03 0.54 0.07 Yes No T501N 0.69 0.14 0.16 0.15 NA NA Yes No T501D 0.12 0.12 -0.12 0.13 NA NA Yes No T501C 0.52 0.09 -0.40 0.11 0.31 0.26 Yes No T501Q - 0.19 0.10 -0.04 0.10 -0.24 0.31 No No T501E -0.39 0.09 0.05 0.08 -0.34 0.26 Yes No T501G 0.12 0.04 0.44 0.04 -0.03 0.09 Yes No T501I 0.13 0.07 0.05 0.07 -0.19 0.11 Yes No T501K -0.30 0.09 0.21 0.08 0.55 0.24 Yes No T501F 0.08 0.08 -0.12 0.08 -0.12 0.14 Yes No T501P -0.29 0.07 0.14 0.06 -0.39 0.13 Yes No T501S 0.06 0.05 0.14 0.05 -0.10 0.09 Yes No T501* -1.18 0.12 -0.58 0.10 -0.85 0.21 No No Q2Q / frn / Lznza / YiAi M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? T501W -0.02 0.07 0.26 0.06 -0.30 0.09 Yes No Τ501Υ -0.08 0.12 0.11 0.12 -0.29 0.29 Yes No G502R 0.14 0.05 0.28 0.05 0.98 0.07 Yes Yes G502E 0. 42 0.08 0.17 0.08 0.19 0.30 Yes Yes G502L 0.45 0.07 0.10 0.07 0.00 0.11 Yes Yes G502S 0.08 0.06 0.23 0.06 0.16 0.12 Yes Yes G502W 0.14 0.07 0.65 0.06 0.36 0.14 Yes Yes G502V 0.21 0.05 0.21 0.05 0.13 0.07 Yes Yes G502A -0.05 0.05 - 0.34 0.05 0.08 0.07 Yes No G502D -0.14 0.08 0.37 0.07 0.10 0.15 Yes No G502C -0.17 0.08 0.23 0.08 -0.04 0.13 Yes No G502Q 0.78 0.11 0.02 0.13 -0.06 0.55 Yes No G502H 0.61 0.15 0.01 0.17 NA NA Yes No G502M -0.34 0.13 0.35 0.11 NA NA Yes No G502F NA NA NA 0.08 0.37 Yes No G502P -0.41 0.14 0.01 0.13 NA NA Yes No G502* -1.16 0.15 -0.82 0.13 NA NA Yes No G502T 0.69 0.10 -0.23 0.13 0.24 0.35 Yes No Ι503Α -0.76 0.09 0.32 0.07 -0.16 0.21 Yes No I503R -0.86 0.07 -0.67 0.07 -0.51 0.17 No No Ι503Ν -0.03 0.09 -0.30 0.10 -0.26 0.17 No No I503D -0.50 0.13 -0.57 0.13 NA NA Yes No I503C -0.24 0.11 0.84 0.09 0.00 0.33 Yes No Ι503Ε NA NA NA NA -0.71 0.36 Yes No I503G -0.69 0.06 -0.30 0.05 -0.53 0.15 No No I503L 0.13 0.06 -0.46 0.07 -0.31 0.15 Yes No Ι503Κ 0.03 0.12 -0.51 0.15 NA NA Yes No Ι503Μ -0.08 0.10 -0.17 0.10 -0.13 0.27 No No I503F -0.17 0.09 -0.17 0.09 -0.25 0.19 No No I503S -0.45 0.07 -0.27 0.07 -0.23 0.19 No No Ι503Τ -0.23 0.08 0.33 0.07 0.20 0.14 Yes No I503W -1.21 0.11 -0.88 0.10 -0.61 0.28 No No I503V -0 .09 0.05 0.34 0.04 -0.03 0.09 Yes No Κ504Α -0.15 0.07 -0.33 0.07 -0.30 0.20 No No K504R -0.05 0.03 0.04 0.03 -0.08 0.06 Yes No Κ504Ν 0.01 0.03 -0.54 0.04 -0.50 0.04 Yes No K504C -0.46 0.13 0.02 0. 12 NA NA Yes No K504Q -0.16 0.05 -0.25 0.05 -0.22 0.07 No No Κ504Ε -0.03 0.05 -0.32 0.06 -0.65 0.11 No No K504G -0.84 0.05 -0.46 0.05 -0.52 0.15 No No Κ504Η -0.59 0.13 -0.01 0.11 -0.51 0.16 No No Q / Q / bn / Lznza / YiAi M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? Κ504Ι -0.07 0.08 0.12 0.07 -0.31 0.14 Yes No K504L -0.39 0.05 -0.05 0.05 -0.10 0.14 No No Κ504Μ -0.32 0.08 -0.06 0.08 -0.06 0.10 No No K504F -0.71 0.14 -0.24 0.12 NA NA Yes No K504S -0.50 0.08 -0.45 0.08 -0.19 0.23 No No Κ504* -0.43 0.09 -0.59 0.10 -0.76 0.15 No No Κ504Τ -0.22 0.08 0.08 0.07 -0.15 0.14 Yes No K504W -0.48 0.08 0.09 0.07 -0.53 0.24 Yes No K504V -0.48 0.05 -0.27 0.05 -0.36 0.12 No No L505A 0.61 0.05 0.50 0.05 0.47 0.13 Yes Yes L505R 0.40 0.03 0.56 0.03 0.81 0.05 Yes Yes L505Q 0.30 0.07 0.82 0.07 0.16 0.11 Yes Yes L505E 0.18 0.06 0.03 0.07 0.14 0.21 Yes Yes L505G 0.18 0.03 0.72 0.03 0.40 0.05 Yes Yes L505H 0.33 0.11 0.83 0.10 0.34 0.32 Yes Yes L505K 0.02 0.10 1.00 0.08 1.00 0.13 Yes Yes L505S 0.13 0.06 0.32 0.06 0.60 0.07 Yes Yes L505N -0.53 0.17 0.27 0.14 NA NA Yes No L505D -0.28 0.11 0.59 0.10 0.10 0.49 Yes No L505C 0.26 0.07 -0.14 0.08 0.47 0.27 Yes No L505M -0.05 0.09 -0.06 0.09 -0.18 0.18 No No L505F -0.97 0.15 0.28 0.11 -0.33 0.41 Yes No L505P -0.55 0.07 -0.09 0.06 - 0.09 0.11 No No L505T -0.23 0.09 0.44 0.08 0.59 0.17 Yes No L505W -0.03 0.06 0.28 0.05 -0.19 0.17 Yes No L505V -0.03 0.04 0.15 0.04 0.45 0.11 Yes No Ε506Α 0.33 0.03 0.47 0.03 0.70 0.05 Yes Yes E506R 0.46 0.03 0.81 0.03 1.20 0.04 Yes Yes Ε506Ν 0.24 0.09 0.53 0.09 0.50 0.29 Yes Yes E506C 0.20 0.06 0.29 0.06 0.49 0.19 Yes Yes E506Q 0.09 0.07 0.74 0.06 0.33 0.15 Yes Yes E506G 0.24 0.02 0.39 0.02 0.53 0.03 Yes Yes Ε506Η 0. 35 0.09 0.10 0.10 0.98 0.31 Yes Yes Ε506Ι 0.47 0.09 0.45 0.09 0.69 0.13 Yes Yes E506L 0.30 0.04 0.61 0.04 0.56 0.07 Yes Yes Ε506Κ 0.18 0.06 0.59 0.05 1.08 0.08 Yes Yes Ε506Μ 0.53 0.06 0.28 0.07 0.47 0.17 Yes Yes E506S 0.01 0.05 0.47 0.04 0.50 0.06 Yes Yes Ε506Τ 0.39 0.06 0.12 0.07 0.90 0.23 Yes Yes Ε506Υ 0.16 0.09 0.29 0.09 0.43 0.25 Yes Yes E506V 0.45 0.03 0.51 0.03 0.75 0.05 Yes Yes a / a / bn / Lznza / YiAi M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? E506D 0.19 0.04 -0.30 0.05 -0.08 0.08 Yes No E506F -0.21 0.10 0.47 0.08 0.20 0.25 Yes No E506P -0.07 0.08 0.37 0.07 0.52 0.26 Yes No E506* -0.79 0.08 -0.79 0.08 -1.11 0.07 No No E506W 0.43 0.04 0.10 0.04 - 0.07 0.05 Yes No M507A -0.47 0.06 -0.34 0.06 -0.32 0.19 No No M507R -0.42 0.02 -0.58 0.03 -0.64 0.04 No No M507C -0.41 0.09 -0.31 0.09 0.15 0.28 Yes No M507Q -0.68 0.07 -0.56 0.07 -0.44 0.17 No No M507E NA NA NA -1.23 0.19 Yes No M507G -0.98 0.05 -0.71 0.05 -1.24 0.12 No No M507H -0.65 0.12 0.68 0.09 -0.86 0.28 Yes No M507I -0.06 0.04 -0.12 0 .04 0.01 0.07 Yes No M507L -0.20 0.03 - 0.35 0.03 -0.16 0.03 No No M507K -1.42 0.13 -0.06 0.09 -1.00 0.19 No No M507F 0.05 0.09 -0.78 0.12 -0.05 0.36 Yes No M507P -2.08 0.12 -2.19 0.13 - 1.58 0.18 No No M507S -1.03 0.09 -0.34 0.07 - 0.46 0.18 No No M507* -1.68 0.15 -0.72 0.11 NA NA Yes No M507T -0.11 0.06 -0.30 0.07 -0.03 0.13 No No M507W -0.94 0.08 -0.59 0.07 -0.82 0.18 No No M507V -0.17 0.03 0.06 0.03 -0.28 0.06 Yes No E508A 0.36 0.03 0.20 0.03 0.18 0.06 Yes Yes E508R 0.54 0.03 0.80 0.03 0.82 0.06 Yes Yes E508Q 0.25 0.06 0.11 0.07 0.51 0.13 Yes Yes E508G 0.16 0.02 0.17 0.02 0.22 0.04 Yes Yes E508L 0.03 0.04 0.10 0.04 0.26 0.11 Yes Yes E508K 0.20 0.06 0.49 0.06 0.66 0.08 Yes Yes E508M 0.25 0.07 0.57 0.06 0.54 0.11 Yes Yes E508F 0.27 0.08 0.19 0.08 0.39 0.29 Yes Yes E508S 0.31 0.05 0.62 0.04 0.34 0.06 Yes Yes E508T 0.19 0.06 0.73 0.06 0.55 0.10 Yes Yes E508Y 0.35 0.09 0.19 0.10 0.21 0.27 Yes Yes E508V 0.16 0.03 0.22 0.03 0.34 0.05 Yes Yes E508N -0.08 0.11 -0.10 0.11 0.55 0.20 Yes No E508D 0.09 0.04 -0.15 0.04 -0.16 0.06 Yes No E508C -0.15 0.08 0.18 0.07 0.02 0.24 Yes No E508H -0.25 0.11 0.57 0.09 0.65 0.24 Yes No E508I 0.29 0.09 -0.12 0.10 0.54 0.15 Yes No E508P -0.52 0.08 -0.67 0.08 -0.63 0.20 No No E508* -0.63 0.06 -0.82 0.07 -0.79 0.09 No No cMQ / bn / Lznza / YiAi M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? E508W -0.29 0.05 0.45 0.05 0.07 0.09 Yes No P509R 0.23 0.03 0.27 0.03 1.04 0.05 Yes Yes P509K 0.01 0.07 0.12 0.07 1.29 0.13 Yes Yes P509M 0.34 0.07 0.34 0.07 0.10 0.22 Yes Yes P509S 0.10 0.04 0.14 0.04 0.14 0.10 Yes Yes P509W 0.04 0.05 0.33 0.05 0.61 0.18 Yes Yes P509Y 0.18 0.09 0.20 0.09 0.53 0.30 Yes Yes P509A 0.45 0.04 -0.19 0.04 -0.04 0.05 Yes No P509N 0.18 0.09 -0.33 0.11 0.63 0.29 Yes No P509D -0.12 0.08 -0.12 0.08 -0.01 0.21 No No P509C 0.00 0.06 -0.37 0.07 0.05 0.20 Yes No P509Q 0.08 0.05 -0.10 0.06 0.36 0.08 Yes No P509E -0.27 0.06 0.33 0.05 0.38 0.17 Yes No P509G -0.06 0.03 0.19 0.03 0.00 0.05 Yes No P509H 0.09 0.03 -0.31 0.03 -0.19 0.05 Yes No P509I - 0.10 0.09 -0.34 0.10 -0.56 0.28 No No P509L 0.11 0.04 0.17 0.04 -0.17 0.05 Yes No P509F -0.12 0.09 0.24 0.08 0.52 0.11 Yes No P509* -2.22 0.15 - 0.93 0.09 NA NA Yes No P509T 0.10 0.06 0.58 0.05 -0.04 0.11 Yes No P509V 0.09 0.04 0.07 0.04 -0.45 0.08 Yes No S510G 0.18 0.03 0.49 0.03 0.21 0.06 Yes Yes S510L 0.57 0.06 0.72 0.06 0.74 0.09 Yes Yes S510A 0.2 9 0.06 -0.25 0.07 0.04 0.22 Yes No S510R -0.38 0.03 -0.43 0.03 -0.53 0.04 No No S510N -0.36 0.09 -0.11 0.09 0.06 0.17 Yes No S510D -1.40 0.15 -1.36 0.15 NA NA Yes No S510C -0.14 0.06 0.03 0.06 0.28 0.14 Yes No S510E -0.71 0.09 -1.10 0.11 -1.07 0.25 No No S510I 0.02 0.05 - 0.39 0.06 -0.76 0.03 Yes No S510M -1.15 0.14 -0.15 0.10 0.36 0.23 Yes No S510F -0.15 0.12 0.48 0.11 NA NA Yes No S510* -1.11 0.13 -1.36 0.15 NA NA Yes No Y 510T 0.18 0.08 0.64 0.08 -0.17 0.16 Yes No S510W -0.06 0.06 -0.94 0.08 -0.37 0.17 No No S510V -0.05 0.05 0.44 0.05 0.44 0.18 Yes No L511A 0.07 0.10 -0.06 0.11 -0.31 0.15 Yes No L511R 0.00 0.03 -0.21 0.04 0.09 0.06 Yes No L511Q -0.72 0.15 0.45 0.11 NA NA Yes No L511E -0.31 0.12 -0.25 0.13 -0.81 0.34 No No L511G -0.42 0.07 0.08 0.06 -0.02 0.27 Yes No α^ο / ^η / ίζηζα / γίΛΐ Mutant Calif. from enriqu. (1) Std. error (D Enrichment qual. (2) Std. error (2) Enrichment qual. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? L511K 0.26 0.13 0.44 0.12 NA NA Yes No L511M -0.67 0.11 0.33 0.08 0.25 0.20 Yes No L511P 0.04 0.08 0.00 0.09 0.26 0.13 Yes No L511S -0.12 0.12 -0.37 0.13 0.02 0.33 Yes No L511W 0.61 0.08 0.02 0.09 -0.40 0.38 Yes No L511V -0.26 0.06 0.38 0.06 -0.02 0.16 Yes No S512R 0.07 0.07 0.34 0.07 0.07 0.19 Yes Yes S512A 0.11 0.05 -0.15 0.06 -0.16 0.06 Yes No S512N -0.12 0.19 0.58 0.16 NA NA Yes No S512D -0.14 0.12 - 0.33 0.13 0.47 0.39 Yes No S512C 0.06 0.08 0.61 0.08 -0.18 0.19 Yes No S512E 0.44 0.10 -0.11 0.12 0.21 0.36 Yes No S512G -0.15 0.05 -0.15 0.05 0.10 0.12 Yes No S512L -0.16 0.10 0.53 0.09 -0.21 0.20 Yes No S512K 0.6 5 0.15 0.57 0.15 NA NA Yes No S512M 0.28 0.14 0.24 0.15 NA NA Yes No S512F -0.28 0.08 -0.16 0.08 -0.32 0.13 No No S512P -0.22 0.08 -0.09 0.08 -0.16 0.13 No No S512T -0.17 0.09 0.05 0.08 -0.07 0.15 Yes No S512W -0.1 3 0.10 0.13 0.10 NA NA Yes No S512Y -0.26 0.13 -0.68 0.15 NA NA Yes No S512V -0.38 0.08 -0.54 0.09 -0.64 0.19 No No F513L 0.53 0.04 0.63 0.04 0.41 0.07 Yes Yes F513W 0.04 0.06 0.35 0.06 0 .28 0.13 Yes Yes F513A -1.58 0.11 0.20 0.06 -0.49 0.25 Yes No F513R -1.56 0.09 -1.47 0.09 -0.89 0.06 No No F513D -1.02 0.15 0.12 0.11 NA NA Yes No F513C -0.83 0.10 -0.27 0.09 -0.27 0.14 No No F513Q 0.00 0.13 0.58 0 .12 NA NA Yes No F513E -0.37 0.09 0.33 0.08 -0.38 0.38 Yes No F513G -1.33 0.06 -0.80 0.05 -1.00 0.13 No No F513I 0.78 0.10 0.21 0.11 NA NA Yes No F513M -0.36 0.12 0.73 0.10 0.49 0.23 Yes No F513S -0.59 0.07 -0.47 0.07 -0.61 0.10 No No F513T NA NA NA NA -0.35 0.19 Yes No F513Y -0.10 0.10 0.26 0.09 0.44 0.12 Yes No F513V -0.53 0.06 -0.27 0.06 0.06 0.19 Yes No Y514A -0.28 0.05 -0.43 0.05 -0.73 0.1 3 No No Y514R -0.23 0.04 -0.47 0.05 -0.86 0.14 No No Y514N -0.17 0.09 0.07 0.08 -0.53 0.17 Yes No Y514D -1.11 0.10 -1.20 0.11 -1.22 0.16 No No Q / Q / frni 7Π7 -1 / ΥΙΛΙ Mutant Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? Y514C -0.39 0.05 -0.35 0.05 -0.55 0.09 No No Y514Q -1.35 0.13 -0.62 0.10 -1.01 0.29 No No Y514E -1.08 0.08 -0.93 0.08 -1.50 0.19 No No Y514G -0.76 0.04 -0.49 0.04 -1.06 0.11 No No Y514H 0.39 0.06 0.29 0.06 -0.31 0.12 Yes No Y514I -0.14 0.09 -0.84 0.11 NA NA Yes No Y514L -0.37 0.05 -0.57 0.05 -0.73 0.10 No No Y514K -0.52 0.09 -1.28 0.12 NA NA Yes No Y514M -0.50 0.07 -0.38 0.07 - 0.59 0.19 No No Y514F -0.29 0.07 0.14 0.06 -0.35 0.11 Yes No Y514S -0.33 0.05 -0.32 0.05 -0.86 0.11 No No Y514* -0.91 0.08 -1.20 0.10 -1.18 0.13 No No Y514T -1.01 0.09 -1.31 0.10 -0.98 0.18 No No Y514W 0.17 0.05 0.46 0.05 -0.09 0.23 Yes No Y514V -0.45 0.04 -0.41 0.04 -0.92 0.06 No No N515A 0.60 0.06 0.82 0.06 0.12 0.11 Yes Yes N515R 0.6 3 0.06 0.82 0.05 0.19 0.11 Yes Yes N515I 0.23 0.07 0.30 0.07 0.16 0.14 Yes Yes N515L 0.33 0.06 0.53 0.06 0.07 0.20 Yes Yes N515T 0.41 0.08 0.14 0.08 0.29 0.16 Yes Yes N515V 0.50 0.05 0.49 0.05 0.45 0.09 Yes Yes N515D 0.05 0.06 -0.17 0.06 -0.30 0.10 Yes No N515C 0.59 0.12 0.62 0.12 -0.02 0.30 Yes No N515Q 0.46 0.11 0.69 0.11 NA NA Yes No N515E 0.47 0.07 0.56 0.07 -0.14 0.19 Yes No N515G -0.10 0.05 0.37 0.04 -0.13 0.07 Yes No N515H 0.09 0.10 -0.59 0 .13 -0.25 0.21 Yes No N515K 0.07 0.08 0.16 0.08 -0.13 0.16 Yes No N515M 0.73 0.09 0.45 0.10 -0.01 0.12 Yes No N515F 0.49 0.12 0.48 0.12 NA NA Yes No N515P -1.10 0.16 -0.13 0.12 -0.32 0.38 No No N515S 0.08 0.05 -0 .15 0.05 0.19 0.08 Yes No N515W 0.79 0.08 0.42 0.09 -0.60 0.31 Yes No N515Y -0.30 0.12 -0.55 0.13 0.03 0.22 Yes No K516R 0.01 0.03 0.26 0.03 0.40 0.06 Yes Yes K516A 0.25 0.05 0.13 0.06 -0.33 0.21 Yes No K516N 0.37 0.09 0.01 0.11 -0.01 0.16 Yes No K516D NA NA NA NA -0.48 0.31 Yes No K516C -1.37 0.13 0.14 0.08 -0.36 0.16 Yes No K516Q 0.08 0.07 -0.76 0.10 -0.08 0.16 Yes No K516E -0.23 0.04 -0.32 0.05 -0.33 0.09 No No ayQ / bn / Lznza / YiAi M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? K516G -0.34 0.03 -0.01 0.03 -0.34 0.05 No No K516I -0.29 0.14 -0.03 0.14 NA NA Yes No K516L -0.29 0.06 -0.06 0.06 -0.56 0.18 No No K516M -0.29 0.08 -0 .21 0.08 -0.31 0.17 No No K516P -0.37 0.10 -0.96 0.12 NA NA Yes No K516S -0.34 0.06 0.23 0.06 -0.22 0.21 Yes No K516* -0.66 0.09 -0.86 0.10 -1.08 0.19 No No K516T -0.18 0.04 -0.43 0.04 -0 .09 0.06 No No K516W -0.42 0.06 -0.55 0.07 -1.18 0.16 No No K516V -0.47 0.05 -0.20 0.05 -1.04 0.11 No No A517R -2.02 0.07 -1.56 0.06 -1.46 0.07 No No A517D -1.35 0.11 -0.85 0.09 -1.19 0.18 No No A517C -0.35 0.08 0.68 0.07 0.14 0.17 Yes No A517E -1.34 0.09 -1.16 0.09 -1.86 0.16 No No A517G -0.69 0.03 -0.65 0.03 -0.77 0.04 No No A517I 0.77 0.10 -0.42 0.13 NA NA Yes No A517L -0.30 0.06 -0.44 0.06 -1.22 0.17 No No A517M - 0.50 0.10 -0.24 0.10 -0.57 0.30 No No A517F -0.50 0.12 -0.90 0.14 NA NA Yes No A517P -0.75 0.08 -1.06 0.09 -0.86 0.12 No No A517S -0.28 0.05 -0.24 0 .05 -0.65 0.14 No No A517T -0.34 0.06 0.06 0.06 -0.42 0.11 Yes No A517W -1.22 0.07 -0.27 0.05 -1.43 0.16 No No A517Y 0.02 0.13 0.04 0.13 NA NA Yes No A517V -0.33 0.04 -0.14 0.04 -0.44 0.07 No No R518K 0.20 0.09 0.72 0.08 0.05 0.17 Yes Yes R518A - 0.12 0.07 -0.28 0.07 -0.87 0.24 No No R518C -1.13 0.12 -0.21 0.09 NA NA Yes No R518E -0.72 0.10 -1.08 0.12 NA NA Yes No R518G -1.34 0.05 -0.78 0.04 -0. 87 0.08 No No R518L -1.49 0.12 -1.84 0.15 NA NA Yes No R518F -0.96 0.16 0.45 0.11 NA NA Yes No R518S -0.74 0.08 -1.20 0.09 -0.73 0.12 No No R518* -0.33 0.08 -0.34 0.08 -0.69 0.13 No No R518T - 0.50 0.10 -0.37 0.10 -0.40 0.15 No No R518W -1.01 0.09 -1.13 0.10 -1.22 0.19 No No R518V -0.44 0.06 -1.39 0.09 -1.43 0.09 No No N519A 0.64 0.06 1.07 0.06 -0.06 0.25 Yes No N519R 0.4 7 0.05 0.46 0.05 -0.02 0.08 Yes No N519D 0.10 0.05 - 0.13 0.05 -0.29 0.07 Yes No N519C 0.21 0.11 0.23 0.11 NA NA Yes No Q / Q / frni 7Π7 -1 / ΥΙΛΙ Mutant Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? N519Q 0.14 0.12 0.71 0.11 NA NA Yes No N519E -0.66 0.10 -0.38 0.09 -0.89 0.23 No No N519G 0.21 0.04 0.10 0.04 -0.54 0.08 Yes No N519H 0.10 0.09 -0 .67 0.11 NA NA Yes No N519I 0.29 0.09 0.18 0.09 -0.02 0.15 Yes No N519L 0.28 0.06 0.47 0.06 -0.37 0.08 Yes No N519K -0.17 0.09 -0.35 0.10 -0.46 0.19 No No N519M -0.19 0.10 0.36 0.09 -0.05 0.13 Yes No N519F 0.38 0.14 0.21 0.15 NA NA Yes No N519P -0.72 0.13 -0.23 0.11 NA NA Yes No N519S 0.08 0.05 -0.03 0.05 0.02 0.12 Yes No N519T 0.24 0.08 0.01 0.09 -0.37 0.16 Yes No N519W -0.02 0.08 0.38 0.08 -0.12 0.31 Yes No N519Y 0.10 0.12 0.65 0.11 -0.09 0.22 Yes No N519V 0.12 0.05 0.14 0.05 -0.39 0.06 Yes No Y520A -1.19 0.12 -0.30 0.09 NA NA Yes No Y520R -0.37 0.08 -1.30 0.11 -1.04 0.24 No No Y520N -0.05 0.09 -0.45 0.10 -0.62 0.14 No No Y520D -0.50 0.12 -0.04 0.10 NA NA Yes No Y520C -0.23 0.07 -0.24 0.07 -0.52 0.12 No No Y520E -0.61 0.13 -0.85 0.15 NA NA Yes No Y520G -1.91 0.10 -1.08 0.08 -1.47 0.09 No No Y520H 0.12 0.07 - 0.14 0.07 -0.34 0.10 Yes No Y520F 0.19 0.13 -0.21 0.15 NA NA Yes No Y520S -0.73 0.11 -0.66 0.11 -1.13 0.18 No No Y520* -0.19 0.07 -0.42 0.08 -0.48 0.15 No No Y520W -0.38 0.10 0.06 0.09 -0.03 0 .16 Yes No Y520V -1.45 0.13 -1.16 0.12 NA NA Yes No A521D -0.72 0.13 -0.50 0.13 NA NA Yes No A521C 0.90 0.16 1.29 0.16 NA NA Yes No A521G -0.52 0.05 -0.73 0.06 -0.98 0.12 No No A521L -0.61 0.10 -0 .13 0.09 -0.98 0.12 No No A521P - 0.19 0.11 -0.78 0.14 NA NA Yes No A521S 0.00 0.09 0.04 0.10 -0.51 0.27 Yes No A521T -0.23 0.07 0.10 0.06 -0.33 0.11 Yes No A521V -0.40 0.06 -0.88 0 .07 -0.60 0.13 No No T522L 1.10 0.05 0.92 0.05 0.28 0.10 Yes Yes T522M 0.92 0.07 0.81 0.08 0.53 0.21 Yes Yes T522V 0.16 0.05 0.28 0.05 0.04 0.07 Yes Yes T522A -0.01 0.05 -0.37 0.06 -0.55 0.08 No No T522R -0.17 0.04 0.31 0.04 -0.40 0.12 Yes No QJQ / frn i 7Π7 -1 / ΥΙΛΙ Mutant Calif. from enriqu. (1) Std. error (D Enrichment qual. (2) Std. error (2) Enrichment qual. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? T522N 0.11 0.07 -1.14 0.11 -0.50 0.13 Yes No T522C 0.09 0.08 0.38 0.08 -0.41 0.38 Yes No T522Q 0.71 0.09 0.47 0.10 -0.51 0.36 Yes No T522E -0.22 0.08 -1.54 0.13 -0.72 0.27 No No T522G -0.3 7 0.04 -0.18 0.04 -0.85 0.08 No No T522I 0.23 0.07 - 0.06 0.08 -0.11 0.17 Yes No T522K -0.16 0.11 -0.23 0.11 -0.67 0.26 No No T522F 0.08 0.13 0.34 0.12 NA NA Yes No T522P -1.16 0.11 -1.52 0.14 -1.14 0 .16 No No T522S 0.23 0.05 -0.20 0.05 -0.38 0.10 Yes No T522W -0.26 0.07 -0.35 0.07 -0.90 0.13 No No K523R 0.17 0.02 0.37 0.02 0.00 0.03 Yes Yes K523A -0.19 0.03 0.15 0.03 -0.48 0.09 Yes No K523N -0.31 0.07 -0.48 0.07 -1.00 0.08 No No K523D -1.14 0.07 - 1.35 0.08 -1.21 0.09 No No K523C -0.22 0.05 0.07 0.04 -0.81 0.12 Yes No K523Q -0.12 0.04 -0.22 0.04 0.01 0.06 Yes No K523E -0.57 0.04 -0.56 0.04 - 0.86 0.06 No No K523G -0.16 0.02 0.09 0.02 -0.56 0.03 Yes No K523H -1.08 0.11 -0.05 0.08 -1.04 0.28 No No K523I -0.20 0.07 0.41 0.06 -1.23 0.21 Yes No K523L -0.78 0.04 -0.30 0.03 -0.70 0.07 No No K523M -0.1 9 0.04 -0.18 0.04 -0.52 0.06 No No K523F -1.08 0.08 -0.93 0.08 -1.27 0.09 No No K523P -1.41 0.08 -0.39 0.06 -1.21 0.15 No No K523S 0.13 0.03 0.10 0.03 -0.36 0.07 Yes No K523* -1.40 0.07 - 1.46 0.08 -1.19 0.12 No No K523T -0.19 0.04 -0.19 0.04 -0.49 0.08 No No K523W -0.97 0.04 -0.87 0.04 -1.41 0.09 No No K523Y -1.25 0.10 -0.43 0.08 -1.36 0.19 No No K523V -0.57 0.03 -0.57 0.03 - 1.12 0.08 No No K524A -0.88 0.09 -0.32 0.08 -0.50 0.24 No No K524R -0.32 0.04 0.15 0.04 -0.28 0.09 Yes No K524N 0.04 0.04 -0.48 0.05 -0.19 0.09 Yes No K524C 0.06 0.10 0.03 0.10 NA NA Yes No K524Q -0.42 0.09 -0.54 0.10 -0.47 0.14 No No K524E -0.53 0.06 -0.11 0.06 -0.49 0.10 No No K524G -0.43 0.04 -0.19 0.04 -0.80 0.06 No No K524L -0.25 0.07 0.32 0.06 -0.81 0.21 Yes No K524M -1.28 0.15 - 0.75 0.13 -0.69 0.15 No No K524P -0.70 0.12 -0.10 0.10 0.02 0.29 Yes No α^ο / ^η / ίζηζα / γίΛΐ M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? K524S -0.67 0.08 -0.04 0.07 -0.73 0.12 No No Κ524* -0.92 0.11 -0.75 0.11 -0.76 0.13 No No Κ524Τ -0.10 0.04 -0.26 0.04 -0.15 0.06 No No K524W - 0.58 0.08 -1.54 0.12 -1.19 0.22 No No K524V -0.71 0.07 -0.01 0.06 -0.68 0.22 No No Ρ525Α -0.21 0.03 0.06 0.03 -0.29 0.07 Yes No P525R -0.30 0.02 -0.10 0.02 -0.62 0.05 No No Ρ525Ν -0.38 0.09 -0.35 0.10 -0.10 0.19 No No P525D 0.42 0.05 - 0.02 0.05 -0.30 0.08 Yes No P525C -0.28 0.05 -0.12 0.05 -0.48 0.14 No No P525Q -0.21 0.06 -0.19 0.06 -0.35 0.13 No No Ρ525Ε -0.22 0.04 0.24 0. 04 -0.30 0.05 Yes No P525G -0.24 0.02 -0.17 0.02 - 0.51 0.05 No No Ρ525Η 0.17 0.06 0.18 0.07 -0.24 0.12 Yes No Ρ525Ι -0.48 0.09 0.06 0.08 0.19 0.22 Yes No P525L -0.37 0.03 0.25 0.03 -0.61 0.06 Yes No Ρ525Κ -0.90 0.08 -1.00 0.09 -0.57 0.17 No No Ρ525Μ -0.55 0.06 -0.18 0.06 -0.54 0.13 No No P525F -0.17 0.07 -0.61 0.08 -0.70 0.16 No No P525S -0.06 0.03 0.04 0.03 -0.42 0.08 Yes No Ρ525* -1.61 0.09 -1.5 4 0.09 -1.56 0.08 No No Ρ525Τ -0.25 0.05 - 0.31 0.05 -0.45 0.11 No No P525W -0.25 0.04 -0.04 0.03 -0.59 0.11 No No Ρ525Υ -1.08 0.10 -1.08 0.10 -0.77 0.08 No No P525V -0.31 0.03 -0.08 0. 03 -0.39 0.08 No No Υ526Α -0.28 0.07 0.17 0.06 - 0.89 0.19 Yes No Y526R -0.71 0.07 -0.17 0.06 -1.09 0.19 No No Υ526Ν -0.64 0.11 -0.15 0.09 -0.25 0.17 No No Y526D -0.44 0.09 0.07 0.08 -0.69 0. 15 Yes No Y526C 0.04 0.06 -0.03 0.06 -0.26 0.12 Yes No Y526Q -0.10 0.11 -0.64 0.13 NA NA Yes No Υ526Ε -0.46 0.08 -0.87 0.10 -0.84 0.21 No No Y526G -0.22 0.05 -0.17 0.05 -0.65 0.16 No No Υ526Η -0.32 0.08 -0.25 0.08 -0.19 0.12 No No Υ526Ι -0.40 0.13 -0.52 0.14 NA NA Yes No Y526L -0.53 0.06 -0.18 0.05 -0.73 0.12 No No Υ526Μ -0.47 0.10 -0.40 0.10 -1.12 0.27 No No Y526F -0.02 0.07 -0.01 0.0 7 -0.44 0.13 No No Υ526Ρ -0.19 0.10 -0.88 0.13 NA NA Yes No Y526S -0.57 0.06 -0.68 0.07 -0.68 0.12 No No Υ526* -0.42 0.05 -0.44 0.06 -0.61 0.09 No No Q / Q / frni ζηζ-ΐ / γίΛΐ M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? Υ526Τ -0.01 0.09 -0.22 0.10 -0.69 0.21 No No Y526W -1.02 0.10 -0.19 0.08 -0.32 0.13 No No Y526V -0.61 0.05 -0.14 0.05 -0.86 0.14 No No S527D 0. 13 0.11 0.01 0.11 0.34 0.41 Yes Yes S527A 0.00 0.06 -0.37 0.07 -0.07 0.20 Yes No S527R -0.14 0.04 -0.73 0.05 -0.70 0.07 No No S527N -0.10 0.10 -0.43 0.11 0.01 0.19 Yes No S527C -0.21 0.09 -0.35 0.09 -0.10 0.22 No No S527Q 0.09 0.12 -0.39 0.14 NA NA Yes No S527E -0.49 0.10 0.57 0.08 0.03 0.16 Yes No S527G -0.43 0.04 -0.21 0.04 -0.53 0.09 No No S527H 0.47 0.15 0.10 0.17 NA NA Yes No S527I -1.06 0.16 - 0.43 0.14 NA NA Yes No S527L -0.12 0.07 -0.24 0.07 -0.44 0.27 No No S527K -0.09 0.11 -0.57 0.13 NA NA Yes No S527P 0.07 0.10 -0.33 0.11 -0.47 0.36 Yes No S527T 0.01 0.09 -0.30 0.10 -0.22 0.18 Yes No S527W 0.03 0.07 0.15 0.07 -0.50 0.23 Yes No S527Y 0.31 0.17 0.05 0.18 NA NA Yes No S527V -0.54 0.07 -0.52 0.07 -0.52 0.10 No No V528D 0.01 0.07 0.27 0.07 0.12 0.12 Yes Yes V528L 0.55 0.03 0.59 0.03 0 .31 0.07 Yes Yes V528M 0.19 0.05 0.02 0.05 0.13 0.10 Yes Yes V528A -0.09 0.04 0.29 0.04 -0.13 0.06 Yes No V528R -0.04 0.04 0.07 0.04 -0.03 0.07 Yes No V528N 0.01 0.11 -0.47 0.14 0.31 0.42 Yes No V528C 0.16 0.07 0.20 0.07 - 0.06 0.24 Yes No V528Q -0.44 0.09 -0.29 0.09 0.07 0.11 Yes No V528E -0.66 0.06 0.16 0.05 0.00 0.11 Yes No V528G -0.14 0.02 -0.19 0.02 -0.19 0.03 No No V528H -0.62 0.15 1.01 0.11 NA NA Yes No V528I 0.16 0.08 -0.09 0 .09 0.07 0.11 Yes No V528K -0.14 0.08 0.36 0.08 0.13 0.14 Yes No V528F -0.10 0.09 0.39 0.08 -0.59 0.21 Yes No V528P -0.10 0.08 -0.66 0.10 0.10 0.11 Yes No V528S -0.12 0.05 0.26 0.05 0.11 0.06 Yes No V528* -1.66 0.13 -1.20 0.12 NA NA Yes No V528T 0.29 0.07 0.00 0.07 0.18 0.17 Yes No V528W -1.31 0.07 -1.47 0.08 -0.99 0.14 No No V528Y -0.77 0.13 -0.50 0.12 0.24 0.12 Yes No Ε529Α -0.38 0.08 -0.18 0.08 0.04 0. 15 Yes No Q / Q / bn / Lznza / YiAi M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? E529R NA NA NA -0.70 0.34 Yes No E529D 0.02 0.07 -0.61 0.08 0.10 0.15 Yes No E529Q -0.43 0.14 -0.49 0.15 NA NA Yes No E529G -0.25 0.05 -0.16 0.05 -0.6 1 0.11 No No E529L -0.45 0.11 -0.56 0.11 NA NA Yes No E529K 0.21 0.10 -0.28 0.11 -0.65 0.19 Yes No E529P 0.08 0.15 -0.30 0.17 NA NA Yes No E529S -0.18 0.11 -0.08 0.11 -0.20 0.45 No No E529* -0.22 0.11 -0.69 0.14 -0.58 0.17 No No E529W -0.19 0.13 -0.11 0.13 NA NA Yes No E529V -0.35 0.06 0.08 0.06 -0.48 0.10 Yes No K530A -0.96 0.10 -0.76 0.10 -0.90 0.14 No No K530R -0.56 0.04 -0 .32 0.04 -0.59 0.08 No No K530N -0.78 0.15 -0.73 0.16 NA NA Yes No K530C -0.10 0.10 -0.43 0.11 NA NA Yes No K530Q -0.22 0.05 -0.56 0.05 -0.60 0.10 No No K530E -0.48 0.05 -0.35 0.05 -0.85 0.09 No No K 530G -1.18 0.07 -1.09 0.07 - 1.15 0.14 No No K530L -1.74 0.09 -1.04 0.07 -1.40 0.14 No No K530M -0.72 0.07 -0.42 0.07 -0.83 0.13 No No K530F -1.17 0.15 -0.40 0.12 NA NA Yes No K530S -1.15 0.09 -0.65 0.08 -1.15 0.13 No No K530* -0.63 0.07 -0.43 0.07 -0.68 0.09 No No K530T -0.51 0.07 -0.72 0.07 -0.68 0.10 No No K530W -1.73 0.12 -0.35 0.08 -1.35 0.20 No No K530V -0.98 0.08 -1.46 0.10 -1.55 0.23 No No F531A -1.39 0.13 -1.72 0.15 NA NA Yes No F531R -1.90 0.12 -1.41 0.10 -1.75 0.23 No No F531C -0.40 0.05 -0.81 0.06 -0.85 0.09 No No F531G -1.68 0.08 -1 .22 0.07 -1.58 0.14 No No F531I -0.43 0.09 -0.86 0.11 -0.62 0.11 No No F531L -0.35 0.05 -0.40 0.05 -0.55 0.07 No No F531S -0.56 0.07 -0.79 0.08 -0.98 0.11 No No F531W -1.68 0.13 -0.86 0.10 -0.27 0.21 No No F531Y -0.99 0.16 - 0.55 0.14 NA NA Yes No F531V -0.22 0.02 -0.64 0.03 -0.74 0.05 No No K532A NA NA NA -0.93 0.19 Yes No K532R -0.63 0.05 -0.63 0.05 -0.56 0.10 No No K532N -0 .39 0.11 -0.71 0.13 -0.45 0.12 No No K532Q -0.42 0.08 -0.74 0.10 -0.96 0.11 No No K532E -0.49 0.05 -0.38 0.05 -0.64 0.12 No No α^ο / ^η / ίζηζα / γίΛΐ Mutant Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? K532G -1.74 0.08 -1.15 0.07 -1.35 0.11 No No K532L -1.28 0.11 -1.26 0.11 -1.36 0.21 No No K532M -0.48 0.09 -0.58 0.10 -0.65 0.09 No No K532S NA NA NA NA -0.93 0.25 Yes No K532* -0.42 0.06 -0.27 0.06 -0.65 0.12 No No K532T -0.37 0.06 -1.05 0.07 -0.52 0.10 No No K532V -1.99 0.11 -1.32 0.09 -1.19 0.12 No No L533R -0.17 0.04 -0.41 0.04 -0.57 0.08 No No L533G -1.82 0.14 - 1.54 0.13 NA NA Yes No L533M -0.36 0.12 -0.29 0.12 -0.12 0.17 No No L533P -0.18 0.07 -0.06 0.07 -0.28 0.12 No No L533V -1.49 0.12 -0.64 0.09 -0.58 0 .19 No No N534A -1.49 0.08 -1.30 0.08 - 0.31 0.09 No No N534R -1.13 0.05 -1.37 0.06 -0.52 0.04 No No N534D -1.07 0.08 -0.72 0.07 -0.75 0.11 No No N534C -1.50 0.13 -1.27 0.12 0.19 0.20 Yes No N534Q NA NA NA NA -0.67 0.24 Yes No N534E -2.05 0.10 -1.48 0.08 -1.32 0.13 No No N534G -1.43 0.04 -0.96 0.04 -1.10 0.04 No No N534H -0.18 0.03 -0.50 0.04 -0.20 0.06 No No N534I -0.54 0.08 0.00 0.07 -0.60 0.18 Yes No N534L -1.92 0.11 -1.79 0.11 -0.26 0.07 No No N534K -1.00 0.07 -0.74 0.07 -0.01 0.10 No No N534M -1.72 0.12 -0.90 0.09 0.88 0.19 Yes No N534F 0.11 0.10 -1.16 0.16 0.16 0.30 Yes No N534P -0.33 0.07 -0.26 0.07 -1.27 0.16 No No N534S -1.00 0.06 -0.72 0.06 0.22 0.05 Yes No N534* -1.20 0.09 -2.22 0.15 -1.84 0.10 No No N534T -0.38 0.04 -0.40 0.04 0.49 0.06 Yes No N534 W -1.54 0.08 -0.69 0.06 -0.29 0.07 No No N534Y -0.97 0.12 -0.47 0.10 -0.57 0.17 No No N534V -1.35 0.07 -1.17 0.06 -0.59 0.06 No No N534A NA NA NA -0.33 0.09 Yes No N534R NA NA NA NA -0.55 0.04 Yes No N534D -0.11 0.09 -0.10 0.09 -0.69 0.10 No No N534C NA NA NA 0.16 0.19 Yes No N534Q NA NA NA NA -0.72 0.24 Yes No N534E NA NA NA -1.34 0.13 Yes No N534G NA NA NA NA -1.11 0.04 Yes No N534H NA NA NA -0.19 0.24 Yes No N534I -0.14 0.19 -0.05 0.19 -0.61 0.19 No No Q / Q / bn / Lznza / YiAi M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? N534L NA NA NA -0.22 0.07 Yes No N534K -0.47 0.14 -0.26 0.13 -0.06 0.09 No No N534M NA NA NA NA 0.83 0.18 Yes No N534F NA NA NA 0.26 0.30 Yes No N534S -0.15 0.07 -0.03 0.07 0.20 0.05 Yes No N534* NA NA NA -1.73 0.10 Yes No N534T NA NA NA 0.91 0.15 Yes No N534W NA NA NA -0.32 0.07 Yes No N534Y -0.01 0.13 0.04 0.13 -0.53 0.16 Yes No N534V NA NA NA NA -0.57 0.06 Yes No F535A -1.29 0.08 -1.38 0.09 -1.53 ​​0.15 No No F535R -2.11 0.10 -1.42 0.08 -1.73 0.13 No No F535C -0.48 0.06 -0.52 0.06 -0.79 0.05 No No F535E -2.4 0 0.14 -1.29 0.09 -1.54 0.09 No No F535G -1.68 0.06 -1.41 0.05 -1.60 0.04 No No F535I -0.99 0.13 -0.63 0.12 NA NA Yes No F535L -0.97 0.06 -0.52 0.05 -0.92 0.05 No No F535M -0.78 0.11 -0 .99 0.13 -0.68 0.24 No No F535S -0.91 0.06 -0.54 0.06 -1.11 0.09 No No F535W -2.13 0.11 -1.41 0.09 -1.73 0.15 No No F535Y -0.65 0.10 -0.50 0.10 -0.62 0.16 No No F535V -0.87 0.04 -1.00 0.05 -0.98 0.04 No No F535A NA NA NA NA -1.47 0.15 Yes No F535R NA NA NA NA -1.74 0.12 Yes No F535C -0.09 0.06 0.09 0.05 -0.54 0.06 Yes No F535E NA NA NA NA -1.65 0.09 Yes No F535G NA NA NA NA -1.93 0.04 Yes No F535L -0.04 0.06 0.03 0.06 -0.69 0.05 Yes No F535M NA NA NA -0.67 0.21 Yes No F535S -0.14 0.08 0.00 0.08 -1.14 0.09 No No F535W NA NA NA NA -1.68 0.14 Yes No F535Y -0.19 0. 12 -0.06 0.12 -0.53 0.17 No No F535V -0.05 0.05 -0.01 0.05 -0.76 0.06 No No Q536A NA NA NA NA -0.02 0.19 Yes No Q536R 0.02 0.08 -0.02 0.09 0.08 0.05 Yes No Q536D NA NA NA 0.23 0.28 Yes No Q536C NA NA NA NA -1.02 0.28 Yes No Q536E 0.00 0.16 0.02 0.16 -0.66 0.08 Yes No Q536G NA NA NA NA 1.22 0.05 Yes No Q536H -0.05 0.19 -0.05 0.19 -0.34 0.22 No No Q536L -0.10 0.15 -0.11 0 .15 -1.09 0.14 No No Q / Q / frOI 7Π7 -1 / ΥΙΛΙ M uta π te Calif. from enriqu. (1) Std. error (D Enrichment qual. (2) Std. error (2) Enrichment qual. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? Q536K 0.56 0.09 -0.36 0.11 -0.09 0.13 Yes No Q536S NA NA NA 0.60 0.09 Yes No Q536* 0.15 0.09 0.03 0.10 -0.74 0.10 Yes No Q536V NA NA NA NA -1.88 0.09 Yes No R537A -1.11 0.10 -1.99 0.15 NA NA Yes No R5 37Q -0.56 0.13 -1.08 0.16 NA NA Yes No R537E -1.40 0.13 -1.33 0.13 NA NA Yes No R537G -1.10 0.05 -1.07 0.05 NA NA Yes No R537L -1.50 0.13 -1.38 0.12 NA NA Yes No R537K -0.58 0.09 -0.81 0. 10 NO NO Yes No R537M - 1.57 0.02 -1.19 0.02 NA NA Yes No R537S -1.30 0.11 -0.65 0.08 NA NA Yes No R537W -1.42 0.10 -1.60 0.11 NA NA Yes No R537V -1.52 0.11 -1.85 0.12 NA NA Yes No Μ 537Α NA NA NA NA -1.52 0.24 Yes No M537R NA NA NA 1.70 0.04 Yes No M537G NA NA NA -1.55 0.08 Yes No Μ537Ι NA NA NA -0.01 0.15 Yes No M537L NA NA NA -0.09 0.13 Yes No Μ537Κ NA NA NA NA 0.19 0.14 Yes No Μ537Τ NA NA NA -0.29 0.13 Yes No M537W NA NA NA -1.30 0.19 Yes No M537V NA NA NA NA -0.62 0.10 Yes No Ρ538Α NA NA NA NA -1.19 0.06 Yes No P538R NA NA NA NA -1. 72 0.08 Yes No P538Q NA NA NA -1.46 0.11 Yes No Ρ538Ε NA NA NA -1.79 0.22 Yes No P538G NA NA NA -1.67 0.09 Yes No Ρ538Η -0.20 0.17 -0.19 0.17 NA NA Yes No P538L -0.23 0.12 -0.09 0.11 -1.49 0.05 No No P538S 0.19 0.12 0.18 0.12 -1.47 0.11 Yes No Ρ538Τ -0.08 0.06 0.13 0.06 -0.38 0.06 Yes No P538W NA NA NA NA -1.82 0.17 Yes No P538V NA NA NA NA -0.71 0.14 Yes No Τ539Α 0.08 0.07 -0.03 0.08 -1.10 0.06 Yes No T539R NA NA NA NA -1.51 0.10 Yes No Τ539Ν 0.16 0.14 0.06 0.15 -1.00 0.17 Yes No T539C NA NA NA NA -1.11 0.14 Yes No T539Q NA NA NA -1.19 0 .20 Yes No Τ539Ε NA NA NA NA -1.61 0.12 Yes No T539G NA NA NA NA -1.63 0.05 Yes No Matante Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? T539I -0.20 0.13 0.00 0.13 -1.04 0.16 No No T539L NA NA NA NA -2.07 0.13 Yes No T539K NA NA NA NA -1.23 0.26 Yes No T539M NA NA NA NA -1.64 0.18 Yes No T539P -0.33 0.14 -0.40 0.14 -1.51 0.14 No No T539S -0.03 0.05 -0.17 0.05 -0.14 0.04 No No T539V NA NA NA NA -1.65 0.11 Yes No L540R -0.17 0.15 -0.30 0.15 -1.27 0.14 No No L540Q 0.12 0.08 0.13 0.08 -0.05 0.08 Yes No L540G NA NA NA NA -1.83 0.13 Yes No L540M 0.04 0.08 -0.02 0.09 -0.13 0.07 Yes No L540P 0.05 0.09 0.09 0.09 -0.40 0.13 Yes No L540V NA NA NA -1.58 0.24 Yes No A541R NA NA NA NA -1.71 0.09 Yes No A541D 0.11 0.12 0.35 0.11 -0.22 0.06 Yes No A541C NA NA NA 0.02 0.39 Yes No A541G 0.38 0.07 0.36 0.07 -0.06 0.12 Yes No A541L NA NA NA NA 0.32 0.23 Yes No A541S -0. 11 0.15 -0.14 0.15 -1.66 0.14 No No A541T - 0.11 0.05 -0.11 0.05 -0.50 0.12 No No A541V -0.06 0.09 0.00 0.09 -0.77 0.12 No No S542N 0.24 0.09 0.02 0.09 0.29 0.07 Yes Yes S542C 0.03 0.17 0.15 0.17 0.42 0.16 Yes Yes S542A NA NA NA NA 0.79 0.05 Yes No S542R - 0.37 0.10 -0.13 0.10 1.34 0.04 Yes No S542D NA NA NA NA -0.70 0.14 Yes No S542Q NA NA NA 0.04 0.23 Yes No S542E NA NA NA NA -1.68 0.07 Yes No S542G 0.23 0.07 -0.10 0.08 -0.79 0.06 Yes No S542H NA NA NA 0.08 0.35 Yes No S542I NA NA NA -0.13 0.32 Yes No S542L NA NA NA 0.67 0.10 Yes No S542K NA NA NA 1.36 0.09 Yes No S542M NA NA NA 1.10 0.11 Yes No S5 42P NA NA NA -0.85 0.27 Yes No S542T 0.68 0.17 0.24 0.19 -0.08 0.10 Yes No S542W NA NA NA NA -0.34 0.06 Yes No S542V NA NA NA 0.38 0.08 Yes No G543A -2.33 0.07 -1.64 0. 05 -2.12 0.10 No No G543R -1.78 0.05 -1.75 0.05 -1.89 0.07 No No G543D -1.02 0.07 -1.88 0.09 NA NA Yes No Q2Q / frn / Lznza / YiAi M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? G543C -0.32 0.04 -0.29 0.04 -0.07 0.06 No No G543E -2.56 0.11 -1.80 0.08 -2.09 0.18 No No G543I -1.30 0.14 -1.24 0.13 NA NA Yes No G543L -1.74 0.08 -1 .17 0.06 -1.85 0.22 No No G543F -0.91 0.09 -0.77 0.08 -0.93 0.14 No No G543P -1.28 0.08 -1.18 0.08 -1.40 0.22 No No G543S -1.21 0.05 -1.22 0.05 -1.63 0.08 No No G543* -1.66 0.13 -1.93 0.14 NA NA Yes No G543W -1.55 0.08 - 1.49 0.07 NA NA Yes No G543V -0.80 0.03 -0.81 0.03 -0.80 0.06 No No W544A -1.17 0.05 -1.90 0.06 -1.67 0.09 No No W544R -1.30 0.03 -1.40 0.03 -1.35 0 .04 No No W544N -1.11 0.10 -1.78 0.13 NA NA Yes No W544D -1.61 0.09 -1.58 0.09 -1.51 0.14 No No W544C -0.88 0.06 -1.34 0.07 -1.21 0.10 No No W544Q -1.24 0.08 -1.17 0.08 NA NA Yes No W544E -1.14 0. 05 -1.44 0.05 -1.54 0.06 No No W544G -1.68 0.03 -1.47 0.03 -1.55 0.04 No No W544H -0.01 0.08 -1.46 0.13 NA NA Yes No W544L -1.76 0.06 -1.40 0.05 -1.41 0.04 No No W544K -2.26 0.11 -1 .33 0.07 -1.39 0.08 No No W544M -2.09 0.11 -1.42 0.08 -1.45 0.15 No No W544F -0.96 0.09 -1.72 0.12 NA NA Yes No W544P -1.84 0.09 -1.34 0.08 -1.51 0.09 No No W544S -0.66 0.03 -0.59 0.03 -0 .57 0.03 No No W544* -0.85 0.05 - 1.05 0.05 -1.09 0.07 No No W544T -1.81 0.09 -1.08 0.07 -1.83 0.17 No No W544V -1.60 0.05 -1.52 0.05 -1.52 0.09 No No D545A -1.34 0.06 -1.18 0.06 - 1.75 0.13 No No D545R -2.22 0.08 -1.82 0.06 -1.53 ​​0.12 No No D545N -1.00 0.10 -0.89 0.09 -1.05 0.15 No No □5450 -2.14 0.13 -1.41 0.10 NA NA Yes No □545E -1.54 0.07 -2.07 0.09 -1.66 0.14 No No D545G -1.30 0.04 -1.13 0.04 - 1.44 0.07 No No D545H -1.20 0.14 -0.72 0.12 NA NA Yes No D545L -1.77 0.08 -1.23 0.06 -1.75 0.21 No No D545K -1.83 0.15 -1.54 0.14 NA NA Yes No □545M -1. 30 0.11 -0.90 0.10 NA NA Yes No D545P -1.73 0.12 -1.07 0.09 NA NA Yes No D545S -0.99 0.06 -0.97 0.06 -1.65 0.18 No No D545T -2.02 0.14 -1.36 0.10 -1.24 0.25 No No ayQ / bn / Lznza / YiAi M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? D545W -2.52 0.12 -2.44 0.12 -1.79 0.16 No No D545Y -1.34 0.12 -1.40 0.12 NA NA Yes No D545V -1.90 0.07 -1.31 0.05 -1.58 0.10 No No V546A 0.05 0.04 -0 .28 0.04 -1.03 0.08 Yes No V546R -0.34 0.04 -0.10 0.04 -0.24 0.05 No No V546D -1.89 0.14 -0.98 0.10 -1.80 0.23 No No V546C -0.63 0.08 0.12 0.06 -1.17 0.18 Yes No V546Q -0.14 0.09 -0.04 0.08 - 0.37 0.22 No No V546E -0.85 0.06 -0.72 0.06 -1.16 0.10 No No V546G -0.89 0.03 -0.75 0.03 -1.38 0.06 No No V546I 0.17 0.09 -0.21 0.10 -0.01 0.36 Yes No V546L -0.09 0.04 -0.03 0.04 -0.77 0.12 No No V546K -0.23 0.09 -0.07 0.09 -0.28 0.09 No No V546M -0.48 0.06 -0.39 0.06 -0.14 0.11 No No V546F -0.58 0.10 -1.20 0.13 NA NA Yes No V546S -0.24 0.05 -0.75 0.06 -1.19 0.07 No No V546* -1.55 0.12 -1.19 0.10 -1.56 0.23 No No V546T 0.15 0.07 -0.59 0.09 -0.82 0.09 Yes No V546W -1.75 0.08 -1.06 0.06 -1.43 0.15 No No V546Y 0.40 0.10 -0.50 0.13 -0.45 0.39 Yes No N547A -0.97 0.06 -0.81 0.06 -1.74 0.12 No No N547R -0.75 0.04 -0.98 0.05 -1.25 0.05 No No N547D -1.06 0.08 -0.98 0.08 -1.08 0.12 No No N547E -1.13 0.07 -1.64 0.09 NA NA Yes No N547G -0.99 0.04 -1.38 0.05 -1.68 0 .04 No No N547I -0.57 0.10 -0.69 0.10 -0.97 0.15 No No N547L -2.14 0.12 -1.01 0.07 -1.56 0.18 No No N547K -0.72 0.08 -0.48 0.07 -0.83 0.12 No No N547S -0.69 0.06 -0.98 0.06 -1.07 0.09 No No N547T -2.13 0.13 -1.62 0.11 NA NA Yes No N547W -1.69 0.09 -1.84 0.10 NA NA Yes No N547Y -0.39 0.10 -0.94 0.12 -1.04 0.21 No No N547V -1.63 0.07 -1.46 0.07 -1.86 0.15 No No K548A -1.24 0.04 -1.12 0.04 -1.74 0.03 No No K548R -0.59 0.02 -0.51 0.02 -0.18 0.03 No No K548N -0.98 0.07 -1.11 0.08 -1.10 0.09 No No K548D -2.69 0.13 -1.63 0.08 -2.01 0.14 No No K548C -0.97 0.06 - 0.64 0.05 -1.44 0.14 No No K548Q -0.31 0.04 -0.24 0.04 -0.41 0.06 No No K548E -1.54 0.05 -1.45 0.05 -1.51 0.04 No No K548G -1.14 0.02 -0.95 0.02 -1.61 0.02 No No Q / Q / frni 7Π7 -1 / ΥΙΛΙ M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? K548H -1.58 0.14 -1.58 0.14 NA NA Yes No K548I -1.05 0.07 -1.27 0.08 -0.98 0.06 No No K548L -1.72 0.06 -1.56 0.05 -1.96 0.08 No No K548M -0.27 0.04 -0 .19 0.04 -1.10 0.10 No No K548F -2.01 0.12 -1.60 0.10 NA NA Yes No K548P -1.78 0.09 -1.04 0.07 -1.86 0.16 No No K548S -0.97 0.04 -0.55 0.03 -1.40 0.08 No No K548* -1.65 0.08 -0.85 0.06 -1 .40 0.13 No No K548T -0.12 0.04 - 0.74 0.05 -1.19 0.07 No No K548W -2.13 0.07 -1.65 0.05 -1.44 0.07 No No K548Y -1.07 0.09 -1.63 0.11 NA NA Yes No K548V -0.72 0.03 -0.39 0.03 -0.97 0 .05 No No E549A -1.80 0.06 -1.49 0.05 - 1.69 0.07 No No E549R -1.64 0.05 -1.69 0.05 -1.80 0.09 No No E549D -1.63 0.09 -1.13 0.07 -1.53 ​​0.14 No No E549C -2.08 0.12 -1.84 0.11 -1.56 0.18 No No E549Q -0.41 0.05 -0.41 0.05 -0.80 0.10 No No E549G -1.50 0.03 -1.53 ​​0.03 -1.60 0.04 No No E549I -1.07 0.12 -1.12 0.13 NA NA Yes No E549L -1.62 0.07 -1.31 0.06 -1.65 0.13 No No E549K -0.91 0.07 -0.89 0.07 -0.99 0.08 No No E549M -2.06 0.12 -1.66 0.10 -1.57 0.17 No No E549F -1.59 0.14 -1.27 0.13 NA NA Yes No E549S -2.21 0.08 -1.69 0.07 -1.91 0.05 No No E549* -1.66 0.09 -1.47 0 .09 -1.59 0.14 No No E549T NA NA NA NA -1.39 0.10 Yes No E549W -0.99 0.05 -1.72 0.07 -1.85 0.11 No No E549V -1.01 0.04 -0.79 0.04 -1.37 0.04 No No K550R 0.05 0.03 0.18 0.03 0.17 0 .07 Yes Yes K550A -0.24 0.04 -0.06 0.04 -0.91 0.13 No No K550N 0.11 0.07 -0.13 0.07 -0.46 0.13 Yes No K550D -0.86 0.09 0.22 0.07 -1.48 0.23 Yes No K550C -0.08 0.07 -0.18 0.07 -0.84 0.21 No No K550Q -0.1 8 0.07 0.45 0.07 -0.64 0.18 Yes No K550E -0.86 0.06 -0.45 0.05 -1.11 0.09 No No K550G -0.25 0.02 -0.16 0.02 -1.14 0.04 No No K550H -0.22 0.15 -0.42 0.16 NA NA Yes No K550I -0.51 0.12 0.79 0.09 NA NA Yes No K550L 0.01 0.05 -0.17 0.05 -0.95 0.06 Yes No K550M -0.71 0.08 -0.17 0.07 -0.72 0.15 No No K550F -0.14 0.10 -0.39 0.11 NA NA Yes No Q2Q / frn / Lznza / YiAi 7β Μ uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? Κ550Ρ -0.02 0.08 -0.78 0.10 -0.95 0.27 No No K550S -0.07 0.05 -0.22 0.05 -1.05 0.08 No No Κ550* -0.98 0.08 -1.14 0.09 -1.19 0.10 No No Κ550 Τ -0.13 0.06 -0.44 0.07 -0.87 0.14 No No K550W 0.18 0.04 0.20 0.04 -0.66 0.07 Yes No Κ550Υ -0.12 0.11 -0.58 0.12 NA NA Yes No K550V -0.12 0.04 -0.70 0.05 -1.02 0.13 No No N551D 0.14 0.04 0.1 5 0.04 0.67 0.07 Yes Yes Ν551Α -0.29 0.04 -0.42 0.04 -0.37 0.05 No No N551R -0.92 0.04 -1.40 0.05 -1.64 0.09 NO No N551C -0.52 0.08 -0.26 0.08 -0.39 0.28 No No N551Q -0.77 0.09 -0.58 0.08 -0.76 0.10 No No Ν5 51Ε -1.32 0.06 -0.66 0.05 -1.51 0.10 No No N551G -0.95 0.03 -0.96 0.03 -1.10 0.04 No No Ν551Η 0.51 0.09 -1.02 0.14 0.55 0.13 Yes No Ν551Ι -0.01 0.05 0.20 0.05 -0.18 0.11 Yes No N551 L -0.07 0.05 -0.83 0.06 -1.35 0.11 No No Ν551Κ -1.43 0.07 -1.28 0.07 -1.22 0.08 No No Ν551Μ -1.01 0.09 -0.58 0.08 -0.94 0.18 No No N551F -0.65 0.11 -0.19 0.09 -0.04 0.24 No No Ν551Ρ -1.24 0.10 -0.91 0.09 -1.21 0.12 No No N551S -0.06 0.03 0.02 0.03 -0.23 0.05 Yes No Ν551* -1.09 0.10 -1.44 0.11 -1.45 0.20 No No Ν551Τ 0.21 0.05 -0.29 0.06 0.07 0.11 Yes No N551W -0.36 0.06 -0.69 0.06 -0.63 0.13 No No Ν551Υ -0.28 0.07 0.04 0.06 0.95 0.10 Yes No N551V -0.31 0.04 -0.21 0.04 0.03 0.05 Yes No Ν552Α -1.33 0.07 -1.21 0.07 -1.32 0.08 No No N552R -1.19 0.04 -1.37 0.05 -1.47 0.04 No No N552D -1. 18 0.07 -1.04 0.06 -1.24 0.06 No No N552C -1.59 0.10 -1.44 0.09 -1.65 0.17 No No N552Q -1.21 0.11 -0.81 0.10 NA NA Yes No Ν552Ε -1.93 0.09 -0.57 0.05 -1.89 0.06 No No N552G -1.80 0.05 -1.17 0.0 4 -2.06 0.03 No No Ν552Η -0.25 0.10 -0.21 0.10 NA NA Yes No Ν552Ι -0.34 0.05 -0.02 0.05 -0.50 0.09 No No N552L -1.13 0.07 -1.91 0.10 -1.73 0.12 No No Ν552Κ -1.34 0.08 -1.25 0.08 -1.07 0.10 No No Ν552Μ -1.92 0.12 -1.44 0.10 -1.67 0.11 No No Ν552Ρ -1.69 0.12 -0.81 0.09 NA NA Yes No N552S -0.11 0.03 -0.20 0.03 -0.58 0.05 No No Q / Q / bn / Lznza / YiAi M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? N552* NA NA NA -1.37 0.20 Yes No N552T -0.16 0.03 0.00 0.03 -1.04 0.10 No No N552W -1.97 0.10 -1.69 0.08 -1.53 ​​0.15 No No N552Y -0.89 0.10 -0.99 0. 10 -1.08 0.18 No No N552V -1.60 0.07 -1.17 0.06 -1.56 0.05 No No G553A -0.56 0.05 -0.61 0.05 -1.53 ​​0.11 No No G553R -1.58 0.06 -1.17 0.05 -0.39 0.07 No No G553D -0.48 0.08 -0.91 0.09 - 0.94 0.19 No No G553Q -1.38 0.15 -1.10 0.14 NA NA Yes No G553E -2.07 0.11 -1.79 0.10 -1.67 0.17 No No G553S -0.78 0.06 -0.54 0.06 -0.72 0.09 No No G553* -1.04 0.12 -1.39 0.14 NA NA Yes No G553W - 1.11 0.07 -1.87 0.09 -1.59 0.16 No No G553V -0.34 0.03 -0.24 0.03 -0.30 0.05 No No A554I 0.15 0.09 0.71 0.08 0.39 0.34 Yes Yes A554T 0.45 0.04 0.32 0.05 0.93 0.07 Yes Yes A554 V 0.57 0.03 0.48 0.03 0.54 0.04 Yes Yes A554R -1.28 0.05 -1.12 0.05 - 2.05 0.11 No No A554N 0.04 0.09 -0.71 0.11 -0.12 0.13 Yes No A554D -1.96 0.10 -0.95 0.07 -0.83 0.04 No No A554C -0.05 0.07 0.32 0.06 1.05 0.09 Yes No A554Q -0.47 0.10 -0.57 0.10 -1.06 0.28 No No A554E -1.85 0.09 -0.79 0.06 -1.86 0.11 No No A554G -0.43 0.03 -0.54 0.03 -0.70 0.04 No No A554L -0.23 0.05 -0.11 0.05 -0.32 0.17 No No A554M 0.27 0.07 - 0.26 0.08 -0.72 0.23 Yes No A554P -1.28 0.09 -1.84 0.12 NA NA Yes No A554S 0.14 0.03 0.15 0.03 -0.07 0.05 Yes No A554* -1.77 0.14 -1.03 0.11 NA NA Yes No A554W -1.54 0.09 -2.63 0.14 NA NA Yes No I555V 0 .41 0.03 0.13 0.03 0.14 0.06 Yes Yes I555A -0.39 0.05 -0.48 0.05 -0.79 0.14 No No I555R -0.47 0.04 -1.21 0.05 -0.58 0.09 No No I555N -0.51 0.08 -0.76 0.08 -0.76 0.13 No No I555D -1.00 0.09 - 1.17 0.10 NA NA Yes No I555C -1.00 0.12 -0.93 0.12 -0.75 0.10 No No I555Q -0.79 0.11 -0.92 0.11 -0.84 0.21 No No I555E -2.31 0.12 -0.09 0.05 -1.79 0.15 No No I555G -1.15 0.04 -1.07 0.04 - 1.57 0.03 No No I555L 0.18 0.05 -0.03 0.05 -0.30 0.14 Yes No I555K -0.71 0.09 -0.03 0.07 -1.33 0.11 No No Q2Q / frn / Lznza / YiAi M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? I555M -0.04 0.05 -0.01 0.05 -0.27 0.08 No No I555F -0.18 0.09 -0.17 0.09 -0.32 0.13 No No I555P -1.29 0.11 -1.66 0.13 -1.11 0.36 No No I555S -0.16 0.03 -0.12 0.03 -0.31 0.05 No No I555T - 0.01 0.05 -0.09 0.05 -0.45 0.11 No No I555W -1.78 0.11 -1.29 0.09 -1.81 0.15 No No I555Y -1.05 0.14 -1.16 0.15 NA NA Yes No L556M 0.08 0.08 0.10 0 .08 0.11 0.21 Yes Yes L556A -0.52 0.07 -1.77 0.12 - 1.33 0.24 No No L556R -1.06 0.06 -0.91 0.06 -1.39 0.10 NO No L556C -1.31 0.13 -0.58 0.10 NA NA Yes No L556Q -0.06 0.06 -0.34 0.07 -0.36 0.11 No No L556G -1.55 0.07 -1.49 0.07 -1.60 0.06 No No L556I 0.58 0.12 0.07 0.14 NA NA Yes No L556P -0.19 0.07 -0.54 0.08 -0.91 0.13 No No L556S -1.56 0.11 -1.28 0.10 NA NA Yes No L556T -0.95 0.12 -0.69 0 .11 NA NA Yes No L556W -1.77 0.12 -1.41 0.11 NA NA Yes No L556V -0.45 0.06 -0.17 0.05 -0.76 0.14 No No F557A -0.39 0.05 -0.06 0.05 -0.75 0.07 No No F557R -1.79 0.06 -1.05 0.05 -1.57 0.08 No No F557N NA NA NA -0.90 0.11 Yes No F557C -0.63 0.06 -0.55 0.06 -0.32 0.13 No No F557Q -1.87 0.15 -0.40 0.09 -0.98 0.25 No No F557E -1.90 0.10 -1.64 0.09 -1.50 0.16 No No F557G -1.17 0.04 -1.02 0.04 -0.98 0.06 No No F557I -0.32 0.05 -0.07 0.04 -0.05 0.08 No No F557L -0.04 0.04 -0.08 0.04 0.14 0.08 Yes No F557K -1.25 0.10 -0.84 0.09 -0.79 0.30 No No F557M 0.33 0.07 - 0.19 0.08 -0.15 0.18 Yes No F557P -1.14 0.10 - 1.38 0.11 -1.69 0.21 No No F557S -0.87 0.05 -0.74 0.05 -0.48 0.09 No No F557* -1.30 0.10 -2.32 0.15 NA NA Yes No F557T -1.21 0.09 -0.72 0.08 -0.44 0 .25 No No F557W -0.87 0.06 -0.37 0.05 -1.24 0.11 No No F557Y -0.74 0.08 -0.15 0.07 -0.87 0.13 No No F557V -0.50 0.04 -0.91 0.05 -0.42 0.04 No No V558M 0.24 0.06 0.15 0.06 0.10 0.12 Yes Yes V558A -0.11 0.04 -0.13 0.04 0.26 0.09 Yes No V558R -0.63 0.06 -0.46 0.05 -0.26 0.14 No No V558D 0.64 0.09 0.05 0.10 -0.46 0.14 Yes No cMQ / bn / Lznza / YiAi M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? V558C -0.01 0.12 0.01 0.12 -0.28 0.55 Yes No V558Q 0.40 0.11 -0.65 0.14 -0.21 0.55 Yes No V558E 0.15 0.04 -0.31 0.05 -0.12 0.07 Yes No V558G -0.07 0.03 -0.48 0.04 -0.36 0.10 No No V558L 0.16 0.04 0.03 0.04 -0.16 0.09 Yes No V558K 0.05 0.10 -0.15 0.11 -0.02 0.48 Yes No V558F -0.21 0.13 -0.36 0.13 NA NA Yes No V558S -0.36 0.09 -0.49 0.09 -0.10 0.27 No No V558T -0.19 0.12 -0.28 0.12 0.15 0.41 Yes No V558W -0.76 0.10 -0.75 0.10 -0.93 0.30 No No K559A 0.17 0.04 0.08 0.04 0.13 0.08 Yes Yes K559R 0.14 0.03 -0.02 0.03 0.11 0.06 Yes No K559N 0.05 0.03 0.05 0.03 -0.04 0.05 Yes No K559D 0.25 0.08 -0.33 0.09 -0.39 0.25 Yes No K559C 0.31 0.08 -0.20 0.09 -0.05 0.22 Yes No K559Q -0.23 0.07 0.03 0.07 0.00 0.21 Yes No K559E -0.20 0.04 -0.52 0.04 -0.40 0.06 No No K559G -0.3 5 0.03 -0.41 0.03 -0.16 0.03 No No K559H 0.53 0.14 -0.21 0.16 NA NA Yes No K559I -0.62 0.12 0.01 0.10 NA NA Yes No K559L -0.39 0.06 -0.29 0.06 -0.71 0.13 No No K559M -0.27 0.06 -0.65 0.07 0.01 0.12 Yes No K 559F -0.45 0.13 0.13 0.11 NA NA Yes No K559S -0.28 0.06 -0.32 0.06 0.22 0.20 Yes No K559* -0.63 0.07 -0.48 0.07 -1.15 0.09 No No K559T 0.30 0.06 0.52 0.06 -0.20 0.15 Yes No K559W -0.64 0.06 -0.34 0.06 -0.32 0.18 No No K559Y -0.13 0.11 -0.01 0.11 NA NA Yes No K559V -0.53 0.05 -0.50 0.05 -0.27 0.13 No No N560A 0.34 0.05 0.18 0.05 0.18 0.08 Yes Yes N560D 0.16 0.04 0.18 0.04 0.16 0 .08 Yes Yes N560E 0.48 0.06 0.28 0.06 0.11 0.25 Yes Yes N560M 0.16 0.09 0.31 0.09 0.18 0.13 Yes Yes N560R 0.10 0.04 0.04 0.04 -0.07 0.06 Yes No N560C -0.11 0.08 -0.20 0.08 -0.15 0.09 No No N560Q 0.55 0.09 -1.07 0.14 -0.09 0.38 Yes No N560G 0.01 0.04 0.03 0.04 -0.02 0.09 Yes No N560H - 0.35 0.13 -0.17 0.13 NA NA Yes No N560I 0.22 0.05 0.28 0.05 -0.13 0.10 Yes No N560L -0.64 0.08 -0.16 0.07 -0.12 0.11 No No N560K 0.11 0.06 -0.29 0 .07 0.14 0.14 Yes No cMQ / bn / Lznza / YiAi M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? N560F 0.14 0.12 -0.03 0.13 NA NA Yes No N560P 0.19 0.09 -0.69 0.11 -0.13 0.29 Yes No N560S 0.03 0.03 0.18 0.03 -0.01 0.05 Yes No N560* -1.15 0.11 -1 .78 0.15 NA NA Yes No N560T -0.40 0.08 0.00 0.07 0.01 0.14 Yes No N560W -0.36 0.07 -0.72 0.08 -0.27 0.16 No No N560Y -0.24 0.09 0.04 0.08 0.07 0.12 Yes No N560V 0.13 0.06 -0.15 0.06 -0.11 0.16 Yes No G561 A -0.10 0.05 -0.36 0.06 -0.05 0.07 No No G561R - 0.20 0.04 0.00 0.04 -0.16 0.05 NO No G561N 0.20 0.16 1.09 0.14 NA NA Yes No G561D -0.43 0.11 0.54 0.08 -0.03 0.27 Yes No G561C -0.19 0.08 0.03 0 .08 -0.26 0.27 Yes No G561Q -0.15 0.12 0.67 0.10 -0.08 0.26 Yes No G561E 0.14 0.06 -0.19 0.06 -0.05 0.14 Yes No G561H 0.74 0.14 1.07 0.14 NA NA Yes No G561L -0.57 0.09 -0.30 0.09 -0.60 0.09 No No G561K 0.24 0.12 0.17 0.12 NA NA Yes No G561M -0.33 0.14 0.12 0.12 NA NA Yes No G561P -0.84 0.12 -0.45 0.11 0.02 0.17 Yes No G561S 0.00 0.06 0.54 0.05 -0.09 0.18 Yes No G561* -0.53 0.11 -0.01 0.09 NA NA Yes No G561T 0.10 0.09 -0.87 0.13 -0.23 0.34 Yes No G561W -0.47 0.06 -0.34 0.06 -0.51 0.17 No No G561V -0.02 0.02 -0.04 0.02 0.08 0.06 Yes No L562A -0.46 0.07 -0.26 0.07 -0.17 0.22 No No L562R -0.38 0.05 0.08 0.04 - 0.17 0.08 Yes No L562D -0.37 0.13 -0.90 0.15 - 0.46 0.35 No No L562C 0.18 0.10 -0.63 0.12 0.13 0.29 Yes No L562Q -0.43 0.09 -0.20 0.08 -0.07 0.17 No No L562E -0.32 0.07 -0.62 0.08 -0.29 0.18 No No L562G -0.75 0.05 -0.60 0.05 -0.36 0.08 No No L562H 0.23 0.12 -0.50 0.15 NA NA Yes No L562K -0.69 0.12 0.32 0.09 -0.53 0.29 Yes No L562M 0.19 0.06 -0.26 0.07 -0.04 0.12 Yes No L562F 0.48 0.14 0 .79 0.13 NA NA Yes No L562P -0.10 0.06 -0.05 0.06 -0.26 0.09 No No L562S -0.65 0.10 -0.27 0.09 -0.04 0.26 No No L562* -1.29 0.14 -1.10 0.13 NA NA Yes No L562T -1.14 0.15 -1.09 0.15 NA NA Yes No L562W -0.37 0.07 - 0.38 0.07 -0.45 0.18 No No Q / Q / frni 7Π7 -1 / ΥΙΛΙ M uta π te Calif. from enriqu. (1) Std. error (D Enrichment Score (2) Std Error (2) Enrichment Score (3) Std Error (3) Any positive enrichment? Constant positive enrichment? L562Y -0.63 0.16 -0.49 0.16 NA NA Yes No L562V -0.20 0.05 -0.49 0.06 -0.71 0.11 No No Υ563Α -1.58 0.09 -1.18 0.08 -1.03 0.07 No No Y563R -1.46 0.06 -1.08 0.05 -1.59 0.11 No No Υ563 Ν -0.16 0.08 0.04 0.07 -0.30 0.16 Yes No Y563D -0.56 0.07 -0.65 0.07 -0.73 0.07 No No Y563C -0.49 0.06 -0.50 0.06 -0.32 0.09 No No Y563Q -0.48 0.10 -0.52 0.10 -0.93 0.25 No No Υ563Ε -1.21 0. 08 0.07 0.06 -1.73 0.14 Yes No Y563G -1.13 0.04 -1.64 0.05 -1.26 0.03 No No Υ563Η -0.25 0.08 -0.14 0.08 -0.06 0.15 No No Y563L -1.95 0.12 -1.69 0.11 -1.15 0.19 No No Y563F 0.13 0.07 0.06 0. 07 -0.06 0.11 Yes No Y563S -0.91 0.07 -0.95 0.07 - 0.96 0.08 No No Υ563* -0.54 0.08 -0.93 0.09 -1.33 0.14 No No Υ563Τ -1.67 0.15 0.09 0.08 -0.51 0.22 Yes No Y563W -0.84 0.06 -0.78 0.05 -1.12 0.11 No No Y563V -1.32 0.08 -1.12 0.07 -1.13 0.17 No No Υ564Α -1.20 0.15 -0.93 0.14 NA NA Yes No Y564R -1.37 0.10 -1.99 0.13 -1.19 0.19 No No Υ564Ν -0.18 0.12 0.08 0.11 -0.14 0.21 Yes No Y564D -0.0 5 0.06 -0.60 0.07 -0.25 0.10 No No Y564C 0.09 0.05 -0.22 0.05 -0.08 0.10 Yes No Y564G -1.96 0.11 -1.74 0.10 -1.32 0.19 No No Υ564Η -0.05 0.08 -0.10 0.08 0.04 0.13 Yes No Y564L -0.24 0.10 -1. 01 0.13 NA NA Yes No Y564F -0.04 0.11 0.35 0.10 NA NA Yes No Y564S -0.47 0.09 -0.36 0.08 -0.35 0.20 No No Υ564* -0.43 0.11 -0.68 0.12 NA NA Yes No Y564W -0.37 0.10 0.03 0.09 -0.52 0.29 Yes No Y564V -1.90 0.15 -0.72 0.10 NA NA Yes No L565A -0.65 0.07 -0.47 0.06 -1.27 0.23 No No L565R -0.27 0.03 -0.79 0.03 -0.12 0.05 No No L565C -1.21 0.13 -0.10 0.09 -0.66 0.24 No No L565Q -0.36 0.08 - 0.84 0.09 -0.76 0.15 No No L565E -1.93 0.12 -1.02 0.09 -1.55 0.19 No No L565G -2.36 0.08 -1.62 0.06 -1.50 0.10 No No L565I -0.07 0.13 -0.42 0.14 NA NA Yes No L565M -0.20 0.07 -0.26 0.07 0 .03 0.10 Yes No L565P -0.60 0.07 -0.92 0.08 -0.67 0.13 No No L565S -1.07 0.09 -0.75 0.08 -1.13 0.08 No No Q / Q / frni ζηζ-ΐ / γίΛΐ Mutant Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? L565W -1.64 0.10 -2.31 0.13 NA NA Yes No L565V -0.57 0.06 -0.48 0.05 -1.19 0.13 No No G566A -0.36 0.08 -0.39 0.08 -0.57 0.21 No No G566R -1.37 0.09 -1 .97 0.12 -1.83 0.11 No No G566D -0.67 0.11 -1.03 0.12 -0.62 0.18 No No G566C -0.08 0.11 -0.83 0.13 NA NA Yes No G566S -0.14 0.06 -0.40 0.07 -0.18 0.11 No No G566V -0.52 0.07 -0.99 0.08 -0 .68 0.10 No No I567A -1.35 0.11 -1.01 0.09 -1.13 0.07 No No I567R -1.78 0.09 -0.11 0.05 -1.44 0.11 No No I567N -0.05 0.07 -0.10 0.07 0.15 0.10 Yes No I567E -1.64 0.12 -1.70 0.13 NA NA Yes No I567G -1.23 0.06 -1.14 0.06 -1.70 0.09 No No I567L -0.67 0.08 0.29 0.06 -0.48 0.13 Yes No I567M -0.51 0.09 -0.82 0.10 -0.88 0.10 No No I567F -0.43 0.12 0.00 0.11 -0.48 0.19 No No I567S -0.5 6 0.07 -0.67 0.07 -0.82 0.12 No No I567T - 0.15 0.05 -0.27 0.06 0.13 0.09 Yes No I567W -1.85 0.12 -2.17 0.14 -1.22 0.13 No No I567V -0.54 0.05 -0.26 0.05 -0.68 0.08 No No M568A -0.52 0.06 - 0.34 0.06 -0.04 0.11 No No M568R -0.30 0.04 - 0.82 0.05 -0.20 0.07 No No M568C -0.33 0.10 -0.78 0.11 -0.18 0.28 No No M568Q -0.61 0.12 -0.40 0.12 NA NA Yes No M568E -1.29 0.09 -0.86 0.08 -1.65 0 .22 No No M568G -1.32 0.05 -0.45 0.04 - 0.80 0.04 No No M568H 0.40 0.14 -0.11 0.15 NA NA Yes No M568I 0.16 0.05 -0.01 0.06 0.15 0.11 Yes No M568L -0.42 0.06 -0.23 0.05 -0.27 0.09 No No M568K -0.19 0.08 -0.20 0.08 -0.17 0.16 No No M568P - 1.11 0.13 -0.81 0.12 NA NA Yes No M568S 0.29 0.06 -0.47 0.07 -0.54 0.22 Yes No M568T -0.13 0.06 -0.25 0.06 -0.07 0.12 No No M568W -0.20 0.06 0.14 0 .05 -0.93 0.18 Yes No M568V -0.26 0.04 -0.28 0.04 0.06 0.08 Yes No P569D 0.60 0.08 0.33 0.08 1.25 0.11 Yes Yes P569A -0.12 0.05 -0.39 0.05 0.23 0.08 Yes No P569R -0.60 0.04 -0.52 0.04 -0.13 0.05 No No P569N -0.14 0.14 -0.71 0.16 NA NA Yes No P569C -1.16 0.09 -0.36 0.07 0.07 0.19 Yes No P569Q -0.26 0.09 -0.13 0.09 0.40 0.21 Yes No QJQ / frn i 7Π7 -1 / ΥΙΛΙ M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? P569E -0.07 0.07 -0.16 0.07 -0.11 0.22 No No P569G -0.54 0.03 -0.49 0.03 -0.65 0.07 No No P569H 0.12 0.09 -0.25 0.10 0.16 0.17 Yes No P569I 0.03 0.13 -0.32 0.14 0.10 0.31 Yes No P569L -0.47 0.05 -0.21 0.04 -0.30 0.11 No No P569K -0.35 0.12 0.36 0.10 0.23 0.31 Yes No P569M -0.98 0.11 -0.54 0.10 -0.28 0.12 No No P569F NA NA NA -0.67 0.31 Yes No P569S - 0.07 0.05 -0.24 0.05 0.02 0.11 Yes No P569T -0.38 0.07 -0.20 0.07 -0.06 0.15 No No P569W -0.74 0.06 -1.07 0.07 -1.18 0.14 No No P569V -0.34 0.04 -0.82 0.05 0.15 0.14 Yes No K570A -0.95 0.06 - 0.28 0.05 -1.70 0.16 No No K570R -0.47 0.03 -0.56 0.04 -0.39 0.05 No No K570N -0.30 0.11 -0.73 0.12 NA NA Yes No K570D -1.38 0.12 -1.42 0.13 NA NA Yes No K570C -1.71 0.11 -1.70 0.11 NA NA Yes No K570Q -0 .90 0.09 -0.32 0.08 -1.25 0.18 No No K570E -1.37 0.07 -0.71 0.05 -1.40 0.10 No No K570G -0.62 0.03 -0.33 0.03 -1.61 0.09 No No K570L -1.83 0.08 -1.48 0.07 -1.35 0.14 No No K570 M -1.02 0.09 -0.76 0.09 -1.52 0.18 No No K570P -1.15 0.12 -0.12 0.09 NA NA Yes No K570S -1.28 0.09 -0.51 0.07 -1.52 0.14 No No K570* -1.31 0.10 -1.26 0.10 -1.24 0.15 No No K570T -0.02 0.03 0.11 0.03 -0.05 0.03 Yes No K570W - 2.06 0.09 -2.64 0.12 -1.61 0.14 No No K570V -1.33 0.06 -0.81 0.05 -1.85 0.11 No No Q571A 0.64 0.07 0.39 0.08 1.09 0.23 Yes Yes Q571P 0.17 0.07 0.61 0.07 0.13 0.14 Yes Yes Q571S 0.25 0.09 0.20 0.09 0.89 0.23 Yes Yes Q571T 0.22 0.13 0.19 0.13 0.87 0.41 Yes Yes Q571R -0.03 0.04 -0.43 0.05 0.19 0.10 Yes No Q571C -0.60 0.16 0.23 0.12 -0.33 0.24 Yes No Q571E -0.22 0.05 - 0.40 0.06 -0.17 0.05 No No Q571G 0.00 0.06 -0.25 0.06 -0.41 0.18 No No Q571H -0.23 0.11 -0.65 0.12 0.06 0.24 Yes No Q571L -0.41 0.07 -0.45 0.07 -0.66 0.11 No No Q571K -0.47 0.16 -0.33 0.15 0.08 0.31 Yes No Q571 * -0.59 0.11 -0.27 0.10 -0.67 0.17 No No Q571W -0.09 0.08 -0.80 0.09 -0.51 0.24 No No Q / Q / frni 7Π7 -1 / ΥΙΛΙ M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? Q571V -0.36 0.11 -0.20 0.10 -0.44 0.32 No No K572E 0.11 0.04 0.25 0.04 0.42 0.08 Yes Yes K572A -0.24 0.04 0.33 0.04 -0.11 0.11 Yes No K572R -0.08 0.03 -0.05 0.03 0.03 0.03 Yes No K572N -0.17 0.07 0.17 0.06 0.02 0.11 Yes No K572D -0.09 0.09 0.03 0.08 0.45 0.19 Yes No K572C 0.23 0.07 -0.87 0.09 -0.19 0.25 Yes No K572Q -0.21 0.06 0.11 0.06 0.37 0.16 Yes No K572 G -0.17 0.03 -0.08 0.03 0.42 0.03 Yes No K572H NA NA NA NA 0.11 0.33 Yes No K572L -0.11 0.05 0.16 0.05 -0.32 0.15 Yes No K572M -0.71 0.08 0.02 0.06 0.21 0.06 Yes No K572P 0.09 0.06 0.91 0.06 -0.88 0.23 Yes No K572S 0.30 0.05 0.01 0.05 -0.29 0.15 Yes No K572* -1.34 0.08 -0.86 0.07 -0.86 0.08 No No K572T -0.04 0.04 -0.09 0.04 -0.24 0.07 No No K572W -0.46 0.05 -0.47 0.05 -0.68 0.14 No No K572Y -1.04 0.16 -1.01 0.15 NA NA Yes No K572V -0.08 0.04 -0.31 0.04 -0.71 0.04 No No G573A 0.04 0.04 -0.11 0.04 -0.99 0.09 Yes No G573R -0.04 0.03 -0.31 0.04 -0.66 0.08 No No G573N 0.45 0.12 -0.94 0.17 -0.29 0.41 Yes No G573D -0.05 0.06 -0.41 0.07 -0.95 0.13 No No G573C -0.22 0.06 -0.35 0.06 -0.42 0.11 No No G573Q 0.40 0.07 -0.29 0.08 -0.43 0.26 Yes No G573E -0.09 0.05 0.36 0.05 -0.50 0.08 Yes No G573H -0.77 0.12 0.37 0.09 -0.51 0.30 Yes No G573L -0.04 0.05 0.07 0.05 -0.43 0.05 Yes No G573K -1.43 0.13 -0.29 0.09 -0.32 0.25 No No G573M -0.32 0.10 -0.32 0.09 -0.28 0.26 No No G573F -0.45 0.14 -0.19 0.12 NA NA Yes No G573P 0.16 0.06 -0.38 0.06 -0.10 0.21 Yes No G573S 0.11 0.04 -0.42 0.05 -0.55 0.10 Yes No G573* -1.18 0.12 -1.27 0.12 -0.75 0.28 No No G573T 0.02 0.08 -0.53 0.09 -0.62 0.08 Yes No G573 W -0.08 0.05 -0.60 0.05 -0.67 0.09 No No G573Y 0.13 0.11 -0.81 0.14 -0.48 0.30 Yes No G573V -0.06 0.04 -0.40 0.04 -0.71 0.06 No No R574A -0.83 0.07 -0.54 0.06 -0.64 0.10 No No R574N -0.85 0.17 -0.69 0.16 NA NA Yes No R574D -0.32 0.10 -1.05 0.13 NA NA Yes No Q / Q / frni 7Π7 -1 / ΥΙΛΙ Muffante Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? R574C 0.58 0.07 0.15 0.07 -1.16 0.22 Yes No R574Q NA NA NA NA -1.08 0.26 Yes No R574E -0.53 0.08 -0.38 0.07 -1.34 0.15 No No R574G -0.21 0.03 -0.27 0. 03 -0.60 0.07 No No R574I -0.50 0.11 -0.47 0.11 NA NA Yes No R574L -0.36 0.07 -0.25 0.07 -0.78 0.18 No No R574K -0.33 0.08 0.42 0.06 -0.33 0.17 Yes No R574M 0.51 0.07 -0.36 0.08 -0.64 0.07 Yes No R574F 0.06 0.12 -0.99 0.16 NA NA Yes No R574P -0.38 0.13 0.11 0.11 -0.72 0.23 Yes No R574S 0.12 0.04 0.02 0.04 -1.04 0.03 Yes No R574* -0.34 0.07 -0.51 0.07 -0.84 0.09 No No R574T -0.65 0.09 0.35 0.07 -0.83 0.16 Yes No R574W -0.10 0.05 -0.10 0.05 -0.73 0.06 No No R574Y -0.25 0.12 0.13 0.11 NA NA Yes No R574V 0.59 0.05 -0.27 0.05 -1.08 0.14 Yes No Y575G 0.53 0.04 0.21 0.04 0.32 0.07 Yes Yes Y575M 0.89 0.11 0.27 0.12 0.31 0.41 Yes Yes Y575A 0.55 0.05 0.01 0.06 -0.07 0.18 Yes No Y575R 0.15 0.05 -0.04 0.06 -0.56 0.10 Yes No Y575N -0.07 0.10 0.34 0.09 -0.21 0.10 Yes No Y575D -0.07 0.09 0.15 0.09 -0.45 0.25 Yes No Y575C 0.20 0.06 0.17 0.06 -0.26 0.09 Yes No Y575Q - 0.22 0.13 -0.32 0.13 -0.16 0.30 No No Y575E 0.03 0.08 -0.32 0.09 -0.41 0.35 Yes No Y575H -0.24 0.08 -0.29 0.08 0.23 0.13 Yes No Y575I 0.04 0.14 - 0.37 0.15 NA NA Yes No Y575L -0.05 0.07 -0.43 0.08 - 0.22 0.23 No No Y575K 0.95 0.11 0.22 0.12 NA NA Yes No Y575F 0.14 0.08 -0.45 0.09 -0.16 0.12 Yes No Y575P -0.06 0.09 -0.22 0.09 -0.14 0.31 No No Y575S 0.02 0.06 0.01 0.06 -0.07 0.09 Yes No Y575* -0.20 0.07 -0.46 0.08 -0.51 0.12 No No Y575T -0.55 0.10 -0.40 0.09 -0.14 0.30 No No Y575W -0.44 0.09 0.31 0.07 -0.36 0.16 Yes No Y575V -0.10 0.07 -0.35 0.07 -0.29 0.24 No No K576C 0.27 0.07 0.25 0.07 0.10 0.26 Yes Yes K576A -0.05 0.05 0.16 0.05 0.27 0.06 Yes No K576R -0.31 0.03 -0.11 0.03 0.05 0.07 Yes No K576N -0.28 0.08 -0.47 0.08 -0.11 0.15 No No K576 D -0.01 0.08 -0.22 0.09 -1.04 0.26 No No Muffante Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? K576Q -0.06 0.06 0.02 0.05 0.57 0.08 Yes No K576E -0.63 0.05 -0.38 0.05 -0.27 0.09 No No K576G -0.03 0.03 -0.13 0.03 0.28 0.04 Yes No K576H -0.26 0.14 -0.46 0.14 NA NA Yes No K576I 0.10 0.11 -0.10 0.12 0.37 0.16 Yes No K576L -0.04 0.05 0.01 0.04 0.24 0.05 Yes No K576M 0.21 0.05 -0.14 0.06 0.07 0.09 Yes No K576F -0.41 0.13 -1.12 0.15 0.20 0.34 Yes No K576P -0.07 0.09 -1.70 0.14 -0.15 0.17 No No K576S -0.20 0.05 -0.43 0.06 0.64 0.15 Yes No K576* -1.75 0.10 -1.41 0.08 -0.09 0.15 No No K576T -0.05 0.06 0.30 0.05 0.20 0.08 Yes No K576W -0.33 0.05 -0.65 0.05 -0.56 0.13 No No K576Y -1.23 0.16 -0.48 0.12 NA NA Yes No K576V -0.36 0.04 -0.69 0.05 0.38 0.07 Yes No A577R -0.12 0.03 -0.60 0.04 0.88 0.06 Yes No A577N 0.11 0.09 -0.85 0.11 0.34 0.13 Yes No A577D -0.06 0.05 -0.11 0.05 -0.37 0.13 No No A577C - 0.24 0.06 -0.02 0.06 -0.39 0.20 No No A577Q -0.37 0.07 0.63 0.06 0.10 0.23 Yes No A577E -0.66 0.05 -2.12 0.09 -0.27 0.14 No No A577G 0.22 0.02 - 0.05 0.03 0.49 0.05 Yes No A577H 0.02 0.08 -0.59 0.10 0.25 0.22 Yes No A577I -0.94 0.12 -0.35 0.10 NA NA Yes No A577L -0.90 0.06 -0.37 0.05 -0.15 0.06 No No A577K -0.40 0.08 -0.80 0.09 1.09 0.07 Yes No A577M -0.40 0.08 -0.20 0.07 -0.28 0.20 No No A577F - 0.79 0.11 -0.99 0.12 -0.78 0.19 No No A577P -0.25 0.06 -0.11 0.05 -0.29 0.11 No No A577S -0.31 0.04 -0.26 0.04 0.08 0.10 Yes No A577* -1.65 0.11 - 1.75 0.11 NA NA Yes No A577T -0.09 0.05 - 0.38 0.05 -0.02 0.08 No No A577W -0.63 0.05 -0.66 0.05 -0.66 0.08 No No A577Y -0.22 0.09 -0.20 0.09 0.05 0.32 Yes No A577V -0.06 0.03 -0.28 0.04 - 0.42 0.09 No No L578A -0.22 0.03 -0.43 0.03 - 0.20 0.07 No No L578R -0.11 0.02 -0.49 0.02 0.04 0.03 Yes No L578N -0.35 0.11 -0.09 0.10 -0.47 0.23 No No L578D -0.09 0.06 -0.41 0.06 -0.92 0.07 No No L578C 0.05 0.04 -0.34 0.05 -0.03 0.10 Yes No L578Q 0.11 0.04 -0.12 0.05 0.00 0.10 Yes No M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? L578E -0.33 0.04 -0.53 0.04 -0.77 0.12 No No L578G -0.26 0.02 -0.45 0.02 -0.29 0.02 No No L578H -0.27 0.07 0.10 0.06 0.03 0.14 Yes No L578I -0.28 0.09 0.32 0.08 0.22 0.23 Yes No L578K -0.62 0.07 -1.21 0.09 0.50 0.20 Yes No L578M -0.12 0.03 -0.21 0.03 -0.03 0.05 No No L578F 0.36 0.06 0.21 0.06 -0.12 0.14 Yes No L578P -0.62 0.05 0.03 0.04 -0.31 0.06 Yes No L578S -0.37 0.04 -0.33 0.04 -0.08 0.09 No No L578* -1.90 0.09 -1.28 0.07 -1.24 0.09 NO No L578T -0.29 0.06 -0.06 0.05 0.26 0.06 Yes No L578W -0.37 0.03 -0.41 0.03 -0.08 0.04 No No L578Y 0.36 0.07 -0.21 0.07 -0.24 0.07 Yes No L578V -0.19 0.03 -0.28 0.03 0.01 0.04 Yes No S579T 0.17 0.04 0.33 0.04 0.01 0.06 Yes Yes S579V 0.04 0.03 0.02 0.03 0.05 0.07 Yes Yes S579A -0.06 0.03 0.06 0.02 0.08 0.03 Yes No S579R 0.04 0.03 -0.11 0.03 -0.15 0.05 Yes No S579N -0.19 0.07 -0.45 0.08 -0.39 0.23 No No S579D -0.39 0.06 -0.43 0.06 0.03 0.06 Yes No S579C 0.02 0.03 0.07 0.03 -0.02 0.05 Yes No S579Q -0.19 0.07 -0.66 0.08 0.30 0.20 Yes No S579E -0.10 0.04 -0.54 0.05 -0.15 0.05 No No S579G -0.25 0.03 -0.12 0.02 0.11 0.05 Yes No S579H 0.09 0.08 -0.15 0.08 -0.18 0.12 Yes No S579I -0.05 0.06 0.25 0.06 0.04 0.15 Yes No S579 L -0.65 0.04 -0.32 0.04 0.11 0.05 Yes No S579K -0.15 0.06 -0.55 0.07 0.13 0.22 Yes No S579M -0.18 0.06 0.05 0.05 0.28 0.19 Yes No S579F 0.27 0.04 0.16 0.04 -0.08 0.07 Yes No S579P -0.19 0.05 -0.75 0.05 - 0.05 0.10 No No S579* -1.34 0.08 -1.06 0.07 -1.30 0.11 No No S579W -0.09 0.04 -0.35 0.04 -0.37 0.06 No No S579Y -0.06 0.05 -0.21 0.05 -0.36 0.04 No No F580A -0.80 0.08 -0.25 0.07 -1.44 0.19 No No F580R -1.5 8 0.09 -1.48 0.08 -1.26 0.19 No No F580C -0.22 0.09 -0.47 0.10 -0.11 0.18 No No F580E -0.96 0.12 -0.21 0.09 NA NA Yes No F580G -0.91 0.05 -1.05 0.05 -1.21 0.04 No No F580I -0.14 0.09 -0 .06 0.09 -0.17 0.28 No No F580L -0.11 0.05 -0.28 0.05 0.01 0.09 Yes No Q2Q / bn / Lznza / YiAi Mufante Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? F580M 0.31 0.12 -0.37 0.14 NA NA Yes No F580P NA NA NA NA -0.75 0.28 Yes No F580S -0.22 0.07 -0.70 0.07 -0.67 0.10 No No F580W -1.14 0.10 0.30 0.07 0.6 7 0.24 Yes No F580Y 0.39 0.11 -0.45 0.14 -0.09 0.23 Yes No F580V 0.18 0.06 -0.33 0.06 -0.52 0.13 Yes No E581A -0.08 0.03 0.16 0.03 -0.13 0.06 Yes No E581R -0.31 0.03 -0.14 0.03 -0.36 0.04 No No E581 N -0.14 0.15 0.56 0.13 NA NA Yes No E581D 0.04 0.06 0.25 0.06 -0.21 0.09 Yes No E581C 0.12 0.07 0.54 0.06 -0.12 0.15 Yes No E581Q 0.01 0.04 0.09 0.04 -0.12 0.06 Yes No E581G -0.15 0.02 -0.05 0.02 - 0.03 0.03 No No E581H -0.31 0.12 1.00 0.10 -0.67 0.35 Yes No E5811 -0.12 0.14 0.03 0.13 0.40 0.44 Yes No E581L 0.09 0.04 -0.12 0.04 0.29 0.12 Yes No E581K -0.10 0.05 -0.02 0.05 -0.33 0.07 No No E581M -0.05 0.08 -0.79 0.09 0.12 0.13 Yes No E581F -0.32 0.11 -0.09 0.10 -0.40 0.30 No No E581P -0.49 0.07 -0.09 0.06 -0.25 0.13 No No E581S 0.00 0.05 -1.01 0.06 -0.11 0.06 Yes No E581* -1.00 0.07 -0.93 0.07 -0.92 0.13 No No E581T -0.23 0.07 -0.29 0.07 0.06 0.09 Yes No E581W 0.25 0.04 -0.31 0.04 0.04 0.05 Yes No E581Y NA NA NA 0.25 0.28 Yes No E581V -0.18 0.04 0.31 0.03 0.26 0.10 Yes No P582A -0.46 0.07 -0.64 0.07 -0.60 0.13 No No P582R 0.24 0.05 -0.24 0.06 - 0.48 0.17 Yes No P582N -0.02 0.05 -0.24 0.05 -0.22 0.11 No No P582D -0.41 0.18 -0.64 0.18 NA NA Yes No P582C 0.14 0.11 -0.07 0.12 0.17 0.64 Yes No P582Q -0.74 0.13 -0.13 0.11 -0.07 0.25 No No P582G -0.10 0.06 -0.80 0.07 -0.50 0.18 No No P582H -0.03 0.02 -0.15 0.02 -0.12 0.04 No No P582L -0.14 0.07 -0.96 0.08 -0.26 0.13 No No P582K -0.33 0.19 0.97 0.15 NA NA Yes No P582F NA NA NA NA 0.02 0.55 Yes No P582S 0.19 0.06 0.48 0.05 -1.33 0.16 Yes No P582T -0.13 0.03 -0.19 0.03 -0.48 0.06 No No P582W -1.46 0.15 -0.73 0.11 -0.12 0.35 No No P582V -0.90 0.10 -0.27 0.08 -0.81 0.09 No No Mutant Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? T583I 0.04 0.08 0.11 0.07 0.07 0.17 Yes Yes T583A 0.02 0.04 -0.22 0.04 -0.17 0.08 Yes No T583R 0.12 0.05 -0.31 0.05 -0.04 0.09 Yes No T583N 0.00 0.06 0.01 0.06 -0.20 0.09 Yes No T583D 0.23 0.12 -0.96 0.16 NA NA Yes No T583C 0.67 0.09 -0.82 0.12 -0.67 0.27 Yes No T583Q NA NA NA NA -0.28 0.36 Yes No T583E -0.62 0.10 0.01 0.09 -0.72 0.28 Yes No T583G -0.17 0.05 -0.35 0 .05 0.16 0.06 Yes No T583L -0.09 0.06 -0.72 0.07 -0.24 0.22 No No T583K NA NA NA -0.15 0.44 Yes No T583M -0.72 0.13 -0.89 0.14 -0.12 0.32 No No T583F -0.41 0.13 -0.83 0.15 -0.13 0.36 No No T583P - 0.14 0.08 -0.64 0.08 -0.37 0.14 No No T583S 0.18 0.05 0.11 0.05 -0.34 0.07 Yes No T583W -0.31 0.07 -0.54 0.08 -0.09 0.08 No No T583V 0.01 0.06 -0.05 0.06 0.15 0.22 Yes No E584H 0.0 9 0.07 0.22 0.07 0.17 0.14 Yes Yes E584V 0.10 0.03 0.06 0.03 0.12 0.04 Yes Yes E584A -0.01 0.03 0.09 0.03 0.10 0.06 Yes No E584R -0.23 0.03 -0.12 0.03 -0.10 0.05 No No E584N -0.50 0.09 -0.38 0.08 -0.11 0.20 No No E584D 0.4 6 0.04 0.51 0.04 -0.02 0.08 Yes No E584C -0.03 0.05 0.09 0.05 0.13 0.07 Yes No E584Q 0.09 0.07 -0.88 0.08 -0.09 0.10 Yes No E584G -0.02 0.02 0.06 0.02 0.16 0.04 Yes No E584I 0.32 0.07 -0.34 0.08 - 0.03 0.20 Yes No E584L -0.27 0.04 0.00 0.04 -0.06 0.10 No No E584K -0.29 0.06 -0.78 0.07 0.39 0.09 Yes No E584M -0.17 0.07 -0.68 0.08 0.34 0.13 Yes No E584F -0.11 0.08 -0.41 0.09 0.27 0.19 Yes No E584P 0.12 0.05 - 0.13 0.06 -0.24 0.17 Yes No E584S -0.44 0.04 0.09 0.04 0.26 0.09 Yes No E584* -1.22 0.09 -1.26 0.08 -1.15 0.13 No No E584T -0.03 0.05 -0.03 0.05 0.17 0.15 Yes No E584W -0.73 0.06 -0.52 0.05 -0.32 0.07 No No E584 Y -0.13 0.07 0.55 0.06 0.05 0.25 Yes No K585R 0.07 0.03 0.32 0.03 0.06 0.05 Yes Yes K585F 0.51 0.09 0.04 0.09 0.61 0.36 Yes Yes K585A 0.21 0.04 -0.23 0.05 0.16 0.13 Yes No K585N -0.13 0.09 0.18 0.08 -0.67 0.12 Yes No Q / Q / bn / Lznza / YiAi M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? K585D -0.05 0.07 -0.08 0.07 -0.05 0.23 No No K585C -0.25 0.07 -0.61 0.08 -0.11 0.29 No No K585Q 0.07 0.06 0.41 0.06 -0.09 0.08 Yes No K585E -0.33 0.05 -0.44 0.05 0.10 0.12 Yes No K585G -0.18 0.03 - 0.04 0.03 0.16 0.04 Yes No K585H 0.12 0.11 -0.60 0.13 0.28 0.14 Yes No K585I -1.45 0.14 0.35 0.08 0.11 0.25 Yes No K585L -0.10 0.04 -0.06 0.04 0.27 0.13 Yes No K585M -0.25 0.07 -0.05 0.06 0.21 0.17 Yes No K585P 0.20 0.06 -0.04 0.07 0.15 0.21 Yes No K585S -0.17 0.05 0.24 0.04 0.20 0.11 Yes No K585* -0.91 0.07 -0.60 0.06 -0.61 0.11 No No K585T 0.08 0.05 -0.30 0.05 0.05 0.07 Yes No K585W -0.21 0.05 -0.15 0.05 0.18 0.16 Yes No K585Y 0.18 0.10 -0.92 0.13 0.07 0.40 Yes No K585V -0.16 0.04 -0.68 0.04 0.37 0.06 Yes No T586A -0.30 0.05 -0.02 0.04 -0.01 0.11 No No T586R -0.5 6 0.05 -0.06 0.04 -0.20 0.14 No No T586N -0.07 0.05 0.15 0.05 -0.02 0.07 Yes No T586D -0.41 0.12 1.10 0.09 0.41 0.30 Yes No T586C -0.60 0.11 -0.45 0.10 0.10 0.29 Yes No T586Q -0.65 0.14 0.28 0.11 NA NA Yes No T586E -0.29 0.09 0.04 0.08 0.16 0.37 Yes No T586G -0.21 0.04 0.22 0.03 -0.07 0.09 Yes No T586I -0.77 0.11 0.90 0.07 -0.48 0.19 Yes No T586L -0.06 0.06 -0.85 0.07 0.01 0.18 Yes No T586K -0.06 0.12 0.80 0.10 -0.12 0.13 Yes No T586M -0.62 0.11 -1.06 0.13 0.22 0.34 Yes No T586F 0.21 0.13 -0.21 0.14 0.02 0.54 Yes No T586P 0.38 0.06 -0.09 0.06 0.22 0.12 Yes No T586S -0.22 0.05 -0.08 0.05 0.01 0.08 Yes No T586W -0.48 0.07 -0.61 0.07 -0.29 0.24 No No T586Y NA NA NA NA 0.24 0.26 Yes No T586V -0.97 0.07 -0.13 0.05 0.13 0.17 Yes No S587A NA NA NA 0.45 0.32 Yes No S587R 0.15 0.08 -0.61 0.09 -0.34 0.15 Yes No S587N -0 .30 0.13 -0.31 0.13 -0.26 0.18 No No S587C 0.01 0.15 0.00 0.14 NA NA Yes No S587E 0.33 0.16 -0.40 0.19 NA NA Yes No S587G -0.32 0.06 -0.81 0.07 -0.21 0.06 No No S587L 0.21 0.14 0.27 0.13 NA NA Yes No Q / Q / frni 7Π7 -1 / ΥΙΛΙ Matante Calif. from enriqu. (1) Std. error (D Enrichment Score (2) Std Error (2) Enrichment Score (3) Std Error (3) Any positive enrichment? Constant positive enrichment? S587T 0.80 0.11 -0.41 0.14 -0.13 0.23 Yes No S587V 0.20 0.11 -0.25 0.12 -0.04 0.12 Yes No E588A -0.01 0.05 0.25 0.05 0.17 0.10 Yes No E588R -0.39 0.05 -0.61 0.05 -0.31 0.07 No No E588D 0.0 0 0.08 -0.12 0.08 -0.55 0.13 Yes No E588C -0.64 0.11 -0.35 0.10 0.00 0.10 No No E588Q 0.11 0.09 -0.25 0.09 -0.08 0.13 Yes No E588G -0.16 0.04 -0.19 0.04 -0.34 0.04 No No E588H -0.35 0.17 -0.26 0.16 NA NA Yes No E588L -0.31 0.07 -0.29 0.07 0.41 0.12 Yes No E588K 0.18 0.07 0.13 0.07 -0.25 0.15 Yes No E588M -0.50 0.12 -0.10 0.11 0.54 0.12 Yes No E588F -0.23 0.15 0.13 0.14 NA NA Yes No E588P -0.04 0.10 0.06 0.09 0.52 0.19 Yes No E588S -0.03 0.07 -0.34 0.08 -0.47 0.08 No No E588* -1.05 0.11 -1.06 0.11 -1.02 0.15 No No E588T 0.32 0.09 -1.53 ​​0.15 NA NA Yes No E588W -0.02 0.07 0.03 0.07 -0.01 0.19 Yes No E588Y -0.11 0.17 0.93 0.14 NA NA Yes No E588V -0.70 0.06 -0.19 0.05 0.07 0.08 Yes No G589A -0.44 0.05 -0.09 0.04 -0.52 0.14 No No G589R -0.21 0.04 -0.73 0.04 -0.69 0.07 No No G589D -0.29 0.08 - 0.88 0.10 -0.70 0.17 No No G589C -0.14 0.04 -0.12 0.04 -0.59 0.07 No No G589Q NA NA NA NA -0.13 0.27 Yes No G589E -0.39 0.06 -1.47 0.08 -0.59 0.24 No No G589L 0.07 0.06 -1.02 0.08 -1.07 0.20 Yes No G 589M -0.45 0.12 -1.01 0.14 NA NA Yes No G589P -0.34 0.08 -2.17 0.15 -1.08 0.12 No No G589S -0.13 0.04 -0.30 0.04 -0.54 0.10 No No G589T -0.52 0.11 -0.51 0.10 -1.12 0.28 No No G589W -0.6 2 0.06 -0.77 0.07 -0.26 0.13 No No G589Y NA NA NA -0.01 0.41 Yes No G589V -0.65 0.05 -0.97 0.06 -0.22 0.13 No No F590A -0.43 0.05 -1.38 0.07 -1.07 0.15 No No F590R -0.22 0.05 -0.83 0. 05 -0.62 0.15 No No F590N -0.95 0.17 -0.65 0.15 NA NA Yes No F590C -0.49 0.08 -0.73 0.08 -1.06 0.20 No No F590E -1.00 0.09 -1.26 0.10 -0.44 0.26 No No F590G -1.05 0.04 -1.44 0.05 -1.47 0 .09 No No F590I 0.01 0.09 0.10 0.08 NA NA But M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? F590L -0.02 0.04 -0.21 0.04 -0.51 0.06 No No F590M -0.27 0.12 -0.41 0.12 NA NA Yes No F590P -1.08 0.10 -1.31 0.10 -1.37 0.17 No No F590S -0.03 0.05 -0 .29 0.05 -0.61 0.07 No No F590T -1.50 0.15 -1.08 0.12 NA NA Yes No F590W 0.04 0.07 -0.11 0.07 -0.87 0.26 Yes No F590Y 0.07 0.06 -0.18 0.07 -0.19 0.17 Yes No F590V -1.03 0.06 -0.97 0.06 -0 .98 0.14 No No D591A 0.20 0.04 0.07 0.04 -0.54 0.05 Yes No D591R -0.94 0.05 -1.06 0.05 -0.45 0.13 No No D591N -0.49 0.10 -0.61 0.10 -0.54 0.14 No No D591C -0.66 0.10 -0.68 0.09 -0.47 0.23 No No D591Q -0.3 4 0.10 0.11 0.09 -0.15 0.38 Yes No D591E -0.43 0.05 -0.39 0.05 -0.84 0.14 No No D591G -0.62 0.03 -0.81 0.03 -0.59 0.03 No No D591H -1.19 0.16 -0.84 0.14 NA NA Yes No D591L -0.17 0.06 -0.59 0 .07 -0.99 0.20 No No D591K -0.51 0.12 -0.27 0.11 NA NA Yes No D591M -0.90 0.12 -0.93 0.12 -0.36 0.27 No No D591S -0.69 0.07 -1.41 0.09 -0.67 0.17 No No D591T -0.15 0.08 -0.93 0.10 -1.04 0 .23 No No D591W -1.02 0.08 -0.91 0.07 -0.42 0.16 No No D591Y 0.08 0.10 -0.62 0.12 -0.50 0.17 Yes No D591V -0.76 0.05 -1.11 0.05 -1.12 0.11 No No K592A -1.60 0.09 -0.60 0.06 -1.42 0.15 No No K592R -0.98 0.05 -0.77 0.04 -1.03 0.05 No No K592N -0.12 0.10 0.07 0.10 -0.91 0.19 Yes No K592Q -0.52 0.07 -0.77 0.08 -0.30 0.10 No No K592E -0.52 0.07 -0.76 0.07 -1.22 0.10 No No K592G -1.7 6 0.06 -1.45 0.05 -1.64 0.08 No No K592L -1.72 0.08 -1.52 0.08 -1.24 0.13 No No K592M -0.70 0.07 -0.58 0.07 -0.68 0.07 No No K592P -1.70 0.14 -1.63 0.13 NA NA Yes No K592S -1.67 0.10 -1.56 0 .10 NA NA Yes No K592* 0.00 0.08 - 1.63 0.13 -0.91 0.18 Yes No K592T -1.38 0.11 -0.98 0.09 NA NA Yes No K592W -1.60 0.10 -1.14 0.08 -0.21 0.20 No No K592V -1.60 0.06 -1.14 0.05 -1.90 0 .08 No No M593A -1.94 0.07 -1.00 0.05 - 1.73 0.06 No No M593R -0.79 0.03 -0.81 0.03 -0.81 0.03 No No M593N -1.58 0.13 -1.89 0.15 NA NA Yes No ayQ / bn / Lznza / YiAi M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? M593D -2.12 0.13 -1.32 0.09 -1.77 0.18 No No M593C -0.95 0.07 -0.04 0.06 -1.27 0.10 No No M593Q NA NA NA -0.83 0.19 Yes No M593E -2.30 0.10 -2.14 0. 09 -1.55 0.14 No No M593G -1.83 0.04 -1.88 0.04 -1.09 0.07 No No M593I -0.83 0.07 -1.05 0.08 -1.17 0.12 No No M593L -0.10 0.03 -0.33 0.03 -0.52 0.06 No No M593K -1.64 0.09 -1.56 0.08 - 1.09 0.05 No No M593F -1.98 0.12 -0.83 0.08 -1.61 0.12 No No M593P -1.56 0.10 -2.23 0.12 -0.38 0.12 No No M593S -1.58 0.06 -1.88 0.07 -1.33 0.11 No No M593* -2.27 0.12 -2.28 0.12 -1.55 0.18 No No M593T -1.01 0.06 -0.79 0.05 -0.64 0.10 No No M593W -0.92 0.05 -1.57 0.07 -2.41 0.16 No No M593V -0.56 0.03 -1.41 0.04 -1.07 0.07 No No Y594A -0.40 0.04 -1.29 0.05 -1.34 0.10 No No Y594R -0.02 0.03 -0.18 0.03 -1.14 0.08 No No Y594N -1.08 0.10 -0.80 0.08 -0.62 0.15 No No Y594D -1.17 0.07 -1.36 0.07 -1.43 0.13 No No Y594C -0.47 0.06 -0.08 0.06 -1.45 0.10 No No Y594 Q -1.06 0.08 -0.26 0.06 -1.14 0.12 No No Y594E -0.42 0.04 -0.82 0.05 -2.58 0.11 No No Y594G -1.21 0.03 -1.58 0.03 -1.51 0.04 No No Y594H 0.04 0.07 -0.11 0.07 -0.42 0.12 Yes No Y594I -0.73 0.10 -0.78 0.10 -0.74 0.27 No No Y594L - 0.88 0.05 -0.67 0.04 -1.45 0.10 No No Y594K -0.40 0.06 -0.88 0.07 -1.41 0.17 No No Y594M 0.05 0.06 -0.76 0.07 -1.47 0.18 Yes No Y594F -0.18 0.07 - 0.07 0.06 -0.45 0.14 No No Y594S -1.00 0.05 - 0.88 0.05 -1.40 0.06 No No Y594* -1.41 0.08 -0.73 0.06 -1.67 0.13 No No Y594T -1.66 0.09 -1.71 0.09 -1.37 0.15 No No Y594W -0.33 0.04 -0.93 0.05 - 1.06 0.10 No No Y594V -0.40 0.04 -0.47 0.04 -0.96 0.08 No No Y595A -1.63 0.05 -1.08 0.04 -2.32 0.10 No No Y595R -1.29 0.04 -1.66 0.05 -2.00 0.06 No No Y595N -1.61 0.14 -0.78 0.10 -0.80 0.19 No No Y595D -1.27 0.09 -1.50 0.09 - 1.84 0.06 No No Y595C -0.14 0.05 -0.50 0.05 -1.06 0.11 No No Y595Q -1.71 0.10 -1.18 0.08 -1.13 0.22 No No Y595E -2.05 0.08 -2.21 0.08 -2.32 0.03 No not a / a / frni ζπζ-ι / υιλι M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? Y595G -1.67 0.03 -1.31 0.03 -1.77 0.03 No No Y595H -0.86 0.09 -0.57 0.08 -0.77 0.13 No No Y595I -1.20 0.14 -1.49 0.15 NA NA Yes No Y595L -0.09 0.04 0 .08 0.04 -0.83 0.12 Yes No Y595K -1.17 0.09 -1.74 0.11 NA NA Yes No Y595M 0.24 0.06 -0.10 0.07 -0.34 0.19 Yes No Y595F -1.21 0.09 -0.70 0.08 -1.09 0.14 No No Y595S -1.31 0.05 -1.19 0.05 -1.64 0 .09 No No Y595* -1.32 0.07 -1.52 0.08 -1.60 0.09 No No Y595T -0.27 0.05 -0.81 0.06 NA NA Yes No Y595W -1.72 0.06 -1.71 0.06 -1.97 0.10 No No Y595V -0.32 0.03 -0.74 0.04 -2.00 0.06 No No D596E 0.04 0.04 0.24 0.04 0.69 0.05 Yes Yes D596A 0.07 0.03 -0.18 0.04 -0.99 0.09 Yes No D596R 0.01 0.03 0.07 0.03 -0.20 0.04 Yes No D596N -0.12 0.08 0.29 0.08 0.39 0.15 Yes No D596C -0.01 0.07 - 0.24 0.07 -0.55 0.06 No No D596Q -0.04 0.09 0.42 0.08 0.46 0.31 Yes No D596G -0.23 0.02 -0.22 0.02 -1.16 0.05 No No D596H 0.24 0.10 -0.18 0.11 0.16 0.26 Yes No D596L -0.92 0.07 -0.10 0.05 -0.75 0.18 No No D596K 0.0 1 0.08 0.36 0.07 -0.07 0.19 Yes No D596M 0.26 0.08 0.29 0.07 -0.27 0.28 Yes No D596F 0.03 0.11 -0.55 0.13 0.09 0.13 Yes No D596P NA NA NA NA -0.56 0.24 Yes No D596S -0.58 0.06 -0.29 0.05 0.37 0.07 Yes No D596* - 0.99 0.11 -1.29 0.12 NA NA Yes No D596T -1.56 0.12 0.65 0.06 -1.10 0.23 Yes No D596W -0.19 0.05 0.12 0.05 -1.34 0.11 Yes No D596Y -0.55 0.09 -0.32 0.08 -0.27 0.16 No No D596V -0.06 0.03 - 0.22 0.03 -1.39 0.08 No No Y597A -2.00 0.06 - 1.33 0.05 -2.10 0.12 No No Y597R -2.18 0.05 -2.13 0.05 -2.18 0.04 No No Y597N -1.28 0.11 -0.66 0.09 -1.35 0.13 No No Y597D -0.30 0.03 -0.28 0.03 - 0.34 0.04 No No Y597C -0.79 0.06 -1.14 0.07 -1.47 0.05 No No Y597E -2.33 0.09 -2.41 0.09 NA NA Yes No Y597G -1.89 0.04 -2.15 0.04 -1.96 0.05 No No Y597H -0.45 0.07 -0.25 0.06 -0.71 0.10 No No Y597I -0.51 0.11 -1.26 0.13 NA NA Yes No Y597L 0.24 0.04 0.32 0.04 -0.31 0.09 Yes No Q2Q / bn / Lznza / YiAi M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? Y597M -0.11 0.07 -1.15 0.10 NA NA Yes No Y597F -0.08 0.07 -0.16 0.07 0.56 0.06 Yes No Y597P -2.03 0.11 -2.30 0.11 NA NA Yes No Y597S -1.25 0.05 -1.04 0. 05 -2.00 0.09 No No Y597* -0.94 0.06 -0.96 0.06 -2.02 0.13 No No Y597T -1.78 0.09 -2.62 0.12 -1.94 0.04 No No Y597W -1.16 0.05 -1.33 0.05 -2.30 0.08 No No Y597V -1.95 0.07 -1.63 0.06 - 2.69 0.08 No No F598A -1.68 0.07 -1.98 0.08 -2.09 0.12 No No F598R -1.81 0.06 -2.21 0.07 -1.57 0.11 No No F598C -1.96 0.12 -2.25 0.13 -1.21 0.15 No No F598G -2.06 0.05 -1.79 0.04 -0.96 0.03 No No F598I -0.32 0.09 -0.44 0.09 - 0.75 0.12 No No F598L -0.25 0.04 -0.09 0.04 -0.65 0.04 No No F598M -0.35 0.09 -0.55 0.09 -0.87 0.27 No No F598P NA NA NA NA -1.93 0.07 Yes No F598S -1.12 0.06 -1.33 0.06 -1.35 0.08 No No F598W -1.23 0.06 -0.34 0.05 -1.74 0.12 No No F598Y -0.52 0.09 -0.44 0.09 -0.60 0.15 No No F598V -1.37 0.06 -1.39 0.05 -2.25 0.09 No No P599G 0.84 0.04 0.83 0.04 1.01 0.05 Yes Yes P599A -1.03 0.07 - 0.85 0.06 -1.42 0.11 No No P599R -1.89 0.09 -1.20 0.06 -2.08 0.14 No No P599N -0.66 0.16 -0.33 0.14 NA NA Yes No P599E -2.04 0.15 -2.07 0.15 NA NA Yes No P 599H -1.01 0.14 -0.99 0.14 NA NA Yes No P599L -1.56 0.09 -1.36 0.08 -1.46 0.11 No No P599S -0.09 0.03 -0.10 0.03 -0.56 0.04 No No P599* -1.14 0.13 -1.42 0.14 NA NA Yes No P599T -0.42 0.07 -0.95 0.08 -1.37 0.14 No No P599V -1.88 0.12 -1.85 0.11 -1.81 0.14 No No □60 OA 0.43 0.06 -0.31 0.07 0.68 0.14 Yes No □600R -0.88 0.07 -0.40 0.06 -1.67 0.19 No No D600N -0.03 0.07 -0.16 0.07 0.67 0.14 Yes No D600C NA NA NA NA -0.32 0.48 Yes No D600Q -0.37 0.15 -0.01 0.13 NA NA Yes No D600E -0.44 0.07 -0.46 0.07 -0.95 0.22 No No □600G -0.19 0.04 -0.33 0.04 1.07 0. 05 Yes No D600H -0.08 0.13 -0.54 0.14 NA NA Yes No D600L -1.26 0.13 -1.19 0.12 -0.50 0.29 No No D600P -0.14 0.11 -1.46 0.16 0.47 0.45 Yes No α^ο / ^η / ίζηζα / γίΛΐ M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? D600S 0.86 0.07 -0.03 0.08 0.74 0.14 Yes No D600T -1.42 0.15 -0.70 0.12 0.43 0.29 Yes No D600W -0.67 0.11 -0.51 0.10 NA NA Yes No D600Y -0.29 0.13 -0 .19 0.12 NA NA Yes No D600V -0.05 0.06 -0.23 0.06 -0.56 0.13 No No A601R -1.65 0.07 -1.62 0.07 NA NA Yes No A601D -1.38 0.13 -1.10 0.11 NA NA Yes No A601C 0.26 0.08 0.26 0.08 -0.25 0.24 Yes No A601G -1.05 0.04 -0.63 0.04 -1.44 0.04 No No A601L -2.16 0.13 -1.44 0.09 NA NA Yes No Α601Ρ -1.40 0.13 -1.20 0.11 NA NA Yes No A601S -0.60 0.06 0.23 0.04 -0.52 0.08 Yes No Α601Τ -0.84 0.08 -0.53 0 .07 -0.99 0.12 No No A601W -1.89 0.12 -1.84 0.11 NA NA Yes No A601V -0.48 0.05 -0.23 0.04 -0.77 0.06 No No A602C 0.64 0.09 0.61 0.09 0.73 0.28 Yes Yes A602R -0.59 0.07 -0.97 0.08 NA NA Yes No A602D 0.04 0.04 -0.09 0.04 -0.40 0.05 Yes No A602G - 0.52 0.05 -0.56 0.05 -1.62 0.06 No No Α602Η NA NA NA NA 0.37 0.35 Yes No A602L -1.97 0.14 -1.06 0.10 NA NA Yes No Α602Ρ -0.80 0.09 -0.42 0.08 -0. 71 0.15 No No A602S -0.38 0.07 -0.14 0.06 - 0.73 0.16 No No Α602Τ -0.28 0.06 -0.03 0.06 -0.51 0.11 No No A602W NA NA NA NA -0.89 0.37 Yes No A602V -0.77 0.06 -0.66 0.05 -1.41 0.10 No No Κ603Α -1.34 0.07 -1.59 0.07 -1.76 0.05 No No K603R -0.56 0.04 -0.37 0.03 -0.46 0.04 No No Κ603Ν -1.59 0.16 -1.11 0.13 NA NA Yes No K603C -1.03 0.10 -1.23 0.10 NA NA Yes No K603Q -1.30 0.11 -1.57 0.12 NA NA Yes No Κ603Ε -1.40 0.07 - 0.68 0.05 -1.60 0.10 No No K603G -1.88 0.05 -1.70 0.04 -1.97 0.08 No No Κ603Η NA NA NA NA -0.51 0.41 Yes No K603L -0.77 0.06 -0.60 0.06 -1.63 0.14 No No Κ603Μ 0.00 0.06 -0.57 0.07 -1.02 0.11 No No Κ603Ρ -1.70 0.12 -1.06 0.09 NA NA Yes No K603S NA NA NA NA -2.06 0.05 Yes No Κ603* -1.20 0.09 -1.66 0.11 -1.37 0.16 No No Κ603Τ -1.11 0.08 -1.1 5 0.08 -1.13 0.13 No No K603W - 2.79 0.14 -1.74 0.09 -1.45 0.14 No No Q / Q / bn / Lznza / YiAi Muffante Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? K603V -1.72 0.07 -1.54 0.06 -2.40 0.07 No No M604A -2.19 0.15 -1.92 0.13 NA NA Yes No M604R -0.96 0.06 -1.76 0.08 -2.02 0.13 No No M604G -2.12 0.08 -0 .82 0.05 -1.81 0.12 No No M604I -0.58 0.10 -0.71 0.10 -0.51 0.15 No No M604L -0.74 0.06 -0.50 0.06 -0.25 0.06 No No M604K -1.08 0.15 -0.78 0.13 NA NA Yes No M604T -0.14 0.06 0.01 0.06 -0 .44 0.09 Yes No M604W -1.97 0.14 -2.03 0.14 NA NA Yes No M604V -1.38 0.08 -1.32 0.07 -1.38 0.09 No No I605A -1.32 0.09 -1.04 0.08 NA NA Yes No I605R -2.07 0.09 -2.36 0.10 -2.12 0.15 No No I605N -0.93 0.10 -0.19 0.08 -0.76 0.16 No No 16050 0.20 0.09 -0.98 0.13 NA NA Yes No I605G -1.69 0.07 -1.41 0.06 -2.04 0.14 No No I605L -0.93 0.07 -0.25 0.06 -1.49 0.14 No No I605M -1.09 0.09 -0.86 0.08 -1.44 0.15 No No I605F -0.50 0.11 -0.52 0.10 NA NA Yes No I605S -1.91 0.11 -1.82 0.10 -1.55 0.10 No No I605T -0.45 0.07 -0.67 0.07 -1.09 0.12 No No I605V 0.13 0.05 -0.04 0.05 -0 .33 0.11 Yes No I605A -1.42 0.10 -0.82 0.08 NA NA Yes No I605R -2.12 0.09 -2.15 0.10 -1.82 0.16 No No I605N 0.04 0.06 0.36 0.06 -0.41 0.09 Yes No I605D -1.00 0.09 -0.60 0.08 -0.72 0.14 No No I605C 0.10 0.10 -0.82 0.13 NA NA Yes No I605G - 1.69 0.07 -1.23 0.06 -1.96 0.13 No No I605L -0.10 0.03 0.14 0.03 -1.00 0.08 Yes No I605M -0.89 0.09 -0.63 0.08 -1.25 0.21 No No I605F -0.55 0.10 - 0.33 0.09 NA NA Yes No I605S -0.22 0.04 0.10 0.04 -1.29 0.08 Yes No I605T -0.02 0.04 0.21 0.04 -0.53 0.07 Yes No I605V 0.19 0.05 0.25 0.05 -0.06 0.10 Yes No P606A -1.59 0.10 -2.27 0.12 -1.25 0.17 No No P606R -1.77 0.08 -2.62 0.12 -1.94 0.15 No No P606G -1.63 0.07 -2.12 0.08 -1.89 0.14 No No P606H -0.89 0.13 -0.93 0.13 NA NA Yes No P606L -0.77 0.07 -1.12 0.08 -1.30 0.15 No No P606S -1.42 0.10 -1 .22 0.09 -1.16 0.14 No No P606T -0.06 0.06 -0.63 0.07 -0.40 0.08 No No P606W -0.88 0.11 -1.05 0.11 NA NA Yes No M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? P606V NA NA NA -1.59 0.24 Yes No P606A -1.59 0.10 -2.27 0.14 -1.33 0.19 No No P606R -1.77 0.09 -1.59 0.08 -1.76 0.15 No No P606Q NA NA NA NA -0.43 0.12 Yes No P606G -1.73 0.08 -2.00 0.09 -1.79 0.16 No No P606H 0.13 0.07 0.17 0.07 -0.14 0.04 Yes No P606L -0.98 0.08 -1.23 0.09 -1.00 0.16 No No P606S -1.64 0.12 -1.35 0.11 -1.37 0.17 No No P606T -0.10 0.07 -0.63 0.08 -0.65 0.11 No No P606W -1.06 0.12 -0.93 0.11 NA NA Yes No P606V NA NA NA -1.33 0.27 Yes No K607A -1.61 0.05 -1.70 0.06 -2.05 0.10 No No K607R -1.65 0.04 -1.32 0.03 -2 .05 0.03 No No K607N -0.51 0.07 -0.19 0.07 NA NA Yes No K607D -2.48 0.14 -1.83 0.11 NA NA Yes No K607C -1.09 0.07 -1.20 0.08 NA NA Yes No K607Q -1.77 0.09 -1.64 0.09 -1.87 0.13 No No K6 07E -1.93 0.06 -1.40 0.05 - 1.61 0.07 No No K607G -1.81 0.03 -1.60 0.03 -1.79 0.03 No No K607H -1.16 0.12 -0.39 0.10 NA NA Yes No K607L -1.08 0.05 -1.66 0.06 -1.63 0.08 No No K607M -0.42 0.06 -1.47 0.08 -0.97 0.05 No No K607F -1.55 0.12 -1.20 0.11 NA NA Yes No K607P NA NA NA NA -1.84 0.14 Yes No K607S -1.89 0.06 -1.43 0.06 -1.53 ​​0.04 No No K607* -1.44 0.07 -0.97 0.06 -1. 20 0.14 No No K607T -2.23 0.09 -1.26 0.06 -1.98 0.11 No No K607W -1.92 0.06 -1.88 0.06 -1.81 0.10 No No K607V -1.80 0.05 -1.85 0.06 -1.86 0.03 No No 060 8A -1.60 0.09 -1.3 2 0.08 -1.81 0.15 No No C608R -0.90 0.04 -0.72 0.04 -1.23 0.09 No No C608E -1.06 0.09 -1.27 0.10 NA NA Yes No C608G -1.44 0.05 -0.58 0.04 -1.66 0.09 No No C608L -1.11 0.08 -0.49 0.07 NA NA Yes No C 608F -1.13 0.12 -0.91 0.12 NA NA Yes No C608P -1.62 0.14 -1.13 0.12 NA NA Yes No C608S -0.62 0.05 -0.49 0.05 -1.56 0.12 No No 0608* -1.61 0.13 -0.66 0.10 NA NA Yes No 060 8W -1.58 0.09 - 1.31 0.08 NA NA Yes No 060 8Y -0.27 0.06 -0.09 0.06 -0.65 0.15 No No C608V -1.32 0.07 -2.23 0.11 NA NA Yes No α^ο / ^η / ίζηζα / γίΛΐ M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? S609A 0.10 0.07 0.21 0.07 -0.16 0.22 Yes No S609R -0.60 0.05 -0.45 0.05 -1.32 0.06 No No S609N -1.18 0.12 -0.49 0.10 NA NA Yes No S609C -0.69 0.12 0 .21 0.09 -0.27 0.25 Yes No S609G 0.00 0.04 -0.27 0.04 -0.17 0.10 No No S609I -0.16 0.12 0.43 0.11 NA NA Yes No S609T -0.76 0.12 0.55 0.09 NA NA Yes No S609W -1.36 0.13 -0.51 0.10 NA NA Yes No Τ610Α -0.40 0.0 5 -0.40 0.05 -0.93 0.09 No No T610R - 1.61 0.07 -0.98 0.06 -1.76 0.15 NO No Τ610Ν -0.27 0.10 -0.20 0.10 -0.58 0.12 No No T610C -0.26 0.09 -0.31 0.09 NA NA Yes No T610Q NA NA NA NA -0.53 0.36 Yes No T610G -1.36 0.05 -1.25 0.05 -1.62 0.12 No No Τ610Ι -0.82 0.11 -0.98 0.12 NA NA Yes No T610L -1.78 0.11 -2.29 0.14 NA NA Yes No Τ610Ρ 0.07 0.04 0.33 0.04 -0.62 0.08 Yes No T610S -0.35 0.06 -0.62 0.06 -0.53 0.07 No No T610V 0.26 0.05 -1.14 0.08 -1.58 0.17 Yes No Q611A -2.61 0.13 -1.23 0.08 -1.40 0.13 No No Q611R -0.68 0.04 -0.69 0.04 -1.33 0.04 No No Q611E -1.22 0.07 - 0.58 0.06 -1.18 0.11 No No Q611G -1.38 0.05 -1.84 0.06 -1.82 0.08 No No Q611H 0.04 0.07 -0.20 0.07 -0.91 0.13 Yes No Q611L -1.21 0.08 -1.74 0.10 -1.67 0.16 No No Q611K -0.93 0.09 -0.83 0.09 - 1.38 0.16 No No Q611P 0.13 0.06 -0.14 0.06 - 0.81 0.08 Yes No Q611S -2.07 0.11 -0.89 0.07 NA NA Yes No Q611* -0.75 0.09 -1.11 0.10 -1.17 0.16 No No Q611W -1.28 0.08 -0.88 0.07 NA NA Yes No Q611V -1.42 0.07 -1.15 0.07 NA NA Yes No L612M 0.70 0.07 0.70 0.07 0.01 0.03 Yes Yes L612A -1.32 0.11 -1.11 0.11 -0.98 0.22 No No L612R 0.03 0.05 0.16 0.05 -0.58 0.11 Yes No L612Q -0.94 0.10 -0.43 0.09 NA NA Yes No L612E -1.18 0.11 -1.65 0.13 NA NA Yes No L612G -0.97 0.07 -2.15 0.11 -1.70 0.17 No No L612I -0.18 0.13 0.66 0.11 -0.24 0.15 Yes No L612K -1.41 0.16 -0.48 0.12 NA NA Yes No L612P -0.34 0. 06 -0.33 0.06 -0.72 0.11 No No L612 * -1.69 0.15 -0.55 0.10 NA NA Yes No Q / Q / frni ζηζ-ΐ / γίΛΐ 100 M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? L612T -0.27 0.09 -1.35 0.13 NA NA Yes No L612V -1.05 0.08 -0.90 0.08 -1.51 0.05 No No K613R -0.22 0.06 -0.18 0.06 -0.40 0.05 No No Κ613Ν 0.04 0.1 0 0.16 0.10 NA NA Yes No K613Q 0.14 0.04 0.38 0.04 NA NA Yes No Κ613Ε -0.75 0.08 0.06 0.07 NA NA Yes No K613G -1.17 0.08 -1.36 0.09 NA NA Yes No K613L 0.12 0.09 0.49 0.09 -0.52 0.26 Yes No Κ613Μ -0.26 0. 11 0.73 0.09 NA NA Yes No Κ613* -0.72 0.11 - 0.72 0.11 NA NA Yes No Κ613Τ 0.26 0.05 0.46 0.05 -0.65 0.08 Yes No K613W -1.27 0.12 -1.60 0.14 NA NA Yes No K613V -0.89 0.10 -0.25 0.08 NA NA Yes No A614 R 0.28 0.04 0.07 0.05 0.16 0.05 Yes Yes Α614Ι 0.52 0.11 0.59 0.11 0.41 0.22 Yes Yes A614D -0.02 0.08 -0.34 0.09 NA NA Yes No A614C -0.54 0.09 -0.12 0.08 0.02 0.22 Yes No A614Q 0.50 0.10 0.17 0.11 NA NA Yes No Α614Ε -0.71 0.08 -0.80 0.09 NA NA Yes No A614G - 0.16 0.03 0.09 0.03 -0.21 0.08 Yes No A614L 0.09 0.06 -0.21 0.06 0.02 0.12 Yes No Α614Κ NA NA NA 0.28 0.38 Yes No Α614Μ -0.39 0.13 1.39 0 .09 NA NA Yes No A614F -0.66 0.14 -0.11 0.12 NA NA Yes No Α614Ρ -0.22 0.09 -0.09 0.09 -0.68 0.25 No No A614S -0.46 0.07 0.19 0.06 -0.55 0.15 Yes No Α614* NA NA NA -0.35 0.32 Yes No Α614Τ 0.03 0.06 0.37 0. 06 -0.49 0.14 Yes No A614W -0.74 0.07 -0.88 0.08 -0.97 0.14 No No A614V 0.17 0.04 0.29 0.04 -0.03 0.11 Yes No V615A -0.05 0.03 0.09 0.03 -0.35 0.04 Yes No V615R -1.73 0.05 -1.23 0.04 -1.21 0.07 No No V615N -0.21 0.08 -1.01 0.11 -0.72 0.15 No No V615D -0.95 0.07 -0.97 0.07 -1.54 0.13 No No V615C -0.18 0.06 -0.18 0.06 -0.01 0.19 No No V615Q -1.87 0.10 -1.41 0.09 NA NA Yes No V615E -0.82 0.04 -0 .59 0.04 -1.03 0.05 No No V615G -0.57 0.03 -0.88 0.03 -1.19 0.04 No No V615I -0.51 0.09 -0.73 0.10 -0.67 0.23 No No V615L -0.07 0.03 0.05 0.03 -0.88 0.05 Yes No V615K -1.22 0.08 -1.81 0.10 -1.56 0.07 No No Q / Q / bn / Lznza / YiAi 101 M uta π te Calif. from enriqu. (1) Std. error (D Enrichment qual. (2) Std. error (2) Enrichment qual. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? V615M -0.52 0.06 -0.54 0.06 -0.54 0.12 No No V615F -1.88 0.14 -1.30 0.12 NA NA Yes No V615P -1.53 ​​0.10 -1.82 0.11 -1.42 0.06 No No V615S 0.17 0.04 -0.23 0.04 -0.63 0.05 Yes No V615* -1.04 0.07 -0.78 0.07 -1.35 0.16 No No V615T 0.19 0.05 -0.12 0.06 -0.07 0.17 Yes No V615W -1.19 0.06 -1.55 0.07 -1.90 0.05 No No Τ616Α 0.32 0.03 0.24 0.04 0.09 0.05 Yes Yes T616R 0. 19 0.03 0.12 0.03 0.62 0.04 Yes Yes T616Q 0.35 0.07 0.38 0.07 0.78 0.20 Yes Yes T616G 0.22 0.03 0.01 0.03 0.16 0.06 Yes Yes Τ616Υ 0.54 0.09 0.64 0.09 0.05 0.38 Yes Yes Τ616Ν -0.11 0.08 0.20 0.08 0.16 0.07 Yes No T616D -0.66 0.08 0.14 0.07 -0.18 0.26 Yes No T616C 0.54 0.06 0.27 0.06 -0.24 0.11 Yes No Τ616Ε -0.28 0.06 -0.38 0.06 -0.17 0.07 No No Τ616Η 0.62 0.08 -0.13 0.10 1.21 0.25 Yes No Τ616Ι -0.33 0.08 0.30 0.07 0.19 0.18 Yes No T616L -0.27 0.05 -0.43 0.05 -0.19 0.13 No No Τ616Κ -0.36 0.08 0.23 0.07 0.66 0.09 Yes No Τ616Μ -0.49 0.08 -0.40 0.08 -0.44 0.25 No No T616F -0.58 0.11 0.07 0.09 0.10 0.36 Yes No Τ616Ρ -0.89 0.07 -0.68 0.07 -0.80 0.06 No No T616S -0.02 0.04 0.12 0.04 0.13 0.07 Yes No Τ616* NA NA NA NA -1.14 0.24 Yes No T616W -0.28 0.05 0.25 0.04 -0.22 0.19 Yes No T616V -0.07 0.04 -0.09 0.04 0.21 0.07 Yes No A617G 0.03 0.03 0.05 0.03 0.24 0.06 Yes Yes A617R -0.10 0.04 0.07 0.04 -0.32 0.11 Yes No Α617Ν NA NA NA 0.12 0.42 Yes No A617D -0.76 0.09 -0.05 0.07 NA NA Yes No A617C -0.73 0.09 0.26 0.07 0.13 0.18 Yes No A617Q 0.25 0.08 0.07 0.09 - 0.48 0.30 Yes No Α617Ε -0.12 0.06 0.08 0.06 -0.40 0.20 Yes No Α617Η -0.11 0.11 -0.46 0.12 NA NA Yes No Α617Ι -0.26 0.11 0.09 0.10 -0.52 0.38 Yes No A617L -0.11 0.05 0.18 0.05 -0.18 0.16 Yes No Α617Κ NA NA NA NA -0.08 0.28 Yes No Α617Μ 0.32 0.07 0.30 0.07 - 0.34 0.27 Yes No A617F -0.17 0.10 -0.39 0.11 -0.42 0.36 No No Α617Ρ -0.48 0.08 -0.88 0.09 0.05 0.18 Yes No Q / Q / frni 7ΠΖ -1 / ΥΙΛΙ 102 M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? A617S -0.13 0.05 0.25 0.05 -0.58 0.06 Yes No A617* -0.96 0.11 -1.57 0.14 NA NA Yes No A617T -0.23 0.05 0.26 0.05 -0.30 0.10 Yes No A617W 0.17 0.05 -0 .93 0.07 -0.69 0.15 Yes No A617V -0.03 0.04 - 0.09 0.04 -0.42 0.12 No No H618A -0.73 0.14 -0.80 0.15 0.36 0.36 Yes No H618R -0.08 0.05 0.24 0.05 -0.46 0.06 Yes No H618N -0.37 0.17 -0.24 0.16 NA NA Yes No H618D 0.48 0.13 0.89 0.12 NA NA Yes No H618Q -0.62 0.14 0.01 0.12 NA NA Yes No H618G -0.56 0.07 -0.91 0.09 -0.91 0.19 No No H618L 0.02 0.06 0.10 0.06 -0.47 0.07 Yes No H618P 0.32 0.08 0.47 0 .08 -0.51 0.08 Yes No H618S -0.50 0.14 -0.26 0.13 NA NA Yes No H618W NA NA NA 0.44 0.31 Yes No H618Y 0.23 0.10 -0.28 0.11 -0.26 0.19 Yes No F619M 0.12 0.07 0.55 0.07 0.22 0.25 Yes Yes F619A -0.57 0.05 -1.25 0.06 -0.78 0.05 No No F619R -1.24 0.05 -1.94 0.07 -0.66 0.07 No No F619N -0.61 0.13 -0.15 0.12 NA NA Yes No F619D -1.39 0.12 -0.62 0.09 NA NA Yes No F619C 0.07 0.03 0.08 0.03 -0.37 0.04 Yes No F619Q -1.13 0.12 -1.57 0.15 NA NA Yes No F619E - 1.58 0.08 -2.40 0.12 -1.54 0.08 No No F619G -1.29 0.03 -1.03 0.03 -1.57 0.05 No No F619H NA NA NA -0.31 0.34 Yes No F619I -0.69 0.12 -0.28 0.11 -0. 42 0.22 No No F619L 0.17 0.03 0.12 0.03 - 0.48 0.05 Yes No F619P -1.00 0.09 -1.22 0.10 NA NA Yes No F619S -0.26 0.04 -0.95 0.06 -0.56 0.06 No No F619* -1.91 0.14 -0.92 0.10 NA NA Yes No F619T NA NA NA NA -1.08 0.24 Yes No F619W -0.08 0.04 -0.81 0.05 0.00 0.07 Yes No F619Y 0.06 0.08 -0.79 0.11 0.28 0.11 Yes No F619V -0.51 0.04 -0.49 0.04 -0.64 0.04 No No Q620A 0.22 0.04 0.00 0.05 0.18 0.09 Yes Yes Q620R 0.25 0.03 0.18 0.03 0.17 0.04 Yes Yes Q620N 0.26 0.14 0.28 0.14 0.36 0.21 Yes Yes Q620L 0.14 0.04 0.45 0.04 0.40 0.16 Yes Yes Q620K 0.10 0.07 0.24 0.07 0.04 0.10 Yes Yes Q620D -0.16 0.07 -0.25 0.08 0.24 0.23 Yes No ayQ / bn / Lznza / YiAi 103 Mutant Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? Q620C -0.22 0.07 -0.95 0.10 0.03 0.23 Yes No Q620E 0.21 0.05 0.13 0.05 -0.09 0.10 Yes No Q620G -0.14 0.02 0.02 0.02 0.19 0.04 Yes No Q620H -0.08 0.08 0.16 0.08 -0.05 0.20 Yes No Q620I 0.27 0.11 -0.38 0.14 NA NA Yes No Q620M 0.70 0.07 -0.03 0.08 0.20 0.26 Yes No Q620F 0.37 0.11 1.00 0.10 -0.47 0.44 Yes No Q620P -0.04 0.06 0.12 0.06 -0.26 0.10 Yes No Q620S 0.1 7 0.05 -0.15 0.06 0.16 0.17 Yes No Q620* -0.82 0.08 -0.58 0.07 -0.64 0.15 No No Q620T -0.20 0.09 0.41 0.08 0.17 0.12 Yes No Q620W -0.12 0.04 0.09 0.04 0.08 0.11 Yes No Q620Y -0.74 0.14 0.21 0.11 -0.19 0.38 Yes No Q620V 0.29 0.03 -0.11 0.04 0.26 0.07 Yes No T621A 0.18 0.04 0.13 0.04 0.17 0.10 Yes Yes T621R -0.04 0.04 -0.45 0.05 -0.06 0.15 No No T621N -0.39 0.12 -0.09 0.11 0.02 0.21 Yes No T621D 0.12 0.12 0.26 0.12 - 0.11 0.44 Yes No T621C 0.07 0.09 -0.29 0.10 NA NA Yes No T621Q -0.90 0.12 0.06 0.10 0.44 0.38 Yes No T621E -0.29 0.07 0.13 0.06 -0.05 0.24 Yes No T621G -0.02 0.03 -0.21 0.04 0.48 0.04 Yes No T621H 0.33 0.15 0.72 0.14 NA NA Yes No T621I 0.36 0.08 -0.09 0.10 0.21 0.20 Yes No T621L 0.16 0.06 -0.40 0.07 -0.30 0.10 Yes No T621K -0.02 0.09 -0.09 0.09 -0.08 0.37 No No T621M 0.21 0.07 -0.15 0.08 1.17 0.09 Yes No T621F -0.61 0.16 -0.16 0.14 NA NA Yes No T621P 0.04 0.04 0.18 0.04 - 0.38 0.06 Yes No T621S -0.06 0.06 -0.08 0.06 0.28 0.09 Yes No T621W -0.21 0.06 0.08 0.06 0.12 0.17 Yes No T621Y -0.23 0.16 0.36 0.14 NA NA Yes No T621V -0.28 0.05 0.32 0.05 0.32 0.19 Yes No H622G 0.05 0.03 0.18 0.03 0.07 0.06 Yes Yes H622S 0.16 0.06 0.59 0.06 0.08 0.10 Yes Yes H622T 0.01 0.09 0.84 0.08 0.31 0.34 Yes Yes H622V 0.18 0.05 0.15 0.05 0.31 0.12 Yes Yes H622A -0.17 0.06 0.16 0.06 0.41 0.08 Yes No H622R -0.19 0.04 0.12 0.04 0.05 0.04 Yes No H622N -0.05 0.07 0.30 0.07 -0.11 0.12 Yes No H622D -0.84 0.11 0.63 0.07 0.48 0.10 Yes No cMQ / bn / Lznza / YiAi 104 M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? H622C -0.50 0.09 -0.10 0.08 0.11 0.11 Yes No H622Q -0.06 0.08 0.29 0.07 -0.14 0.05 Yes No H622E -0.11 0.07 0.15 0.06 0.23 0.10 Yes No H622I -0.05 0.14 0.45 0.13 0.36 0.49 Yes No H622L -0.49 0.06 0.06 0.05 -0.14 0.11 Yes No H622K 0.29 0.10 1.39 0.08 0.00 0.28 Yes No H622M -0.07 0.11 -0.07 0.11 0.05 0.34 Yes No H622F 0.14 0.11 -0.61 0.14 0.07 0.13 Yes No H622 P 0.14 0.03 0.25 0.03 -0.44 0.04 Yes No H622* -1.50 0.13 -1.18 0.12 -0.74 0.16 No No H622W 0.08 0.05 0.21 0.05 -0.08 0.19 Yes No H622Y 0.07 0.09 0.14 0.09 -0.08 0.18 Yes No T623E 0.32 0.05 0.23 0.05 0.02 0.05 Yes Yes T623H 0.60 0.10 0.01 0.11 0.58 0.55 Yes Yes T623L 0.33 0.05 0.18 0.05 0.17 0.16 Yes Yes T623M 0.21 0.07 0.28 0.07 0.59 0.22 Yes Yes T623F 0.80 0.10 0.61 0.10 0.47 0.32 Yes Yes T623A -0.14 0.04 0.35 0.03 -0.04 0.07 Yes No T623 R -0.16 0.03 -0.40 0.04 0.15 0.09 Yes No T623N 0.02 0.09 0.19 0.09 -0.28 0.16 Yes No T623D -0.69 0.09 0.41 0.07 -0.34 0.14 Yes No T623C -0.39 0.08 0.01 0.08 0.40 0.28 Yes No T623Q 0.23 0.07 0.38 0.07 -0.01 0.32 Yes No T623 G -0.40 0.03 -0.09 0.03 -0.05 0.03 No No T623I -0.59 0.10 0.11 0.08 -0.13 0.13 Yes No T623K 1.10 0.07 -0.02 0.08 0.53 0.17 Yes No T623P -0.16 0.06 -0.29 0.07 -0.11 0.17 No No T623S 0.67 0.04 0.21 0.04 - 0.06 0.07 Yes No T623W -0.01 0.05 -0.29 0.06 -0.27 0.10 No No T623Y NA NA NA -0.11 0.29 Yes No T623V -0.26 0.04 -0.20 0.04 0.41 0.05 Yes No T624P 0.92 0.02 0.92 0.02 0.04 0.03 Yes Yes T624A 0.65 0.02 0.76 0 .02 -0.07 0.03 Yes No T624R 0.41 0.07 0.34 0.07 -0.55 0.23 Yes No T624N 0.15 0.10 0.20 0.10 NA NA Yes No T624C -0.20 0.15 0.21 0.14 NA NA Yes No T624E 0.38 0.09 -0.63 0.12 -0.11 0.55 Yes No T624G -0.21 0.06 0.12 0 .06 0.15 0.21 Yes No T624I 0.58 0.11 0.35 0.11 NA NA Yes No T624L 0.41 0.09 -0.84 0.13 0.96 0.48 Yes No T624S 1.15 0.04 1.20 0.04 -0.13 0.04 Yes No Q2Q / bn / Lznza / YiAi 105 M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? T624W 0.56 0.10 -0.20 0.12 0.10 0.16 Yes No T624V -0.12 0.08 -0.52 0.10 0.18 0.23 Yes No Ρ625Α -0.27 0.11 0.30 0.10 0.31 0.10 Yes No P625R 0. 06 0.07 -1.01 0.10 -0.04 0.22 Yes No P625C 0.56 0.14 -0.17 0.16 -0.02 0.82 Yes No Ρ625Ε -0.24 0.13 -0.22 0.13 -0.41 0.64 No No P625G -0.41 0.08 0.40 0.06 0.04 0.24 Yes No Ρ625Η -0.25 0.15 -0.02 0.15 NA NA Yes No P625 L -0.48 0.09 -0.82 0.11 -0.56 0.17 No No P625S - 0.38 0.08 -0.55 0.09 0.03 0.20 Yes No Ρ625Τ 0.30 0.08 0.23 0.08 -0.06 0.10 Yes No P625W -0.60 0.13 -0.64 0.13 NA NA Yes No P625V -0.17 0.09 -0.6 3 0.11 NA NA Yes No Ι626Α 0.16 0.12 0.80 0.11 NA NA Yes No I626R -0.89 0.12 0.14 0.09 -0.09 0.31 Yes No Ι626Ν 0.42 0.04 0.61 0.04 -0.37 0.06 Yes No Ι626Ε NA NA NA NA -0.15 0.55 Yes No I626G -1.04 0.10 -1 .35 0.12 -0.48 0.27 No No I626L 0.61 0.11 -0.85 0.16 NA NA Yes No I626S 0.36 0.04 0.60 0.04 -0.65 0.07 Yes No Ι626Τ 0.17 0.02 0.34 0.02 -0.37 0.03 Yes No I626W -0.74 0.16 0.22 0.13 NA NA Yes No I626V -0.51 0.10 0.05 0.09 0.10 0.18 Yes No L627C 0.14 0.13 0.84 0.11 0.57 0.48 Yes Yes L627A 0.00 0.08 0.24 0.08 1.31 0.29 Yes No L627R 0.29 0.04 0.03 0.04 -0.10 0.05 Yes No L627N 0.71 0.15 1.09 0.15 NA NA Yes No L627D 0.32 0.10 -1.12 0.16 1.13 0.55 Yes No L627Q 0.23 0.07 0.39 0.07 -0.27 0.11 Yes No L627E 0.29 0.07 -0.06 0.08 0.17 0.11 Yes No L627G -0.04 0.04 -0.01 0.04 0.23 0.10 Yes No L627K 0.57 0.11 0.27 0.12 NA NA Yes No L627M -0.57 0.12 0 .33 0.10 -0.09 0.22 Yes No L627P 0.10 0.05 0.31 0.05 -0.25 0.08 Yes No L627S 0.34 0.08 0.18 0.08 -0.29 0.27 Yes No L627* 0.52 0.10 -0.87 0.15 NA NA Yes No L627T 0.60 0.09 -0.76 0.14 NA NA Yes No L627W -0.71 0.09 0.85 0 .07 0.27 0.32 Yes No L627V -0.89 0.08 0.48 0.06 -0.23 0.19 Yes No L628C 0.31 0.09 0.10 0.10 0.29 0.31 Yes Yes L628W 0.25 0.06 0.01 0.07 0.67 0.15 Yes Yes Q / Q / frni 7ηΖ -1 / ΥΙΛΙ 106 Mutant Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? L628A -0.22 0.06 -0.58 0.07 -0.36 0.11 No No L628R -0.13 0.04 -0.50 0.05 0.53 0.06 Yes No L628Q -0.10 0.10 -0.04 0.10 -0.36 0.23 No No L628E -0.73 0.10 -1.59 0.14 NA NA Yes No L628G -0.65 0.04 -1.57 0.06 -0.96 0.14 No No L628I -0.47 0.17 -0.57 0.17 NA NA Yes No L628K 0.75 0.11 -0.44 0.15 -0.21 0.31 Yes No L628M -0.49 0.09 -0.37 0.09 -0.21 0 .12 No No L628P -0.27 0.08 -0.45 0.08 - 0.39 0.14 No No L628S -0.78 0.08 -1.36 0.10 -0.83 0.21 No No L628T -0.16 0.10 -0.52 0.12 -0.60 0.27 No No L628V -0.13 0.05 0.34 0.05 -0.31 0.09 Yes No S629A -0.99 0.12 0.49 0.08 -0.09 0.29 Yes No S629R 0.10 0.02 0.29 0.02 -0.37 0.03 Yes No S629N 0.40 0.05 0.36 0.05 -0.32 0.08 Yes No S629D -0.54 0.18 -0.23 0.17 NA NA Yes No S629C 0.30 0.10 0 .10 0.11 -0.08 0.21 Yes No S629Q 0.76 0.17 0.40 0.18 NA NA Yes No S629E 0.84 0.10 0.61 0.11 -0.08 0.48 Yes No S629G -0.30 0.05 0.40 0.05 0.09 0.08 Yes No S629I 0.05 0.14 0.42 0.13 NA NA Yes No S629L NA NA NA 0.0 3 0.36 Yes No S629K 0.37 0.13 0.80 0.12 NA NA Yes No S629P -0.03 0.15 -0.34 0.17 NA NA Yes No S629T -0.60 0.13 0.01 0.11 0.22 0.32 Yes No S629W -0.03 0.11 -0.66 0.13 0.42 0.54 Yes No S629V -0.87 0.11 -0.82 0.11 0 .05 0.14 Yes No N630R 0.53 0.05 0.06 0.06 0.94 0.08 Yes Yes N630A -0.53 0.09 0.62 0.07 -0.06 0.23 Yes No N630D -0.33 0.09 0.49 0.07 -0.22 0.14 Yes No N630C 0.42 0.10 -0.12 0.12 NA NA Yes No N630E -0.67 0.09 0.69 0 .07 -0.30 0.26 Yes No N630G 0.32 0.04 -0.11 0.04 0.22 0.10 Yes No N630H 0.06 0.10 0.51 0.09 -0.29 0.13 Yes No N630I -0.45 0.12 0.44 0.10 -0.27 0.18 Yes No N630L -0.24 0.09 0.55 0.08 -0.78 0.15 Yes No N630K 0.3 7 0.10 0.93 0.09 -0.25 0.18 Yes No N630F -0.58 0.18 -0.11 0.16 NA NA Yes No N630S 0.34 0.06 -0.21 0.07 0.16 0.13 Yes No N630T 0.16 0.03 0.38 0.02 -0.53 0.04 Yes No N630W -0.11 0.09 -1.04 0.12 NA NA Yes No Q / Q / bn / Lznza / YiAi 107 M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? N630Y -0.24 0.12 0.59 0.10 0.14 0.19 Yes No N630V -0.20 0.06 -0.90 0.08 -0.26 0.18 No No N631A -0.03 0.07 0.06 0.07 -0.70 0.25 Yes No N631R -0.11 0.06 0.27 0.05 1.20 0.07 Yes No N631D -0.56 0.10 -0.38 0.09 -0.77 0.13 No No N631C -0.71 0.15 -0.64 0.15 NA NA Yes No N631E NA NA NA NA -0.95 0.23 Yes No N631G -0.67 0.05 -0.39 0.05 -1.02 0.07 No No N631I 0.31 0.10 -0 .62 0.13 NA NA Yes No N631L - 1.12 0.10 -0.57 0.08 NA NA Yes No N631K -0.05 0.08 -0.20 0.09 0.70 0.11 Yes No N631M -0.10 0.10 0.36 0.09 -0.27 0.30 Yes No N631P 0.06 0.12 0.30 0 .12 NA NA Yes No N631S 0.15 0.06 0.06 0.06 -0.36 0.13 Yes No N631T 0.07 0.04 0.24 0.04 -0.37 0.05 Yes No N631Y -0.48 0.12 -0.03 0.11 NA NA Yes No N631V -0.66 0.07 -1.17 0.08 -0.78 0.23 No No F632A -0.79 0.07 -1 .34 0.09 -1.29 0.12 No No F632R -0.76 0.05 - 0.40 0.05 -0.13 0.05 No No F632D -1.62 0.15 -1.61 0.15 NA NA Yes No F632C 0.66 0.02 0.78 0.02 -0.06 0.02 Yes No F632Q NA NA NA -0.18 0.55 Yes No F632E -1 .35 0.10 -0.87 0.09 NA NA Yes No F632G -0.01 0.03 0.12 0.03 -0.03 0.02 Yes No F632H -0.31 0.16 0.08 0.15 NA NA Yes No F632I -0.33 0.10 -0.01 0.10 -0.87 0.13 No No F632L -0.28 0.05 0.22 0 .05 -0.26 0.07 Yes No F632K -0.49 0.13 0.74 0.10 NA NA Yes No F632M 0.00 0.10 0.16 0.10 NA NA Yes No F632S -0.75 0.06 -0.56 0.06 -0.83 0.06 No No F632* -0.69 0.12 -0.55 0.12 NA NA Yes No F632T -0.09 0.09 -0.8 0 0.12 NA NA Yes No F632W 0.17 0.06 -0.14 0.06 -0.44 0.19 Yes No F632Y -0.15 0.08 0.38 0.07 -0.07 0.10 Yes No F632V 0.38 0.02 0.41 0.02 -0.07 0.02 Yes No I633N 0.16 0.06 0.65 0.06 0.15 0.10 Yes Yes I633M 0.17 0.07 0.28 0.07 0.10 0.19 Yes Yes I633S 0.02 0.04 0.35 0.04 0.22 0.08 Yes Yes I633A 0.15 0.05 -0.24 0.06 0.42 0.13 Yes No I633R -0.42 0.04 0.41 0.04 0.22 0.06 Yes No I633D -0.62 0.09 -0.01 0.08 - 0.12 0.10 No No ayQ / bn / Lznza / YiAi 108 M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? I633C 0.15 0.07 -0.34 0.08 -0.04 0.14 Yes No I633Q -0.26 0.10 1.05 0.08 -0.37 0.22 Yes No I633E -0.98 0.07 -0.34 0.06 0.30 0.11 Yes No I633G -0.09 0.03 0.10 0.03 0.05 0.06 Yes No I633H -0.71 0.14 -0.16 0.13 NA NA Yes No I633L -0.10 0.05 0.00 0.05 0.25 0.06 Yes No I633K -0.29 0.09 0.17 0.08 0.63 0.29 Yes No I633F -0.11 0.09 0.24 0.09 0.51 0.22 Yes No I633P 0.23 0.08 -0.90 0.12 0.19 0.31 Yes No I633* -1.45 0.12 - 1.53 0.13 NA NA Yes No I633T 0.13 0.04 0.40 0.04 -0.17 0.06 Yes No I633W -0.35 0.05 0.14 0.05 -0.07 0.09 Yes No I633Y NA NA NA -0.09 0.34 Yes No I633V 0 .09 0.04 -0.06 0.04 0.39 0.06 Yes No E634N 0.52 0.12 0.46 0.12 0.00 0.36 Yes Yes E634A 0.20 0.02 0.38 0.02 -0.36 0.03 Yes No E634R -0.06 0.04 0.30 0.04 0.33 0.08 Yes No E634D -0.10 0.06 0.30 0.06 0.01 0.10 Yes No E634C -0.12 0.08 -0.30 0.09 0.42 0.13 Yes No E634Q -0.28 0.09 0.79 0.07 0.35 0.10 Yes No E634G -0.12 0.03 0.10 0.02 0.33 0.03 Yes No E634I 0.43 0.13 -0.05 0.15 NA NA Yes No E634L 0.12 0.05 -0.46 0.06 0 .47 0.19 Yes No E634K 0.14 0.06 -0.04 0.07 0.16 0.13 Yes No E634M -0.14 0.08 -0.22 0.08 0.42 0.27 Yes No E634F 0.25 0.14 0.08 0.15 NA NA Yes No E634P -0.23 0.10 -0.95 0.13 NA NA Yes No E634S -0.22 0.06 0.07 0.05 0.30 0. 07 Yes No E634* 0.11 0.03 0.29 0.03 -0.34 0.05 Yes No E634T 0.01 0.09 0.30 0.08 -0.51 0.28 Yes No E634W -0.46 0.06 0.16 0.05 0.45 0.17 Yes No E634V -0.20 0.04 0.26 0.04 0.33 0.08 Yes No P635A 0.04 0.05 0.29 0.05 0.59 0.07 Yes Yes P635D 0.14 0.09 0.49 0.09 0.52 0.14 Yes Yes P635E 0.51 0.06 0.49 0.06 0.70 0.16 Yes Yes P635T 0.36 0.06 0.06 0.06 0.01 0.08 Yes Yes P635R -0.51 0.04 -0.39 0.04 0.24 0.08 Yes No P635N 0.13 0.14 -0.31 0.16 NA NA Yes No P635C -0.65 0.10 -0.70 0.11 0.26 0.25 Yes No P635Q -0.86 0.12 -0.40 0.11 0.43 0.38 Yes No P635G -0.01 0.03 -0.02 0.03 0.15 0.06 Yes No Q2Q / bn / Lznza / YiAi 109 M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? Ρ635Η -0.05 0.10 0.20 0.09 0.22 0.07 Yes No Ρ635Ι NA NA NA NA 0.13 0.37 Yes No P635L -0.02 0.05 -0.33 0.06 0.22 0.10 Yes No Ρ635Κ NA NA NA NA 0.18 0.41 Yes No Ρ635Μ 0.96 0.08 -0.61 0.12 0.06 0.31 Yes No P635F 1.00 0.11 0.14 0.13 NA NA Yes No P635S -0.22 0.06 0.35 0.05 0.02 0.12 Yes No P635W -0.24 0.06 0.25 0.06 -0.12 0.20 Yes No Ρ635Υ -0.31 0.15 -0.0 1 0.14 NA NA Yes No P635V -0.06 0.05 -0.29 0.05 0.44 0.20 Yes No L636A -0.52 0.05 -1.17 0.06 0.08 0.11 Yes No L636R -1.28 0.04 -1.29 0.04 -1.27 0.08 No No L636C -0.14 0.07 -0.19 0.07 -0.07 0.17 No No L636Q -0.25 0.05 -0.09 0.05 -0.16 0.09 No No L636E - 1.02 0.07 -0.96 0.07 -1.27 0.21 No No L636G -1.44 0.04 -1.31 0.04 -1.36 0.06 No No L636I -0.87 0.13 -0.24 0.11 NA NA Yes No L636K -0.17 0.08 -0.33 0 .09 -1.00 0.28 No No L636M -0.40 0.07 - 0.08 0.06 0.16 0.16 Yes No L636F -0.45 0.10 0.29 0.09 NA NA Yes No L636P 0.24 0.05 -0.84 0.06 -0.88 0.11 Yes No L636S -1.62 0.07 -1.47 0.07 -0.73 0 .15 No No L636* -1.09 0.10 -1.51 0.12 NA NA Yes No L636T 0.12 0.06 -2.04 0.13 -0.41 0.09 Yes No L636W -0.55 0.05 -1.36 0.06 -0.68 0.11 No No L636V -0.35 0.04 -0.05 0.03 -0.65 0.08 No No Ε637Α 0 .15 0.04 0.23 0.04 -0.25 0.07 Yes No E637R -0.23 0.07 1.02 0.06 0.18 0.32 Yes No E637D -0.88 0.14 -0.01 0.11 NA NA Yes No E637Q 0.83 0.14 0.47 0.15 NA NA Yes No E637G -0.05 0.04 0.22 0.04 0.06 0.05 Yes No E 637L NA NA NA 0.35 0.32 Yes No Ε637Κ -0.33 0.12 - 0.66 0.13 NA NA Yes No Ε637Μ 0.60 0.15 1.04 0.14 NA NA Yes No E637S 0.23 0.10 -0.55 0.12 0.66 0.39 Yes No Ε637* -0.03 0.09 0.24 0.08 NA NA Yes No E6 37W -0.18 0.10 -0.73 0.12 -0.20 0.34 No No E637V - 0.15 0.07 -0.36 0.07 -0.45 0.10 No No I638R -1.56 0.13 -0.55 0.10 NA NA Yes No Ι638Ν 0.35 0.16 0.42 0.16 -0.63 0.15 Yes No I638C 1.11 0.14 -0.0 5 0.17 NA NA Yes No Q / Q / frni 7ηΖ -1 / ΥΙΛΙ 110 Matante Calif. from enriqu. (1) Std. error (D Enrichment qual. (2) Std. error (2) Enrichment qual. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? I638L NA NA NA NA -0.24 0.30 Yes No I638S 0.04 0.05 0.05 0.05 -0.18 0.05 Yes No I638T -0.43 0.12 -0.42 0.12 -0.14 0.18 No No I638V 0.39 0.07 -0.45 0.08 -0.04 0.13 Yes No T639G 0.52 0.06 0.44 0.06 0.06 0.23 Yes Yes T639A 0.25 0.05 0.47 0.05 -0.34 0.06 Yes No T639R -0.48 0.10 -0.68 0.11 -0.16 0.35 No No T639N 0.03 0.16 -0.02 0.17 NA NA Yes No T639D 0.61 0.17 0.43 0.18 NA NA Yes No T639E 0.71 0.12 0.82 0.12 NA NA Yes No T639I 0.17 0.13 -0.19 0.14 NA NA Yes No T639L -0.28 0.15 -0.39 0.16 NA NA Yes No T639P -0.10 0.12 0.08 0.12 -0.21 0.22 Yes No T639S 0.07 0.07 0.09 0.07 -0.53 0.12 Yes No T639V 0.75 0. 09 -1.09 0.14 0.78 0.28 Yes No K640A -0.31 0.07 - 0.59 0.07 0.20 0.26 Yes No K640R -0.15 0.04 0.07 0.04 0.01 0.11 Yes No K640N 0.07 0.03 0.32 0.03 -0.43 0.05 Yes No K640D -0.14 0.09 -0.73 0.11 - 0.52 0.30 No No K640C 0.06 0.08 0.34 0.08 -0.51 0.27 Yes No K640Q - 0.86 0.12 0.36 0.09 0.29 0.31 Yes No K640E -0.30 0.06 0.08 0.06 -0.03 0.15 Yes No K640G -0.26 0.04 -0.59 0.04 -0.48 0.12 No No K640H 0.81 0.12 - 0.26 0.15 NA NA Yes No K640I -0.10 0.12 -0.11 0.12 NA NA Yes No K640L 0.21 0.06 0.05 0.06 -0.31 0.20 Yes No K640M -1.04 0.15 0.36 0.10 -0.12 0.31 Yes No K640F 0.24 0.12 -0.13 0.13 NA NA Yes No K640P 0.40 0.09 0.14 0.10 -0.03 0.55 Yes No K640S -0.60 0.07 0.52 0.06 - 0.11 0.22 Yes No K640* -0.85 0.10 -0.19 0.09 -0.96 0.21 No No K640T 0.10 0.03 0.35 0.03 -0.52 0.06 Yes No K640W -0.53 0.07 0.41 0.06 0.12 0.25 Yes No K640Y -0.76 0.15 -0.28 0.14 0.36 0.37 Yes No K640V - 0.26 0.05 -0.56 0.05 0.05 0.11 Yes No D840S 0.37 0.08 0.33 0.08 0.10 0.16 Yes Yes D840A -0.07 0.07 0.40 0.06 0.18 0.13 Yes No □840R -0.03 0. 05 0.09 0.05 0.10 0.33 Yes No D840N -0.64 0.12 -0.31 0.11 -0.04 0.16 No No D840C 0.62 0.12 -1.20 0.16 0.07 0.48 Yes No D840Q -0.22 0.14 -0.03 0.13 0.34 NA Yes No Q2Q / bn / Lznza / YiAi 111 M uta π te Calif. from enriqu. (1) Std. error (D Enrichment qual. (2) Std. error (2) Enrichment qual. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? D840E 0.32 0.07 -0.07 0.07 0.08 0.06 Yes No D840G 0.21 0.04 -0.26 0.04 0.02 0.05 Yes No D840L -0.64 0.10 -0.25 0.09 -0.27 0.82 No No D840K 0.13 0.13 0.33 0.12 -0.03 0.82 Yes No D840M NA NA NA NA -0.30 0.13 Yes No D840P -0.09 0.12 -0.12 0.12 0.11 0.82 Yes No D840T -1.14 0.14 0.11 0.10 0.29 0.15 Yes No D840W -0.33 0.09 0.05 0.08 -0.39 0.19 Yes No D840Y 0.13 0.08 0.11 0.08 -0.18 0.11 Yes No D840V 0.16 0.06 -0.03 0.06 -0.10 0.07 Yes No E841A -0.26 0.06 -0.54 0.06 0.08 0.08 Yes No E841R -0.66 0.06 -0.57 0.05 -0.18 0.10 No No E841N 0.04 0.14 -0.53 0.15 -0.14 0.48 Yes No E841D -0.33 0.09 -0.04 0.08 0.12 0.15 Yes No E841C -0.43 0.13 -0.39 0.12 -0.46 0.16 No No E841Q -0.64 0.12 -0.41 0.11 0.21 0.14 Yes No E841G 0.21 0.04 -0.11 0.04 -0.04 0.04 Yes No E841H -0.71 0.18 -0.82 0.18 NA NA Yes No E841L -1.39 0.10 -0.35 0.07 -0.41 0.06 No No E841K - 0.55 0.09 -0.26 0.09 -0.34 0.17 No No E841M -1.21 0.14 -0.41 0.11 -0.24 0.54 No No E841P -0.22 0.11 -0.23 0.11 0.00 0.08 No No E841S -0.16 0.07 - 0.22 0.07 0.04 0.10 Yes No E841* -0.19 0.06 - 0.19 0.06 0.07 0.03 Yes No E841T 0.40 0.09 -0.59 0.10 -0.27 0.19 Yes No E841W -1.06 0.09 -1.15 0.09 -1.11 0.33 No No E841V -0.99 0.07 -0.68 0.06 - 0.53 0.08 No No A842S 0.36 0.06 0.08 0.06 0.04 0.10 Yes Yes A842R -2.56 0.11 -1.06 0.06 -1.25 0.15 No No A842D -0.37 0.11 -1.49 0.15 -1.07 0.19 No No A842C 0.15 0.10 -0.39 0.11 -0.26 0.13 Yes No A842E NA NA NA NA -1.19 0.12 Yes No A842G -0.18 0.04 - 0.18 0.04 -0.09 0.04 No No A842L -1.71 0.11 -1.29 0.09 -1.19 0.33 No No A842K -0.53 0.13 -1.41 0.16 NA NA Yes No A842P -0.87 0.10 -0.94 0.10 NA NA Yes No A 842T -1.47 0.11 -0.57 0.08 -1.03 0.10 No No A842W -1.87 0.12 -1.92 0.12 -1.46 0.40 No No A842V -1.40 0.08 -0.77 0.06 -1.17 0.20 No No R843A -0.28 0.10 0.30 0.09 0.15 0.11 Yes No R843 E -1.03 0.17 -1.31 0.17 0.09 0.64 Yes No ayQ / bn / Lznza / YiAi 112 Mufante Calif. from enriqu. (1) Std. error (D Enrichment qual. (2) Std. error (2) Enrichment qual. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? R843G 0.18 0.05 -0.37 0.06 -0.43 0.07 Yes No R843L -0.31 0.13 -0.08 0.12 -0.05 0.30 No No R843K -0.16 0.13 0.01 0.12 0.45 0.16 Yes No R843M NA NA NA 0.26 0.83 Yes No R843S -0.08 0.07 0.08 0.07 -0.08 0.10 Yes No R843* -0.64 0.17 - 0.23 0.15 NA NA Yes No R843T NA NA NA -0.19 0.30 Yes No R843W -0.99 0.15 0.22 0.12 -0.55 0.14 Yes No R843V -0.09 0.10 -0.23 0.10 0.04 0.17 Yes No A844E 0 .38 0.10 0.06 0.10 0.13 0.21 Yes Yes A844R 0.45 0.07 -0.04 0.07 0.03 0.37 Yes No A844D NA NA NA 0.36 0.11 Yes No A844C NA NA NA NA 0.02 0.19 Yes No A844Q -0.26 0.18 0.84 0.15 -0.11 0.44 Yes No A844G -0.48 0. 06 -0.26 0.05 -0.01 0.06 No No A844L 0.54 0.10 -0.25 0.11 0.18 0.14 Yes No A844K NA NA NA 0.14 0.27 Yes No A844M NA NA NA NA 0.23 0.41 Yes No A844P 0.28 0.11 -1.04 0.14 -0.72 0.25 Yes No A844S -0. 22 0.08 -0.06 0.07 0.17 0.10 Yes No A844T - 0.37 0.11 -0.05 0.10 0.22 0.21 Yes No A844W -1.01 0.13 -0.64 0.11 -0.10 NA No No A844V -0.19 0.08 0.12 0.07 0.06 0.08 Yes No L845A -0.70 0.08 -0.2 3 0.07 -0.59 0.11 No No L845R -2.01 0.10 -1.83 0.09 -1.29 0.05 No No L845C -0.27 0.14 -0.84 0.15 -0.37 0.82 No No L845Q NA NA NA NA -0.49 0.25 Yes No L845E -0.93 0.12 -1.26 0.13 -0.79 0.48 No No L845G -1.31 0.06 -1.09 0.06 -1.46 0.20 No No L845K -0.17 0.18 0.03 0.17 NA NA Yes No L845M -0.15 0.12 -0.17 0.12 -0.20 0.25 No No L845P -0.64 0.10 -0.71 0.10 -0.61 0.11 No No L845S -1.48 0.13 - 0.91 0.10 -0.82 0.35 No No L845T -0.85 0.14 0.43 0.11 NA NA Yes No L845W -0.12 0.08 -1.89 0.13 -0.47 0.33 No No L845V -0.31 0.06 -0.80 0.07 -0.20 0.10 No No L846A -1.10 0.08 -0.78 0.07 -0 .78 0.82 No No L846R -0.86 0.06 -0.85 0.05 -1.09 0.11 No No L846C -1.57 0.15 -1.32 0.13 -0.93 0.14 No No L846Q -1.21 0.15 -0.87 0.13 -0.99 0.27 No No L846E -0.34 0.08 -0.41 0.08 -0.71 0.17 No not 113 M uta π te Calif. from enriqu. (1) Std. error (D Enrichment qual. (2) Std. error (2) Enrichment qual. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? L846G -1.11 0.05 -0.81 0.05 -1.29 0.15 No No L846I NA NA NA 0.11 0.49 Yes No L846M -0.29 0.09 0.19 0.08 -0.28 0.13 Yes No L846F -0.48 0.14 -0.27 0.13 NA NA Yes No L846P -1.04 0.10 -0.74 0 .09 -0.74 0.13 No No L846S -0.77 0.09 -0.24 0.08 -1.23 0.37 No No L846T -0.74 0.12 -1.37 0.14 -0.56 0.12 No No L846W -1.13 0.09 -0.51 0.08 -0.35 0.06 No No L846Y -0.02 0.16 -0.98 0.19 NA NA Yes No L846V -1.23 0.07 -0.61 0.06 -0.40 0.06 No No P847A 0.24 0.11 -1.48 0.16 NA NA Yes No P847R -0.47 0.09 -0.88 0.10 -1.09 0.26 No No P847G -0.32 0.07 -1.12 0.08 -0.48 0.43 No No P847H -0.24 0.18 -0.19 0.17 -0.10 0.18 No No P847L -1.09 0.12 -0.92 0.11 -0.76 0.15 No No P847S -0.42 0.11 -0.55 0.11 -0.76 0.23 No No P847T -0.69 0.19 -0.89 0.19 NA NA Yes No P847V -0.31 0.12 - 1.08 0.14 NA NA Yes No N848A -0.53 0.11 0.02 0.10 0.14 0.43 Yes No N848R -0.30 0.07 -0.60 0.07 -0.35 0.10 No No N848D 0.06 0.11 -0.08 0.11 -0.13 0.15 Yes No N848C -0.16 0.14 -0.15 0.14 -0.31 NA No No N848Q -0.31 0.18 -0.55 0.19 NA NA Yes No N848E -0.64 0.11 0.35 0.09 0.48 0.09 Yes No N848G -0.87 0.07 -0.40 0.06 -0.33 0.11 No No N848H -0.07 0.05 0.05 0.05 -0.06 0.05 Yes No N848I 0 .00 0.17 -0.09 0.17 NA NA Yes No N848L 0.08 0.10 - 1.50 0.14 -0.10 NA Yes No N848K -0.25 0.14 -0.45 0.14 -0.20 0.19 No No N848M NA NA NA NA 0.10 0.64 Yes No N848S -0.89 0.10 -0.37 0.08 -0.30 0.16 No No N848 T 0.37 0.12 -0.11 0.12 -0.17 0.11 Yes No N848W -0.76 0.12 -0.04 0.10 0.22 0.40 Yes No N848Y -0.61 0.18 0.16 0.16 -0.20 0.24 Yes No N848V -0.51 0.09 -0.84 0.10 -0.29 0.64 No No V849A -0.93 0.12 0.41 0.09 -0.39 0.18 Yes No V849R -1.79 0.16 -1.96 0.16 -1.01 0.29 No No V849G -1.07 0.08 -1.40 0.08 -1.48 0.05 No No V849L 0.90 0.09 -0.43 0.11 -0.12 0.13 Yes No V849M -0.12 0.12 -0.31 0.12 - 0.19 0.19 No No I850A 0.25 0.05 -0.76 0.06 - 0.17 0.06 Yes No a / a / frni ζπζ-ι / υιλι 114 M uta π te Calif. from enriqu. (1) Std. error (D Enrichment qual. (2) Std. error (2) Enrichment qual. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? I850R -0.32 0.04 -0.27 0.04 -0.21 0.06 No No I850N -0.38 0.13 -0.44 0.13 -0.50 0.10 No No I850D -1.19 0.12 -0.73 0.10 -0.71 0.54 No No I850C -0.30 0.08 0.19 0.08 0.13 0.14 Yes No I850 Q -0.08 0.11 -0.31 0.11 0.00 0.43 No No I850E - 0.24 0.07 -0.45 0.07 -0.35 0.25 No No I850G -0.90 0.04 -0.86 0.04 -0.96 0.06 No No I850H 0.45 0.12 -0.44 0.13 -0.29 0.54 Yes No I850L -0.15 0.04 - 0.17 0.04 -0.26 0.05 No No I850K -1.20 0.13 - 0.19 0.10 -0.01 0.82 NO No I850M -0.83 0.09 -0.82 0.09 -0.28 0.18 No No I850F -0.83 0.11 -0.97 0.11 -0.61 0.17 No No I850P -0.43 0.09 -1.72 0.12 - 1.01 0.12 No No I850S -0.42 0.06 -0.18 0.05 -0.52 0.06 No No I850T 0.00 0.07 -0.22 0.07 0.06 0.07 Yes No I850W -1.02 0.07 -1.26 0.08 -0.97 0.10 No No I850V -0.03 0.04 0.12 0.04 0.22 0.05 Yes No T851A 0.41 0.06 0.14 0.06 0.08 0.10 Yes Yes T851V 0.32 0.06 0.13 0.06 0.54 0.07 Yes Yes T851R -0.18 0.06 -0.82 0.06 -0.93 0.17 No No T851C 0.00 0.14 -0.03 0.14 -0.11 0.82 No No T851Q NA NA NA NA -0.17 0.29 Yes No T851E - 0.44 0.09 -0.88 0.10 -0.08 0.08 No No T851G -1.22 0.06 -0.82 0.05 -0.95 0.19 No No T851I 0.21 0.13 -0.17 0.13 0.20 0.20 Yes No T851L 0.35 0.08 0.01 0.09 -0.05 0.37 Yes No T851K -0.23 0.14 -0.49 0.14 NA NA Yes No T851M 0.52 0.11 -0.71 0.14 - 0.02 0.23 Yes No T851F -0.32 0.18 0.44 0.16 0.28 NA Yes No T851P -0.06 0.04 0.04 0.04 0.03 0.05 Yes No T851S -0.01 0.07 -0.04 0.07 -0.08 0.13 No No T8 51W 0.07 0.09 -0.34 0.09 -0.01 0.48 Yes No K852A -1.49 0.14 -1.41 0.13 NA NA Yes No K852R -0.07 0.06 -0.48 0.07 -0.37 0.10 No No K852N 0.12 0.10 -0.39 0.11 0.01 0.08 Yes No K852Q -0.04 0.05 0.10 0.04 0 .14 0.06 Yes No K852E -0.99 0.12 -0.80 0.11 -1.03 0.07 No No K852G -1.42 0.09 -2.60 0.13 -1.20 0.18 No No K852P -0.25 0.07 -0.24 0.07 -0.22 0.08 No No K852S -1.14 0.13 -0.56 0.10 -0.56 0.48 No No K852* -0.9 8 0.15 -1.24 0.16 NA NA Yes No cpcufrn / Lznza / YiAi 115 Muffante Calif. from enriqu. (1) Std. error (D Enrichment qual. (2) Std. error (2) Enrichment qual. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? K852T -0.16 0.03 -0.02 0.03 0.16 0.04 Yes No K852V -0.65 0.09 -0.18 0.08 -0.78 0.48 No No E853V 0.14 0.07 0.10 0.07 0.38 0.09 Yes Yes E853A -0.49 0.08 -0.35 0.08 -0.05 0.09 No No E853R 0.2 3 0.06 -0.13 0.06 -0.20 0.31 Yes No E853D -0.30 0.10 -0.26 0.10 0.42 0.18 Yes No E853C 0.07 0.11 0.12 0.11 -0.24 0.13 Yes No E853Q -0.55 0.17 0.09 0.14 0.17 0.31 Yes No E853G -0.18 0.04 -0.41 0.05 - 0.47 0.07 No No E853L -0.85 0.10 0.03 0.08 0.08 0.08 Yes No E853K 0.05 0.12 -0.95 0.15 0.21 0.20 Yes No E853M -0.08 0.15 -0.94 0.17 0.01 0.11 Yes No E853P 0.46 0.13 -0.02 0.14 0.28 0.40 Yes No E853S -0.30 0.09 - 0.41 0.09 0.07 0.15 Yes No E853* -0.52 0.09 -0.38 0.09 - 0.25 0.08 No No E853T -0.33 0.15 -0.61 0.15 0.57 0.25 Yes No E853W 0.25 0.08 -1.68 0.12 -0.52 0.14 Yes No V854A -0.95 0.08 -0.31 0.06 -0.94 0.15 No No V854R -1.42 0.07 -1.14 0.06 -1.31 0.13 No No V854D -0.58 0.13 -1.22 0.15 NA NA Yes No V854C -0.91 0.13 -0.17 0.11 -0.54 0.35 No No V854E -1.32 0.11 -1.01 0.09 -1.15 0.18 No No V854G -1.40 0.06 -1 .44 0.06 -1.28 0.09 No No V854L -1.49 0.10 -0.60 0.07 -1.28 0.13 No No V854M -1.32 0.13 -1.02 0.11 -0.94 0.16 No No V854P -1.29 0.16 -1.22 0.15 NA NA Yes No V854S -1.58 0.12 -0.89 0.09 -1 .26 0.21 No No V854W -1.48 0.10 -0.37 0.07 -1.34 0.06 No No S855A 0.70 0.10 -0.77 0.12 0.01 0.40 Yes No S855R 0.40 0.10 -0.66 0.11 0.61 0.12 Yes No S855C -0.24 0.17 0.37 0.15 NA NA Yes No S855G 0.01 0.07 -0.69 0.08 -0.49 0.48 Yes No S855L NA NA NA NA -0.20 0.82 Yes No S855F -0.02 0.17 0.31 0.16 NA NA Yes No S855P -0.31 0.12 0.14 0.10 -0.08 0.16 Yes No S855T 0.53 0.13 -0.42 0.15 0.41 0.24 Yes No Y 855Y NA NA NA 0.21 0.29 Yes No S855V 0.17 0.13 0.00 0.14 0.24 0.82 Yes No H856R -0.04 0.07 -0.29 0.07 -0.62 0.16 No No H856N -1.01 0.17 -0.62 0.15 NA NA Yes No H856E -0.49 0.12 -0.23 0.11 NA NA Yes No 116 Muffante Calif. from enriqu. (1) Std. error (D Enrichment qual. (2) Std. error (2) Enrichment qual. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? H856G -0.96 0.07 -1.35 0.07 -1.43 0.08 No No H856L -0.83 0.12 -0.29 0.10 -0.42 0.20 No No H856P -0.26 0.09 0.07 0.09 -0.29 0.09 Yes No H856S -1.39 0.17 -0.13 0.12 NA NA Yes No H856W NA NA NA NA -0.62 0.17 Yes No H856Y -0.65 0.16 -0.05 0.13 0.50 0.20 Yes No H856V NA NA NA -0.60 0.21 Yes No E857A -0.23 0.05 -0.30 0.05 -0.51 0.06 No No E857R -0.92 0.06 -1.30 0.06 -1.05 0. 13 No No E857D 0.50 0.09 -0.31 0.10 -1.09 0.21 Yes No E857C -0.44 0.13 -1.14 0.15 -0.59 0.40 No No E857Q -0.89 0.14 -1.04 0.14 -0.73 0.29 No No E857G -0.98 0.04 -0.90 0.04 -1.19 0.03 No No E857 L -0.09 0.08 -0.75 0.09 -0.99 0.22 No No E857K 0.23 0.09 -0.93 0.11 -0.76 0.14 Yes No E857M -0.36 0.13 -0.31 0.12 NA NA Yes No E857P -0.10 0.11 -0.53 0.12 -0.58 0.54 No No E857S -0.17 0.08 - 0.67 0.08 -0.71 0.16 No No E857* - 1.28 0.15 -0.53 0.12 NA NA Yes No E857T -1.10 0.14 0.08 0.10 -0.09 0.54 Yes No E857W -0.75 0.08 -1.02 0.08 -1.03 0.15 No No E857V -0.10 0.05 -0.43 0 .05 -0.29 0.08 No No I858R -1.30 0.11 -1.37 0.10 -1.32 0.24 No No I858G -2.03 0.11 -0.89 0.07 -1.33 0.09 No No I858L -0.32 0.08 -0.64 0.08 -0.25 0.08 No No I858F -0.53 0.17 -0.64 0.17 NA NA Yes No I858S -1.55 0.16 -0.66 0.12 NA NA Yes No I858T -0.49 0.13 -0.72 0.13 -0.26 0.20 No No I858V -0.43 0.08 -0.43 0.08 -0.69 0.11 No No I859A -2.25 0.14 -1.44 0.10 -0.96 0.35 No No I859R -1.4 6 0.08 -1.27 0.07 -1.13 0.07 No No I859N -0.63 0.17 -0.59 0.16 -0.31 0.21 No No I859D -1.17 0.15 -1.53 ​​0.16 NA NA Yes No I859Q -0.35 0.17 0.41 0.15 NA NA Yes No I859E -0.25 0.09 -0.09 0. 08 -0.48 0.11 No No I859G -1.65 0.07 - 1.30 0.06 -1.32 0.22 No No I859L -0.20 0.04 -0.01 0.04 -0.26 0.04 No No I859M -0.66 0.12 0.38 0.10 -0.64 0.11 Yes No I859F -0.18 0.12 -0.15 0.12 - 0.59 0.12 No No I859S -0.34 0.08 -1.05 0.09 - 1.12 0.17 No No I859T -0.26 0.09 -0.27 0.09 -0.35 0.15 No No 117 M uta π te Calif. from enriqu. (1) Std. error (D Enrichment qual. (2) Std. error (2) Enrichment qual. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? I859W -1.84 0.15 -0.31 0.09 -0.74 0.64 No No I859V 0.30 0.04 -0.13 0.05 0.24 0.05 Yes No Κ860Α -0.50 0.06 -0.35 0.06 -1.06 0.07 No No K860R -0.39 0.05 -0.83 0.05 -0.83 0.10 No No Κ860Ν -0.63 0.12 -1.47 0.14 -0.88 0.16 No No K860C -0.36 0.10 -0.81 0.11 NA NA Yes No K860Q -0.18 0.04 -0.19 0.04 -0.15 0.06 No No Κ860Ε -0.89 0.06 -1.15 0.07 -1.08 0.05 No No K860G -1.23 0.05 -1.2 2 0.05 -1.28 0.06 No No K860L -0.68 0.07 -1.58 0.09 -1.19 0.11 No No Κ860Μ -0.24 0.09 -0.56 0.09 -1.00 0.15 No No Κ860Ρ -0.21 0.07 -0.49 0.07 -0.50 0.09 No No K860S -1.38 0.08 -1.80 0.09 -1.30 0.07 No No Κ860* -1.43 0.12 - 1.23 0.11 -1.17 0.16 No No Κ860Τ -0.15 0.04 -0.15 0.04 -0.07 0.06 No No K860W -1.18 0.08 -1.46 0.09 -1.24 0.09 No No K860V -0.88 0.06 -1.87 0. 08 -1.03 0.04 No No D861A -0.47 0.05 -0.76 0.06 -1.12 0.11 No No D861R -1.43 0.06 -1.83 0.06 -1.24 0.09 No No D861N -0.46 0.10 -0.59 0.10 -0.60 0.17 No No D861C -0.40 0.08 -0.50 0.08 -0.69 0.08 No No D861Q -0.65 0.11 0.09 0.09 NA NA Yes No D861E -0.97 0.07 -0.89 0.06 -0.50 0.12 No No D861G -0.85 0.03 -1.00 0.03 -1.03 0.03 No No D861H 0.92 0.12 -0.60 0.15 -0.36 0.21 Yes No D861L -0.37 0.07 0.09 0.06 -0.18 0.27 Yes No D861K 0.55 0.09 -1.49 0.13 -1.22 0.43 Yes No D861M -0.29 0.10 -0.57 0.10 -0.68 0.40 No No D861F -1.05 0.15 -0.55 0.13 -0.22 0.12 No No D861S -1.43 0.09 -1.60 0.09 - 1.45 0.28 No No D861W -0.88 0.07 -0.84 0.07 -0.15 0.08 No No □861Y -0.18 0.17 0.14 0.16 -0.35 0.14 Yes No □861V -1.18 0.06 -0.99 0.05 -1.28 0.12 No No R862K 0.04 0.14 0.54 0.13 0.02 0.38 Yes Yes R862A -1.76 0.13 -0.42 0.08 -0.71 0.31 No No R862C -0.64 0.12 -1.78 0.16 -0.65 0.28 No No R862Q -0.27 0.10 -0.07 0.09 -0.28 0.13 No No R862E -0.64 0.12 -1.63 0.15 -0.76 0.09 No No R862G -0.7 2 0.05 -0.83 0.05 -0.85 0.07 No No R862L -0.90 0.08 -0.16 0.07 -0.39 0.09 No No R862M -1.06 0.17 -0.69 0.15 NA NA Yes No Q / Q / frni ζηζ-ΐ / γίΛΐ 118 M uta π te Calif. from enriqu. (1) Std. error (D Enrichment qual. (2) Std. error (2) Enrichment qual. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? R862P -1.33 0.17 -1.10 0.15 NA NA Yes No R862W -1.35 0.11 -0.91 0.09 -1.10 0.14 No No R862V NA NA NA -1.61 0.43 Yes No R863Q -0.49 0.13 -0.79 0.14 NA NA Yes No R863G -1.68 0.09 -1.14 0.07 -1 .45 0.07 No No R863L -1.18 0.15 -1.68 0.17 -1.02 0.13 No No R863W -1.27 0.11 -1.06 0.10 -1.17 0.14 No No F864I -0.25 0.11 -0.08 0.11 -0.19 0.12 No No F864L 0.01 0.07 -0.06 0.07 0.06 0.08 Yes No F864S -0.34 0.14 -0.27 0.14 -0.35 0.17 No No F864W -0.66 0.18 -0.77 0.18 NA NA Yes No F864V -0.11 0.06 -0.13 0.05 0.00 0.08 No No Τ865Α -0.65 0.14 -0.29 0.12 -0.09 0.18 No No Τ865Ν 0.07 0.03 -0.05 0.03 -0.15 0.04 Yes No Τ865Ι -0.01 0.10 0.20 0.09 0.20 0.13 Yes No T865L NA NA NA NA 0.57 0.29 Yes No Τ865Ρ -0.10 0.05 -0.07 0.05 -0.01 0.06 No No T865S -0.20 0.02 -0 .20 0.02 0.01 0.03 Yes No Τ865Υ -0.16 0.06 -0.17 0.05 - 0.16 0.10 No No S866F 0.00 0.13 0.06 0.12 0.10 0.14 Yes Yes S866T 0.05 0.13 0.02 0.13 0.40 0.15 Yes Yes S866A -0.10 0.09 -0.40 0.10 0.05 0.07 Yes No S866R NA NA NA -0.33 0.09 Yes No S866D NA NA NA NA 0.02 0.24 Yes No S866C NA NA NA -0.05 0.43 Yes No S866Q NA NA NA -0.04 0.27 Yes No S866E NA NA NA 0.58 0.22 Yes No S866G NA NA NA NA -0.97 0.29 Yes No S866L NA NA NA 0.57 0 .10 Yes No S866M NA NA NA 0.85 0.14 Yes No S866P 0.08 0.03 -0.07 0.03 0.00 0.03 Yes No S866W NA NA NA -0.67 0.37 Yes No S866Y 0.13 0.16 -0.17 0.17 0.03 0.11 Yes No S866V NA NA NA 1.00 0.08 Yes No D867A 0.05 0.02 -0.05 0.02 -0.05 0.02 Yes No D867R NA NA NA -1.39 0.06 Yes No D867N NA NA NA NA -0.17 0.14 Yes No □867C NA NA NA NA -0.98 0.17 Yes No D867E -0.16 0.11 -0 .21 0.11 -0.99 0.09 No No D867G 0.06 0.02 0.00 0.02 -0.11 0.02 Yes No D867H -0.04 0.09 0.11 0.08 NA NA Yes No Q / Q / bn / Lznza / YiAi 119 M uta π te Calif. from enriqu. (1) Std. error (D Enrichment Score (2) Std Error (2) Enrichment Score (3) Std Error (3) Any positive enrichment? Constant positive enrichment? D867S NA NA NA NA -0.98 0.09 Yes No D867W NA NA NA -1.25 0.13 Yes No D867Y NA NA NA -1.02 0.12 Yes No D867V -0.04 0.10 -0.07 0.10 -0.92 0.07 No No K868A NA NA NA -1.23 0.28 Yes No K868R -0.0 1 0.02 0.02 0.02 - 0.76 0.04 Yes No K868N NA NA NA -1.00 0.11 Yes No K868Q -0.14 0.09 -0.02 0.09 -0.11 0.08 No No K868E -0.43 0.19 -0.52 0.19 -1.33 0.19 No No K868G NA NA NA NA -1.49 0.08 Yes No K868P NA NA NA NA -1.00 0.09 Yes No K868S NA NA NA -1.32 0.15 Yes No K868* NA NA NA -1.02 0.18 Yes No K868T -0.15 0.03 -0.12 0.03 -0.14 0.07 No No K868W NA NA NA NA -1.5 0 0.15 Yes No K868V NA NA NA -1.12 0.16 Yes No F869A NA NA NA -1.10 0.15 Yes No F869R NA NA NA NA -1.47 0.27 Yes No F869C NA NA NA NA -1.20 0.15 Yes No F869E NA NA NA -1.41 0. 09 yes No F869G NA NA NA -1.40 0.04 Yes No F869I 0.06 0.10 -0.10 0.10 0.04 0.09 Yes No F869L -0.16 0.03 -0.17 0.03 -0.01 0.06 No No F869M NA NA NA NA 0.14 0.0 9 Yes No F869S NA NA NA NA -1.16 0.09 Yes No F869W NA NA NA -1.32 0.12 Yes No F869Y NA NA NA -0.21 0.24 Yes No F869V -0.16 0.05 -0.18 0.05 -0.62 0.05 No No L870A -0.86 0.11 -0.83 0.10 NA NA Yes No L8 70R -1.55 0.08 - 1.55 0.07 NA NA Yes No L870E -1.23 0.14 -1.60 0.15 NA NA Yes No L870G -1.54 0.07 -1.47 0.07 NA NA Yes No L870M -0.94 0.16 -1.13 0.17 NA NA Yes No L870F -1.01 0. 07 -0.78 0.07 NA NA Yes No L870P -0.29 0.06 -0.36 0.06 NA NA Yes No L870V -0.67 0.08 -0.82 0.08 NA NA Yes No F870A NA NA NA NA -1.06 0.37 Yes No F870R NA NA NA NA -1.61 0.14 Yes No F870C NA NA NA NA -0.66 0.43 Yes No F870G NA NA NA -1.20 0.19 Yes No F870I NA NA NA NA 0.71 0.17 Yes No ayQ / bn / Lznza / YiAi 120 M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? F870L NA NA NA 1.11 0.06 Yes No F870M NA NA NA -0.04 0.44 Yes No F870S NA NA NA -0.82 0.17 Yes No F870V NA NA NA 0.05 0.09 Yes No F871R NA NA NA -1.55 0.2 8 Yes No F871C - 0.24 0.17 -0.04 0.16 NA NA Yes No F871G NA NA NA -1.08 0.22 Yes No F871L -0.17 0.07 -0.16 0.07 -0.50 0.08 No No F871S NA NA NA NA -0.74 0.12 Yes No F871V 0.1 9 0.12 -0.06 0.12 -0.68 0.22 Yes No H872R -0.49 0.19 -0.27 0.18 -1.33 0.16 No No H872Q -0.40 0.10 -0.32 0.10 -0.60 0.11 No No H872G NA NA NA -1.61 0.11 Yes No H872L 0.00 0.08 -0.15 0.08 -0.43 0.08 No No Η872Ρ 0.04 0.02 -0.01 0.02 0.34 0.02 Yes No Η872Υ NA NA NA 0.10 0.21 Yes No H872V NA NA NA NA -1.51 0.48 Yes No V873A 0.16 0.11 0.05 0.11 0.08 0.16 Yes Yes V873E -0.40 0.14 -0.35 0.14 NA NA Yes No V873G -0.13 0.04 -0.20 0.03 -0.27 0.07 No No V873L -0.20 0.05 0.24 0.05 -0.40 0.08 Yes No V873M -0.48 0.12 -0.33 0.11 -0.16 0.16 No No Ρ874Α -0.12 0.06 0.06 0. 06 0.03 0.11 Yes No P874G NA NA NA NA -0.22 0.17 Yes No P874S -0.06 0.10 -0.17 0.10 0.58 0.11 Yes No Ρ874Τ -0.23 0.06 -0.24 0.06 -0.09 0.04 No No I875R -0.33 0.12 -0.24 0.11 -0.82 0.10 No No Ι875 Ν -0.01 0.07 -0.09 0.07 0.03 0.08 Yes No I875G NA NA NA NA -1.64 0.10 Yes No Ι875Η 0.10 0.11 -0.01 0.11 -0.25 0.11 Yes No I875L 0.08 0.02 0.02 0.02 -0.08 0.02 Yes No Ι875Μ -0.44 0.17 -0.26 0.16 0.05 0.17 Yes No I875F -0.20 0.09 -0.13 0.09 -0.12 0.10 No No I875S -0.06 0.07 -0.04 0.07 -0.22 0.07 No No Ι875Τ -0.01 0.10 -0.10 0.09 -0.11 0.11 No No I875V -0.24 0.17 -0.16 0.16 -0.44 0.10 No No Τ876 Α NA NA NA NA -1.21 0.20 Yes No T876R NA NA NA NA -1.72 0.26 Yes No Τ876Ν -0.10 0.03 -0.09 0.03 -0.07 0.05 No No T876G NA NA NA NA -1.44 0.22 Yes No Τ876Ρ -0.03 0.06 -0.07 0.06 -0.30 0.05 No No Q / Q / bn / Lznza / YiAi 121 M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? T876S NA NA NA -0.63 0.19 Yes No T876V NA NA NA -1.34 0.33 Yes No L877A 0.09 0.12 -0.51 0.13 NA NA Yes No L877R -0.89 0.08 -1.39 0.09 -1.53 ​​0.08 No No L877 C -0.26 0.17 -0.47 0.17 NA NA Yes No L877Q -0.43 0.11 -0.45 0.11 -0.39 0.13 No No L877G -1.42 0.09 -2.38 0.13 -1.74 0.35 No No L877P -0.08 0.07 -0.22 0.07 -0.40 0.12 No No L877S -1 .11 0.16 -0.99 0.15 NA NA Yes No L877V -1.25 0.14 0.04 0.10 -0.96 0.08 Yes No L877A -0.03 0.10 -0.76 0.11 NA NA Yes No L877R -0.15 0.04 -0.31 0.04 -0.02 0.04 No No L877C -0.29 0.15 -0 .65 0.15 NA NA Yes No L877Q -0.26 0.11 - 0.47 0.11 NA NA Yes No L877E NA NA NA -0.74 0.64 Yes No L877G -1.40 0.08 -2.82 0.12 -1.79 0.22 No No L877M -0.19 0.11 0.18 0.10 0.26 0.10 Yes No L877P -0 .28 0.09 -0.39 0.08 -0.46 0.15 No No L877S -1.31 0.14 -1.01 0.12 NA NA Yes No L877V -1.10 0.10 -0.29 0.08 -0.58 0.06 No No N878D 0.03 0.06 0.02 0.06 0.04 0.08 Yes Yes N878A 0.17 0.16 -0 .41 0.17 -0.06 0.25 Yes No N878Q -0.22 0.17 -0.53 0.17 NA NA Yes No N878E -0.73 0.15 -0.44 0.13 -0.84 0.13 No No N878G -0.57 0.10 -0.98 0.11 -0.70 0.06 No No N878H -0.01 0.05 -0.10 0.05 0.03 0.05 Yes No N878L NA NA NA NA -0.13 0.64 Yes No N878K -0.01 0.02 -0.05 0.02 -0.06 0.02 No No N878S -1.08 0.15 -0.43 0.12 -0.38 0.10 No No N878T -0.16 0.06 0.09 0.06 0.15 0.07 Yes No N878Y -0.05 0.07 0.00 0.06 0.06 0.04 Yes No N878V -1.01 0.17 -0.32 0.14 -0.19 0.34 No No N878A 0.03 0.14 -0.32 0.14 -0.19 0.54 Yes No N878D -0.11 0.12 -0.34 0.12 -0.62 0.15 No No N878C NA NA NA NA 0.58 0.42 Yes No N878G -0.62 0.10 -1.09 0.11 -0.81 0.05 No No N878I -0.35 0.16 -0.02 0.15 -0.41 0.17 No No N878L NA NA NA NA -0.12 0.82 Yes No N878K -0.34 0.13 -0.40 0.13 -0.39 0.08 No No N878M NA NA NA NA 0.25 0.16 Yes No N87 8S -0.54 0.11 -0.30 0.10 - 0.50 0.07 No No Q2Q / bn / Lznza / YiAi 122 Mutant Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? N878T -0.19 0.05 -0.20 0.05 -0.37 0.09 No No N878Y -0.34 0.18 -0.28 0.17 -0.12 0.21 No No N878V -0.98 0.15 -0.37 0.12 -0.51 0.32 No No Y879A -2.04 0.15 -1.14 0.10 NA NA Yes No Y879R -0.78 0.08 -1.40 0.08 -1.48 0.11 No No Y879D 0.39 0.05 -0.19 0.06 -0.18 0.07 Yes No Y879C 0.50 0.06 -0.02 0.07 -0.50 0.09 Yes No Y879Q -0.72 0.19 -0.38 0.17 NA NA Yes No Y879E -1.40 0.13 -1.23 0.11 NA NA Yes No Y879G -0.58 0.05 -1.93 0.07 -1.84 0.23 No No Y879H 0.35 0.09 0.04 0.09 -0.16 0.12 Yes No Y879L -1.45 0.13 0.26 0.08 -1.39 0.33 Yes No Y879K 0 .13 0.14 -1.11 0.17 NA NA Yes No Y879F -0.05 0.12 -0.01 0.11 0.01 0.17 Yes No Y879S 0.37 0.04 -0.29 0.04 -0.43 0.07 Yes No Y879* -0.20 0.11 0.92 0.09 -0.81 0.15 Yes No Y879W -0.05 0.08 -0.07 0.07 0.60 0.07 Yes No Y879V -0.53 0.08 -0.97 0.08 NA NA Yes No Q880R 0.13 0.05 0.02 0.05 0.01 0.06 Yes Yes Q880G 0.25 0.04 0.19 0.04 0.64 0.05 Yes Yes Q880A -0.10 0.08 0.40 0.07 -0.19 0.20 Yes No Q880D 0.8 1 0.14 -1.10 0.18 NA NA Yes No Q880C -0.08 0.14 -1.19 0.17 0.17 0.14 Yes No Q880E -0.73 0.10 -1.06 0.10 -0.58 0.08 No No Q880H 0.24 0.08 -0.08 0.08 -0.10 0.08 Yes No Q880L -0.80 0.08 -0.59 0.07 -1.39 0.07 No No Q880K -0.2 3 0.13 -0.27 0.13 -0.44 0.09 No No Q880M -0.93 0.16 -0.77 0.14 -0.49 0.17 No No Q880P -0.07 0.10 -0.40 0.10 0.12 0.07 Yes No Q880S -0.31 0.09 -0.76 0.10 -0.09 0.07 No No Q880* -1.27 0.14 - 0.76 0.11 -1.05 0.11 No No Q880T -0.52 0.14 -0.18 0.12 0.07 0.29 Yes No Q880W -0.68 0.08 -0.91 0.08 -0.82 0.06 No No Q880V -1.77 0.10 -0.81 0.07 -0.63 0.07 No No A881R -0.95 0.07 -1.75 0.08 -1.43 0.18 No No A881D -0.36 0.11 -0.32 0.10 -0.48 0.19 No No A881C -0.35 0.14 -0.78 0.15 -0.49 0.10 No No A881G 0.14 0.04 0.32 0.04 -0.41 0.04 Yes No A881L -1.36 0.11 -2.39 0.15 NA NA Yes No A881P -1.05 0.16 -0.99 0.14 -0.80 0.18 No No A881S 0.13 0.05 0.13 0.05 -0.13 0.06 Yes No cMQ / bn / Lznza / YiAi 123 Muffante Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? A881T -0.73 0.10 -0.95 0.10 -0.44 0.14 No No A881W -1.25 0.12 -1.48 0.12 NA NA Yes No A881V -1.66 0.09 -1.28 0.07 -0.91 0.08 No No A882D 0.32 0.05 0 .22 0.05 0.10 0.07 Yes Yes A882S 0.11 0.12 0.14 0.11 0.23 0.22 Yes Yes A882R -0.10 0.10 0.54 0.09 0.51 0.35 Yes No A882G -0.43 0.07 -0.32 0.06 -0.14 0.06 No No A882L -1.02 0.19 0.32 0.14 NA NA Yes No A882P -0.12 0.14 -0.11 0.13 -0.12 0.24 No No A882T -0.14 0.09 0.05 0.09 -0.09 0.13 Yes No A882V 0.39 0.08 0.04 0.08 -0.17 0.15 Yes No N883G 0.42 0.08 0.37 0.08 0.03 0.11 Yes Yes N883K 0.12 0.16 0.23 0.16 0.16 0.10 Yes Yes N883A -0.26 0.15 -1.10 0.17 0.05 0.55 Yes No N883R NA NA NA NA 0.84 0.11 Yes No N883D -0.02 0.13 -0.37 0.14 -0.36 0.18 No No N883I 0.00 0.16 0.08 0.15 -0.37 0.12 Yes No N883S 0.08 0.10 0.04 0.10 -0.13 0 .09 Yes No N883T 0.27 0.11 -0.02 0.11 -0.21 0.12 Yes No S884V 0.05 0.11 0.61 0.10 0.03 0.14 Yes Yes S884A 0.07 0.13 -0.01 0.12 0.02 NA Yes No S884R -0.28 0.06 -0.11 0.06 0.34 0.07 Yes No S884N 0.14 0.14 0.4 8 0.13 -0.07 0.25 Yes No S884C NA NA NA NA 0.18 0.19 Yes No S884E - 0.10 0.16 -0.04 0.15 NA NA Yes No S884G -0.09 0.06 -0.11 0.06 0.01 0.10 Yes No S884L NA NA NA 0.02 0.55 Yes No S884T -0.01 0.10 0.05 0.10 NA NA Yes No S88 4W -0.99 0.18 -0.38 0.14 0.43 0.82 Yes No P885A -0.36 0.06 -0.32 0.05 -0.12 0.13 No No P885R -0.03 0.04 -0.89 0.05 0.00 0.06 Yes No P885N -0.47 0.17 -0.73 0.17 NA NA Yes No P885D -0.73 0.12 -1 .21 0.12 -0.83 0.35 No No P885C -1.54 0.14 -0.39 0.09 -0.01 0.09 No No P885Q -1.26 0.18 -0.04 0.13 -0.65 0.33 No No P885E -0.08 0.08 -1.01 0.09 -0.98 0.16 No No P885G -1.22 0.05 -0.98 0.04 - 0.39 0.04 No No P885H -0.06 0.13 -0.41 0.13 0.09 0.12 Yes No P885I NA NA NA -0.01 0.44 Yes No P885L -0.66 0.07 -0.90 0.07 -0.60 0.05 No No P885K -0.12 0.12 -0.28 0.12 -0.32 0.22 No No 124 M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? Ρ885Μ -1.32 0.15 -1.01 0.13 -0.52 0.13 No No P885F -0.98 0.16 -0.49 0.14 -0.31 0.10 No No P885S -0.88 0.07 -0.65 0.06 -0.11 0.12 No No Ρ885Τ -0.35 0.04 -0.29 0.04 0.03 0.05 Yes No P885W -0.76 0.07 -1.20 0.08 -0.94 0.23 No No Ρ885Υ -0.19 0.16 0.72 0.13 0.22 0.48 Yes No P885V -0.86 0.06 -0.46 0.05 0.05 0.12 Yes No S886L 0.09 0.08 0. 12 0.08 0.05 0.11 Yes Yes S886M 0.32 0.11 0.15 0.11 0.40 0.35 Yes Yes S886W 0.23 0.07 0.01 0.07 0.70 0.19 Yes Yes S886A -0.52 0.07 -0.42 0.07 -0.04 0.14 No No S886R 0.12 0.04 -0.08 0.04 0.36 0.04 Yes No S886N 0.34 0.10 -0.34 0.11 -0.03 0.14 Yes No S886D 0.60 0.10 -0.69 0.12 NA NA Yes No S886C 0.11 0.09 -0.64 0.09 0.34 0.23 Yes No S886Q -0.33 0.14 -0.65 0.14 0.19 0.64 Yes No S886E -0.60 0.10 -0.56 0.10 NA NA Yes No S886G -0.20 0.04 -0 .18 0.04 0.10 0.05 Yes No S886I 0.89 0.13 -0.13 0.14 0.07 0.29 Yes No S886K -0.70 0.14 0.01 0.12 0.56 0.12 Yes No S886F NA NA NA 0.75 0.44 Yes No S886P NA NA NA -0.28 0.14 Yes No S886T 0.07 0.07 -0.05 0.07 -0. 29 0.10 Yes No S886Y NA NA NA NA 0.79 0.55 Yes No S886V -0.10 0.07 -0.15 0.06 0.35 0.20 Yes No Κ887Α 0.03 0.04 -0.38 0.05 -0.54 0.04 Yes No K887R -0.09 0.03 -0.04 0.03 0.21 0.03 Yes No Κ887 Ν 0.24 0.10 0.07 0.10 -0.45 0.24 Yes No K887D -1.19 0.10 - 0.97 0.09 -1.27 0.28 No No K887C -0.76 0.08 0.16 0.07 -0.59 0.06 Yes No K887Q 0.10 0.08 -0.05 0.07 -0.25 0.11 Yes No Κ887Ε -0.33 0.05 -0.39 0. 05 -0.97 0.06 No No K887G -0.14 0.03 -0.22 0.02 -0.42 0.03 No No Κ887Η -0.04 0.12 -1.21 0.15 -0.21 0.40 No No Κ887Ι -0.31 0.12 -0.04 0.11 NA NA Yes No K887L -0.88 0.06 -0.67 0.05 -0.68 0.07 No No Κ8 87Μ -0.12 0.07 -0.23 0.07 -0.44 0.16 No No K887F 0.22 0.11 -0.22 0.11 -0.74 0.25 Yes No Κ887Ρ -0.29 0.08 -0.61 0.08 -0.32 0.18 No No K887S -0.03 0.05 -0.50 0.05 -0.66 0.08 No No Κ887* - 0.88 0.08 -1.30 0.08 -1.22 0.10 No No Q / Q / frni ΖΠΖ -Ι / ΥΙΛΙ 125 Mutant Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? K887T -0.79 0.08 -0.22 0.07 -0.74 0.11 No No K887W -0.59 0.05 -0.69 0.05 -0.65 0.07 No No K887Y 0.36 0.10 -0.98 0.13 -0.40 0.17 Yes No K887V 0.09 0.04 -0.88 0.04 -0.89 0.07 Yes No F888A -2.01 0.10 -1.31 0.07 -1.30 0.28 No No F888R -1.27 0.07 -1.04 0.06 -1.82 0.18 No No F888D -1.09 0.12 -1.32 0.12 NA NA Yes No F888C 0.01 0.04 -0.10 0.04 0.10 0 .03 Yes No F888Q -0.58 0.13 -1.37 0.15 NA NA Yes No F888E -0.89 0.08 -2.09 0.11 -1.77 0.12 No No F888G -1.75 0.05 -1.53 ​​0.05 -1.57 0.03 No No F888I 0.09 0.11 -0.24 0.11 -0.50 0.15 Yes No F888L -0.1 3 0.04 -0.06 0.03 -0.23 0.05 No No F888M -0.65 0.12 0.31 0.10 -0.04 0.10 Yes No F888P -0.69 0.12 -1.56 0.15 NA NA Yes No F888S -1.42 0.08 -1.17 0.07 -1.14 0.12 No No F888* -1.06 0.13 -0.77 0 .11 -1.31 0.08 No No F888T -0.62 0.11 -1.69 0.13 -1.19 0.64 No No F888W -1.15 0.08 -2.14 0.11 -1.37 0.05 No No F888Y -0.73 0.13 -1.27 0.14 -0.60 0.12 No No F888V 0.07 0.04 0.10 0.04 - 0.31 0.03 Yes No N889A NA NA NA NA -0.86 0.64 Yes No N889R -0.94 0.09 -0.07 0.07 -0.55 0.48 No No N889D -0.34 0.10 -0.44 0.10 -0.39 0.14 No No N889G -0.87 0.06 -1.32 0.07 -0.83 0.07 No No N889I -0.5 1 0.17 -0.43 0.16 NA NA Yes No N889K -0.76 0.17 -0.47 0.15 -0.34 0.24 No No N889S -1.13 0.11 0.08 0.08 -0.26 0.14 Yes No N889T -0.55 0.16 -0.45 0.14 -0.36 0.30 No No N889V -1.82 0.15 - 1.28 0.12 -1.16 0.64 No No Q890C 0.03 0.11 0.64 0.10 0.08 0.54 Yes Yes Q890H 0.39 0.09 0.07 0.09 0.04 0.11 Yes Yes Q890W 0.03 0.08 0.23 0.07 0.03 0.08 Yes Yes Q890A 0.39 0.06 0.05 0.06 -0.02 0.11 Yes No Q890R -0.10 0.05 -0.24 0.05 -0.05 0.10 No No Q890N -0.25 0.15 - 0.66 0.16 0.31 NA Yes No Q890D 0.54 0.10 -0.52 0.11 -0.35 0.20 Yes No Q890E 0.17 0.06 -0.62 0.07 -0.33 0.06 Yes No Q890G -0.35 0.04 -0.60 0.04 -0.1 5 0.07 No No Q890I -0.26 0.16 -0.94 0.18 NA NA Yes No Q890L 0.09 0.06 -0.14 0.06 0.29 0.17 Yes No 126 Mufante Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? Q890K 0.23 0.10 0.25 0.10 -0.22 0.16 Yes No Q890M 0.32 0.11 -0.13 0.11 -0.07 0.48 Yes No Q890F 0.25 0.15 -0.11 0.15 0.09 0.82 Yes No Q890P -1.20 0.12 -0.75 0.10 -0.11 0.17 No No Q890S -0.58 0.08 -0.01 0.07 -0.19 0.08 No No Q890* -1.12 0.11 -1.26 0.11 -0.88 0.13 No No Q890T -0.36 0.10 0.11 0.09 0.08 0.09 Yes No Q890Y NA NA NA 0.03 0.13 Yes No Q890V -0.39 0.06 -0.33 0.06 0.21 0.06 Yes No R891A - 0.41 0.08 -0.46 0.07 -0.44 0.31 No No R891D -1.17 0.16 -0.76 0.14 -0.63 0.64 No No R891C -0.10 0.10 -0.56 0.11 -0.05 0.17 No No R891Q NA NA NA NA -0. 08 0.64 Yes No R891E -1.06 0.11 -0.65 0.09 -0.59 0.64 No No R891G -0.70 0.04 -0.40 0.04 -0.11 0.04 No No R891L 0.07 0.08 -0.02 0.08 -0.25 0.33 Yes No R891K -0.04 0.11 -0.37 0.11 -0.03 0.26 No No R891M NA NA NA NA -0.14 NA Yes No R891S -0.18 0.07 -0.49 0.07 -0.28 0.08 No No R891* -0.88 0.13 -0.57 0.11 -0.74 0.20 No No R891T -0.20 0.10 -0.28 0.10 -0.16 0.10 No No R891W -1.03 0.08 -1.42 0.08 -0.78 0.43 No No R891V -0.28 0.07 -0.77 0.07 -0.53 0.09 No No V892A -1.02 0.08 -1.08 0.08 -0.18 0.07 No No V892R -1.49 0.09 -1.55 0.08 -1.41 0.09 No No V892C -0.58 0.14 -0.80 0.14 -0.01 0.13 No No V892E - 0.97 0.10 -1.28 0.10 -0.93 0.17 No No V892G -1.01 0.05 -1.11 0.05 -0.90 0.05 No No V892L -0.58 0.09 -1.35 0.10 -0.93 0.14 No No V892M -0.59 0.12 - 0.62 0.12 NA NA Yes No V892S -1.15 0.13 - 1.21 0.12 NA NA Yes No V892T -0.34 0.15 0.05 0.13 0.11 0.64 Yes No V892W -1.99 0.15 -1.09 0.10 NA NA Yes No N893A -1.02 0.07 -0.18 0.05 -0.37 0.05 No No N 893R -0.35 0.04 -0.57 0.04 -0.42 0.06 No No N893D -0.71 0.10 -0.39 0.08 -0.71 0.11 No No N893C -0.80 0.10 -0.20 0.09 -0.24 0.07 No No N893Q -1.58 0.15 -0.86 0.11 -0.57 0.20 No No N893E -0.89 0.07 -1.03 0.07 -1.10 0.10 No No N893G -0.30 0.03 -0.68 0.03 -0.34 0.04 No No N893H 0.02 0.13 -0.74 0.14 NA NA Yes No 127 M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? N893I 0.33 0.11 -0.24 0.12 -0.68 0.11 Yes No N893L -1.03 0.08 -0.46 0.07 -0.86 0.17 No No N893K -0.39 0.07 -0.07 0.06 -0.27 0.07 No No N893M 0.26 0.08 -0.81 0.10 -1.04 0.33 Yes No N893S 0.64 0.05 0.08 0.05 -0.47 0.06 Yes No N893* -1.54 0.12 -1.43 0.11 -1.26 0.17 No No N893T 1.09 0.06 -0.04 0.06 -0.62 0.08 Yes No N893W -0.63 0.06 -0.48 0.06 -0.78 0.10 No No N893Y -0.51 0.12 -0.87 0.12 - 0.38 0.18 No No N893V -0.70 0.06 -0.74 0.06 -0.59 0.05 No No A894R 0.19 0.06 0.06 0.06 0.04 0.08 Yes Yes A894D 0.04 0.06 0.09 0.06 0.21 0.05 Yes Yes A894C -0.13 0.15 -0.29 0.14 NA NA Yes No A894Q 0.87 0.14 -0.47 0.16 NA NA Yes No A894E -0.35 0.10 -0.85 0.10 -0.45 0.20 No No A894G -0.47 0.05 0.09 0.05 0.21 0.06 Yes No A894L -0.45 0.11 0.57 0.09 0.08 0.12 Yes No A894K NA NA NA 0.27 0.15 Yes No A894M 0.14 0.13 - 0.17 0.13 0.25 0.18 Yes No A894P -0.67 0.14 -1.05 0.15 NA NA Yes No A894S 0.57 0.08 -0.97 0.10 0.12 0.23 Yes No A894* -0.76 0.19 0.06 0.16 NA NA Yes No A 894T -0.68 0.10 -0.49 0.09 0.21 0.15 Yes No A894W 0.67 0.09 -0.44 0.10 0.02 0.54 Yes No A894V -0.22 0.07 -0.05 0.06 0.12 0.18 Yes No Y895D 0.16 0.04 0.00 0.04 0.09 0.04 Yes Yes Y895A -1.08 0.12 - 0.85 0.11 -0.53 0.37 No No Y895R NA NA NA NA -0.75 0.07 Yes No Y895N -0.12 0.11 -0.43 0.11 -0.07 0.23 No No Y895C 0.61 0.06 0.14 0.06 -0.26 0.07 Yes No Y895E -0.53 0.11 -0.74 0.10 -0.62 0.13 No No Y895G -0.59 0.06 -1.69 0.08 -1.72 0.07 No No Y895H -0.21 0.10 -0.10 0.10 -0.25 0.16 No No Y895F 0.70 0.12 -0.28 0.13 -0.20 0.21 Yes No Y895S 0.18 0.05 -0.17 0.05 -0.12 0.06 Yes No Y895* -0.03 0.05 -0.04 0.05 0.16 0.06 Yes No Y895W -0.08 0.11 0.17 0.10 - 0.18 0.31 Yes No Y895V -1.60 0.12 -0.11 0.08 -0.61 0.40 No No L896A -1.48 0.09 -1.26 0.08 -1.68 0.35 No No L896R 0.19 0.04 -0.11 0.04 -0.30 0.04 Yes No L896Q 0.42 0.04 0.08 0.04 -0.17 0.05 Yes No ayQ / bn / Lznza / YiAi 128 M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? L896E -1.31 0.11 -1.65 0.12 NA NA Yes No L896G -2.17 0.07 -1.66 0.05 -1.77 0.05 No No L896M 0.31 0.11 -0.22 0.11 -0.74 0.17 Yes No L896F -0.69 0.18 -0 .97 0.18 NA NA Yes No L896P -0.37 0.08 - 0.52 0.08 -0.53 0.10 No No L896S NA NA NA NA -1.38 0.48 Yes No L896W -1.69 0.12 -1.64 0.11 -0.97 0.54 No No L896V -0.04 0.06 -0.69 0.06 -0.81 0.07 No No Κ897Α -0.76 0.08 -0.22 0.07 -0.07 0.15 No No K897R 0.03 0.04 -0.01 0.04 -0.05 0.05 Yes No Κ897Ν 0.58 0.11 0.26 0.11 -0.06 0.09 Yes No K897D -1.39 0.13 -0.61 0.10 -0.10 0.25 No No K 897C 0.02 0.09 -0.54 0.10 -0.11 0.08 Yes No K897Q -0.06 0.10 0.16 0.10 -0.04 0.21 Yes No Κ897Ε 0.17 0.05 -0.03 0.05 -0.29 0.08 Yes No K897G 0.01 0.04 -0.29 0.04 -0.07 0.03 Yes No Κ897Η -0.18 0.15 0.06 0.14 0.22 0.36 Yes No Κ897Ι -0.29 0.13 -1.02 0.14 -0.06 0.06 No No K897L -0.19 0.07 -0.26 0.07 0.28 0.35 Yes No Κ897Μ -0.35 0.09 -0.01 0.08 0.23 0.11 Yes No K897F -0.72 0.18 0.16 0.15 -0.08 0.64 Yes No Κ897 Ρ -1.22 0.13 -1.78 0.14 NA NA Yes No K897S -0.22 0.07 -0.29 0.07 -0.13 0.10 No No Κ897* -0.92 0.11 -0.93 0.11 -0.93 0.11 No No Κ897Τ 0.27 0.08 -0.32 0.08 -0.02 0.06 Yes No K897W -0.08 0.07 -0.54 0.07 0.00 0.19 No No Κ897Υ -0.95 0.19 0.19 0.14 - 0.23 0.13 Yes No K897V -0.30 0.05 -0.29 0.05 0.19 0.07 Yes No Ε898Α -0.19 0.06 0.08 0.06 -0.25 0.07 Yes No E898R -0.44 0.07 -0.49 0.07 -0.10 0. 31 No No E898D 0.42 0.10 -0.32 0.11 -0.12 0.16 Yes No E898C NA NA NA 0.23 0.15 Yes No E898Q -0.43 0.14 -0.57 0.13 0.29 0.39 Yes No E898G -0.27 0.05 -0.27 0.05 0.12 0.06 Yes No E898L 0.07 0.11 -0.46 0.12 0. 15 0.12 Yes No Ε898Κ -0.93 0.16 -0.35 0.14 0.13 0.31 Yes No Ε898Ρ -0.40 0.19 -0.60 0.19 NA NA Yes No E898S 0.17 0.14 -1.32 0.18 0.38 0.55 Yes No E898W -1.01 0.12 -1.33 0.12 -0.16 0.14 No No E898V -0.06 0. 07 0.31 0.07 0.01 0.07 Yes No Η899Α 0.21 0.08 0.16 0.07 0.01 0.48 Yes Yes Q / Q / frni ζηζ-ΐ / γίΛΐ 129 Matante Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? H899N 0.15 0.15 0.70 0.14 0.08 0.18 Yes Yes H899R -0.20 0.04 -0.12 0.04 -0.12 0.03 No No H899D -0.84 0.13 -0.16 0.11 -0.47 0.25 No No H899C -0.98 0.14 -0.02 0.11 -0.12 0.13 No No H899Q -0.15 0.05 - 0.20 0.05 0.00 0.03 No No H899E -0.85 0.10 -0.64 0.09 -0.36 0.27 No No H899G -0.79 0.05 -0.96 0.05 -0.65 0.05 No No H899L -0.27 0.08 -0.41 0.08 - 0.50 0.14 No No H899K NA NA NA NA 0.05 0.49 Yes No H899P -0.07 0.07 0.01 0.07 -0.33 0.10 Yes No H899S -0.31 0.10 -0.33 0.09 0.07 0.32 Yes No H899T -0.37 0.15 -0.14 0.14 -0.03 0.48 No No H899W -0.32 0.08 -0.24 0.07 -0.25 0.48 No No H899Y -0.09 0.12 -0.87 0.13 0.11 0.16 Yes No H899V -0.07 0.07 -0.99 0.08 0.05 0.22 Yes No P900A -0.09 0.05 0.03 0.04 0.04 0.11 Yes No P900R -0.17 0.04 -0.23 0.03 0.09 0.04 Yes No P900N -1.13 0.14 0.05 0.11 0.35 0.30 Yes No P900D -0.42 0.08 -0.19 0.07 0.19 0.12 Yes No P900C -0.28 0.07 0.15 0.06 0.12 0.15 Yes No P900Q 0.28 0.08 -0.19 0.09 0.23 0.30 Yes No P900E -0.19 0.06 0.18 0.05 0.29 0.08 Yes No P900G -0.03 0.03 -0.15 0.03 0.11 0.03 Yes No P900H 0.07 0.08 -0.18 0.08 0.25 0.12 Yes No P900I -0.83 0.12 -0.36 0.10 0.33 0.33 Yes No P900L 0.03 0.04 -0.20 0.04 0.07 0.04 Yes No P900K 0.1 6 0.08 -0.61 0.08 0.05 0.13 Yes No P900M -1.26 0.10 -0.21 0.07 0.06 0.12 Yes No P900F 0.33 0.10 -0.07 0.10 -0.19 0.09 Yes No P900S -0.10 0.05 0.15 0.04 0.14 0.04 Yes No P900* -0.32 0.08 -1.30 0.10 NA NA Yes No P900T 0.24 0.06 -0.22 0.06 0.19 0.09 Yes No P900W -0.16 0.05 -0.48 0.06 -0.04 0.06 No No P900Y -0.49 0.11 -0.86 0.11 -0.25 0.82 No No P900V 0.10 0.04 -0.35 0.04 0.14 0.05 Yes No E901D 0.07 0.10 0.05 0.10 0.14 0.15 Yes Yes E901A -0.81 0.08 0.24 0.07 0.08 0.08 Yes No E901R -0.15 0.06 -0.19 0.06 -0.03 0.06 No No E901C -0.08 0.13 -0.32 0.13 0.21 0.64 Yes No E901Q -0.69 0.16 0.04 0.13 -0.16 0.40 Yes No E901G -0.44 0.04 0.07 0.04 0.10 0.06 Yes No Q2Q / bn / Lznza / YiAi 130 M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? E901L -0.12 0.08 -0.80 0.09 -0.13 0.20 No No E901K -0.11 0.10 0.20 0.10 0.08 0.13 Yes No E901M 0.16 0.12 -0.14 0.12 0.03 0.82 Yes No E901P -0.99 0.19 -1.23 0.19 NA NA Yes No E901S -1.40 0.13 0.16 0.08 0.05 0.11 Yes No E901* -0.29 0.13 -1.11 0.15 -0.63 0.14 No No E901T NA NA NA NA -0.05 0.44 Yes No E901W 0.02 0.08 -0.49 0.09 0.21 0.08 Yes No E901V -1.13 0.07 - 0.49 0.06 0.11 0.06 Yes No T902A -0.07 0.05 -0.35 0.05 -0.20 0.09 No No T902R -0.60 0.06 -1.09 0.07 -0.48 0.12 No No T902C 0.17 0.11 -0.55 0.12 -0.25 0.82 Yes No T902Q -0.92 0.15 -0.24 0.13 NA NA Yes No T902E -0.55 0.10 -1.12 0.11 NA NA Yes No T902G -1.03 0.06 -1.00 0.06 -0.74 0.15 No No T902I -0.22 0.14 0.19 0.12 -0.10 0.20 Yes No T902L -0.92 0.11 -0.09 0.09 -0.12 0.09 No No T902K -0.31 0.04 -0.01 0.04 0.13 0.06 Yes No T902M NA NA NA 0.01 0.54 Yes No T902P -1.06 0.13 -0.32 0.10 -0.81 0.21 No No T902S -0.15 0.07 -0.38 0.07 -0.15 0.07 No No T902W NA NA NA NA -0.80 0.54 Yes No T902V -0.15 0.07 0.06 0.07 - 0.03 0.14 Yes No P903T 0.64 0.13 0.52 0.12 0.39 0.18 Yes Yes P903A -0.22 0.11 -0.37 0.10 -0.12 0.31 No No P903R -1.86 0.13 -0.87 0.09 -0.31 0.27 No No P903C 0.75 0.15 -0.71 0.18 NA NA Yes No P903E NA NA NA NA 0.05 0.22 Yes No P903G -1.37 0.10 -1.66 0.10 -0.49 0.35 No No P903H NA NA NA 0.04 0.17 Yes No P903L -0.52 0.11 -0.93 0.12 0.29 0.10 Yes No P903S -0 .61 0.12 0.03 0.10 0.07 0.22 Yes No P903V - 0.44 0.12 -0.77 0.12 0.25 0.16 Yes No I904A 0.28 0.05 0.32 0.05 -0.01 0.10 Yes No I904R -0.52 0.05 -0.28 0.04 -0.14 0.04 No No I904N -0.26 0.11 0.07 0.10 -0.29 0.13 Yes No I904D NA NA NA NA -1.33 0.37 Yes No I904C -0.37 0.09 -0.06 0.08 0.16 0.09 Yes No I904Q -0.28 0.11 0.17 0.10 0.03 0.37 Yes No I904E -1.15 0.08 -1.73 0.09 -0.77 0.30 No No I904G -1.0 5 0.04 -0.45 0.04 -0.39 0.03 No No α^ο / ^η / ίζηζα / γίΛΐ 131 M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? I904H NA NA NA NA -0.20 0.48 Yes No I904L -0.35 0.07 0.47 0.06 0.12 0.09 Yes No I904K -1.71 0.15 -0.48 0.10 0.05 0.09 Yes No I904M 0.19 0.08 -0.04 0. 08 0.03 0.05 Yes No I904F -0.71 0.13 0.38 0.11 0.15 0.20 Yes No I904S 0.20 0.04 -0.09 0.04 0.07 0.03 Yes No I904* -1.37 0.12 -1.64 0.13 NA NA Yes No I904T 0.33 0.07 -0.20 0.07 -0.13 0.08 Yes No I904W -0.01 0.06 - 0.07 0.06 -0.35 0.24 No No I904Y 0.53 0.12 - 0.47 0.13 0.01 0.64 Yes No I904V -0.13 0.05 0.08 0.04 0.00 0.04 Yes No I905A -0.31 0.06 -0.49 0.06 -0.02 0.14 No No I905R -1.93 0.08 -1.23 0.06 - 1.47 0.09 No No I905N -0.95 0.15 -0.68 0.14 NA NA Yes No I905D -1.69 0.14 -1.47 0.12 NA NA Yes No I905C -0.01 0.10 0.49 0.09 -0.12 0.11 Yes No I905E -1.48 0.10 -2.09 0.12 -1.57 0.43 No No I905G -1.25 0.05 - 0.83 0.04 -0.80 0.04 No No I905L -0.65 0.07 -0.31 0.06 -0.12 0.07 No No I905M 0.15 0.06 -0.40 0.07 -0.10 0.06 Yes No I905F -0.10 0.11 -0.09 0.11 -0.55 0.18 No No I905S -1.01 0.07 -1.06 0.07 -0.63 0.06 No No I905T -0.17 0.09 -0.86 0.09 -0.52 0.12 No No I905W -1.31 0.10 -1.78 0.11 -1.43 0.28 No No I905V -0.18 0.05 -0.21 0.05 0.10 0.06 Yes No G906A 0.41 0.05 0.56 0.04 0.42 0.05 Yes Yes G906S 0.40 0.05 0.16 0.05 0.15 0.06 Yes Yes G906R -1.82 0.06 -2.39 0.07 -1.63 0.08 No No G906D -1.49 0.10 -1.05 0.08 -1.38 0.18 No No G906C -1.50 0.11 -1.21 0.09 -1.62 0.11 No No G906E -2.26 0.12 -1.63 0.09 -1.49 0.11 No No G906L -1.51 0.09 - 2.32 0.11 -1.69 0.27 No No G906P -1.68 0.12 -1.05 0.09 -1.66 0.10 No No G906* NA NA NA NA -1.21 0.40 Yes No G906T -1.69 0.11 -2.68 0.15 NA NA Yes No G906W -2 .22 0.11 -1.14 0.07 -1.71 0.08 No No G906V -0.85 0.05 -1.20 0.05 -1.27 0.06 No No I907A 0.70 0.10 0.42 0.10 0.27 0.54 Yes Yes I907V 0.15 0.07 0.12 0.07 0.13 0.06 Yes Yes I907 R -0.92 0.08 -1.15 0.08 -0.89 0.09 No No I907D -0.44 0.17 - 0.97 0.18 NA NA Yes No ayQ / bn / Lznza / YiAi 132 M uta π te Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? I907C -0.16 0.16 0.84 0.13 0.12 0.64 Yes No I907E -1.06 0.15 -0.42 0.12 NA NA Yes No I907G -0.42 0.06 -0.40 0.06 -0.03 0.06 No No I907L 0.34 0.09 0 .24 0.08 -0.33 0.09 Yes No I907M NA NA NA NA 0.12 0.25 Yes No I907F -0.50 0.19 -0.17 0.17 NA NA Yes No I907S -0.29 0.03 -0.18 0.03 0.25 0.03 Yes No I907T -0.44 0.15 0.78 0.12 0.28 0.12 Yes No D908A -2.26 0.13 -1.92 0.11 -1.10 0.16 No No D908R NA NA NA NA -1.53 ​​0.09 Yes No D908N -0.27 0.12 -0.30 0.12 -0.70 0.14 No No D908E -1.61 0.13 -1.42 0.11 -1.11 0.11 No No D908G -2.25 0.09 -2.15 0.08 -1.77 0.1 4 No No D908S -1.92 0.16 -1.78 0.14 NA NA Yes No D908W -1.93 0.15 -2.11 0.15 NA NA Yes No D908Y 0.26 0.11 -0.07 0.12 -0.15 0.12 Yes No D908V -1.74 0.10 -1.76 0.10 -1.52 0.09 No No R909A NA NA NA NA -1.45 0.37 Yes No R909Q -0.25 0.18 -0.94 0.20 NA NA Yes No R909G -1.30 0.05 -1.49 0.05 -1.38 0.06 No No R909K -0.87 0.16 -0.60 0.14 NA NA Yes No R909S -1.08 0.10 -0.84 0.09 -0.58 0. 12 No No R909T -1.28 0.15 -0.89 0.13 NA NA Yes No R909W -0.96 0.10 -1.94 0.13 NA NA Yes No R909V -1.36 0.11 -2.33 0.14 -1.34 0.47 No No G910R -1.03 0.08 -1.62 0.09 -1.75 0.16 No No G910D NA NA NA NA -0.69 0.19 Yes No G910C -0.91 0.13 -1.29 0.14 NA NA Yes No G910S -1.15 0.10 -1.28 0.10 -1.41 0.19 No No G910W -1.93 0.15 -1.82 0.13 NA NA Yes No G910V -1.34 0.08 -1.15 0.07 -0. 66 0.13 No No E911A -0.79 0.12 - 1.56 0.14 -0.93 0.10 No No E911R -1.42 0.12 -2.19 0.14 NA NA Yes No E911D -0.45 0.14 -0.47 0.13 -0.18 0.25 No No E911G -0.65 0.06 -0.80 0.06 -0.83 0 .08 No No E911L NA NA NA NA -0.50 0.15 Yes No E911K -0.39 0.13 -0.14 0.12 -0.57 0.15 No No E911* -0.20 0.11 0.12 0.10 -0.18 0.16 Yes No E911V -0.21 0.08 -0.62 0.08 -0.61 0.09 No No R912A 0.4 6 0.09 0.49 0.09 0.31 0.64 Yes Yes R912L 0.53 0.08 0.38 0.08 0.21 0.16 Yes Yes Q2Q / bn / Lznza / YiAi 133 Muffante Calif. from enriqu. (1) Std. error (1) Qual. from enriqu. (2) Std. error (2) Qual. from enriqu. (3) Std. error (3) Any positive enrichment? Constant positive enrichment? R912S 1.04 0.11 0.30 0.11 0.31 0.54 Yes Yes R912V 0.19 0.09 0.23 0.09 0.03 0.09 Yes Yes R912C 0.43 0.15 0.54 0.15 -0.29 0.16 Yes No R912Q 0.22 0.05 0.15 0.05 -0.05 0.09 Yes No R912E 0.53 0.12 -0.67 0.14 NA NA Yes No R912G - 0.21 0.05 -1.04 0.06 -0.56 0.05 No No R912P 0.53 0.09 0.79 0.09 -0.40 0.14 Yes No R912T -0.54 0.17 -0.07 0.15 0.52 0.65 Yes No R912W -0.09 0.07 - 0.14 0.07 -0.43 0.10 No No N913A -1.19 0.13 -0.97 0.11 -0.87 0.33 NO No N913R -2.49 0.14 -0.64 0.07 -1.67 0.40 No No N913D -0.62 0.13 -0.44 0.12 -0.75 0.10 No No N913E -0.91 0.12 -1.92 0.16 NA NA Yes No N913G -1.34 0.07 -0.91 0.06 -1.56 0.30 No No N913H 0.12 0.07 0.13 0.07 -0.20 0.12 Yes No N913I -0.16 0.09 -0.18 0.09 -0.18 0.12 No No N913L -0.39 0.11 -0.72 0.11 NA NA Yes No N913K -0.37 0.05 -0.29 0.04 -0.27 0.08 No No N913S -0.29 0.08 -0.06 0.07 -0.20 0.12 No No N913T 0.09 0.11 -0.67 0.12 -0.35 0.24 Yes No N913Y -0.47 0.18 -0.44 0.17 NA NA Yes No N913V -1.32 0.12 -0.89 0.10 -1 .09 0.18 No No 1 Key to Heading Abbreviations: Mutants are defined by a single letter a / a / bn / Lznza / YiAi amino acid (wild-type) at a given position in the wild-type AsCas12a polypeptide (eg, amino acid position 500 ), followed by the variant amino acid change thereafter, “Calif. from enriqu. (1)” refers to the qualification of enrichment of the variant in a Fund of Condition 1; “Std error (1)” refers to the standard error for experiments performed for a given variant on a Condition 1 background; “Calif. from enriqu. (2)” refers to the qualification of enrichment of the variant in a Fund of Condition 2; “Std error (2) refers to the standard error of experiments performed for a given variant against a Condition 2 background; “Calif. from enriqu. (3)'' refers to the variant enrichment qualification in a Condition 3 fund; “Std error (3)'' refers to the standard error for experiments performed for a given variant against a background of Condition 3; “Any positive enrichment?” refers to the occurrence of positive enrichment for a given variant under at least one background of the Experimental Condition; “Constant positive enrichment?” refers to the occurrence of positive enrichment for a given variant under all backgrounds of the Experimental Condition analyzed. One hundred eighty-seven (187) variants (~6% of the total) consistently improved the survival rate in all conditions (Table 4). These variants, including the four individually validated, can be stacked on the WT- or M537R / F870L-AsCasY2a, to drive its DNA-cleavage activity in TTTT-PAM. 134 Table 4. Point mutations were consistently enriched for reference proteins under all conditions.1qyq / bn / Lznza / YiAi Qualification Qualification of the Qualification of 5 SEQ ID NO.: M ufante R499C Position .......... of the variant (condition 1) θ14±θ θθ variant (condition 2) ....... .......θ^θθ- the variant (condition 3) ..........θ 06±ü 1 R499L ........... θ θ8±θ θ5 . ............ θ θθ .........θ θ9±θ γθ R499K ......... θ 54±θ θθ ........ ... θ 23±0 θθ .........θ 38±θ 1 L5ÓÓM ...........5θθ ........θ 01±0 Q5 .. ............θ .........θ 2810 12 10 63 T501L....... ...........501... ......... θ 18±0 Q4......... ....0.3210.04.......... .... ..........0.1210.07 T5OÍM ......... ..........θ-^θθ- ........ ..θ 35±007 .........θ 171Ο29 65......... T5Ó1V ......... ........ θ 22±0 Q6 ..........θ 29±0 θθ .........θ 13±θ 2 θθ G5Ó2R .........----- .... ..... θ 14±Q Q5 ..........θ 28±θ θ5 .........θ 98±θ θ7 G5Ó2É ........-- --- .......... θ 42±θ ..........θ 17±θθ8 ......... θ ^9±θ 3 15 68 G502L 502 0.45+0.07 0.110.07 010.11 θθ G5Ó2S ........----- θ θ8±0 θθ ............θ 23^θ θθ ...... .θ 18±θ 12 70..... G5Ó2W .........----- .........θ 14±0 θ7 ...... ......θ θθ±θ θθ .......θ 3θ±θ 14 G502V ..........----- ......... θ 21 ±0 Q5 .............θ 21±θ θθ .........θ 13±θ θ7 L505Á .........----- . .........θ θ1±θ θθ .............θ θ±θ θθ .......θ 47±θ 13 ...... ...73.........L505R .........-----............ ....... --- --------- .............0.56+0.03 ........θ81+θ θ5 20 74 L505Q 505 0.310.07 0.8210.07 0.1610. 11 75 ......L505E ............505..... θ 18±θ θθ......... ... ...........0.0310.07 ..........0.1410.21............ 76 L505G 505 0.1810.03 0.7210.03 0.410. 05 L505H ...........----- ........ θ 3g±0 γγ ..............θ 83±θ . ........θ 34±θ 32 L505K ...........----- .........θ θ2±θ 1 ...... ......1±0 θθ ..............1±θ 13 25 _________________________ .................. .......... _______________________________ .................................. .................................................... .. ________________________________________ 79 L505S 505 0.1310.06 0.3210.06 0.610.07 80 E506A 506 θ 33±θ θ3 0.47+0.03 0.710.05 ........ É506R ........---- - θ 4θ±θ θ3 ..........θ 81±θ θθ .........1 2±θ θ4 82......... É5Ó6Ñ .... .....----- .........θ 24±0 θθ ...........θ 53±θ θθ ........05± 029 30 É506C .........----- ............θ 2±θ θθ ..........θ 29±θ θθ . .......θ 49±θ 19 É5Ó6Q .........----- θ θ9±θ θ7 ..........θ 74±θ θθ ... .....θ 33±θ 18 85 E506G 506 θ 24±θ θ2 0.39+0.02 075310703 86 E506H 506 0.3510.09 0.110.1 0.9810.31 87 E506I 506 0.4710.09 0.4510.09 0.69+0.13 35 88 E506L 506 0.310.04 0.6110.04 0.56+0.07 89 E506K 506 0.1810.06 0.59+0.05 1.08+0.08 90 E506M 506 0.5310.06 0.2810.07 0.4710.17 135 SEQ ID Variant Qualification (Condition 1) Variant Qualification (Condition 2) Variant Qualification (Condition 3) NO.: M ufante Position 91 E506S 506 0.01+0.05 0.4710.04 0.510.06 5 92 E506T 506 0.39+ 0.06 0.12+0.07 0.9+0.23 93 E506Y 506 0.16+0.09 0.2910.09 0.4310.25 94 E506V 506 0.4510.03 0.5110.03 0.75+0.05 95 E508A 508 0 .36+0.03 0.2+0.03 0.18+0.06 96 E508R 508 0.54+0.03 0.810 .03 0.82+0.06 10 97 E508Q 508 0.25+0.06 0.11+0.07 0.51+0.13 98 E508G 508 0.16+0.02 0.1710.02 0.2210.04 99 E508L 508 0.03+0.0 4 0.110.04 0.26+0.11 100 E508K ...... .....508............ ............0.210.06.......... ....... ......0.4910.06 ..........0.66+0.08.......... 101 E508M 508 0.2510.07 0.5710.06 0.5410.11 15 102 E508F 508 0.2710. 08 0.19+0.08 0.39+0.29 103 E508S 508 0.3110.05 0.6210.04 0.3410.06 104 E508T 508 0.1910.06 0.7310.06 0.5510.1 105 E508Y 508 0.3510.09 0.19+0.1 0.2110.27 106 E508V 508 0.1610.03 0.2210 .03 0.3410.05 20 107 P509R 509 0.2310.03 0.27+0.03 1.04+0.05 108 P509K 509 0.0110.07 0.12+0.07 1.29+0.13 109 P509M 509 0.341 0.07 0.34+0.07 0.1+0.22 110 P509S 509 0.110.04 0.14+ 0.04 0.14+0.1 111 P509W 509 0.0410.05 0.33+0.05 0.61+0.18 25 112 P509Y 509 0.1810.09 0.2+0.09 0.53+0.3 113 S510G 510 0.1810. 03 0.49+0.03 0.21+0.06 114 S510L 510 0.5710.06 0.72+0.06 0.74+0.09 115 S512R 512 0.0710.07 0.34+0.07 0.0710.19 116 F513L 513 0.5310.04 0.63+0.04 0.4110.07 30 117 F513W 513 0.0410.06 0.35+0.06 0.2810.13 118 N515A 515 0.610.06 0.8210.06 0.1210 .11 119 N515R 515 0.6310.06 0.82+0.05 0.19+0.11 N515l θ 23±Q Q7 .............θ 3±0 07 .........θ 16± 0 14 N515L θ 33±0 06 ............θ 53±0 θθ ...........00?i02 122 N515T 515 0.41+0.08 0.14+0.08 θ 2g ±Q 16 35 Ϊ23 N515X / ----- ........θ 5±0 05 ............θ 4g±0 θ5 ........ .0 45±0 org 124 K516R 516 0.0110.03 0.26+0.03 0.4+0.06 α^ο / ^η / ίζηζα / γίΛΐ 136 SEQ ID Variant Qualification (Condition 1) Variant Qualification (Condition 2) Variant Qualification (Condition 3) NO.: M ufante Position 125 R518K 518 0.2+0.09 0.7210.08 0.0510.17 5 126 T522L 522 1.1 ± 0.05 0.9210.05 0.2810.1 127 T522M 522 0.92+0.07 0.8110.08 0.5310.21 128 T522V 522 0.16+0.05 0.2810.05 0.04+0.07 129 K523R 52 3 0.1710.02 0.3710.02 0+0.03 130 S527D 527 0.13+0.11 0.0110 .11 0.34+0.41 10 131 V528D 528 0.01+0.07 0.27+0.07 0.12+0.12 132 V528L 528 0.55+0.03 0.5910.03 0.3110.07 133 V528M 528 0.19+ 0.05 0.02+0.05 0.13+0.1 134 .....S542N . ..........542............ ..0.2410.09......... .... .......0.0210.09 ..........0.29+0.07.......... 135 S542C 542 0.0310.17 0.1510.17 0.4210.16 15 136 K550R 550 0.0510.03 0.1810.03 0.17+0.07 137 N551D 551 0.1410.04 0.1510.04 0.6710.07 138 A554I 554 0.1510.09 0.7110.08 0.39+0.34 1 39 A554T 554 0.4510.04 0.3210.05 0.9310.07 140 A554V 554 0.5710 .03 0.4810.03 0.5410.04 20 141 I555V 555 0.4110.03 0.1310.03 0.14+0.06 142 L556M 556 0.0810.08 0.110.08 0.11+0.21 143 V558M 558 0.2410.06 0.15+0.06 0.1+0.12 144 K559A 559 0.1710. 04 0.0810.04 0.1310.08 145 N560A 560 0.3410.05 0.1810.05 0.18+0.08 25 146 N560D 560 0.1610.04 0.1810.04 0.1610.08 147 N560E 560 0.4810.06 0.2810.06 0.1110.25 148 N560M 560 0.1610.09 0.31+0.09 0.18+0.13 149 P569D 569 0.610.08 0.3310.08 1.2510.11 150 Q571A 571 0.6410.07 0.3910.08 1.0910.23 30 151 Q571P 571 0.1710.07 0.6110.07 0.1310.14 152 Q571S 571 0.2510.09 0.210 .09 0.8910.23 153 Q571T 571 0.2210.13 0.1910.13 0.87+0.41 K572E ----- θ11±0 Q4 ........... θ 25±Q Q4 θ 42±Q Q8 Y575G - ---- .......θ----- ............θ 21±0 04 θ 32±θ θ7 156 Y575M 575 0.8910.11 0.2710.12 0.3110. 41 35 157 Κ57θθ ----- .......θ 27±0 θ7 ............θ 25±0 07 ............θ 1±0 2θ 158 S579T 579 0.1710.04 0.3310.04 0.01+0.06 Q / Q / bn / Lznza / YiAi 137 SEQ ID Variant Qualification (Condition 1) Variant Qualification (Condition 2) Variant Qualification (Condition 3) NO.: M ufante Position 159 S579V 579 0.04+0.03 0.0210.03 0.05+0.07 5 160 T583I 583 0.04+ 0.08 0.1110.07 0.07+0.17 161 E584H 584 0.09+0.07 0.2210.07 0.1710.14 162 E584V 584 0.1+0.03 0.0610.03 0.12+0.04 163 K585R 58 5 0.07+0.03 0.32+0.03 0.06+0.05 164 K585F 585 0.51+0.09 0.0410 .09 0.61+0.36 10 165 D596E 596 0.04+0.04 0.24+0.04 0.69+0.05 166 P599G 599 0.84+0.04 0.8310.04 1.0110.05 167 A602C 602 0.64+ 0.09 0.61+0.09 0.73+0.28 168 .....L612M . ..........612........... ............0.7+0.07.......... .. .............0.710.07 ..........0.01+0.03.......... 169 A614R 614 0.2810.04 0.0710.05 0.1610. 05 15 170 A614I 614 0.5210.11 0.5910.11 0.41+0.22 171 T616A 616 0.3210.03 0.2410.04 0.0910.05 172 T616R 616 0.1910.03 0.1210 .03 0.62+0.04 173 T616Q 616 0.3510.07 0.3810.07 0.78+0.2 174 T616G 616 0.2210.03 0.0110.03 0.1610.06 20 175 T616Y 616 0.5410.09 0.6410.09 0.05+0.38 176 A617G 617 0.0310.03 0.0510.03 0.24+0.06 177 F619M 619 0.1210.07 0.55+0.07 0.22+0.25 178 Q620A 620 0.2210.04 010.05 0.1810.09 179 Q620R 620 0.25+0.03 0.1810.03 0.17+0.04 25 180 Q620N 620 0.2610.14 0.2810.14 0.36+0 .21 181 Q620L 620 0.1410.04 0.4510.04 0.4+0.16 182 Q620K 620 0.1 +0.07 0.24+0.07 0.04+0.1 183 T621A 621 0.1810.04 0.1310.04 0.17+0.1 184 H622G 622 0.0510.03 0.1810.03 0.0710.06 30 185 H622S 622 0.1610.06 0.5910.06 0.08+0.1 186 H622T 622 0.0110. 09 0.8410.08 0.3110.34 187 H622V 622 0.1810.05 0.15+0.05 0.31+0.12 188 T623E ----- θ 32±Q Q5 ........... θ 23±Q Q5 θ 02± 0 05 T623H ----- .........----------- ............θ 01±0 1ή 0.58+0.55 190 T623L 623 0.33+0.05 0.18+0.05 017±0 16 35 ' 19j T623M ----- .......θ 21±0 θ7 ............θ 28±007 0.59+ 0.22 192 T623F 623 0.810.1 0.61+0.1 0.47+0.32 Q / Q / frni 7Π7 -1 / ΥΙΛΙ 138 SEQ ID Variant Qualification (Condition 1) Variant Qualification (Condition 2) Variant Qualification (Condition 3) NO.: M ufante Position 193 T624P 624 0.92+0.02 0.92+0.02 0.04+0.03 5 194 L627C 627 0.14+ 0.13 0.84+0.11 0.57+0.48 195 L628C 628 0.31+0.09 0.110.1 0.2910.31 196 L628W 628 0.25+0.06 0.01+0.07 0.67+0.15 197 N630R 630 0.53+0.05 0.06+0.06 0.94+0.08 198 I633N 633 0.16+0.06 0.65 +0.06 0.15+0.1 10 199 I633M 633 0.17+0.07 0.28+0.07 0.1+0.19 200 I633S 633 0.02+0.04 0.35+0.04 0.2210.08 201 E634N 634 0.52+0 .12 0.46+0.12 010.36 202 .....P635A ... .......635............ ..0.0410.05......... ...... .......0.29+0.05 ..........0.59+0.07.......... 203 P635D 635 0.1410.09 0.4910.09 0.5210.14 15 204 P635E 635 0.5110 .06 0.49+0.06 0.7+0.16 205 P635T 635 0.3610.06 0.0610.06 0.0110.08 206 T639G 639 0.5210.06 0.44+0.06 0.06+0.23 207 D840S 840 0.3710.08 0.33+0.08 0.1+0.16 208 A842S 842 0.3610.06 0.0810.06 0.0410.1 20 209 A844E 844 0.38+0.1 0.06+0.1 0.13+0.21 210 T851A 851 0.41+0.06 0.14+0.06 0.08+0.1 211 T851V 851 0.3 2+0.06 0.13+0.06 0.54+0.07 212 E853V 853 0.14+0.07 0.1 +0.07 0.3810.09 213 R862K 862 0.04+0.14 0.54+0.13 0.02+0.38 25 214 S866F 866 0+0.13 0.06+0.12 0.1+0.14 215 S866T 866 0.05+0.1 3 0.02+0.13 0.4+0.15 216 V873A 873 0.16+0.11 0.05+ 0.11 0.08+0.16 217 N878D 878 0.03+0.06 0.02+0.06 0.0410.08 218 Q880R 880 0.13+0.05 0.02+0.05 0.0110.06 30 219 Q880G 880 0.25 +0.04 0.19+0.04 0.6410.05 220 A882D 882 0.3210.05 0.2210.05 0.1+0.07 221 A882S 882 0.11+0.12 0.14+0.11 0.23+0.22 222 N883G θ 42±Q Q8 ........... θ 37±Q Q8 θ 03±0 223 N883K ...... .θ 12l0 16 ............θ 23±0 16 ...........θ 16±0 ή 224 S884V 884 0.05+0.11 0Γ6Ϊ±0.ΐ 0.03+ 0.14 35 225 S886L ----- .......0 og±o 08 ............θ 12±0 θ8 0.05-10 11 226 S886M 886 0.32+0.11 0.15+ 0.11 0.4+0.35 Q / Q / bn / Lznza / YiAi 139 SEQ ID Position Variant Qualification (Condition 1) Variant Qualification (Condition 2) Variant Qualification (Condition 3) NO.: M ufante 227 S886W 886 0.2310.07 0.0110.07 0.710.19 228 Q890C 890 0.0310.11 0.6410.1 0.0810.54 229 Q890H 890 0.3910.09 0.0710.09 0.0410.11 230 Q890W 890 0.0310.08 0.2310.07 0.03+0.08 231 A894R 894 0.1 910.06 0.0610.06 0.0410.08 232 A894D 894 0.0410.06 0.0910. 06 0.2110.05 233 Y895D 895 0.1610.04 010.04 0.0910.04 234 ...

Claims

1. A clustered regularly interspaced short palindromic repeat (“CRISPR”) associated protein characterized in that it comprises a polypeptide encoding a Prevotella and Francisella 1 (“Cpf1”) CRISPR variant (“AsCpfl”) of Acidaminococcus sp. (“AsCpfl”), wherein the AsCpfl variant is selected from the group consisting of M537R (SEQ ID NO.: 472), F870L (SEQ ID NO.: 473), and M537R / F870L (SEQ ID NO.: 465).

2. The CRISPR-associated protein according to claim 1, characterized in that the AsCpfl variant is M537R (SEQ ID NO.: 472).

3. The CRISPR-associated protein according to claim 1, characterized in that the AsCpfl variant is F870L (SEQ ID NO.: 473).

4. The CRISPR-associated protein according to claim 1, characterized in that the AsCpfl variant is M537R / F870 (SEQ ID NO.: 465).

5. A CRISPR ribonucleoprotein complex, characterized in that it comprises: a guide RNA; and a CRISPR-associated protein comprising a polypeptide encoding a variant of AsCpfl, wherein the AsCpfl variant is selected from the group consisting of M537R (SEQ ID NO.: 472), F870L (SEQ ID NO.: 473), and M537R / F870L (SEQ ID NO.: 465).

6. The CRISPR ribonucleoprotein complex according to claim 5, characterized in that the AsCpfl variant is M537R (SEQ ID NO.: 472).

7. The CRISPR ribonucleoprotein complex according to claim 5, characterized in that the AsCpfl variant is F870L (SEQ ID NO.: 473) 8. The CRISPR ribonucleoprotein complex according to claim 5, characterized in that the AsCpfl variant is M537R / F870 (SEQ ID NO.: 465).

9. A method for increasing the efficiency of gene editing at protospacer (“PAM”) adjacent motif sites TTTN in a cell with a CRISPR ribonucleoprotein complex, characterized in that it comprises: contacting a cell with the CRISPR ribonucleoprotein complex according to any of claims 5-8.

10. The method according to claim 9, characterized in that the TTTN PAM sites consist of one selected from the group of TTTA, TTTT and TTTC PAM sites.

11. A kit characterized in that it comprises a guide RNA and a CRISPR-associated protein comprising a polypeptide encoding a variant of AsCpfl, wherein the 176 variant of AsCpfl is selected from the group consisting of M537R (SEQ ID NO.: 472), F870L (SEQ ID NO.: 473), and M537R / F870L (SEQ ID NO.: 465).

12. The kit according to claim 11, characterized in that the variant of AsCpfl is M537R (SEQ ID NO.: 472).

13. The kit according to claim 11, characterized in that the variant of AsCpfl is F870L (SEQ ID NO.: 473).

14. The kit according to claim 11, characterized in that the AsCpfl variant is M537R / F870L (SEQ ID NO.: 465).

15. A CRISPR-associated protein characterized in that it comprises a polypeptide encoding a variant of CRISPR-associated protein 12a (“AsCas12a”) from Acidaminococcus sp. (“AsCas12a”), wherein the AsCas12a variant is selected from the pool consisting of at least one amino acid variant selected from amino acid positions 499-640 and 840-913, provided that the AsCas12a variant provides an enhancement of CRISPR / AsCas12a-associated nuclease activity at non-canonical TTTT PAM sites.

16. The CRISPR-associated protein according to claim 15, characterized in that the AsCas12a variant is selected from the group consisting of SEQ ID Nos.: 59-245.

17. The CRISPR-associated protein according to claim 15 or 16, characterized in that the AsCas12a variant further comprises M537R / F870L mutations (SEQ ID NO.: 465).

18. A CRISPR ribonucleoprotein complex, characterized in that it comprises: a guide RNA; and a CRISPR-associated protein comprising a polypeptide encoding a variant of AsCas12a, wherein the AsCas12a variant is selected from the pool consisting of at least one amino acid variant selected from amino acid positions 499-640 and 840-913, provided that the AsCas12a variant provides an enhancement in CRISPR / AsCas12a-associated nuclease activity at non-canonical TTTT PAM sites.

19. The CRISPR ribonucleoprotein complex according to claim 18, characterized in that the AsCas12a variant is selected from the group consisting of SEQ ID Nos.: 59-245.

20. The CRISPR ribonucleoprotein complex according to claim 18 or 19, characterized in that the AsCas12a variant further comprises M537R / F870L mutations (SEQ ID NO.: 465).

21. A method for increasing the efficiency of gene editing at non-canonical TTTT PAM sites in a cell with a CRISPR ribonucleoprotein complex, characterized in that it comprises: Q / Q / bn / Lznza / YiAi 177 contacting a cell with the CRISPR ribonucleoprotein complex according to any of claims 18-20.

22. A kit characterized in that it comprises a guide RNA and a CRISPR-associated protein comprising a polypeptide encoding a variant of AsCas12a, wherein the AsCas12a variant is selected from the group consisting of at least one amino acid variant selected from amino acid positions 499-640 and 840-913, provided that the AsCas12a variant provides an enhancement of CRISPR / AsCas12a-associated nuclease activity at non-canonical TTTT PAM sites.

23. The kit according to claim 22, characterized in that the variant of AsCas12a is selected from the group consisting of SEQ ID Nos.: 59-245.

24. The kit according to claims 22 or 23, characterized in that the AsCas12a variant further comprises mutations of M537R / F870L (SEQ ID NO.: 465).

25. A nucleic acid characterized in that it encodes a CRISPR-associated protein comprising a polypeptide encoding a variant of AsCas12a, wherein the AsCas12a variant is selected from the pool consisting of at least one amino acid variant selected from amino acid positions 499-640 and 840-913, provided that the AsCas12a variant provides an enhancement in CRISPR / AsCas12a-associated nuclease activity at non-canonical TTTT PAM sites.

26. The nucleic acid according to claim 25, characterized in that the AsCas12a variant is selected from the group consisting of SEQ ID Nos.: 59-245.

27. The nucleic acid according to claim 25 or 26, characterized in that the AsCas12a variant further comprises M537R / F870L mutations (SEQ ID NO.: 465).

28. The nucleic acid according to claims 25-27, characterized in that the nucleic acid is operatively linked to transcription elements suitable for expressing the nucleic acid.

29. The nucleic acid according to claims 25-28, characterized in that the nucleic acid is either DNA or RNA.

30. A polynucleotide sequence encoding a Cas12a polypeptide, characterized in that it comprises a selected member of the group consisting of SEQ ID NOs.: 5-17.

31. An amino acid sequence encoding a Casi 2a polypeptide, characterized in that it comprises a selected member of the group consisting of SEQ ID NOs.: 18-30.

32. A CRISPR-associated endonuclease (“CAS”) system characterized in that it comprises an expression cassette encoding a polynucleotide sequence oyo / bni zdz-1 / uili 178 encoding a Cas12a polypeptide, comprising a member selected from the group consisting of SEQ ID Nos.: 5-17.

33. A CAS endonuclease system characterized in that it comprises an amino acid sequence encoding a Cas12a polypeptide, comprising a member selected from the group consisting of SEQ ID NOs.: 18-30.

34. A method for performing genome editing in a eukaryotic cell, characterized in that it comprises: introducing a CAS endonuclease system into the eukaryotic cell, said CAS endonuclease system comprising an expression cassette encoding a polynucleotide sequence encoding a Cas12a polypeptide, comprising a member selected from the group consisting of SEQ ID NOs.: 5-17.

35. A method for performing genome editing in a eukaryotic cell, characterized in that it comprises: introducing a CAS endonuclease system into the eukaryotic cell, said CAS endonuclease system comprising an amino acid sequence encoding a Cas12a polypeptide comprising a member selected from the group consisting of SEQ ID NOs.: 1830.

36. A CRISPR-associated protein characterized in that it comprises a fusion polypeptide encoding an open AsCas12a reading frame, a nuclear localization signal, optionally an amino acid linker, and optionally an affinity tag.

37. The CRISPR-associated protein according to claim 36, characterized in that the open reading frame of AsCas12a is selected from the group consisting of SEQ ID Nos.: 59-245.

38. The CRISPR-associated protein according to claim 36, characterized in that the nuclear localization signal is selected from SEQ ID Nos.: 475, 477, 479, 481 and 483.

39. The CRISPR-associated protein according to claim 36, characterized in that the CRISPR-associated protein is encoded by SEQ ID Nos.: 488491.

40. The CRISPR-associated protein according to claim 36, characterized in that the CRISPR-associated protein is selected from SEQ ID Nos.: 492 and 493.

41. A method for performing genome editing in a eukaryotic cell, characterized in that it comprises: introducing a CAS endonuclease system into the eukaryotic cell, said CAS endonuclease system comprising a CRISPR-associated protein according to claims 36-40.