Xylanase variants and polynucleotides encoding the same

Abstract

To provide a xylanase variant of a parent xylanase, the xylanase variant having increased thermostability when compared to the parent xylanase.SOLUTION: The present invention relates to xylanase variants of a parent xylanase, wherein the xylanase variant has increased thermostability when compared to the parent xylanase. The present invention also relates to polynucleotides encoding the variants, nucleic acid constructs, vectors, and host cells comprising the polynucleotides as well as methods of producing the variants of the invention.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Sequence Listing Reference This application contains a Sequence Listing in computer readable format, which is incorporated herein by reference.

[0002] The present invention relates to polypeptides having xylanase activity and polynucleotides encoding the polypeptides. The invention also relates to nucleic acid constructs, vectors, and host cells comprising the polynucleotides, as well as methods for producing and using the polynucleotides. The invention also relates to compositions comprising the polypeptides of the invention and to the use of the polypeptides of the invention to improve starch and / or gluten yield from corn kernels in a wet-milling process. [Background technology]

[0003] Conventional wet milling of corn is a process designed to recover and purify starch and several by-products, such as germ, gluten (protein), and fiber. Fiber is the lowest-value by-product, and as such, the industry is making great efforts to increase the yield of more valuable products, such as starch and gluten, while decreasing the proportion of fiber. High-quality starch is highly valuable because it can be used for a variety of commercial purposes after further processing into products such as dry starch, modified starch, dextrins, sweeteners, and alcohol. Gluten is typically used in animal feed as corn gluten meal (about 60% protein) or corn gluten feed (about 20% protein).

[0004] While the wet milling process can vary widely depending on the specific milling equipment used, the process typically involves washing the grain, soaking, milling, germ separation, a second milling, fiber separation, gluten separation, and starch separation. After washing the corn kernels, the kernels are typically softened by soaking in water or a dilute SO2 solution under controlled conditions of time and temperature. The kernels are then milled to break down the pericarp and separate the germ from the rest of the kernel. The remaining slurry, consisting primarily of fiber, starch, and gluten, is finely milled and sieved in a fiber washing process to separate the fiber from the starch and gluten, after which the gluten and starch are separated and the starch can be refined in a washing / filtration process.

[0005] The use of enzymes in some steps of the wet-milling process has been proposed, such as for the steeping step of the wet-milling process. The commercially available enzyme product Steepzyme® (available from Novozymes A / S) has been shown to be suitable for the first step in the wet-milling process, i.e., the steeping step in which the corn kernels are soaked in water.

[0006] Recently, a modified wet-milling process, "enzymatic milling," has been developed that uses proteases to significantly reduce the total processing time during corn wet-milling and eliminates the need for sulfur dioxide as a processing agent. Johnston et al., Cereal Chem, 81, pp. 626-632 (2004).

[0007] U.S. Pat. No. 6,566,125 discloses a method for obtaining starch from corn, comprising steeping corn kernels in water to form steeped corn kernels, grinding the steeped corn kernels to form a ground corn slurry, and incubating the ground corn slurry with an enzyme (e.g., protease).

[0008] U.S. Pat. No. 5,066,218 discloses a method for grinding grain, particularly corn, which includes washing the grain, soaking the grain in water to soften it, and then grinding the grain with a cellulase enzyme.

[0009] WO 2002 / 000731 discloses a method for treating crop kernels, which comprises soaking the kernels in water for 1 to 12 hours, wet-milling the soaked kernels, and treating the kernels with one or more enzymes, such as an acid protease.

[0010] WO 2002 / 000911 discloses a method for starch gluten separation, which comprises exposing ground starch to an acid protease.

[0011] WO 2002 / 002644 discloses a method for washing a starch slurry obtained from the starch gluten separation step of a milling process, the method comprising washing the starch slurry with an aqueous solution containing an effective amount of an acid protease.

[0012] WO 2014 / 082566 and WO 2014 / 082564 disclose cellulolytic compositions for use in wet milling.

[0013] Although the art has investigated the effects of using enzymes during corn wet milling, corn kernel steeping / soaking, corn kernel milling, and starch gluten separation, there remains a need for improved enzyme technologies that can reduce the energy consumption and costs associated with corn wet milling and increase starch and gluten yields.

[0014] WO 2016 / 005522 discloses a GH5 xylanase gene isolated from Chryseobacterium sp.-10696 as SEQ ID NO:25 and the encoded polypeptide as SEQ ID NO:26.

[0015] WO 2019 / 023222 discloses a method for improving the total starch yield and / or total gluten yield obtainable from corn kernels in a wet milling process, the method comprising mixing corn kernels or a fraction of corn kernels with an enzyme composition comprising an effective amount of one or more hydrolytic enzymes, at least one of which is selected from the group consisting of a GH30 polypeptide, a GH5 polypeptide, and combinations thereof. Summary of the Invention [Means for solving the problem]

[0016] The present invention provides xylanase variants that have improved properties compared to their parents.

[0017] The present invention provides xylanase variants that have improved properties compared to the parent xylanase.

[0018] The present invention relates to xylanase variants of a parent xylanase comprising substitutions at one or more positions corresponding to positions 45, 149, 364, 258, 276 and 388 of SEQ ID NO:1, wherein the xylanase variants have at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO:1, and have xylanase activity and increased thermostability compared to the xylanase of SEQ ID NO:1.

[0019] The present invention relates to xylanase variants of parent xylanases, including those of SEQ ID NO: 1, 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, The present invention also relates to xylanase variants that further comprise substitutions at one or more positions corresponding to positions 526, 527, 528, 529, 530, and 540, and have at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO:1, and have xylanase activity and increased thermostability compared to the xylanase of SEQ ID NO:1.

[0020] The present invention also relates to compositions comprising the xylanase variants of the present invention.

[0021] The present invention also relates to polynucleotides encoding the variants of the present invention, nucleic acid constructs comprising polynucleotides encoding the variants of the present invention, expression vectors comprising polynucleotides encoding the variants of the present invention, and host cells comprising polynucleotides encoding the variants of the present invention.

[0022] The present invention also relates to a method for producing a xylanase variant, comprising (a) culturing a host cell of the present invention under conditions suitable for expression of the variant, and (b) recovering the variant.

[0023] The present invention provides a method for obtaining a xylanase variant of a parent xylanase, comprising the step of introducing substitutions at one or more positions corresponding to positions 45, 149, 364, 258, 276 and 388 of SEQ ID NO: 1, thereby providing a xylanase variant of said parent xylanase, said variant having an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118%, at least 119%, at least 120%, at least 121%, at least 122%, at least 123%, at least 124%, at least 125%, at least 126%, at least 127%, at least 128%, at least 129%, at least 130%, at least 131%, at least 132%, at least 133%, at least 134%, at least 135%, at least 136%, at least 137%, at least 138%, at The present invention further relates to a method of preparing a xylanase variant having at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity but less than 100%, wherein the variant has a xylanase, and the xylanase variant has increased thermostability compared to the xylanase of SEQ ID NO: 1.

[0024] The present invention also relates to a method for increasing starch and / or gluten yield from corn kernels in a wet-milling process, comprising contacting corn kernels or a fraction of the corn kernels, particularly a fiber-rich fraction, with an effective amount of a xylanase variant of the present invention and optionally one or more hydrolytic enzymes.

[0025] The present invention also relates to methods for producing fermentation products, such as ethanol, from starch- or cellulose-containing materials using fermenting organisms.

[0026] The present invention also relates to an enzyme blend or enzyme composition comprising at least one or more xylanase variants of the present invention.

[0027] The present invention also relates to recombinant host cells comprising a heterologous polynucleotide encoding at least one or more xylanase variants of the present invention.

[0028] The present invention also relates to (i) compositions (e.g., fermented or fermented mash compositions) comprising a recombinant host cell or fermenting organism comprising a heterologous polynucleotide encoding an alpha-amylase and / or protease and at least one or more xylanase variants of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0029] definition In accordance with this Detailed Description, the following definitions apply: Please note that the singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise.

[0030] Reference herein to "about" a value or parameter includes aspects directed to that value or parameter itself. For example, a description that refers to "about X" includes the aspect "X."

[0031] Unless otherwise defined or clearly indicated by context, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0032] Allelic variant: The term "allelic variant" refers to any of two or more alternative forms of a gene occupying the same chromosomal locus. Allelic variations arise naturally through mutation and can result in polymorphism within a population. Gene mutations can be silent (no change in the encoded polypeptide) or can encode a polypeptide with an altered amino acid sequence. An allelic variant of a polypeptide is one encoded by an allelic variant of a gene.

[0033] Amino Acid: As used herein, the term "amino acid" refers to the 20 standard genetically encoded amino acids and their corresponding stereoisomers of the "d" form (as compared to the naturally occurring "l" form), omega-amino acids, other naturally occurring amino acids, unconventional amino acids (e.g., α,α-disubstituted amino acids, N-alkyl amino acids, etc.), and chemically derivatized amino acids. Chemical derivatives of one or more amino acids can be obtained by reaction with a functional side group. Such derivatized molecules include, for example, molecules in which a free amino group has been derivatized to form an amine hydrochloride, p-toluenesulfonyl group, carboxybenzoxy group, t-butyloxycarbonyl group, chloroacetyl group, or formyl group. Free carboxyl groups can be derivatized to form salts, methyl and ethyl esters or other types of esters, and hydrazides. Free hydroxyl groups can be derivatized to form O-acyl or O-alkyl derivatives. Also included as chemical derivatives are peptides containing naturally occurring amino acid derivatives of the 20 standard amino acids. For example, proline may be substituted with 4-hydroxyproline; lysine with 5-hydroxylysine; histidine with 3-methylhistidine; serine with homoserine; and lysine with ornithine. Derivatives also include peptides containing one or more additions or deletions, so long as the required activity is maintained. Other included modifications are amidation, amino-terminal acylation (e.g., acetylation or thioglycolic acid amidation), terminal carboxyamidation (e.g., with ammonia or methylamine), and similar terminal modifications.

[0034] When an amino acid is specifically listed (e.g., "alanine" or "Ala" or "A"), the term refers to both l-alanine and d-alanine unless otherwise specified. Other non-conventional amino acids may also be suitable components of the polypeptides of the invention, so long as the desired functional properties are retained by the polypeptide. When peptides are depicted, each encoded amino acid residue is represented, where appropriate, by a single-letter designation corresponding to the trivial name of the conventional amino acid. In one embodiment, the polypeptides of the invention comprise or consist of 1-amino acids.

[0035] Arabinofuranosidase / Polypeptide with Arabinofuranosidase Activity: The term "arabinofuranosidase" refers to an alpha-L-arabinofuranoside arabinofuranohydrolase (EC 3.2.1.55) that catalyzes the hydrolysis of terminal non-reducing alpha-L-arabinofuranoside residues in alpha-L-arabinosides. This enzyme acts on alpha-L-arabinofuranosides, alpha-L-arabinans containing (1,3)- and / or (1,2)- and / or (1,5)-linkages, arabinoxylans, and arabinogalactans. Alpha-L-arabinofuranosidase is also known as arabinosidase, alpha-arabinosidase, alpha-L-arabinosidase, alpha-arabinofuranosidase, polysaccharide alpha-L-arabinofuranosidase, alpha-L-arabinofuranoside hydrolase, L-arabinosidase, or alpha-L-arabinanase. Arabinofuranosidase activity can be determined using 5 mg of medium viscosity wheat arabinoxylan (Megazyme International Ireland, Ltd., Bray, Co. Wicklow, Ireland) per ml of 100 mM sodium acetate pH 5 in a total volume of 200 μl for 30 minutes at 40° C., followed by arabinose analysis by AMINEX® HPX-87H column chromatography (Bio-Rad Laboratories, Inc., Hercules, CA, USA). Arabinofuranosidases can be found in the GH43, GH62, and GH51 families, for example, according to Henrissat, 1991, "A classification of glycosyl hydrolases based on amino-acid sequence similarities," Biochem. J. 280:309-316, and Henrissat and Bairoch, 1996, "Updating the sequence-based classification of glycosyl hydrolases," Biochem. J. 316:695-696.

[0036] Beta-glucosidase / Polypeptide Having Beta-glucosidase Activity: The term "beta-glucosidase" refers to a beta-D-glucoside glucohydrolase (EC 3.2.1.21) that catalyzes the hydrolysis of terminal non-reducing beta-D-glucose residues with the release of beta-D-glucose. Beta-glucosidase activity can be determined using p-nitrophenyl-beta-D-glucopyranoside as a substrate according to the procedure of Venturi et al., 2002, J. Basic Microbiol. 42:55-66. One unit of beta-glucosidase is defined as 1.0 μmole of p-nitrophenolate anion produced per minute from 1 mM p-nitrophenyl-beta-D-glucopyranoside as a substrate in 50 mM sodium citrate containing 0.01% TWEEN® 20 at 25°C, pH 4.8.

[0037] Beta-xylosidase / Polypeptide Having Beta-Xylosidase Activity: The term "beta-xylosidase" refers to a beta-D-xyloside xylohydrolase (EC 3.2.1.37) that catalyzes the exohydrolysis of short beta(1→4)-xylooligosaccharides to sequentially remove D-xylose residues from the non-reducing ends. Beta-xylosidase activity can be determined using 1 mM p-nitrophenyl-beta-D-xyloside as a substrate in 100 mM sodium citrate containing 0.01% TWEEN® 20 at pH 5 and 40°C. One unit of beta-xylosidase is defined as 1.0 μmole of p-nitrophenolate anion produced per minute from 1 mM p-nitrophenyl-beta-D-xyloside in 100 mM sodium citrate containing 0.01% TWEEN® 20 at 40°C and pH 5.

[0038] Cellobiohydrolase / Polypeptides with Cellobiohydrolase Activity: The term "cellobiohydrolase" refers to 1,4-beta-D-glucan cellobiohydrolases (EC 3.2.1.91 and EC 3.2.1.176) that catalyze the hydrolysis of 1,4-beta-D-glucosidic linkages in cellulose, cellooligosaccharides, or any beta-1,4-linked glucose-containing polymer, releasing cellobiose from either the reducing end (cellobiohydrolase I) or the non-reducing end (cellobiohydrolase II) of the chain (Teeri, 1997, Trends in Biotechnology 15:160-167; Teeri et al., 1998, Biochem. Soc. Trans. 26:173-178). Cellobiohydrolase activity can be determined according to the procedures described by Lever et al., 1972, Anal. Biochem. 47:273-279; van Tilbeurgh et al., 1982, FEBS Letters 149:152-156; van Tilbeurgh and Claeyssens, 1985, FEBS Letters 187:283-288; and Tomme et al., 1988, Eur. J. Biochem. 170:575-581.

[0039] Contact time: In order for one or more enzymes to react with a substrate, the enzyme(s) must be in contact with the substrate. "Contact time" refers to the period of time during which an effective amount of one or more enzymes is in contact with at least a portion of the substrate mass. The enzyme(s) need not be in contact with all of the substrate mass during this contact time, but mixing the enzyme(s) with the substrate mass allows them to enzymatically catalyze the hydrolysis of a portion of the substrate mass during this contact time.

[0040] Cellulolytic enzymes or cellulases / polypeptides with cellulase activity or cellulolytic activity: The terms "cellulolytic enzyme," "cellulase," and "cellulolytic activity" or "polypeptides with cellulolytic activity" are used interchangeably herein to refer to one or more (e.g., several) enzymes that hydrolyze cellulosic materials, including any cellulose-containing material such as fibers. Cellulolytic enzymes include endoglucanases (EC 3.2.1.4), cellobiohydrolases (EC 3.2.1.91 and EC 3.2.1.150), beta-glucosidases (EC 3.2.1.21), or combinations thereof. As outlined in Zhang et al., 2006, Biotechnology Advances 24:452-481, basic approaches to measuring cellulolytic enzyme activity include (1) measuring total cellulolytic enzyme activity and (2) measuring individual cellulolytic enzyme activities (endoglucanases, cellobiohydrolases, and beta-glucosidases). Total cellulolytic enzyme activity can be measured using insoluble substrates (e.g., Whatman No. 1 filter paper, microcrystalline cellulose, bacterial cellulose, algal cellulose, cotton, pretreated lignocellulose, etc.). The most common total cellulolytic activity assay is the filter paper assay, which uses Whatman No. 1 filter paper as the substrate. This assay was established by the International Union of Pure and Applied Chemistry (IUPAC) (Ghose, 1987, Pure Appl. Chem. 59:257-68).

[0041] Cellulolytic enzyme activity may also be determined by measuring the increase in sugar production / release during hydrolysis of cellulosic material with cellulolytic enzymes under the following conditions: a suitable temperature (e.g., 40°C to 80°C, e.g., 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, or 80°C) and a suitable pH (e.g., 4 to 9, e.g., 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, or 9.0) at 1 to 50 mg of cellulolytic enzyme protein / g of cellulose in pretreated corn stover (PCS) (or other pretreated cellulosic material) for 3 to 7 days, compared to a control hydrolysis in which no cellulolytic enzyme protein is added. Typical conditions were: 1 ml reaction, washed or unwashed PCS, 5% insoluble solids (dry weight), 50 mM sodium acetate pH 5, 1 mM MnSO, ​​50°C, 55°C, or 60°C, 72 hours, sugar analysis by AMINEX® HPX-87H column chromatography (Bio-Rad Laboratories, Inc., Hercules, CA, USA).

[0042] Corn Kernel: Various corn kernels are known, including dent corn, flint corn, pod corn, striped maize, sweet corn, waxy corn, and the like. Some corn kernels have an outer covering called the "pericarp" that protects the embryo within the kernel. The pericarp is resistant to water and water vapor and is undesirable to insects and microorganisms. The only area of ​​the kernel not covered by the "pericarp" is the "tip cap," which is the attachment of the kernel to the cob.

[0043] Corn kernel or corn kernel fraction: This term is used to describe corn kernel that has undergone the process of wet milling. When used to break down and process corn kernels, all fractional portions of the corn kernel are considered to be included. This term includes, for example, soaked kernels, milled kernels, corn kernel chunks, a first fraction, a second fraction, one or more fractions of the corn kernel chunks, etc.

[0044] Corn kernel mass: Preferably used to refer to a mass containing fiber, gluten, and starch, preferably obtained by steaming and crushing the kernels of a crop and separating the mass containing fiber, gluten, and starch from the germ. When the corn kernel mass undergoes fiber washing, it is separated into several fractions (e.g., a first fraction and a second fraction). Thus, "a fraction of the corn kernel mass" and "one or more fractions of the corn kernel mass" refer specifically to the first fraction (s) and the second fraction (f).

[0045] cDNA: The term "cDNA" refers to a DNA molecule that can be prepared by reverse transcription from a mature, spliced ​​mRNA molecule obtained from a eukaryotic or prokaryotic cell. cDNA lacks intron sequences that may be present in the corresponding genomic DNA. The initial, primary RNA transcript is a precursor to mRNA that is processed through a series of steps, including splicing, before appearing as the mature, spliced ​​mRNA.

[0046] Coding sequence: The term "coding sequence" refers to a polynucleotide that directly specifies the amino acid sequence of a polypeptide. The boundaries of the coding sequence are generally determined by an open reading frame, which begins with a start codon such as ATG, GTG, or TTG and ends with a stop codon such as TAA, TAG, or TGA. The coding sequence can be genomic DNA, cDNA, synthetic DNA, or a combination thereof.

[0047] Control sequence: The term "control sequence" refers to a nucleic acid sequence necessary for expression of a polynucleotide encoding a mature polypeptide of the present invention. Each control sequence can be native (i.e., from the same gene) or foreign (i.e., from different genes) to the polynucleotide encoding the polypeptide, and can be native or foreign to each other. Such control sequences include, but are not limited to, a leader, polyadenylation sequence, propeptide sequence, promoter, signal peptide sequence, and transcription terminator. At a minimum, control sequences include a promoter and transcriptional and translational stop signals. Control sequences may be provided with linkers for the purpose of introducing specific restriction sites to facilitate ligation of the control sequence with the coding region of a polynucleotide encoding the polypeptide.

[0048] Corresponding to: The term "corresponding to," as used herein, refers to a method of determining a particular amino acid of a sequence when referring to a particular amino acid sequence. For example, for purposes of the present invention, when referring to a particular amino acid position, one of skill in the art could align another amino acid sequence to the amino acid sequence being referred to in order to determine which particular amino acid may be of interest in that other amino acid sequence. Alignment of another amino acid sequence with, for example, the sequence set forth in SEQ ID NO: 1 or any other sequence listed herein is described elsewhere herein. Alternative alignment methods may be used and are known to those of skill in the art.

[0049] "Expression": The term "expression" includes all steps involved in the production of a polypeptide, including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion.

[0050] Expression vector: The term "expression vector" means a linear or circular DNA molecule containing a polynucleotide encoding a polypeptide, operably linked to a control sequence that provides for the expression of that molecule.

[0051] Endoglucanase: The term "endoglucanase" refers to endo-1,4-(1,3;1,4)-beta-D-glucan 4-glucanohydrolase (EC 3.2.1.4), which catalyzes the endohydrolysis of beta-1,4 linkages in cellulose, cellulose derivatives (e.g., carboxymethylcellulose and hydroxyethylcellulose), lichenin, mixed beta-1,3 glucans such as cereal beta-D-glucans or xyloglucans, and 1,4-beta-D-glycosidic linkages in other plant materials containing cellulosic components. Endoglucanase activity can be determined by measuring the decrease in substrate viscosity or the increase in reducing ends as determined by a reducing sugar assay (Zhang et al., 2006, Biotechnology Advances 24:452-481). For purposes of the present invention, endoglucanase activity is determined at pH 5 and 40°C using carboxymethylcellulose (CMC) as a substrate according to the procedure of Ghose, 1987, Pure and Appl. Chem. 59:257-268.

[0052] Family 61 glycoside hydrolase: The term "family 61 glycoside hydrolase," or "family GH61," or "GH61" refers to a polypeptide classified as glycoside hydrolase family 61 according to Henrissat, 1991, "A classification of glycosyl hydrolases based on amino-acid sequence similarities," Biochem. J. 280:309-316, and Henrissat and Bairoch, 1996, "Updating the sequence-based classification of glycosyl hydrolases," Biochem. J. 316:695-696. Enzymes in this family were originally classified as glycoside hydrolases based on the measurement of very weak endo-1,4-beta-D-glucanase activity of one family member. The structure and mechanism of action of these enzymes are non-canonical and cannot be considered true glycosidases. However, they are retained in the CAZy classification based on their ability to enhance lignocellulose degradation when used in combination with a cellulase or mixture of cellulases. GH61 polypeptides have recently been classified as lytic polysaccharide monooxygenases (Quinlan et al., 2011, Proc. Natl. Acad. Sci. USA 208:15079-15084; Phillips et al., 2011, ACS Chem. Biol. 6:1399-1406; Lin et al., 2012, Structure 20:1051-1061) and are referred to as "auxiliary activity 9" or "AA9" polypeptides.

[0053] Fragment: The term "fragment" refers to a polypeptide having one or more (e.g., several) amino acids not present at the amino and / or carboxyl terminus of the mature polypeptide, which fragment has xylanase activity.

[0054] Embryo: The "embryo" is the only living part of the corn kernel. It contains the genetic information, enzymes, vitamins, and minerals necessary for the kernel to develop into a corn plant. In yellow dent corn, about 25 percent of the embryo is corn oil. The endosperm, which is covered or surrounded by the embryo, makes up about 82 percent of the kernel's dry weight and is the seed's source of energy (starch) and protein during germination. There are two types of endosperm: soft and hard. In hard endosperm, the starch is tightly packed. In soft endosperm, the starch is loose.

[0055] GH5 polypeptide: refers to a polypeptide with enzymatic activity, which is classified as a member of glycoside hydrolase family 5 in the Carbohydrate-Active enZYmes (CAZymes) (http: / / www.cazy.org / ) database.

[0056] GH8 polypeptide: refers to a polypeptide having enzymatic activity, which is classified as a member of glycoside hydrolase family 8 in the Carbohydrate-Active enZYmes (CAZymes) (http: / / www.cazy.org / ) database.

[0057] GH10 polypeptide: refers to a polypeptide with enzymatic activity, which is classified as a member of glycoside hydrolase family 10 in the Carbohydrate-Active enZYmes (CAZymes) database available at http: / / www.cazy.org / (Lombard, V.; Golaconda Ramulu, H.; Drula, E.; Coutinho, PM; Henrissat, B. (21 November 2013) "The carbohydrate-active enzymes database (CAZy) in 2013". Nucleic Acids Research. 42(D1):D490-D495; Cantarel BL, Coutinho PM, Rancurel C, Bernard T, Lombard V, Henrissat B (January 2009) "The Carbohydrate-Active EnZymes database (CAZy): an expert resource for Glycogenomics". Nucleic Acids Res. 37(Database issue):D233-8).

[0058] GH11 polypeptide refers to a polypeptide having enzymatic activity, and this polypeptide is classified as a member of glycoside hydrolase family 11 in the Carbohydrate-Active enZYmes (CAZymes) database.

[0059] GH30 polypeptide: refers to a polypeptide having enzymatic activity, which is classified as a member of glycoside hydrolase family 30 in the Carbohydrate-Active enZYmes (CAZymes) (http: / / www.cazy.org / ) database.

[0060] GH62 polypeptide: refers to a polypeptide having enzymatic activity, which is classified as a member of glycoside hydrolase family 62 in the Carbohydrate-Active enZYmes (CAZymes) database.

[0061] GH43 polypeptide: refers to a polypeptide having enzymatic activity, which is classified as a member of glycoside hydrolase family 43 in the Carbohydrate-Active enZYmes (CAZymes) database.

[0062] GH51 polypeptide: refers to a polypeptide having enzymatic activity, which is classified as a member of glycoside hydrolase family 51 in the Carbohydrate-Active enZYmes (CAZymes) database.

[0063] Gluten: Gluten is a protein composed of two smaller proteins, glutenin and gliadin. Here, "gluten" refers to the majority of the protein found in corn kernels. The primary products of gluten from corn wet-milling are corn gluten meal (about 60% protein) and corn gluten feed (about 20% protein).

[0064] Grinding or Comminuting: The term "comminuting" refers to breaking down corn kernels into smaller components.

[0065] Host cell: The term "host cell" refers to any cell type that is susceptible to transformation, transfection, transduction, or the like, with a nucleic acid construct or expression vector containing a polynucleotide of the invention. The term "host cell" encompasses any progeny of a parent cell that is not identical to the parent cell due to mutations that occur during replication.

[0066] Hyperbranched xylan: The term "hyperbranched xylan" means that more than 50% of the xylosyl units in the arabinoxylan backbone are substituted, preferably as calculated from the chain analysis carried out in Huismann et al. Carbohydrate Polymers, 2000, 42:269-279.

[0067] Hydrolase or Hydrolase / Polypeptide with Hydrolase Activity: "Hydrolytic enzyme" and polypeptide with hydrolase activity are used interchangeably herein and refer to any catalytic protein that uses water to break down a substrate. Hydrolytic enzymes include cellulases (EC 3.2.1.4), xylanases (EC 3.2.1.8), arabinofuranosidases (EC 3.2.1.55 (non-reducing-end alpha-L-arabinofuranosidases); EC 3.2.1.185 (non-reducing-end beta-L-arabinofuranosidases), cellobiohydrolase I (EC 3.2.1.150), cellobiohydrolase II (EC 3.2.1.91), cellobiosidase (EC 3.2.1.176), beta-glucosidase (EC 3.2.1.21), and beta-xylosidase (EC 3.2.1.37).

[0068] Isolated: The term "isolated" refers to a substance in a form or setting that is not found in nature. Non-limiting examples of isolated substances include: (1) any substance that is not naturally occurring; (2) any substance that is at least partially removed from one or more or all of the naturally occurring components with which it is associated in nature (e.g., without limitation, any enzyme, variant, nucleic acid, protein, peptide, or cofactor); (3) any substance that has been modified by the hand of man compared to the substance found in nature; or (4) any substance that has been modified by increasing the amount relative to other components with which it is naturally associated (e.g., recombinant production in a host cell; multiple copies of the gene encoding the substance; and use of a more aggressive promoter compared to the promoter naturally associated with the gene encoding the substance).

[0069] Incubation time: The time during fiber washing that one or more fractions of the corn kernel mass are in contact with the hydrolytic enzyme without being screened. In many preferred embodiments, the methods of the present invention utilize a system that includes a space (V) or "incubator" within which the material "remains affected" by the enzyme; in such situations, the incubation time is

number

number

[0070] Grinding Equipment: "Grinding Equipment" refers to all equipment used by a mill. The wet milling process varies depending on the milling equipment available. Examples of milling equipment can be immersion tanks, evaporators, screw presses, rotary dryers, dewatering screens, centrifuges, hydrocyclones, etc. The size and number of each milling equipment / grinding line can vary in different mills and affect the milling process. For example, the number of fiber washing screen units can vary, and the size of the centrifuge can also vary.

[0071] Nucleic Acid Construct: The term "nucleic acid construct" refers to a nucleic acid molecule, either single-stranded or double-stranded, that is isolated from a naturally occurring gene or that has been modified or synthetic to contain segments of nucleic acid in a form that would not otherwise occur in nature, including one or more regulatory sequences.

[0072] Operably linked: The term "operably linked" refers to a configuration in which a control sequence is positioned appropriately relative to a coding sequence of a polynucleotide so that the control sequence directs the expression of the coding sequence.

[0073] Parent or Parent Xylanase: The term "parent" xylanase, as used herein, refers to a xylanase that has been modified to produce a variant xylanase of the invention. This term also refers to a polypeptide to which a variant of the invention is compared. A parent can be a naturally occurring (wild-type) polypeptide or even a mutant thereof prepared by any suitable means. By way of example, a parent protein can be a variant of a naturally occurring polypeptide in which the amino acid sequence has been modified or altered. Thus, a parent xylanase can have one or more (or one or several) amino acid substitutions, deletions, and / or insertions. Thus, this parent xylanase can be a variant of the parent xylanase. A parent can also be an allelic variant, which is a polypeptide encoded by any of two or more alternative forms of a gene occupying the same chromosomal locus. The term "parent" or "parent xylanase," as used herein, refers to the xylanase of SEQ ID NO: 1 or any xylanase having at least 60% sequence identity to SEQ ID NO: 1. A parent xylanase can also be a polypeptide comprising a fragment of SEQ ID NO: 1.

[0074] Holding Time: The time during the fiber washing procedure during which one or more hydrolytic enzymes are allowed to react with the corn kernel or a fraction of the corn kernel.

[0075] In some embodiments, the retention time is the period during which the corn kernel mass received at the first screen unit (S1) and one or more fractions thereof are in contact with an effective amount of one or more hydrolytic enzymes before leaving the fiber cleaning system again. During the retention time, one or more fractions of the corn kernel mass are incubated with one or more hydrolytic enzymes in the space (V) before leaving the fiber cleaning system as part of the first fraction (s1) from the most upstream screen unit (S1) or as part of the second fraction (f4) from the most downstream screen unit (S4).

[0076] The retention time may preferably be estimated as the average duration that a solid material remains in the textile washing system as defined in the context of the present invention, and may be estimated by the following relationship:

number

number

[0077] The volume of a system is typically set equal to the sum of the volumes of all spaces in the system, but since the tubes in the system are typically made small, it may be preferable to ignore the volume of the tubes.

[0078] Screened: The term "screened" or "screening" refers to the process of separating the corn kernel mass into a first fraction s and a second fraction g and transferring these fractions from one screen unit to another. The non-screening period is a non-separation period for incubating the corn kernel mass or fractions thereof with the enzyme.

[0079] Sequence identity: The relatedness between two amino acid sequences or two nucleotide sequences is described by the parameter "sequence identity." For the purposes of the present invention, the degree of sequence identity between two amino acid sequences is determined using the Needleman-Wunsch algorithm (Needleman and Wunsch, 1970, J. Mol. Biol. 48:443-453) as implemented in the Needle program in the EMBOSS package (EMBOSS: The European Molecular Biology Open Software Suite, Rice et al., 2000, Trends Genet. 16:276-277), preferably version 3.0.0 or later. Version 6.1.0 was used.

[0080] Optional parameters used are a gap open penalty of 10, a gap extension penalty of 0.5, and the EBLOSUM62 (EMBOSS version of BLOSUM62) substitution matrix. The Needle label "longest identity" output (obtained using the -nobrief option) is used as the percent identity, calculated as follows: (identical residues x 100) / (length of alignment - total number of gaps in the alignment).

[0081] Starch: The term "starch" refers to a complex polysaccharide of plants, composed of glucose units that are widely present in plant tissues in the form of storage granules, and consists of amylose and amylopectin, and is a saccharide of the formula (CH). 10 O5)n (where n is any number).

[0082] Steeping or soaking: The term "steeping" refers to soaking crop kernels in water and optionally SO 2 This means immersion in

[0083] Wild-type enzyme: The term "wild-type" xylanase refers to a xylanase expressed by a naturally occurring microorganism (e.g., a bacterium, yeast, or filamentous fungus as found in nature). The terms "wild-type enzyme" and "parent enzyme" may be used interchangeably when the parent enzyme is not a variant enzyme.

[0084] Variant: The term "variant" refers to a polypeptide having xylanase activity that contains an alteration (i.e., substitution, insertion and / or deletion) of one or more (several) amino acid residues at one or more (several) positions. A substitution refers to the replacement of an amino acid occupying a position with another amino acid, a deletion refers to the removal of an amino acid occupying a position, and an insertion refers to the addition of an amino acid adjacent to and immediately following the amino acid occupying a position. Variants of the present invention have at least 20%, e.g., at least 40%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to the xylanase polypeptide of SEQ ID NO: 1, but less than 100%.

[0085] Xylanase / Polypeptide with Xylanase Activity: The terms "xylanase" and polypeptide with xylanase activity are used interchangeably herein and refer to 1,4-beta-D-xylan-xylohydrolase (EC 3.2.1.8), which catalyzes the endohydrolysis of 1,4-beta-D-xylosidic linkages in xylan. Xylanase activity can be determined at 37°C with 0.2% AZCL-arabinoxylan as a substrate in 0.01% TRITON® X-100 and 200 mM sodium phosphate, pH 6. One unit of xylanase is defined as the amount of xylanase activity that produces 1.0 μmol of azurin per minute at 37°C and pH 6 from 0.2% AZCL-arabinoxylan as a substrate in 200 mM sodium phosphate, pH 6.

[0086] nomenclature For purposes of the present invention, the nomenclature [Y / F] means that the amino acid at this position can be tyrosine (Try, Y) or phenylalanine (Phe, F). Similarly, the nomenclature [V / G / A / I] means that the amino acid at this position can be valine (Val, V), glycine (Gly, G), alanine (Ala, A), or isoleucine (Ile, I), and similarly for other combinations described herein. The amino acid X is defined to be any of the 20 naturally occurring amino acids, unless otherwise specified.

[0087] Conventions for specifying variants For the purposes of the present invention, SEQ ID NO: 1 is used to determine the corresponding amino acid residue in another xylanase. The amino acid sequence of another xylanase is aligned with SEQ ID NO: 1, and based on this alignment, the amino acid position number corresponding to any amino acid residue in SEQ ID NO: 1 is determined using the Needleman-Wunsch algorithm (Needleman and Wunsch, 1970, J. Mol. Biol. 48:443-453) implemented in the EMBOSS package (EMBOSS: The European Molecular Biology Open Software Suite, Rice et al., 2000, Trends Genet. 16:276-277), e.g., the Needle program version 5.0.0 or later. The parameters used are a gap open penalty of 10, a gap extension penalty of 0.5, and the EBLOSUM62 (EMBOSS version of BLOSUM62) substitution matrix.

[0088] The identification of corresponding amino acid residues in other xylanases can be determined by alignment of multiple polypeptide sequences using several computer programs with their respective default parameters, including, but not limited to, MUSCLE (multiple sequence comparison with logarithmic prediction; version 3.5 or later; Edgar, 2004, Nucleic Acids Research 32:1792-1794), MAFFT (version 6.857 or later; Katoh and Kuma, 2002, Nucleic Acids Research 30:3059-3066; Katoh et al., 2005, Nucleic Acids Research 33:511-518; Katoh and Toh, 2007, Bioinformatics 23:372-374; Katoh et al., 2009, Methods in Molecular Biology 537:39-64; Katoh and Toh, 2010, Bioinformatics 26:1899-1900) and EMBOSS EMMA employing ClustalW (1.83 or later; Thompson et al., 1994, Nucleic Acids Research 22:4673-4680).

[0089] Other pairwise sequence comparison algorithms can be used for other enzymes that are divergent from the polypeptide of SEQ ID NO: 1 and cannot detect these relationships using conventional sequence-based comparisons (Lindahl and Elofsson, 2000, J. Mol. Biol. 295:613-615). Greater sensitivity in sequence-based searches can be achieved using search programs that use probabilistic representations of polypeptide families (profiles) to search databases. For example, the PSI-BLAST program can generate profiles through an iterative database search process and detect distant homologs (Atschul et al., 1997, Nucleic Acids Res. 25:3389-3402). Even greater sensitivity can be achieved when a polypeptide family or superfamily has one or more representatives in a protein structure database. Programs such as GenTHREADER (Jones, 1999, J. Mol. Biol. 287:797-815; McGuffin and Jones, 2003, Bioinformatics 19:874-881) use information from a variety of sources (PSI-BLAST, secondary structure prediction, structural alignment profiles, and solvation potential) as input to a neuronal network that predicts a structural fold for a query sequence. Similarly, the method of Gough et al., 2000, J. Mol. Biol. 313:903-919 can be used to align a sequence of unknown structure with superfamily models present in the SCOP database. This alignment can then be used to generate a homology model of the polypeptide, and such models can be evaluated for accuracy using various tools developed for this purpose.

[0090] For proteins with known structures, several tools and resources are available for searching and creating structural alignments. For example, proteins of the SCOP superfamily have been structurally aligned, and this alignment can be accessed and downloaded. Two or more protein structures can be aligned using various algorithms, such as distance alignment matrices (Holm and Sander, 1998, Proteins 33:88-96) or combinatorial extension (Shindyalov and Bourne, 1998, Protein Engineering 11:739-747), and implementations of these algorithms can be further used to search structural databases with a structure of interest to find possible structural homologs (e.g., Holm and Park, 2000, Bioinformatics 16:566-567).

[0091] In describing the variants of the present invention, the nomenclature described below is adapted for ease of reference: Accepted IUPAC single-letter or three-letter amino acid abbreviations are employed.

[0092] Substitutions. For amino acid substitutions, the following nomenclature is used: original amino acid, position, substituted amino acid. Thus, a substitution of threonine with alanine at position 226 is designated "Thr226Ala" or "T226A." Multiple mutations are separated by an additional mark ("+"), e.g., "Gly205Arg+Ser411Phe" or "G205R+S411F" represent substitutions of glycine (G) with arginine (R) and serine with phenylalanine (F) at positions 205 and 441, respectively.

[0093] Deletions. In the case of amino acid deletions, the following nomenclature is used: original amino acid, position, *. Thus, a deletion of glycine at position 195 is designated "Gly195*" or "G195*". Multiple deletions are separated by an additional marker ("+"), for example, "Gly195*+Ser411*" or "G195*+S411*".

[0094] Insertions. In the case of an amino acid insertion, the following nomenclature is used: original amino acid, position, original amino acid, inserted amino acid. Thus, an insertion of a lysine after a glycine at position 195 would be designated "Gly195GlyLys" or "G195GK." An insertion of multiple amino acids is designated [original amino acid, position, original amino acid, inserted amino acid #1, inserted amino acid #2, etc.]. For example, an insertion of a lysine and an alanine after a glycine at position 195 would be designated "Gly195GlyLysAla" or "G195GKA." In such cases, the inserted amino acid residue is numbered by adding a lowercase letter to the position number of the amino acid residue preceding the inserted amino acid residue. In the above example, the sequence would be as follows:

[0095] [Table 1]

[0096] Multiple Changes. Variants containing multiple changes are separated by a plus sign ("+"), e.g., "Arg170Tyr+Gly195Glu" or "R170Y+G195E" represent substitutions of arginine and glycine with tyrosine and glutamic acid at positions 170 and 195, respectively.

[0097] Different modifications. When different modifications can be introduced at a certain position, the different modifications are separated by commas, for example, "Arg170Tyr,Glu" represents a substitution of arginine at position 170 with tyrosine or glutamic acid. Thus, "Tyr167Gly,Ala+Arg170Gly,Ala" represents the following variants: "Tyr167Gly+Arg170Gly", "Tyr167Gly+Arg170Ala", "Tyr167Ala+Arg170Gly", and "Tyr167Ala+Arg170Ala".

[0098] The present invention relates to xylanase variants of a parent xylanase comprising substitutions at one or more positions corresponding to positions 45, 149, 364, 258, 276 and 388 of SEQ ID NO: 1, wherein the xylanase variants have at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1 and have xylanase activity.

[0099] The present invention relates to the amino acids 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 352, 354, 356, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, ​​383, 384, 385, 386, 387, 388, 389, 390, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 4 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, The present invention relates to xylanase variants of a parent xylanase that further comprise substitutions at one or more positions corresponding to positions 28, 529, 530 and 540, wherein the xylanase variants have at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1, and have xylanase activity.

[0100] In one aspect, the present invention relates to a xylanase variant comprising a substitution at one or more positions corresponding to positions 45, 149, 364, 258, 276 and 388 of SEQ ID NO:1, wherein the xylanase variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO:1, and has xylanase activity and improved properties compared to the xylanase of SEQ ID NO:1.

[0101] In one aspect, the present invention provides the amino acids 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334 of SEQ ID NO: 1. , 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 5 The present invention relates to xylanase variants that further comprise substitutions at one or more positions corresponding to positions 27, 528, 529, 530 and 540, which have at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1, and which have improved properties relative to said parent.

[0102] The present invention relates to xylanase variants with one or more substitutions that have improved properties, such as improved (increased) thermostability.

[0103] In one aspect, the invention relates to a xylanase variant comprising a substitution at one or more positions corresponding to positions 45, 149, 364, 258, 276 and 388 of SEQ ID NO:1, wherein the xylanase variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO:1, and wherein the xylanase variant has xylanase activity and increased thermostability compared to the xylanase of SEQ ID NO:1.

[0104] In one aspect, the present invention provides the amino acids 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 379, 380, 381, 382, ​​383, 384, 385, 386, 387, 388, 389, 390, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432 50, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, The present invention relates to a xylanase variant that further comprises a substitution at one or more positions corresponding to positions 530 and 540, and that has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100%, sequence identity to the polypeptide of SEQ ID NO: 1, and that has xylanase activity and increased thermostability compared to the xylanase of SEQ ID NO: 1.

[0105] Xylanase variants The present invention provides xylanase variants of a parent xylanase that contain substitutions at one or more positions corresponding to positions 45, 149, 364, 258, 276 and 388 of SEQ ID NO: 1, and that have increased thermostability compared to the xylanase of SEQ ID NO: 1.

[0106] The present invention is directed to the following sequences: 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, Also provided are xylanase variants of a parent xylanase further comprising substitutions at one or more positions corresponding to positions 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530 and 540, which have increased thermostability compared to the xylanase of SEQ ID NO:1.

[0107] In one aspect, the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the amino acid sequence of the parent alpha-amylase.

[0108] In one aspect, the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to SEQ ID NO:1.

[0109] In one aspect, the substituted amino acid residue is different from the amino acid residue naturally occurring at that position, hi one embodiment, the substitution is selected from the group consisting of A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y, provided that the substituted amino acid residue is different from the amino acid residue naturally occurring at that position.

[0110] In one aspect, the number of substitutions is 1 to 50 substitutions, for example, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, or 1 to 5 substitutions, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 substitutions.

[0111] In another aspect, the variant comprises substitutions at two or more positions corresponding to any of positions 45, 149, 364, 258, 276 and 388 of SEQ ID NO:1, wherein said variant has xylanase activity, and further wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO:1.

[0112] In another aspect, the variant comprises substitutions at three or more positions corresponding to any of positions 45, 149, 364, 258, 276 and 388 of SEQ ID NO:1, wherein said variant has xylanase activity, and further wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO:1.

[0113] In another aspect, the variant comprises substitutions at four or more positions corresponding to any of positions 45, 149, 364, 258, 276 and 388 of SEQ ID NO:1, wherein said variant has xylanase activity, and further wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO:1.

[0114] In another aspect, the variant comprises substitutions at five or more positions corresponding to any of positions 45, 149, 364, 258, 276 and 388 of SEQ ID NO:1, wherein said variant has xylanase activity, and further wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO:1.

[0115] In another aspect, the variant comprises substitutions at six or more positions corresponding to any of positions 45, 149, 364, 258, 276 and 388 of SEQ ID NO:1, wherein said variant has xylanase activity, and further wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO:1.

[0116] In another aspect, the variant comprises a substitution at each position corresponding to any of positions 45, 149, 364, 258, 276 and 388 of SEQ ID NO:1, wherein said variant has xylanase activity, and further wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO:1.

[0117] In another embodiment, the variant is any of 45, 149, 364, 258, 276, 388, 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 253, 254, 255, 256, 257, 258, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 3 60, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501 , 503, 522, 525, 526, 527, 528, 529, 530 and 540, wherein the variant has xylanase activity, and further wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO:1.

[0118] In another embodiment, the variant is any of 45, 149, 364, 258, 276, 388, 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 253, 254, 255, 256, 257, 258, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 3 60, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501 , 503, 522, 525, 526, 527, 528, 529, 530 and 540, wherein the variant has xylanase activity, and further wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO:1.

[0119] In another embodiment, the variant is any of 45, 149, 364, 258, 276, 388, 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 253, 254, 255, 256, 257, 258, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 3 60, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501 , 503, 522, 525, 526, 527, 528, 529, 530 and 540, wherein the variant has xylanase activity, and further wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO:1.

[0120] In another embodiment, the variant is any of 45, 149, 364, 258, 276, 388, 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 253, 254, 255, 256, 257, 258, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 3 60, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501 , 503, 522, 525, 526, 527, 528, 529, 530 and 540, wherein the variant has xylanase activity, and further wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO:1.

[0121] In another embodiment, the variant is any of 45, 149, 364, 258, 276, 388, 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 253, 254, 255, 256, 257, 258, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 3 60, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501 , 503, 522, 525, 526, 527, 528, 529, 530 and 540, wherein the variant has xylanase activity, and further wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO:1.

[0122] In another embodiment, the variant is any of 45, 149, 364, 258, 276, 388, 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 253, 254, 255, 256, 257, 258, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 3 60, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501 , 503, 522, 525, 526, 527, 528, 529, 530 and 540, wherein the variant has xylanase activity, and further wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO:1.

[0123] In another embodiment, the variant is any of 45, 149, 364, 258, 276, 388, 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 253, 254, 255, 256, 257, 258, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 3 60, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501 , 503, 522, 525, 526, 527, 528, 529, 530 and 540, wherein the variant has xylanase activity, and further wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO:1.

[0124] In another embodiment, the variant is any of 45, 149, 364, 258, 276, 388, 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 253, 254, 255, 256, 257, 258, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 3 60, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501 , 503, 522, 525, 526, 527, 528, 529, 530 and 540, wherein the variant has xylanase activity, and further wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO:1.

[0125] In another embodiment, the variant is any of 45, 149, 364, 258, 276, 388, 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 253, 254, 255, 256, 257, 258, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 3 60, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501 , 503, 522, 525, 526, 527, 528, 529, 530 and 540, wherein the variant has xylanase activity, and further wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO:1.

[0126] In another embodiment, the variant is selected from the group consisting of 45, 149, 364, 258, 276, 388, 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 262, 264, 266, 268, 270, 272, 276, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 33 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 504 and wherein the variant comprises a substitution at each position corresponding to positions 22, 525, 526, 527, 528, 529, 530 and 540, and wherein the variant has xylanase activity, and wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO:1.

[0127] In one aspect, the variant has the following substitutions at positions corresponding to positions in SEQ ID NO: 1: D9, D11, A18, S19, A20, A24, A25, M28, C40, V45, C60, Q61, C69, T70, Q77, A79, S92, A93, D95, D113, A117, N127, L149, C161, N163, N168, A170, S173, T180, G187, S190, D192, T211, S214, T215, H219, V 234, W250, A252, V258, N260, A276, L281, S282, A286, Q314, H334, A340, V350, N355, L356, H358, A364, T366, C375, Q384 , Q385, Y386, S388, S389, Y391, V393, G394, N395, C396, D446, ​​R459, C468, I469, D470, L471, A472, A472, S473, S473, N4 and C540, wherein the variant comprises one or more of the amino acids 74, N476, T477, L478, T480, S481, R483, L484, W495, Q496, V497, V498, A499, V500, S501, G503, C522, D525, G526, N527, S528, N529, L530, and C540, and wherein the variant has a sequence similar to that of the polypeptide of SEQ ID NO: 1, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 87%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118%, at least 119%, at least 120%, at least 121%, at least 122%, at least 123%, at least 124%, at least 125%, at least 126%, at least 127%, at least 128%, at least 129%, at least 130%, at least 131%, at least 132%, at least 133%, at least 134 0%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity.

[0128] In one aspect, the variant has the following substitutions at positions corresponding to positions in SEQ ID NO: 1: D9E, D11E, A18V, S19T, A20H, A20P, A24H, A24K, A25W, M28P, C40A, C40L, C40S, C40V, V45C, V45I, V45L, V45N, V45T, C60A, C60L, C60S, C60V, Q61K, Q61R, C69A, C69L, C69S, C69V, T70R, Q77E, A79C, S92D, S92N, A93S, A93T, D95N, D113T, A117C, A117S, N127D, L149R, C 161L, C161S, C161V, N163H, N168G, A170S, S173Y, T180Q, G187K, G187L, G18 7S, S190E, D192E, T211H, S214E, S214Q, S214Y, T215I, T215K, T215V, H219I, H219V, V234P, C243L, C243S, C243V, W250Y, A252S, V258P, V258R, N260H, A2 76C, A276D, A276F, A276N, A276Q, A276S, A276T, L281V, S282N, A286E, A286S , Q314A, H334D, A340G, V350L, N355G, L356M, H358D, H358T, A364G, T366I, T 366V, C375A, C375L, C375S, C375V, Q384A, Q385C, Y386G, S388A, S388H, S38 8K, S388L, S388R, S389H, S389V, Y391V, V393H, V393R, G394A, G394D, G394Q , N395D, C396A, C396L, C396A, C396S, C396V, D446T, R459V, C468A, C468L, C4 68S, C468V, I469T, D470A, D470K, D470T, D470V, L471R, A472I, A472L, S473 G, S473K, N474G, N476D, T477K, T477V, L478N, L478P, T480L, T480N, S481A, R 483V, L484D, L484K, L484S, W495E, W495I, W495S, Q496E, Q496W, Q496R, V49 7D, V497E, V497P, V497W, V498I, A499L, A499Y, V500T, S501E, S501N, G503L,and one or more of C522A, C522S, C522V, D525L, G526T, N527H, S528H, N529T, L530R, C540A, C540L, C540S, and C540V, wherein the variants have at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100%, sequence identity to the polypeptide of SEQ ID NO: 1.

[0129] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 9 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 9 is substituted with Ala, Arg, Asn, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution D9E in the polypeptide of SEQ ID NO: 1.

[0130] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 11 of SEQ ID NO: 1. In another embodiment, the amino acid at a position corresponding to position 3 is substituted with Ala, Arg, Asn, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution D11E in the polypeptide of SEQ ID NO: 1.

[0131] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 18 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 18 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution A18V in the polypeptide of SEQ ID NO: 1.

[0132] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 19 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 19 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution S19T in the polypeptide of SEQ ID NO: 1.

[0133] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 20 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 20 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution A20H or A20P in the polypeptide of SEQ ID NO: 1.

[0134] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 24 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 24 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution A24H or A24K in the polypeptide of SEQ ID NO: 1.

[0135] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 25 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 25 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution A25W in the polypeptide of SEQ ID NO: 1.

[0136] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 28 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 28 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution M28P in the polypeptide of SEQ ID NO: 1.

[0137] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 40 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 40 is substituted with Ala, Arg, Asn, Asp, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution C40A, or C40L, or C40S, or C40V in the polypeptide of SEQ ID NO: 1.

[0138] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 45 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 45 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, or Tyr. In another embodiment, the variant comprises or consists of the substitution V45C, or V45I, or V45L, V45N, or V45T of the polypeptide of SEQ ID NO: 1.

[0139] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 60 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 60 is substituted with Ala, Arg, Asn, Asp, Gln, Glu, Gly, His, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution C60A, or C60L, or C60S, or C60V in the polypeptide of SEQ ID NO: 1.

[0140] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 61 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 61 is substituted with Ala, Arg, Asn, Asp, Cys, Glu, Gly, His, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution Q61K or Q61R of the polypeptide of SEQ ID NO: 1.

[0141] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 69 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 69 is substituted with Ala, Arg, Asn, Asp, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution C69A, or C69L, or C69S, or C69V in the polypeptide of SEQ ID NO: 1.

[0142] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 70 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 70 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution T70R in the polypeptide of SEQ ID NO: 1.

[0143] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 77 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 77 is substituted with Ala, Arg, Asn, Asp, Cys, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution Q77E in the polypeptide of SEQ ID NO: 1.

[0144] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 79 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 79 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution A79C in the polypeptide of SEQ ID NO: 1.

[0145] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 92 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 92 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution S92D or S92N in the polypeptide of SEQ ID NO: 1.

[0146] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 93 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 93 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution A93S or A93T in the polypeptide of SEQ ID NO: 1.

[0147] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 95 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 95 is substituted with Ala, Arg, Asn, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution D95N in the polypeptide of SEQ ID NO: 1.

[0148] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 113 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 113 is substituted with Ala, Arg, Asn, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution D113T in the polypeptide of SEQ ID NO: 1.

[0149] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 117 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 117 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution A117C or A117S in the polypeptide of SEQ ID NO: 1.

[0150] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 127 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 127 is substituted with Ala, Arg, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution N127D in the polypeptide of SEQ ID NO: 1.

[0151] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 149 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 149 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, He, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution L149R in the polypeptide of SEQ ID NO: 1.

[0152] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 161 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 161 is substituted with Ala, Arg, Asn, Asp, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution C161L, or C161S, or C161V in the polypeptide of SEQ ID NO: 1.

[0153] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 163 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 163 is substituted with Ala, Arg, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution N163H in the polypeptide of SEQ ID NO: 1.

[0154] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 168 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 168 is substituted with Ala, Arg, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution N168G of the polypeptide of SEQ ID NO: 1.

[0155] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 170 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 170 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution A170S in the polypeptide of SEQ ID NO: 1.

[0156] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 173 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 173 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution S173Y in the polypeptide of SEQ ID NO: 1.

[0157] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 180 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 180 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution T180Q in the polypeptide of SEQ ID NO: 1.

[0158] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 187 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 187 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution G187K, or G187L, or G187S of the polypeptide of SEQ ID NO: 1.

[0159] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 190 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 190 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution S190E in the polypeptide of SEQ ID NO: 1.

[0160] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 192 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 192 is substituted with Ala, Arg, Asn, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution D192E in the polypeptide of SEQ ID NO: 1.

[0161] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 211 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 211 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution T211H in the polypeptide of SEQ ID NO: 1.

[0162] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 214 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 214 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution S214E, or S214Q, or S214Y in the polypeptide of SEQ ID NO: 1.

[0163] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 215 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 215 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution T215I, or T215K, or T215V in the polypeptide of SEQ ID NO: 1.

[0164] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 219 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 219 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution H219I or H219V in the polypeptide of SEQ ID NO: 1.

[0165] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 234 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 234 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, or Tyr. In another embodiment, the variant comprises or consists of the substitution V234P in the polypeptide of SEQ ID NO: 1.

[0166] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 243 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 243 is substituted with Ala, Arg, Asn, Asp, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution C243L, or C243S, or C243V in the polypeptide of SEQ ID NO: 1.

[0167] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 250 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 250 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution W250Y in the polypeptide of SEQ ID NO: 1.

[0168] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 252 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 252 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution A252S in the polypeptide of SEQ ID NO: 1.

[0169] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 258 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 258 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, or Tyr. In another embodiment, the variant comprises or consists of the substitution V258P or V258R of the polypeptide of SEQ ID NO: 1.

[0170] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 260 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 260 is substituted with Ala, Arg, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution N260H in the polypeptide of SEQ ID NO: 1.

[0171] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 276 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 276 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution A276C, or A276D, or A276F, or A276N, or A276Q, or A276S, or A276T of the polypeptide of SEQ ID NO: 1.

[0172] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 281 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 281 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, He, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution L281V in the polypeptide of SEQ ID NO: 1.

[0173] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 282 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 282 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution S282N in the polypeptide of SEQ ID NO: 1.

[0174] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 286 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 286 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution A286E or A286S in the polypeptide of SEQ ID NO: 1.

[0175] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 314 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 314 is substituted with Ala, Arg, Asn, Asp, Cys, Glu, Gly, His, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution Q314A in the polypeptide of SEQ ID NO: 1.

[0176] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 334 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 334 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution H334D in the polypeptide of SEQ ID NO: 1.

[0177] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 340 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 340 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, Ile, Leu, Lys, Met, His, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution A340G in the polypeptide of SEQ ID NO: 1.

[0178] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 350 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 3 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, or Tyr. In another embodiment, the variant comprises or consists of the substitution V350L of the polypeptide of SEQ ID NO: 1.

[0179] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 355 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 355 is substituted with Ala, Arg, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of a substitution N355G in the polypeptide of SEQ ID NO: 1.

[0180] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 356 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 356 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, He, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution L256M in the polypeptide of SEQ ID NO: 1.

[0181] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 358 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 358 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution H358D or H358T in the polypeptide of SEQ ID NO: 1.

[0182] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 364 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 364 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution A364G in the polypeptide of SEQ ID NO: 1.

[0183] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 366 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 366 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution T366I or T366V in the polypeptide of SEQ ID NO: 1.

[0184] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 375 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 375 is substituted with Ala, Arg, Asn, Asp, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution C375A, or C375L, or C375S, or C375V in the polypeptide of SEQ ID NO: 1.

[0185] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 384 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 384 is substituted with Ala, Arg, Asn, Asp, Cys, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution Q384A in the polypeptide of SEQ ID NO: 1.

[0186] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 385 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 385 is substituted with Ala, Arg, Asn, Asp, Cys, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution Q385C in the polypeptide of SEQ ID NO: 1.

[0187] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 386 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 386 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, or Val. In another embodiment, the variant comprises or consists of the substitution Y386G in the polypeptide of SEQ ID NO: 1.

[0188] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 388 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 388 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, He, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution S388A, or S388H, or S388K, or S388L, or S388R of the polypeptide of SEQ ID NO: 1.

[0189] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 389 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 389 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution S389H or S389V in the polypeptide of SEQ ID NO: 1.

[0190] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 391 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 391 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, or Val. In another embodiment, the variant comprises or consists of the substitution Y391V in the polypeptide of SEQ ID NO: 1.

[0191] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 393 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 393 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, or Tyr. In another embodiment, the variant comprises or consists of the substitution V393H or V393R of the polypeptide of SEQ ID NO: 1.

[0192] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 394 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 394 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution G394A, or G394D, or G394Q of the polypeptide of SEQ ID NO: 1.

[0193] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 395 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 395 is substituted with Ala, Arg, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution N395D in the polypeptide of SEQ ID NO: 1.

[0194] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 396 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 396 is substituted with Ala, Arg, Asn, Asp, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution C396A, or C396L, or C396S, or C396V of the polypeptide of SEQ ID NO: 1.

[0195] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 446 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 446 is substituted with Ala, Arg, Asn, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution D446T in the polypeptide of SEQ ID NO: 1.

[0196] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 459 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 459 is substituted with Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution R459V in the polypeptide of SEQ ID NO: 1.

[0197] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 468 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 468 is substituted with Ala, Arg, Asn, Asp, Gln, Glu, Gly, His, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution C468A, or C468L, or C468S, or C468V in the polypeptide of SEQ ID NO: 1.

[0198] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 469 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 469 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution I469T in the polypeptide of SEQ ID NO: 1.

[0199] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 470 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 470 is substituted with Ala, Arg, Asp, Cys, Gln, Glu, Gly, His, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of a substitution D470A, or D470K, or D470T, or D470V in the polypeptide of SEQ ID NO: 1.

[0200] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 471 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 471 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, He, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution L471R in the polypeptide of SEQ ID NO: 1.

[0201] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 472 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 472 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution A472I or A472L in the polypeptide of SEQ ID NO: 1.

[0202] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 473 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 473 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of a substitution S473G or S473K in the polypeptide of SEQ ID NO: 1.

[0203] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 474 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 474 is substituted with Ala, Arg, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution N474G in the polypeptide of SEQ ID NO: 1.

[0204] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 476 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 476 is substituted with Ala, Arg, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution N476D in the polypeptide of SEQ ID NO: 1.

[0205] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 477 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 477 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution T477K or T477V in the polypeptide of SEQ ID NO: 1.

[0206] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 478 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 478 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, He, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution L478N or L478P in the polypeptide of SEQ ID NO: 1.

[0207] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 480 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 480 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution T480L or T480N in the polypeptide of SEQ ID NO: 1.

[0208] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 481 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 481 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution S481A in the polypeptide of SEQ ID NO: 1.

[0209] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 483 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 483 is substituted with Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution R483V in the polypeptide of SEQ ID NO: 1.

[0210] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 484 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 484 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, He, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution L484D, or L484K, or L484S of the polypeptide of SEQ ID NO: 1.

[0211] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 495 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 495 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution W495E, or W495I, or W495S in the polypeptide of SEQ ID NO: 1.

[0212] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 496 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 496 is substituted with Ala, Arg, Asn, Asp, Cys, Glu, Gly, His, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution Q496E, or Q496W, or Q496R of the polypeptide of SEQ ID NO: 1.

[0213] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 497 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 497 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, or Tyr. In another embodiment, the variant comprises or consists of the substitution V497D, or V497E, or V497P, or V497W in the polypeptide of SEQ ID NO: 1.

[0214] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 498 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 498 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, or Tyr. In another embodiment, the variant comprises or consists of the substitution V498I in the polypeptide of SEQ ID NO: 1.

[0215] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 499 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 499 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of a substitution A499L or A499Y in the polypeptide of SEQ ID NO: 1.

[0216] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 500 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 500 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, or Tyr. In another embodiment, the variant comprises or consists of the substitution V500T of the polypeptide of SEQ ID NO: 1.

[0217] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to position 501 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to position 501 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of a substitution S501E or S501N in the polypeptide of SEQ ID NO: 1.

[0218] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 503 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 503 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution G503L in the polypeptide of SEQ ID NO: 1.

[0219] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 522 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 522 is substituted with Ala, Arg, Asn, Asp, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution C522A, or C522S, or C522V in the polypeptide of SEQ ID NO: 1.

[0220] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 525 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 525 is substituted with Ala, Arg, Asn, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution D525L in the polypeptide of SEQ ID NO: 1.

[0221] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 526 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 526 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution G526T of the polypeptide of SEQ ID NO: 1.

[0222] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 527 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 527 is substituted with Ala, Arg, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution N527H in the polypeptide of SEQ ID NO: 1.

[0223] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 528 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 528 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution S528H in the polypeptide of SEQ ID NO: 1.

[0224] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 529 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 529 is substituted with Ala, Arg, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution N529T in the polypeptide of SEQ ID NO: 1.

[0225] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 530 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 530 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, He, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution L530R in the polypeptide of SEQ ID NO: 1.

[0226] In another embodiment, the variant comprises or consists of a substitution at a position corresponding to 540 of SEQ ID NO: 1. In another embodiment, the amino acid at the position corresponding to 540 is substituted with Ala, Arg, Asn, Asp, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another embodiment, the variant comprises or consists of the substitution C540A, or C540L, or C540S, or C540V in the polypeptide of SEQ ID NO: 1.

[0227] In one aspect, the variants are selected from the group consisting of Y386G, Q385C, A276S, A276C, A276Q, A276F, A79C, A276N, V45L, S19T, H358D, L149R, A25W, V45N, I469T, S388A, A276T, S388H, S92D, D525L, S214Q, A364G, S388L, S388R, S473G of SEQ ID NO: 1 , S389V, A20H, W495E, Y386Y, V393H, G187L, Q61K, G187S, A286E, A276Y, V258P, Q496E, G394A, V393 R, T366V, S389S, S92N, N527H, Q384A, V497D, D470T, A18V, Q496Q, Q496R, S214E, P362P, S389H, V25 and comprising at least one substitution at a position corresponding to a position selected from the group consisting of 8R, A276D, L281V, V45I and A117C, wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1.

[0228] In one aspect, the variants are selected from the group consisting of V45L+L149R, V45N+L149R, L149R+A364G, V258P+A276Q, V258P+A276S, A25WL+149R, V45L+A276S, A25W+A276S, V45L+A276Q, V45L+V258P, A25W+V258P, A25W+A276Q, L149R+W250Y, V45L+S388K, V45L+A364G, V45N+V258P, V258P+S388K, A25W+V45L, A276Q+S388K, W250Y+A276Q, A276 S+S388K, A276Q+L281V, W250Y+A276S, A25W+S388K, A276S+L281V, G187S+A 276Q, S92D+A276S, L149R+V258R, V45N+S388K, A25W+A364G, V258P+L281V, V 258R+A276S, G187S+A276S, G187K+A276S, V45L+S92D, V45L+L281V, V45N+W 250Y, V258R+A276Q, V45L+V258R, W250Y+S388K, V45N+G187K, A25W+V258R, G 187K+S388K, A25W+S92D, L281V+S388K, V45N+V258R, L281V+A364G, S92D+A 364G, A25W+G187S, A25W+G187K, W250Y+V258P, S92D+V258P, G187K+W250Y, V45N+S92D, G187S+A364G, G187S+L281V, G187S+S388K, G187S+V258R, S92D+G187S, V45L+D11E, L149R+S388K, L149R+D11E, A364G+D11E and S388K+D11E and wherein the variant comprises a substitution at a position corresponding to a position selected from the group consisting of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%,At least 98% or at least 99%, but less than 100%, sequence identity.

[0229] In one aspect the variant comprises a substitution at a position corresponding to a position selected from the group consisting of V45L+L149R+V258P, V45L+L149R+A364G, V45L+L149R+W250Y, V45L+L149R+G187S, V45L+L149R+S282N and V45L+S92D+L149R in SEQ ID NO: 1, said variant having ... 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity.

[0230] In one aspect, the variants are V45L+L149R+A252S+H334D, V45L+L149R+S190E+D446T, V45L+L149R+V258P+A364G, V45L+L149R+A276Q+A364G, V45L+L149R+A276S+A364G, V45L+L149R+V258P+A276S, V45L+L149R+V258P+A276S, V45L+L149R+V258P+A276Q+A364G ... 45L+L149R, L281V+A364G, L149R+V258P+A276S+A364G, V45L+V258P+A276S+A364G, A25W+V45L+ L149R+A364G, V45L+L149R+V258R+A364G, V45L+L149R+G187K+A364G, V45L+L149R+G187S+A364 and V45L+L149R+W250Y+A364G, wherein the variant comprises a substitution at a position corresponding to a position selected from the group consisting of V45L+L149R+W250Y+A364G, V45L+L149R+W250Y+A364G, and V45L+L149R+W250Y+A364G, wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1.

[0231] In one aspect, the variants are selected from the group consisting of V45L+A93S+L149R+A252S+H334D, V45L+A93S+L149R+A252S+H334D, V45L+A93S+L149R+V234P+A252S, V45L+A93S+L149R+A252S+H334D, V45L+A93S, L149R+A252S+H334D, V45L+A93S+L149R+A252S+H334D, V45L+L149R, S190E+D446T+R459V, V45L+L149R+V258P+A276S, A364G ... L+L149R+V258P+A276Q+A364G, A25W+V45L+L149R+V258P+A276S, V45L+L14 9R+A276Q+L281V+A364G, V45L+L149R+A276Q+S282N+A364G, A25W+V45L+L1 49R+V258P+A276Q, V45L+T70R+L149R+A276Q+A364G, V45L+L149R+V258P+L 281V+A364G, A25W+V45L+L149R, A276Q+A364G, V45L+L149R+A276Q+Q314A+ A364G, V45L+L149R+G187K+V258P+A364G, V45L+L149R+A276Q+A286E+A364 G, V45L+L149R+A276Q+H358T+A364G, A25W+V45N+L149R+V258P+A276S, V45 L+N127D+L149R+A276Q+A364G, V45L+L149R+W250Y+A276Q+A364G, V45L+L1 49R+W250Y+V258P+A364G, V45L+L149R+A276Q+A364G+S388K, A25W+V45L+L 149R+V258P+A364G, V45L+L149R+N168G+A276Q+A364G, V45L+A117S+L149R +A276Q+A364G, A24K+V45L+L149R+A276Q+A364G, V45L+L149R+A276Q+A286 S+A364G, V45L+L149R+A170S+A276Q+A364G, V45L+L149R+T180Q+A276Q+A3 64G, V45L+L149R+A276Q, V350L+A364G, V45L+L149R+V258P+S282N+A364G,A25W+V45L+L149R+A276S+A364G, V45L+L149R+G187S+V258P+A364G, A25W+L149R+V258P+A276S+A364G, V45L+L149R+G187L+A276Q , A364G, A25W+V45L+V258P+A276S+A364G, V45L+L149R+N260H+A276Q+A364G, V45L+L149R+W250Y+V258R+A364G, V45L+L149R+N163 H+A276Q+A364G, V45L+S92D+L149R+A276Q+A364G, V45L+L149R+S173Y+A276Q+A364G, V45L+S92D+L149R+V258P+A364G, V45L+D113 T+L149R+A276Q+A364G, V45L+L149R+G187S+V258R+A364G, V45L+L149R+V258R+A364G+S388K, V45L+L149R+G187K, V258R+A364G, V and V45L+L149R+V258R+S282N+A364G, V45L+L149R+V258R+L281V+A364G, V45L+S92N+L149R+V258P+A364G, V45L+L149R+V258P+A364G+S388K and V45L+S92N+L149R+V258R+A364G, wherein said variants are at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 8 ... At least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity.

[0232] In one aspect, the variants are A25W+V45L+A79C+L149R+V258P+A276S, V45L+L149R+V258P+A276S+H358T+A364G, A25W+V45L+L149R+V258P+A276S+A364G, V45L+L149R+V258P+A276S+L281V+A364G, V45L+A93S+L149R+A252S+H334D+A340G, V45L+L149R+V258P+A276S+A364G+S388K, V45L+L149R+N168G+V258 P+A276S+A364G, V45L+L149R+S173Y+V258P+A276S+A364G, V45L+A93S+L1 49R+A252S+H334D+A340G, A25W+V45L+L149R+V258P+A276S+H358T, A25W+V 45L+L149R+V258P+A276Q+A364G, A25W+V45L+L149R+S214E+V258P+A276S , V45L+L149R+A170S+V258P+A276S+A364G, A25W+V45L+L149R+S214Q+V258 P+A276S, A25W+V45L+L149R+V258P+A276S+S388K, V45L+A93S+L149R+V23 4P+A252S+H334D, V45L+N127D+L149R+V258P+A276S+A364G, V45L+L149R+W 250Y+V258P+A276S+A364G, A25W+V45L+L149R+W250Y+A276Q+A364G, V45L +L149R+T180Q+V258P+A276S+A364G, V45L+L149R+V258P+A276S+Q314A+A3 64G, V45L+A117S+L149R+V258P+A276S+A364G, V45N+L149R+V258P+A276S +A364G+S388K, V45L+L149R+V258P+A276Q+L281V+A364G, A25W+V45L+L149 R+V258P+A276S+Q314A, V45L+L149R+V258P+A276S+A286E+A364G, A25W+V 45L+L149R+A276Q+L281V+A364G, A25W+V45L+L149R+V258P+A276S+A286E,A25W+V45L+L149R+V258P+A276S+L281V、A25W+V45L+D113T+L149R+V258P+A276S、A25W+V45L+L149R+T180Q+V258P+276S、A25W+V45L+L149R+V258P+A276S+A286S、V45L+L149R+G187L+A276Q+L281V+A364G、V45L+L149R+A276Q+L281V+V350L+A364G、V45L+L149R+A276Q+L281V+A364G+S388K、A25W+V45L+S92D+L149R+V258P+A276S、A25W+V45L+L149R+G187L+V258P+A276S、A25W+V45L+L149R+W250Y+V258P+A276S、V45L+D113T+L149R+V258P+A276S+A364G、V45L+T70R+L149R+A276Q+L281V+A364G、V45L+S92D+L149R+A276Q+L281V+A364G、V45L+D113T+L149R+A276Q+L281V+A364G、V45L+L149R+A276Q+L281V+Q314A+A364G、A25W+V45L+Q61K+L149R+V258P+A276S、D9E+A25W+V45L+L149R+V258P+A276S、V45L+T70R+L149R+V258P+A276S+A364G、V45L+L149R+N163H+V258P+A276S+A364G、V45L+L149R+T180Q+A276Q+L281V+A364G、V45L+L149R+A276Q+L281V+A286S+A364G、A25W+V45L+L149R+A170S+V258P+A276S、A25W+V45L+T70R+L149R+V258P+A276S、V45L+L149R+N168G+A276Q+L281V+A364G、V45L+L149R+S173Y+A276Q+L281V+A364G、V45L+L149R+W250Y+A276Q+L281V+A364G、A25W+V45L+L149R+A276Q+A286E+A364G、A25W+V45L+L149R+A276Q+A364G+S388K、V45L+N127D+L149R+A276Q+L281V+A364G、V45L+L149R+A276Q+L281V+A286E+A364G、A25W+V45L+A117S+L149R+V258P+A276S、A24K+V45L+L149R+V258P+A276S+A364G、V45L+L149R+V258P+A276S+S282N+A364G、V45L+A117S+L149R+A276Q+L281V+A364G、V45L+L149R+N260H+A276Q+L281V+A364G、A25W+V45L+L149R+N168G+V258P+A276S、A25W+V45L+L149R+G187S+V258P+A276S、A25W+V45L+L149R+V258P+A276S+V350L、A25W+V45L+Q61R+L149R+V258P+A276S、V45N+L149R+V258P+A276S+L281V+A364G、A25W+V45L+L149R+V258P+A276S+S282N、A25W+V45L+L149R+S173Y+V258P+A276S、A25W+V45L+L149R+A276Q+A286S+A364G、A25W+V45L+L149R+T215V+V258P+A276S、A25W+V45L+L149R+T215I+V258P+A276S、A25W+V45L+L149R+T211H+V258P+A276S、V45L+L149R+V258P+A276S+V350L+A364G、A25W+V45L+D113T+L149R+A276Q+A364G、A25W+V45N+L149R+V258P+A276S+A364G、A25W+V45L+L149R+H219I+V258P+A276S、M28P+V45L+L149R+V258P+A276S+A364G、A25W+V45L+T70R+L149R+A276Q+A364G、A25W+V45L+L149R+A276Q+Q314A+A364G、A25W+V45L+L149R+S214Y+V258P+A276S、V45L+L149R+A276Q+L281V+H358T+A364G、A25W+V45L+L149R+H219V+V258P+A276S、D11E+A25W+V45L+L149R+V258P+A276S、A25W+V45L+A117S+L149R+A276Q+A364G、A25W+V45L+L149R+G187L+A276Q+A364G, V45N+L149R+V258P+A276S+H358 T+A364G, A25W+V45L+L149R+N163H+A276Q, A364G, A25W+V45L+L149R+S173 Y+A276Q+A364G, A25W+V45L+L149R+A276Q+S282N+A364G, A25W+V45L+L149 R+A276Q+H358T+A364G, A25W+V45L+L149R+T180Q+A276Q+A364G, A25W+V45 L+N127D+L149R+A276Q+A364G, A25W+V45L+L149R+A170S+A276Q+A364G, A2 5W+V45L+N127D+L149R+V258P+A276S, A25W+V45L+L149R+N168G+A276Q+A3 64G, A25W+V45L+L149R+N260H+A276Q+A364G, A25W+V45L+L149R+G187K+V2 58P+A276S, A25W+M28P+V45L+L149R+V258P+A276S, V45L+L149R+N163H+A2 and A25W+V45L+L149R+V258P+A276S+N355G+A364G, A25W+V45L+L149R+V258P+A276S+N355G+A364G, A25W+V45L+L149R+V258P+A276S+N355G+A364G, A25W+V45L+S92D+L149R+A276Q+A364G, and A25W+V45L+L149R+A276Q+N355G+A364G. and wherein the variant is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% relative to the polypeptide of SEQ ID NO: 1,have less than 100% sequence identity.

[0233] In one aspect, the variants are selected from the group consisting of V45L+A79C+L149R+V258P+A276S+A364G+S388K, V45N+A79C+L149R+V258P+A276S+A364G+S388K, V45L+L149R+S214Q+V258P+A276S+H358D+A364G, A25W+V45L+A79C+L149R+V258P+A276S+A364G, V45L+A79C+L149R+V258P+A276S+L281V+A364G, A25W+V45L+L149R+S214E+V258P+A of SEQ ID NO: 1 276S+A364G, V45L+L149R+S214Q+V258P+A276Q+A364G+S388K, V45N+L149R +S214Q+V258P+A276S+A364G+S388K, V45L+L149R+S214Q+V258P+A276S+A3 64G+S388K, V45L+L149R+S214E+V258P+A276S+H358T+A364G, A25W+V45L+L 149R+S214E+V258P+A276Q+A364G, V45L+L149R+S214Q+V258P+A276S+L281 V+A364G, V45L+N127D+L149R+V258P+A276S+A364G+S388K, V45L+L149R+V2 58P+A276S+H358T+A364G+S388K, V45L+L149R+G187L+V258P+A276S+A364G +S388K, V45L+L149R+W250Y+V258P+A276S+A364G+S388K, V45L+L149R+V25 8P+A276S+A286E+A364G+S388K, V45L+L149R+V258P+A276S+S282N+A364G+ S388K, A25W+V45L+L149R+V258P+A276S+A364G+S388K, V45L+L149R+S214Q +V258P+A276S+H358T+A364G, A25W+V45L+L149R+S214Q+V258P+A276S+A36 4G, V45L+L149R+N168G+V258P+A276S+A364G+S388K, V45L+A117S+L149R+V 258P+A276S+A364G+S388K, A25W+V45L+L149R+V258P+A276S+H358T+A364G,V45L+L149R+V258P+N260H+A276S+A364G+S388K、V45L+L149R+T215I+V258P+A276S+A364G+S388K、V45L+Q61K+L149R+V258P+A276S+H358T+A364G、V45L+L149R+V258P+A276S+Q314A+H358T+A364G、V45L+L149R+T180Q+V258P+A276S+A364G+S388K、V45L+L149R+V258P+A276S+Q314A+A364G+S388K、A25W+V45L+L149R+V258P+A276S+A286S+A364G、V45L+L149R+H219I+V258P+A276S+H358T+A364G、V45L+L149R+V258P+A276S+V350L+A364G+S388K、D11E+V45L+L149R+V258P+A276S+A364G+S388K、V45L+D113T+L149R+V258P+A276S+A364G+S388K、V45L+L149R+G187K+V258P+A276S+A364G+S388K、M28P+V45L+L149R+V258P+A276S+A364G+S388K、V45L+L149R+S173Y+V258P+A276S+A364G+S388K、A25W+V45L+L149R+V258P+A276S+Q314A+A364G、V45L+L149R+G187L+V258P+A276S+H358T+A364G、V45L+L149R+T215V+V258P+A276S+H358T+A364G、V45L+T70R+L149R+V258P+A276S+A364G+S388K、V45L+L149R+V258P+A276S+V350L+H358T+A364G、D9E+V45L+L149R+V258P+A276S+H358T+A364G、V45L+L149R+T211H+V258P+A276S+H358T+A364G、V45L+L149R+V258P+A276S+L281V+A364G+S388K、V45L+L149R+V258P+A276S+S282N+H358T+A364G、V45L+L149R+T215I+V258P+A276S+H358T+A364G、A25W+V45L+L149R+S173Y+V258P+A276S+A364G、V45L+Q61K+L149R+V258P+A276S+A364G+S388K、A25W+V45L+Q61K+L149R+V258P+A276S+A364G、V45L+L149R+S214E+V258P+A276S+L281V+A364G、V45L+L149R+V258P+A276S+A286E+H358T+A364G、D9E+V45L+L149R+V258P+A276S+A364G+S388K、V45L+S92D+L149R+V258P+A276S+A364G+S388K、A25W+V45L+L149R+V258P+A276S+A286E+A364G、V45L+L149R+N168G+V258P+A276S+L281V+A364G、V45L+Q61R+L149R+V258P+A276S+H358T+A364G、V45L+L149R+G187S+V258P+A276S+A364G+S388K、V45L+L149R+V258P+A276S+L281V+Q314A+A364G、V45L+L149R+V258P+A276S+L281V+H358T+A364G、V45L+L149R+A170S+V258P+A276S+H358T+A364G、V45L+L149R+A170S+V258P+A276S+A364G+S388K、V45L+L149R+T215V+V258P+A276S+A364G+S388K、V45L+L149R+V258P+A276Q+H358T+A364G+S388K、A25W+V45N+L149R+S214E+V258P+A276S+A364G、V45L+L149R+V258P+A276S+A286S+H358T+A364G、A25W+V45L+L149R+G187S+V258P+A276S+A364G、V45L+L149R+T180Q+V258P+A276S+L281V+A364G、V45L+S92D+L149R+V258P+A276S+L281V+A364G、V45L+Q61R+L149R+V258P+A276S+L281V+A364G、V45L+L149R+A170S+V258P+A276S+L281V+A364G、D11E+A25W+V45L+L149R+V258P+A276S+A364G、A25W+V45L+Q61R+L149R+V258P+A276S+A364G、A25W+V45L+L149R+T215V+V258P+A276S+A364G、D9E+V45L+L149R+V258P+A276S+L281V+A364G、A25W+V45L+L149R+V258P+A276S+V350L+A364G、V45L+L149R+H219V+V258P+A276S+L281V+A364G、V45L+L149R+T180Q+V258P+A276S+H358T+A364G、V45L+L149R+T215V+V258P+A276S+L281V+A364G、A25W+V45L+L149R+V258P+A276S+S282N+A364G、A25W+V45L+L149R+T215I+V258P+A276S+A364G、A25W+V45L+L149R+H219I+V258P+A276S+A364G、V45L+A117S+L149R+V258P+A276S+L281V+A364G、D9E+A25W+V45L+L149R+V258P+A276S+A364G、V45L+L149R+S214Y+V258P+A276S+A364G+S388K、A25W+V45L+L149R+T180Q+V258P+A276S+A364G、A25W+V45L+L149R+V258P+A276S+L281V+A364G、V45L+N127D+L149R+V258P+A276S+L281V+A364G、V45L+L149R+S173Y+V258P+A276S+H358T+A364G、V45L+Q61R+L149R+V258P+A276S+A364G+S388K、V45L+L149R+V258P+A276S+L281V+A286E+A364G、A25W+V45L+L149R+W250Y+V258P+A276S+A364G、A25W+V45L+L149R+V258P+N260H+A276S+A364G、V45L+L149R+V258P+A276S+L281V+V350L+A364G、A25W+V45L+L149R+A170S+V258P+A276S+A364G、V45L+L149R+V258P+A276S+L281V+A286S+A364G、V45L+L149R+V258P+A276S+L281V+S282N+A364G、D11E+V45L+L149R+V258P+A276S+L281V+A364G、V45L+Q61K+L149R+V258P+A276S+L281V+A364G、V45L+L149R+T215I+V258P+A276S+L281V+A364G、A25W+V45L+S92D+L149R+V258P+A276S+A364G、V45L+L149R+S214Y+V258P+A276S+L281V+A364G、V45L+L149R+T211H+V258P+A276S+L281V+A364G、A25W+V45L+L149R+G187L+V258P+A276S+A364G、V45L+S92D+L149R+V258P+A276S+H358T+A364G、V45L+L149R+G187K+V258P+A276S+H358T+A364G、V45L+L149R+N163H+V258P+A276S+L281V+A364G、A25W+V45L+T70R+L149R+V258P+A276S+A364G、V45L+L149R+S173Y+V258P+A276S+L281V+A364G、V45L+L149R+G187L+V258P+A276S+L281V+A364G、V45L+L149R+G187K+V258P+A276S+L281V+A364G、V45L+L149R+W250Y+V258P+A276S+H358T+A364G、V45L+L149R+T211H+V258P+A276S+A364G+S388K、V45L+L149R+N163H+V258P+A276S+A364G+S388K、V45L+L149R+V258P+A276S+A286S+A364G+S388K、A25W+V45L+L149R+S214Y+V258P+A276S+A364G、A25W+V45L+D113T+L149R+V258P+A276S+A364G、V45L+T70R+L149R+V258P+A276S+L281V+A364G、A25W+V45L+N127D+L149R+V258P+A276S+A364G、V45L+T70R+L149R+V258P+A276S+H358T+A364G、V45L+L149R+H219I+V258 P+A276S+L281V+A364G、A25W+V45L+A117S+L149R+V258P+A276S+A364G、A 25W+V45L+L149R+N168G+V258P+A276S+A364G、V45L+N127D+L149R+V258P +A276S+H358T+A364G、A25W+V45L+L149R+H219V+V258P+A276S+A364G、D1、 1E+V45L+L149R+V258P+A276S+H358T+A364G、V45L+L149R+G187S+V258P+A276S+L281V+A364G、A25W+V45L+L149R+N163H+V258P+A276S+A364G、A25W+V45L+L149R+G187K+V258P+A276S+A364G、V45L+L149R+V258P+N260H+A276S+H358T+A364G、V45L+D113T+L149R+V258P+A276S+L281V+A364G、V45L+D113T+L149R+V258P+A276S+H358T+A364G、V45L+L149R+N168G+V258P+A276S+H358T+A364G、V45L+L149R+S214Y+V258P+A276S+H358T+A364G、V45L+A117S+L149R+V258P+A276S+H358T+A364G、A25W+M28P+V45L+L149R+V258P+A276S+A364G、M28P+V45L+L149R+V258P+A276S+L281V+A364G、M28P+V45L+L149R+V258P+A276S+H358T+A364G、V45L+L149R+N163H+V258P+A276S+H358T+A364G、V45L+L149R+T215K+V258P+A276S+H358T+A364G、V45L+L149R+H219I+V258P+A276S+A364G+S388K、V45L+L149R+T215K+V258P+A276S+A364G+S388K、V45L+L149R+W250Y+V258P+A276S+L281V+A364G、V45L+L149R+H219V+V258P+A276S+A364G+S388K、A25W+V45L+L149R+V258P+A276S+N355G+A364G、V45L+L149R+V258P+A276S+N355G+A364G+S388K、V45L+L149R+V258P+A276S+L281V+N355G+A364G、and V45L+L149R+V258P+A276S+N355G+H358T+A364G and V45L+L149R+H219V+V258P+A276S+H358T+A364G, wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1.

[0234] In one aspect, the variants are selected from the group consisting of V45L+A79C+L149R+S214E+V258P+A276S+A364G+S388K, V45L+A79C+L149R+S214Q+V258P+A276S+A364G+S388K, V45L+A79C+L149R+V258P+A276S+Q314A+A364G+S388K, V45L+A79C+L149R+V258P+A276S+L281V+A364G+S388K, V45L+A79C+L149R+S173Y+V258P+A276S+A364G+S388K, V45L+A79C+L149R+S173Y+V258P+A276S+A364G+S388K of SEQ ID NO: 1. 8K, V45L+A79C+L149R+G187K+V258P+A276S+A364G+S388K, V45L+Q61R+A7 9C+L149R+V258P+A276S+A364G+S388K, V45L+A79C+L149R+N168G+V258P+A 276S+A364G+S388K, V45L+A79C+L149R+T215V+V258P+A276S+A364G+S388 K, V45L+A79C+L149R+V258P+A276S+A286S+A364G+S388K, V45L+A79C+L149 R+H219V+V258P+A276S+A364G+S388K, V45L+A79C+L149R+A170S+V258P+A 276S+A364G+S388K, D11E+V45L+A79C+L149R+V258P+A276S+A364G+S388K, V45L+A79C+L149R+V258P+A276S+A286E+A364G+S388K, V45L+A79C+L149R +T180Q+V258P+A276S+A364G+S388K, V45L+A79C+L149R+H219I+V258P+A27 6S+A364G+S388K, V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T , V45L+A79C+L149R+V258P+A276S+V350L+A364G+S388K, V45L+L149R+S214 E+V258P+A276S+H358D+A364G+D470T, V45L+A79C+D113T+L149R+V258P+A2 76S+A364G+S388K, V45L+A79C+N127D+L149R+V258P+A276S+A364G+S388K,D9E+V45L+A79C+L149R+V258P+A276S+A364G+S388K、V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T、V45L+A79C+L149R+W250Y+V258P+A276S+A364G+S388K、V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T、V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T、V45L+A79C+L149R+N163H+V258P+A276S+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G、A25W+V45L+A79C+L149R+S214E+V258P+A276S+A364G、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+D470T、V45L+A79C+S92D+L149R+V258P+A276S+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G、V45L+L149R+S214Q+V258P+A276S+A286E+A364G+S388K、V45L+L149R+S214Q+T215I+V258P+A276S+A364G+S388K、A25W+V45L+L149R+S214Q+V258P+A276S+A364G+S388K、V45L+L149R+A170S+S214Q+V258P+A276S+A364G+S388K、V45L+Q61K+L149R+S214Q+V258P+A276S+A364G+S388K、V45L+L149R+N168G+S214Q+V258P+A276S+A364G+S388K、V45L+A79C+D95D+L149R+V258P+A276S+A364G+S388K、V45L+Q77E+A79C+L149R+V258P+A276S+A364G+S388K、V45L+L149R+S214Q+V258P+A276S+S282N+A364G+S388K、V45L+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K、V45L+T70R+L149R+S214Q+V258P+A276S+A364G+S388K、V45L+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K、V45L+L149R+G187K+S214Q+V258P+A276S+A364G+S388K、V45L+L149R+V258P+A276S+L281V+H358T+A364G+S388K、M28P+V45L+L149R+S214Q+V258P+A276S+A364G+S388K、V45L+L149R+G187L+S214Q+V258P+A276S+A364G+S388K、V45L+L149R+S214Q+V258P+A276S+A286S+A364G+S388K、D9E+V45L+L149R+S214Q+V258P+A276S+A364G+S388K、V45L+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K、V45L+A79C+L149R+V258P+A276S+H358T+A364G+S388K、A25W+V45L+L149R+S214E+V258P+A276S+H358T+A364G、A25W+V45L+L149R+S214E+V258P+A276S+A286E+A364G、A25W+V45L+Q61K+L149R+S214E+V258P+A276S+A364G、A25W+V45L+L149R+V258P+A276S+H358T+A364G+S388K、V45L+L149R+S214Q+V258P+A276S+V350L+A364G+S388K、D11E+V45L+L149R+S214Q+V258P+A276S+A364G+S388K、V45L+L149R+H219I+V258P+A276S+H358T+A364G+S388K、V45L+S92D+L149R+S214Q+V258P+A276S+A364G+S388K、A25W+V45L+L149R+T211H+S214E+V258P+A276S+A364G、A25W+V45L+L149R+S214E+H219V+V258P+A276S+A364G、V45L+L149R+W250Y+V258P+A276S+H358T+A364G+S388K、D9E+V45L+L149R+V258P+A276S+H358T+A364G+S388K、V45L+L149R+H219V+V258P+A276S+H358T+A364G+S388K、V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K、D11E+A25W+V45L+L149R+S214E+V258P+A276S+A364G、V45L+L149R+V258P+A276S+Q314A+H358T+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L、V45L+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K、V45L+D113T+L149R+S214Q+V258P+A276S+A364G+S388K、A25W+V45L+Q61R+L149R+S214E+V258P+A276S+A364G、A25W+V45L+L149R+S214E+V258P+A276S+L281V+A364G、D9E+A25W+V45L+L149R+S214E+V258P+A276S+A364G、V45L+Q61R+L149R+V258P+A276S+H358T+A364G+S388K、V45L+D113T+L149R+V258P+A276S+H358T+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R、V45L+Q61R+L149R+S214Q+V258P+A276S+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K、V45L+L149R+T180Q+V258P+A276S+H358T+A364G+S388K、A25W+V45L+S92D+L149R+S214E+V258P+A276S+A364G、A25W+V45L+L149R+S214E+V258P+A276S+V350L+A364G、V45L+L149R+T211H+S214Q+V258P+A276S+A364G+S388K、A25W+V45L+L149R+S214E+H219I+V258P+A276S+A364G、V45L+L149R+T211H+V258P+A276S+H358T+A364G+S388K、A25W+V45L+A117S+L149R+S214E+V258P+A276S+A364G、A25W+V45L+L149R+S214E+T215V+V258P+A276S+A364G、V45L+A117S+L149R+V258P+A276S+H358T+A364G+S388K、V45L+L149R+N168G+V258P+A276S+H358T+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H、A25W+V45L+L149R+S214E+T215I+V258P+A276S+A364G、V45L+N127D+L149R+V258P+A276S+H358T+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A、V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K、A25W+V45L+L149R+G187S+S214E+V258P+A276S+A364G、V45L+A117S+L149R+S214Y+V258P+A276S+A364G+S388K、A25W+V45L+L149R+S214E+V258P+A276S+A286S+A364G、V45L+L149R+V258P+A276S+A286S+H358T+A364G+S388K、V45L+L149R+S173Y+V258P+A276S+H358T+A364G+S388K、V45L+A79C+L149R+V258P+A276S+N355G+A364G+S388K、A25W+V45L+L149R+G187L+S214E+V258P+A276S+A364G、V45L+L149R+S214Q+V258P+A276S+L281V+A364G+S388K、V45L+L149R+S214Q+T215V+V258P+A276S+A364G+S388K、V45L+L149R+N163H+V258P+A276S+H358T+A364G+S388K、V45L+A79C+A117S+L149R+V258P+A276S+A364G+S388K, V45L+L149R+A17 0S+V258P+A276S+H358T+A364G+S388K, A25W+V45L+L149R+S214E+T215K +V258P+A276S+A364G, V45L+S92D+L149R+V258P+A276S+H358T+A364G+S 388K, V45L+L149R+S214Q+V258P+A276S+N355G+A364G+S388K, A25W+V4, 5L+L149R+S214E+V258P+A276S+N355G+A364G and A25W+V45L+L149R+S214E+V258P+A276S+Q314A+A364G, wherein the variant comprises a substitution at a position corresponding to a position selected from the group consisting of: 5L+L149R+S214E+V258P+A276S+N355G+A364G and A25W+V45L+L149R+S214E+V258P+A276S+Q314A+A364G, wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1.

[0235] In one aspect, the variants are selected from the group consisting of V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K ... 149R+D192E+S214Q+V258P+A276S+H358D+A364G, V45L+A117S+L149R+S2 14Q+V258P+A276S+A364G+S388A+D470T, V45L+A117S+L149R+S214Q+V258 P+A276S+A364G+S388H+D470T, V45N+A117S+L149R+S214Q+V258P+A276S+ A364G+S388K+D470T, V45L+A117S+L149R+S214E+V258P+A276S+H358D+A3 64G+S388K, V45L+A117S+L149R+D192E+S214Q+V258P+A276S+H358D+A36 4G, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K, V45L+ A117S+L149R+S214Q+V258P+A276S+A364G+S388K+R483V, V45L+A117S+L1 49R+S214E+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+S214 Q+V258P+A276S+H358D+A364G+S388R, V45L+A117S+L149R+S214Q+V258P+ A276S+H358D+A364G+S388A, V45L+A117S+L149R+S214Q+V258P+A276S+A3 64G+Q384A+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364 G+S388L, V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K,V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394D、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S473G、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A、V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+L478P、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S481A、V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K、V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+L478N、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366V+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K、D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S501E、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S528H、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366I+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N474G、V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+A499Y、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V500V、V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+T480N、V45L+A117S+L149R+G187S+S214Q+V258P+A276S+A364G+S388K、A25W+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N476N、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N476D、D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S481S、V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K、V45L+A117S+L149R+S214Q+T215I+V258P+A276S+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Q496R、V45L+A117S+L149R+A170S+S214Q+V258P+A276S+A364G+S388K、V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V497P、V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K、V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K、V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V、V45L+A117S+L149R+N168G+S214Q+V258P+A276S+A364G+S388K、V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K、M28P+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+T477K、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V、V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V500T、V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K, V45L+S92D +A117S+L149R+S214Q+V258P+A276S+A364G+S388K, V45L+A117S+L149R+S2 14Q+V258P+A276S+A364G+S388K+A472L, V45L+A117S+L149R+S214Q+V258P +A276S+A364G+S388K+S473K, V45L+A117S+L149R+S214Q+V258P+A276S+A3 64G+S388K+A499L, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K +V498I, V45L+A117S+L149R+N163H+S214Q+V258P+A276S+A364G+S388K, V4 5L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N527H,V45L+A117S+ L149R+S214Q+V258P+A276S+A364G+S388K+T477V, V45L+A117S+L149R+S21 4Q+V258P+A276S+A364G+S388K+G503L, V45L+A117S+L149R+G187L+S214Q+ V258P+A276S+A364G+S388K, V45L+A117S+L149R+S214Q+T215K+V258P+A27 6S+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q385C+S388K and V45L+A117S+L149R+S214Q+V258P+A276S+N355G+A364G+S388K and the variant comprises a substitution at a position corresponding to a position selected from the group consisting of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118%, at least 119%, at least 120%, at least 121%, at least 122%, at least 123%, at least 124%, at least 125%, at least 126%, at least 127%, at least 128%, at least 129%, at least 130%, at least 131%, at least 132%, at least 133%, at least 134%, at least 135%, at least 136%, at least 137%, at least 138%, at least 139%, at least 140%, at least 141%, at least 142%, at least 143%, at least 144%, at least 145%, at least 146%, at least 147%, at least 148%, at least 14At least 98% or at least 99%, but less than 100%, sequence identity.

[0236] In one aspect, the variants are selected from the group consisting of V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K ... 4G+S388H+D470T, V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D +A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+ S388L+D470T, V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K+D 470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R+D4 70T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D47 0A+R483V, V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K+D470 T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T +R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+ D470T, V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R 483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H+D470T+R4 83V, V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470 T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T,V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477K、V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476D、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478N、V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K+D470T、V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K+D470T、D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+S282N+A364G+S388K+D470T、D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476N、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394D+D470T、V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478P、V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K+D470T、V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T、V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496R、V45L+A117S+N127D+L149R+S214Q+V258P+A276S+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+A499Y、V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K+D470T、V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N529T、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478N、V45L+T70R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T、M28P+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T、V45L+A117S+L149R+S214Y+V258P+A276S+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477K、V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K、V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+T215I+V258P+A276S+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496E、V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+W495I、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V498I、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V500V、D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K、V45L+A117S+L149R+A170S+S214Q+V258P+A276S+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q、V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496Q、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A499Y、V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q385C+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T480N、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V497P、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+A499L、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S501N、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V498I、V45L+A117S+L149R+S214Q+H219I+V258P+A276S+A364G+S388K+D470T、V45L+A117S+L149R+N163H+S214Q+V258P+A276S+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+Q31、 4A+H358D+A364G+S388K、V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D、V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K 4G+T366V+S388K、V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K、V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K、V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S3 88K+N476D、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S38 8K+T477V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388 K+L478P、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K +S481A、V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K+D 470T、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V5 00T、V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S38 8K、V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388 K、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470V+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V500V、V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S481S、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V500T、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+W495S、V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N474G、V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Q496Q、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S501E、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N476N、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473K、V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Q496E、A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K、V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T480L、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K、V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K、V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Y391V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T480N、D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K、V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A499L、V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K、V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H、V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A472L、V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A3 64G+S388K+T480L, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R, V45L+A117S+L149R+S214Q+V258P +A276S+A286S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K, V45L+A117S+L1 49R+S214Q+V258P+A276S+N355G+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388 K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Y386G+S388K and V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S501E, wherein the variant comprises a substitution at a position corresponding to a position selected from the group consisting of: V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S501E, wherein the variant is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity.

[0237] In one aspect, the variants are selected from the group consisting of V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V, V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T of SEQ ID NO: 1 358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214E+V258P+A276 S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A 276Q+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258 P+A276Q+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V 258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214 Q+V258P+A276S+H358D+A364G+S388K+D470A+R483V, V45N+A117S+L149R+S 214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149 R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T+L530R, V45N+A117S+L 149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A117 S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T+L530R, V45L+A 117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T+R483V, V45 L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L+D470T+R483V,V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N、V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366I+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S473G、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N529T、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T、V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T、V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S528H、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496R、V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T、D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S473K、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K+D470T+R483V、V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+N260H+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+G187S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N474G、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501N、V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R+D470T、V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N、V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T、V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V、V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366V+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496Q、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366I+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L484S、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499L、V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V498I、V45L+T70R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476D+R483V、D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501E、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A、V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S、V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D+D470T+R483V、V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V497P、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N527H、V45L+A117S+L149R+S214Q+V258P+A276S+A364G、 +S388K+D470T+R483V+Q496Q、V45L+A117S+L149R+N168G+S214Q+V258P+A276S+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476N+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477V+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478N+R483V、M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H+D470T+R483V、V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497P、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V498I、V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477K+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496E、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496R、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+A499L、V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+S501E、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+N529T、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+S501N、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S481S+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478P+R483V、D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V、V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K+D470T+R483V、V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+N527H、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T、V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H+D470T+R483V、V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496E、V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T、V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+H219I+V258P+A276S+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+A499Y、V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V500T、V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G526T、V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+D525L、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H+D470T、V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T+L530R、A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K+D470T+R483V、V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K+D470T+R483V、V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473G、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G503L、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+D525L、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500T、V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480L、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497E、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470V+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470K+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A472L、V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+T215K+V258P+A276S+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497W、V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+W495E、V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+D470T、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T+R483V and V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T, wherein the variant comprises a substitution at a position corresponding to a position selected from the group consisting of: V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T, wherein the variant is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87% or less relative to the polypeptide of SEQ ID NO: 1; All have 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity, but less than 100%.

[0238] In one aspect, the variants are V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388 of SEQ ID NO: 1 K+D470T+R483V, V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V 258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366I+S388K+D47 0T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T+L530R, V45L+Q61K+A117S+L149R+S214Q+ V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R4 83V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276 S+H358D+A364G+S388K+G394A+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T+L530R,V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T+R483V+D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T+R483V、V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+L530R、V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+W495E、V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T+L530R、V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Y391V+D470T+R483V、D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480L+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A+L530R、V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S+R483V、V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R、D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496Q、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496E、V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P+R483V、A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484K、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N474G+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T+R483V、V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484S、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484D、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S528H、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S501N、V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+A499L、V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496E+L530R、V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V498I+L530R、V、 45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+A499Y、V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501N+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N+L530R、V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500V+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V500V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S501E、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+D525L+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G526T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N527H+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K+L530R、M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R、D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501E+L530R、V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499L+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A472I+L530R、V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+N527H、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497P、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V498I、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N+R483V、V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K+D470T+L530R、M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H+D470T+L530R、V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R、V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V500T、V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V、V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T、V45L+A93T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499Y、V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+G503L、V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A+R483V、V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T+L530R、V45L+A117S+L149R+G187S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R、V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+G526T、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+D525L、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S528H+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+I469T+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N529T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G503L+L530R、V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V497P+L530R、V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T+L530R、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497D、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N+R483V、V45L+T70R+D95N+A117S+L149R+S214Q+V258P+A276S+L356M+H358D+A364G+S388K、V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497W、V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R、V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+D470T+L530R、V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T+R483V、V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497E, V45L+A117S+ L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214, and V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Y386G+S388K+D470T+R483V, and V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D+D470T+R483V, wherein the variant is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity.

[0239] In one aspect, the variants are selected from the group consisting of V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H 358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483 V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V25 8P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+ G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S +L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H3 58D+A364G+S388K+G394A+D470T+R483V, V45L+Q61K+A117S+L149R+S2 14Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+L530R,V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D47 0T+R483V+L530R, V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+ at a position corresponding to a position selected from the group consisting of A364G+S388K+D470T+R483V+L530R and V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V Substitutions, wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100%, sequence identity to the polypeptide of SEQ ID NO: 1.

[0240] In one aspect, the variant is selected from the group consisting of V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R, V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R, V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+ A364G+S388K+G394A+D470T+R483V+L530R, V45L+Q61K+A117S+L149R+S214 Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R, V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A286E+H358D+A364G+Q38 4A+S388K+V393H+D470T+R483V, V45L+A117S+L149R+G187K+S214Q+V258P+ A276S+A286E+H358D+A364G+Q384A+S388K+N395D+D470T+R483V, V45L+A11 7S+L149R+G187K+S214E+T215I+V258P+A276S+A286E+H358D+A364G+S388K +V393H+D470T+R483V, V45L+A117S+L149R+G187K+S214E+T215I+V258P+A2 76S+A286E+H358D+A364G+S388K+N395D+D470T+R483V, V45L+T70R+A117S+ L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468V+D4 70T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+ A364G+S388K+G394A+C468A+D470T+R483V, V45L+T70R+A117S+L149R+S214 Q+C243V+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V,V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468L+D470T+R483V、V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375V+S388K+G394A+D470T+R483V、V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468S+D470T+R483V、V45L+C60L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V、V45L+C69L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V、V45L+C60A+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V、V45L+T70R+A117S+L149R+S214Q+C243L+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V、V45L+C60S+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V、V45L+C69A+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V、V45L+T70R+A117S+L149R+C161S+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V、V45L+C69V+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V、V45L+C60V+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V、V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375A+S388K+G394A+D470T+R483V、V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375S+S388K+G394A+D470T+R483V、V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540A、V45L+C69S+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V、V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375L+S388K+G394A+D470T+R483V、V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540L、V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C522S、V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540S、V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396S+D470T+R483V、V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396A+D470T+R483V、C40L、V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V、C40A、V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C40S、V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V、C40V、V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V、V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396V+D470T+R483V、V45L+T70R+A117S+L149R+C161V+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V、V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396L+D470T+R483V、V45L+T70R+A117S+L149R+C161L+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V、V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C522A、V45L+T70R+A117S+L149R+S214Q+C243S+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V、V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C522V and V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540V, wherein the variant comprises a substitution at a position corresponding to a position selected from the group consisting of: V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540V, wherein the variant has at least or at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity.

[0241] In one aspect, the variant is V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394Q+D470T+R483V, V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V, V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S +L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V, V45L+Q61K+T70 R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V 393H+D470T+R483V, V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+ L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V, V45L+Q61K+T70R+ A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V3 93H+D470T+R483V, V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L2 81V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V, V45L+Q61K+T70R+A 117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393 H+D470T+R483V and V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V, wherein the variant comprises a substitution at a position corresponding to a position selected from the group consisting of: H+D470T+R483V and V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V, wherein the variant comprises a substitution at ...At least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity.

[0242] In one aspect the variant comprises a substitution at a position corresponding to a position selected from the group consisting of V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V and V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V in SEQ ID NO: 1, said variant comprising at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO:1.

[0243] In one aspect, the xylanase variant of the present invention has improved properties relative to the parent polypeptide, the improved properties being selected from the group consisting of increased catalytic efficiency, increased catalytic rate, increased chemical stability, increased oxidative stability, increased pH activity, increased pH stability, increased specific activity, increased stability under storage conditions, increased substrate binding, increased substrate cleavage, increased substrate specificity, increased substrate stability, increased surface properties, increased thermal activity and increased thermostability.

[0244] In one aspect, the xylanase variants of the invention have improved properties relative to the parent polypeptide.

[0245] In one aspect, the xylanase variant of the invention has improved properties relative to said parent polypeptide, said improved property being increased thermostability.

[0246] In one aspect, the xylanase variants have improved (increased) thermostability relative to the parent xylanase.

[0247] In one aspect, the xylanase variant has improved (increased) thermostability relative to SEQ ID NO:1.

[0248] In one aspect, the xylanase variants have increased thermostability, measured as an elevated melting point using TSA.

[0249] In one aspect, the xylanase variant has increased thermostability, measured as an increased melting point of at least 1°C, at least 1.5°C, at least 2°C, at least 2.5°C, at least 3°C, at least 3.5°C, at least 4.0°C, at least 4.5°C, or at least 5°C relative to SEQ ID NO:1 using TSA.

[0250] In one aspect, the xylanase variants have increased thermostability, measured as an elevated melting point using n-DSF.

[0251] In one aspect, the xylanase variant has increased thermostability, measured as an increased melting point of at least 1°C, at least 1.5°C, at least 2°C, at least 2.5°C, at least 3°C, at least 3.5°C, at least 4.0°C, at least 4.5°C, or at least 5°C relative to SEQ ID NO:1 using n-DSF.

[0252] In one aspect, the present invention provides the following substitutions or combinations of substitutions: V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V; V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394Q+D470T+R483V; V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V; V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V; V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V; V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V; V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V; V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V; V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V; V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V; V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V; V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+L530R; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V+L530R; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V+L530R; V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V; V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A286E+H358D+A364G+Q384A+S388K+N395D+D470T+R483V; V45L+A117S+L149R+G187K+S214E+T215I+V258P+A276S+A286E+H358D+A364G+S388K+V393H+D470T+R483V; V45L+A117S+L149R+G187K+S214E+T215I+V258P+A276S+A286E+H358D+A364G+S388K+N395D+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T+R483V; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366I+S388K+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T+L530R; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T+R483V; D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468V+D470T+R483V; V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T、 V45L+A79C+L149R+S214E+V258P+A276S+A364G+S388K; V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T+R483V; V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496R; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+W495E; V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Y391V+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480L+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A+L530R; V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S+R483V; V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+C243V+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496Q; V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496E; V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P+R483V; A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484K、 V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N474G+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T+R483V; V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484S; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484D; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S528H; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S501N; V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+A499L; V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T+R483V; V45L+A79C+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496E+L530R; V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V498I+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A+R483V; V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+A499Y; V45L+A79C+L149R+V258P+A276S+Q314A+A364G+S388K; V45L+A79C+L149R+V258P+A276S+L281V+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501N+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N+L530R; V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500V+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V500V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S501E; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+D525L+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G526T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N527H+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K+L530R; M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501E+L530R; V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499L+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A472I+L530R; V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+N527H; V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497P; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V498I; V45L+A79C+L149R+S173Y+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N+R483V; V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T+L530R; M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A79C+L149R+G187K+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H+D470T+L530R; V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L+D470T+R483V; V45L+Q61R+A79C+L149R+V258P+A276S+A364G+S388K; V45L+A79C+L149R+N168G+V258P+A276S+A364G+S388K; V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A79C+L149R+T215V+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V500T; V45L+A79C+L149R+V258P+A276S+A286S+A364G+S388K; V45L+A79C+L149R+H219V+V258P+A276S+A364G+S388K; V45L+A79C+L149R+A170S+V258P+A276S+A364G+S388K; V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T; V45L+A79C+L149R+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T+R483V; V45L+A93T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499Y; V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N; V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468L+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366I+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S473G; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T+R483V; D11E+V45L+A79C+L149R+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N529T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T; V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A79C+L149R+V258P+A276S+A286E+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+G503L; V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T; V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S528H; V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496R; V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T; D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S473K; V45L+A79C+L149R+T180Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K+D470T+R483V; V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+N260H+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+G187S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N474G; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501N; V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R+D470T; V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T; V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+G187S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N; V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A79C+L149R+H219I+V258P+A276S+A364G+S388K; V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366V+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R+D470T+R483V; V45N+A79C+L149R+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496Q; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q+D470T+R483V; V45L+A79C+L149R+V258P+A276S+V350L+A364G+S388K; V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366I+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+G526T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L484S; V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499L; V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T+L530R; V45L+A79C+D113T+L149R+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+D525L; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V498I; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L+D470T; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S528H+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476D+R483V; D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501E; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A; V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S; V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+I469T+D470T+R483V; V45L+A79C+N127D+L149R+V258P+A276S+A364G+S388K; D9E+V45L+A79C+L149R+V258P+A276S+A364G+S388K; V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T; V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N529T+L530R; V45L+A79C+L149R+W250Y+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V497P; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N527H; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496Q; V45L+A117S+L149R+N168G+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476N+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477V+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478N+R483V; V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K+D470T+R483V; M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H+D470T+R483V; V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497P; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V498I; V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T+L530R; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375V+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470A+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477K+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496E; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496R; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+A499L; V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T; V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T; V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468S+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G503L+L530R; V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+S501E; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+N529T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+S501N; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S481S+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478P+R483V; D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V497P+L530R; V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K+D470T+R483V; V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+N527H; V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T; V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H+D470T+R483V; V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496E; V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+H219I+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A79C+L149R+N163H+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+A499Y; V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V500T; V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G526T; V45L+C60L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+C69L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497D; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+D525L; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N; V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H+D470T; V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476D; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N+R483V; V45L+C60A+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D+D470T; A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+T70R+A117S+L149R+S214Q+C243L+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478N; V45L+C60S+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K+D470T+R483V; V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K+D470T; D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G; V45L+C69A+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+T70R+A117S+L149R+C161S+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+S282N+A364G+S388K+D470T; V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473G; V45L+T70R+D95N+A117S+L149R+S214Q+V258P+A276S+L356M+H358D+A364G+S388K; D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476N; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394D+D470T; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G503L; V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478P; V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K+D470T; V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+C69V+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+D525L; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496R; V45L+A117S+N127D+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+A499Y; V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480L; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L+D470T; V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N529T; V45L+C60V+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497E; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478N; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; M28P+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470V+R483V; V45L+A117S+L149R+S214Y+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477K; V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K; V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+T215I+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496E; V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+W495I; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V498I; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470K+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V500V; D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+A170S+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477V; A25W+V45L+A79C+L149R+S214E+V258P+A276S+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q; V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496Q; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375A+S388K+G394A+D470T+R483V; V45L+A117S+L149R+D192E+S214Q+V258P+A276S+H358D+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A472L; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A499Y; V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q385C+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T480N; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V497P; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+A499L; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S501N; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375S+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L+D470T+R483V; V45L+A79C+S92D+L149R+V258P+A276S+A364G+S388K; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540A; V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A; V45L+C69S+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V498I; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G; V45L+A117S+L149R+S214Q+H219I+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+N163H+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+L149R+S214Q+V258P+A276S+H358D+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K; V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D; A25W+V45L+A79C+L149R+V258P+A276S+A364G; V45L+L149R+S214Q+V258P+A276S+A286E+A364G+S388K; V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K; V45L+A117S+L149R+D192E+S214Q+V258P+A276S+H358D+A364G; V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K; V45L+L149R+S214Q+T215I+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N476D; V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+T215K+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478P; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S481A; A25W+V45L+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A79C+L149R+V258P+A276S+L281V+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V500T; V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K; V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375L+S388K+G394A+D470T+R483V; V45L+L149R+A170S+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470V+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V500V; V45L+Q61K+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+L149R+N168G+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A79C+D95D+L149R+V258P+A276S+A364G+S388K; V45L+Q77E+A79C+L149R+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497W; V45L+L149R+S214Q+V258P+A276S+S282N+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S481S; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V500T; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540L; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C522S; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+W495S; V45L+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K; V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497W; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540S; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396S+D470T+R483V; V45L+T70R+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N474G; V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Q496Q; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V+D470T; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S501E; A25W+V45L+L149R+S214E+V258P+A276S+A364G; V45L+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K; V45L+L149R+G187K+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N476N; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473K; V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K; C40L+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Q496E; A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+L149R+V258P+A276S+L281V+H358T+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A; V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H; M28P+V45L+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T480L; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K; V45L+A93S+L149R+A252S+H334D; C40A+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+L149R+G187L+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K; V45L+L149R+S214Q+V258P+A276S+A286S+A364G+S388K; V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L; V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K; D9E+V45L+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Y391V; V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394D; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S473G; V45L+A79C+L149R+V258P+A276S+H358T+A364G+S388K; V45L+L149R+S214Q+V258P+A276Q+A364G+S388K; A25W+V45L+L149R+S214E+V258P+A276S+H358T+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T480N; D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K; C40S+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; C40V+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; A25W+V45L+L149R+S214E+V258P+A276S+A286E+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A499L; A25W+V45L+Q61K+L149R+S214E+V258P+A276S+A364G; V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K; A25W+V45L+L149R+V258P+A276S+H358T+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+W495E; A25W+V45L+A79C+L149R+V258P+A276S; V45L+L149R+S214Q+V258P+A276S+V350L+A364G+S388K; D11E+V45L+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+L149R+H219I+V258P+A276S+H358T+A364G+S388K; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396V+D470T+R483V; V45N+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K; V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+S92D+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+L149R+V258P+A276S+H358T+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+L478P; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S481A; V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K; A25W+V45L+L149R+T211H+S214E+V258P+A276S+A364G; A25W+V45L+L149R+S214E+H219V+V258P+A276S+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H; V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K; V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+L149R+W250Y+V258P+A276S+H358T+A364G+S388K; D9E+V45L+L149R+V258P+A276S+H358T+A364G+S388K; V45L+L149R+H219V+V258P+A276S+H358T+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A472L; A25W+V45L+L149R+V258P+A276S+A364G; V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+L478N; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R; V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366V+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K; D11E+A25W+V45L+L149R+S214E+V258P+A276S+A364G; V45L+T70R+A117S+L149R+C161V+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+L149R+V258P+A276S+Q314A+H358T+A364G+S388K; D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S501E; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S528H; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396L+D470T+R483V; V45L+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K; V45L+D113T+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T480L; V45L+A93S+L149R+A252S+H334D; V45L+A93S+L149R+V234P+A252S; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H; A25W+V45L+Q61R+L149R+S214E+V258P+A276S+A364G; V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366I+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N474G; A25W+V45L+L149R+S214E+V258P+A276S+L281V+A364G; D9E+A25W+V45L+L149R+S214E+V258P+A276S+A364G; V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R; V45L+Q61R+L149R+V258P+A276S+H358T+A364G+S388K; V45L+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+D113T+L149R+V258P+A276S+H358T+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+A499Y; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V500V; V45L+Q61R+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+L149R+S214E+V258P+A276S+H358T+A364G; V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K; V45L+L149R+V258P+A276S+L281V+A364G; V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+T480N; V45L+A117S+L149R+G187S+S214Q+V258P+A276S+A364G+S388K; A25W+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N476N; A25W+V45L+L149R+S214E+V258P+A276Q+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N476D; V45L+L149R+S214Q+V258P+A276S+L281V+A364G; V45L+A93S+L149R+A252S+H334D+A340G; V45L+A93S+L149R+A252S+H334D; V45L+A93S+L149R+A252S+H334D; V45L+L149R+A252S+H334D; V45L+N127D+L149R+V258P+A276S+A364G+S388K; V45L+L149R+V258P+A276S+H358T+A364G+S388K; V45L+L149R+V258P+A276S+A364G+S388K; D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S481S; V45L+L149R+N168G+V258P+A276S+A364G; V45L+L149R+T180Q+V258P+A276S+H358T+A364G+S388K; V45L+L149R+G187L+V258P+A276S+A364G+S388K; V45L+L149R+W250Y+V258P+A276S+A364G+S388K; V45L+L149R+V258P+A276S+A286E+A364G+S388K; V45L+L149R+V258P+A276S+S282N+A364G+S388K; A25W+V45L+L149R+V258P+A276S+A364G+S388K; V45L+L149R+S214Q+V258P+A276S+H358T+A364G; V45L+L149R+S173Y+V258P+A276S+A364G; V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K; V45L+A93S+L149R+A252S+H334D; V45L+A93S+L149R+A252S+H334D+A340G; V45L+L149R+S190E+D446T+R459V; A25W+V45L+L149R+V258P+A276S+H358T; A25W+V45L+S92D+L149R+S214E+V258P+A276S+A364G; A25W+V45L+L149R+S214E+V258P+A276S+V350L+A364G; A25W+V45L+L149R+S214Q+V258P+A276S+A364G; V45L+L149R+N168G+V258P+A276S+A364G+S388K; V45L+A117S+L149R+V258P+A276S+A364G+S388K; A25W+V45L+L149R+V258P+A276S+H358T+A364G; V45L+L149R+V258P+N260H+A276S+A364G+S388K; V45L+L149R+T215I+V258P+A276S+A364G+S388K; A25W+V45L+L149R+V258P+A276Q+A364G; V45L+T70R+A117S+L149R+C161L+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; A25W+V45L+L149R+S214E+V258P+A276S; V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K; V45L+L149R+T211H+S214Q+V258P+A276S+A364G+S388K; V45L+Q61K+L149R+V258P+A276S+H358T+A364G; V45L+L149R+V258P+A276S+Q314A+H358T+A364G; V45L+L149R+T180Q+V258P+A276S+A364G+S388K; V45L+L149R+V258P+A276S+Q314A+A364G+S388K; A25W+V45L+L149R+V258P+A276S+A286S+A364G; V45L+L149R+S190E+D446T; V45L+L149R+V258P+A276S+A364G; V45L+L149R+A170S+V258P+A276S+A364G; V45L+L149R+V258P+A276Q+A364G; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C522A; V45L+L149R+H219I+V258P+A276S+H358T+A364G; V45L+L149R+V258P+A276S+V350L+A364G+S388K; D11E+V45L+L149R+V258P+A276S+A364G+S388K; V45L+D113T+L149R+V258P+A276S+A364G+S388K; V45L+L149R+G187K+V258P+A276S+A364G+S388K; M28P+V45L+L149R+V258P+A276S+A364G+S388K; V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; A25W+V45L+L149R+S214Q+V258P+A276S; V45L+A117S+L149R+S214Q+T215I+V258P+A276S+A364G+S388K; A25W+V45L+L149R+V258P+A276S+S388K; A25W+V45L+L149R+S214E+H219I+V258P+A276S+A364G; V45L+A93S+L149R+V234P+A252S+H334D; V45L+L149R+T211H+V258P+A276S+H358T+A364G+S388K; A25W+V45L+A117S+L149R+S214E+V258P+A276S+A364G; V45L+L149R+S173Y+V258P+A276S+A364G+S388K; A25W+V45L+L149R+V258P+A276S+Q314A+A364G; V45L+L149R+G187L+V258P+A276S+H358T+A364G; V45L+L149R+T215V+V258P+A276S+H358T+A364G; V45L+T70R+L149R+V258P+A276S+A364G+S388K; V45L+N127D+L149R+V258P+A276S+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Q496R; V45L+L149R+W250Y+V258P+A276S+A364G; V45L+L149R+V258P+A276S+V350L+H358T+A364G; D9E+V45L+L149R+V258P+A276S+H358T+A364G; V45L+L149R+T211H+V258P+A276S+H358T+A364G; A25W+V45L+L149R+W250Y+A276Q+A364G; V45L+L149R+V258P+A276S+L281V+A364G+S388K; V45L+L149R+V258P+A276S+S282N+H358T+A364G; V45L+L149R+T215I+V258P+A276S+H358T+A364G; A25W+V45L+L149R+S173Y+V258P+A276S+A364G; V45L+Q61K+L149R+V258P+A276S+A364G+S388K; V45L+L149R+T180Q+V258P+A276S+A364G; V45L+A117S+L149R+A170S+S214Q+V258P+A276S+A364G+S388K; V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K; A25W+V45L+L149R+S214E+T215V+V258P+A276S+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V497P; V45L+L149R+V258P+A276S+Q314A+A364G; V45L+A117S+L149R+V258P+A276S+A364G; V45L+A117S+L149R+V258P+A276S+H358T+A364G+S388K; V45L+L149R+N168G+V258P+A276S+H358T+A364G+S388K; A25W+V45L+Q61K+L149R+V258P+A276S+A364G; V45L+L149R+S214E+V258P+A276S+L281V+A364G; V45N+L149R+V258P+A276S+A364G+S388K; V45L+L149R+V258P+A276S+A286E+H358T+A364G; D9E+V45L+L149R+V258P+A276S+A364G+S388K; V45L+S92D+L149R+V258P+A276S+A364G+S388K; V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H; V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K; A25W+V45L+L149R+S214E+T215I+V258P+A276S+A364G; V45L+N127D+L149R+V258P+A276S+H358T+A364G+S388K; A25W+V45L+L149R+V258P+A276S+A286E+A364G; V45L+L149R+N168G+V258P+A276S+L281V+A364G; V45L+Q61R+L149R+V258P+A276S+H358T+A364G; V45L+L149R+G187S+V258P+A276S+A364G+S388K; V45L+L149R+V258P+A276S+L281V+Q314A+A364G; V45L+L149R+V258P+A276S+L281V+H358T+A364G; V45L+L149R+A170S+V258P+A276S+H358T+A364G; V45L+L149R+A170S+V258P+A276S+A364G+S388K; V45L+L149R+T215V+V258P+A276S+A364G+S388K; V45L+L149R+V258P+A276Q+L281V+A364G; V45L+T70R+A117S+L149R+S214Q+C243S+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C522V; A25W+V45L+L149R+V258P+A276S+Q314A; V45L+L149R+V258P+A276Q+H358T+A364G+S388K; A25W+V45N+L149R+S214E+V258P+A276S+A364G; V45L+L149R+V258P+A276S+A286E+A364G; V45L+L149R+V258P+A276S+A286S+H358T+A364G; A25W+V45L+L149R+G187S+V258P+A276S+A364G; V45L+L149R+T180Q+V258P+A276S+L281V+A364G; A25W+V45L+L149R+A276Q+L281V+A364G; V45L+S92D+L149R+V258P+A276S+L281V+A364G; V45L+Q61R+L149R+V258P+A276S+L281V+A364G; V45L+L149R+A170S+V258P+A276S+L281V+A364G; D11E+A25W+V45L+L149R+V258P+A276S+A364G; A25W+V45L+Q61R+L149R+V258P+A276S+A364G; A25W+V45L+L149R+T215V+V258P+A276S+A364G; D9E+V45L+L149R+V258P+A276S+L281V+A364G; A25W+V45L+L149R+V258P+A276S+V350L+A364G; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V; V45L+A117S+L149R+N168G+S214Q+V258P+A276S+A364G+S388K; V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K; A25W+V45L+L149R+V258P+A276S+A286E; A25W+V45L+L149R+V258P+A276S+L281V; A25W+V45L+D113T+L149R+V258P+A276S; V45L+L149R+H219V+V258P+A276S+L281V+A364G; V45L+L149R+T180Q+V258P+A276S+H358T+A364G; V45L+L149R+T215V+V258P+A276S+L281V+A364G; A25W+V45L+L149R+V258P+A276S+S282N+A364G; A25W+V45L+L149R+T215I+V258P+A276S+A364G; A25W+V45L+L149R+H219I+V258P+A276S+A364G; V45L+A117S+L149R+V258P+A276S+L281V+A364G; D9E+A25W+V45L+L149R+V258P+A276S+A364G; V45L+L149R+S214Y+V258P+A276S+A364G+S388K; A25W+V45L+L149R+T180Q+V258P+A276S+A364G; A25W+V45L+L149R+V258P+A276S+L281V+A364G; V45L+N127D+L149R+V258P+A276S+L281V+A364G; V45L+L149R+S173Y+V258P+A276S+H358T+A364G; V45L+Q61R+L149R+V258P+A276S+A364G+S388K; M28P+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A; V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+T477K; A25W+V45L+L149R+T180Q+V258P+A276S; A25W+V45L+L149R+V258P+A276S+A286S; A25W+V45L+L149R+G187S+S214E+V258P+A276S+A364G; V45L+L149R+V258P+A276S+L281V+A286E+A364G; A25W+V45L+L149R+W250Y+V258P+A276S+A364G; A25W+V45L+L149R+V258P+N260H+A276S+A364G; V45L+L149R+V258P+A276S+L281V+V350L+A364G; A25W+V45L+L149R+A170S+V258P+A276S+A364G; V45L+L149R+V258P+A276S+L281V+A286S+A364G; V45L+L149R+V258P+A276S+L281V+S282N+A364G; D11E+V45L+L149R+V258P+A276S+L281V+A364G; V45L+Q61K+L149R+V258P+A276S+L281V+A364G; V45L+L149R+T215I+V258P+A276S+L281V+A364G; A25W+V45L+S92D+L149R+V258P+A276S+A364G; V45L+L149R+S214Y+V258P+A276S+L281V+A364G; V45L+L149R+T211H+V258P+A276S+L281V+A364G; A25W+V45L+L149R+G187L+V258P+A276S+A364G; V45L+S92D+L149R+V258P+A276S+H358T+A364G; V45L+L149R+G187L+A276Q+L281V+A364G; V45L+L149R+A276Q+L281V+V350L+A364G; V45L+L149R+A276Q+L281V+A364G+S388K; V45L+A117S+L149R+S214Y+V258P+A276S+A364G+S388K; A25W+V45L+S92D+L149R+V258P+A276S; A25W+V45L+L149R+G187L+V258P+A276S; A25W+V45L+L149R+W250Y+V258P+A276S; V45L+D113T+L149R+V258P+A276S+A364G; V45L+L149R+G187K+V258P+A276S+H358T+A364G; V45L+L149R+N163H+V258P+A276S+L281V+A364G; A25W+V45L+T70R+L149R+V258P+A276S+A364G; V45L+L149R+S173Y+V258P+A276S+L281V+A364G; V45L+L149R+G187L+V258P+A276S+L281V+A364G; V45L+L149R+G187K+V258P+A276S+L281V+A364G; V45L+L149R+W250Y+V258P+A276S+H358T+A364G; V45L+L149R+T211H+V258P+A276S+A364G+S388K; V45L+L149R+N163H+V258P+A276S+A364G+S388K; V45L+T70R+L149R+A276Q+L281V+A364G; V45L+S92D+L149R+A276Q+L281V+A364G; V45L+D113T+L149R+A276Q+L281V+A364G; V45L+L149R+A276Q+L281V+Q314A+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V; A25W+V45L+Q61K+L149R+V258P+A276S; D9E+A25W+V45L+L149R+V258P+A276S; V45L+T70R+L149R+V258P+A276S+A364G; V45L+L149R+V258P+A276S+A286S+A364G+S388K; A25W+V45L+L149R+S214Y+V258P+A276S+A364G; A25W+V45L+D113T+L149R+V258P+A276S+A364G; V45L+T70R+L149R+V258P+A276S+L281V+A364G; A25W+V45L+N127D+L149R+V258P+A276S+A364G; V45L+T70R+L149R+V258P+A276S+H358T+A364G; V45L+L149R+N163H+V258P+A276S+A364G; V45L+L149R+T180Q+A276Q+L281V+A364G; V45L+L149R+A276Q+L281V+A286S+A364G; A25W+V45L+L149R+A170S+V258P+A276S; A25W+V45L+T70R+L149R+V258P+A276S; A25W+V45L+L149R+S214E+V258P+A276S+A286S+A364G; V45L+L149R+V258P+A276S+A286S+H358T+A364G+S388K; V45L+L149R+H219I+V258P+A276S+L281V+A364G; A25W+V45L+A117S+L149R+V258P+A276S+A364G; A25W+V45L+L149R+N168G+V258P+A276S+A364G; V45L+L149R+N168G+A276Q+L281V+A364G; V45L+L149R+S173Y+A276Q+L281V+A364G; V45L+L149R+W250Y+A276Q+L281V+A364G; V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K; A25W+V45L+L149R+A276Q+A286E+A364G; A25W+V45L+L149R+A276Q+A364G+S388K; V45L+N127D+L149R+V258P+A276S+H358T+A364G; A25W+V45L+L149R+V258P+A276S; V45L+N127D+L149R+A276Q+L281V+A364G; V45L+L149R+A276Q+L281V+A286E+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V500T; A25W+V45L+A117S+L149R+V258P+A276S; A25W+V45L+L149R+H219V+V258P+A276S+A364G; V45L+L149R+S173Y+V258P+A276S+H358T+A364G+S388K; D11E+V45L+L149R+V258P+A276S+H358T+A364G; V45L+A79C+L149R+V258P+A276S+N355G+A364G+S388K; A24K+V45L+L149R+V258P+A276S+A364G; V45L+L149R+V258P+A276S+S282N+A364G; V45L+A117S+L149R+A276Q+L281V+A364G; V45L+L149R+N260H+A276Q+L281V+A364G; V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K; A25W+V45L+L149R+N168G+V258P+A276S; A25W+V45L+L149R+G187S+V258P+A276S; A25W+V45L+L149R+V258P+A276S+V350L; A25W+V45L+Q61R+L149R+V258P+A276S; A25W+V45L+L149R+G187L+S214E+V258P+A276S+A364G; V45L+L149R+G187S+V258P+A276S+L281V+A364G; A25W+V45L+L149R+N163H+V258P+A276S+A364G; A25W+V45L+L149R+G187K+V258P+A276S+A364G; V45N+L149R+V258P+A276S+L281V+A364G; V45L+L149R+A276Q+L281V+A364G; V45L+L149R+V258P+N260H+A276S+H358T+A364G; V45L+L149R+A276Q+S282N+A364G; V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K; A25W+V45L+L149R+V258P+A276S+S282N; A25W+V45L+L149R+S173Y+V258P+A276S; A25W+V45L+L149R+A276Q+A286S+A364G; V45L+D113T+L149R+V258P+A276S+L281V+A364G; V45L+L149R+S214Q+V258P+A276S+L281V+A364G+S388K; V45L+D113T+L149R+V258P+A276S+H358T+A364G; A25W+V45L+L149R+T215V+V258P+A276S; V45L+L149R+N168G+V258P+A276S+H358T+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+A472L; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S473K; A25W+V45L+L149R+T215I+V258P+A276S; A25W+V45L+L149R+T211H+V258P+A276S; A25W+V45L+L149R+V258P+A276Q; V45L+L149R+S214Q+T215V+V258P+A276S+A364G+S388K; V45L+L149R+N163H+V258P+A276S+H358T+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+A499L; V45L+L149R+V258P+A276S+V350L+A364G; V45L+A79C+A117S+L149R+V258P+A276S+A364G+S388K; A25W+V45L+D113T+L149R+A276Q+A364G; A25W+V45N+L149R+V258P+A276S+A364G; V45L+T70R+L149R+A276Q+A364G; A25W+V45L+L149R+H219I+V258P+A276S; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V498I; M28P+V45L+L149R+V258P+A276S+A364G; A25W+V45L+T70R+L149R+A276Q+A364G; A25W+V45L+L149R+A276Q+Q314A+A364G; V45L+L149R+A170S+V258P+A276S+H358T+A364G+S388K; A25W+V45L+L149R+S214Y+V258P+A276S; V45L+L149R+S214Y+V258P+A276S+H358T+A364G; V45L+L149R+A276Q+L281V+H358T+A364G; A25W+V45L+L149R+H219V+V258P+A276S; V45L+A117S+L149R+N163H+S214Q+V258P+A276S+A364G+S388K; D11E+A25W+V45L+L149R+V258P+A276S; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N527H; A25W+V45L+A117S+L149R+A276Q+A364G; V45L+L149R+V258P+L281V+A364G; A25W+V45L+L149R+G187L+A276Q+A364G; V45N+L149R+V258P+A276S+H358T+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T+R483V; A25W+V45L+L149R+A276Q+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497E; A25W+V45L+L149R+N163H+A276Q+A364G; A25W+V45L+L149R+S173Y+A276Q+A364G; A25W+V45L+L149R+A276Q+S282N+A364G; A25W+V45L+L149R+A276Q+H358T+A364G; A25W+V45L+L149R+T180Q+A276Q+A364G; V45L+A117S+L149R+V258P+A276S+H358T+A364G; V45L+L149R+A276Q+Q314A+A364G; V45L+L149R+G187K+V258P+A364G; V45L+L149R+A276Q+A286E+A364G; A25W+V45L+N127D+L149R+A276Q+A364G; A25W+V45L+L149R+A170S+A276Q+A364G; A25W+V45L+N127D+L149R+V258P+A276S; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+T477V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G503L; A25W+M28P+V45L+L149R+V258P+A276S+A364G; V45L+L149R+A276Q+H358T+A364G; A25W+V45L+L149R+N168G+A276Q+A364G; A25W+V45L+L149R+N260H+A276Q+A364G; V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+T215K+V258P+A276S+A364G+S388K; A25W+V45L+L149R+G187K+V258P+A276S; A25W+M28P+V45L+L149R+V258P+A276S; A25W+V45N+L149R+V258P+A276S; V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T; V45L+N127D+L149R+A276Q+A364G; V45L+L149R+W250Y+A276Q+A364G; V45L+L149R+W250Y+V258P+A364G; V45L+L149R+N163H+A276Q+L281V+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q385C+S388K; A25W+V45L+L149R+S214E+T215K+V258P+A276S+A364G; M28P+V45L+L149R+V258P+A276S+L281V+A364G; V45L+L149R+A276Q+A364G+S388K; A25W+V45L+L149R+V258P+A364G; M28P+V45L+L149R+V258P+A276S+H358T+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540V; V45L+L149R+N168G+A276Q+A364G; V45L+A117S+L149R+A276Q+A364G; V45L+L149R+N163H+V258P+A276S+H358T+A364G; V45L+L149R+T215K+V258P+A276S+H358T+A364G; A24K+V45L+L149R+A276Q+A364G; V45L+L149R+A276Q+A286S+A364G; V45L+L149R+V258P+A364G; V45L+L149R+H219I+V258P+A276S+A364G+S388K; V45L+L149R+A170S+A276Q+A364G; V45L+L149R+T180Q+A276Q+A364G; V45L+L149R+A276Q+V350L+A364G; V45L+L149R+V258P+S282N+A364G; V45L+L149R+A276Q+A364G; V45L+L149R+A276S+A364G; V45L+L149R+T215K+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+N355G+A364G+S388K+D470T; V45L+L149R+V258P+A276S; A25W+V45L+L149R+A276S+A364G; V45L+L149R+G187S+V258P+A364G; V45L+S92D+L149R+V258P+A276S+H358T+A364G+S388K; A25W+L149R+V258P+A276S+A364G; V45L+L149R+G187L+A276Q+A364G; A25W+V45L+V258P+A276S+A364G; V45L+L149R+N260H+A276Q+A364G; V45L+L149R+W250Y+V258R+A364G; V45L+L149R+N163H+A276Q+A364G; V45L+S92D+L149R+A276Q+A364G; V45L+L149R+S173Y+A276Q+A364G; V45L+S92D+L149R+V258P+A364G; V45L+L149R+W250Y+V258P+A276S+L281V+A364G; V45L+L149R+L281V+A364G; V45L+D113T+L149R+A276Q+A364G; L149R+V258P+A276S+A364G; V45L+L149R+G187S+V258R+A364G; V45L+V258P+A276S+A364G; V45L+L149R+V258R+A364G+S388K; A25W+V45L+L149R+A364G; V45L+L149R+G187K+V258R+A364G; V45L+L149R+V258P; V45L+L149R+V258R+S282N+A364G; V45L+L149R; V45L+L149R+V258R+L281V+A364G; V45L+L149R+A364G; V45L+L149R+S214Q+V258P+A276S+N355G+A364G+S388K; V45L+S92N+L149R+V258P+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K; A25W+V45L+L149R+S214E+V258P+A276S+N355G+A364G; V45L+L149R+G187L+V258P+A276S+A364G; V45L+L149R+V258R+A364G; V45L+L149R+V258P+A364G+S388K; A25W+V45L+L149R+A276Q+V350L+A364G; V45L+L149R+H219V+V258P+A276S+A364G+S388K; V45L+L149R+G187K+A364G; V45L+L149R+G187S+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+N355G+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Y386G+S388K+D470T+R483V; V45L+L149R+W250Y; V45L+S92N+L149R+V258R+A364G; A25W+V45L+L149R+V258P+A276S+N355G+A364G; V45L+L149R+V258P+A276S+N355G+A364G+S388K; V45L+L149R+G187S; V45N+L149R; V45L+L149R+S282N; L149R+A364G; Y386G; V258P+A276Q; V258P+A276S; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D+D470T+R483V; A25W+L149R; V45L+A276S; V45L+S92D+L149R; A25W+A276S; Q385C; V45L+L149R+W250Y+A364G; V45L+A276Q; V45L+V258P; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Y386G+S388K; A25W+V258P; A25W+A276Q; L149R+W250Y; V45L+L149R+V258P+A276S+L281V+N355G+A364G; V45L+S388K; V45L+L149R+V258P+A276S+N355G+H358T+A364G; V45L+A364G; V45N+V258P; A276S; V258P+S388K; A25W+V45L; A276Q+S388K; A276C; A276Q; A276F; W250Y+A276Q; A79C; A276S+S388K; A276Q+L281V; V45L+L149R+V258P+A276S+N355G+A364G; A276N; W250Y+A276S; A25W+S388K; A276S+L281V; G187S+A276Q; A25W+V45L+L149R+V258P+A276S+N355G; V45L; S92D+A276S; S19T; L149R+V258R; V45N+S388K; A25W+V45L+S92D+L149R+A276Q+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S501E、 H358D; A25W+A364G; V258P+L281V; L149R; V45L+L149R+H219V+V258P+A276S+H358T+A364G; A25W; V258R+A276S; V45N; G187S+A276S; G187K+A276S; I469T; V45L+S92D; V45L+L281V; V45N+W250Y; V258R+A276Q; V45L+V258R; W250Y+S388K; A25W+V45L+L149R+A276Q+N355G+A364G; V45N+G187K; A25W+V45L+L149R+S214E+V258P+A276S+Q314A+A364G; S388A; A276T; A25W+V258R; G187K+S388K; A25W+S92D; L281V+S388K; V45N+V258R; S388H; S92D; D525L; S214Q; L281V+A364G; A364G; S388L; S388R; S473G; S92D+A364G; A25W+G187S; A25W+G187K; W250Y+V258P; S92D+V258P; S389V; A20H; W495E; G187K+W250Y; Y386Y; V393H; G187L; Q61K; V45N+S92D; G187S+A364G; G187S+L281V; G187S; A286E; A276Y; V258P; Q496E; G394A; V393R; G187S+S388K; T366V; S389S; S92N; N527H; Q384A; V497D; D470T; A18V; Q496Q; Q496R; S214E; P362P; S389H; V258R; A276D; L281V; V45I; A117C; N395N; Y391Y; A24H; A472I; D470K; S473K; S473S; W495I; V497E; A24K; V45T; L471R; A472L; A20P; N395D; G394D; G394Q; G187S+V258R; S92D+G187S; V45C; N476N; G207G; A364A; D470A; N474G; D470V wherein the variant has xylanase activity, wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% but less than 100% sequence identity to SEQ ID NO:1, and wherein the variant has increased thermostability, wherein the increased thermostability is measured as an increased melting point of at least 0.5°C compared to the xylanase of SEQ ID NO:1, as measured by TSA.

[0253] In one aspect, the present invention provides the following substitutions or combinations of substitutions: V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V; V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394Q+D470T+R483V; V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V; V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V; V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V; V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V; V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V; V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V; V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V; V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V; V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V; V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+L530R; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V+L530R; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V+L530R; V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V; V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A286E+H358D+A364G+Q384A+S388K+N395D+D470T+R483V; V45L+A117S+L149R+G187K+S214E+T215I+V258P+A276S+A286E+H358D+A364G+S388K+V393H+D470T+R483V; V45L+A117S+L149R+G187K+S214E+T215I+V258P+A276S+A286E+H358D+A364G+S388K+N395D+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T+R483V; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366I+S388K+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T+L530R; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T+R483V; D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468V+D470T+R483V; V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A79C+L149R+S214E+V258P+A276S+A364G+S388K; V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T+R483V; V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496R; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+W495E; V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Y391V+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480L+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A+L530R; V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S+R483V; V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+T70R+A117S+L149R+S214Q+C243V+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T+L530R、 V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496Q; V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496E; V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P+R483V; A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N474G+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T+R483V; V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484S; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484D; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S528H; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S501N; V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+A499L; V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T+R483V; V45L+A79C+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496E+L530R; V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V498I+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A+R483V; V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+A499Y; V45L+A79C+L149R+V258P+A276S+Q314A+A364G+S388K; V45L+A79C+L149R+V258P+A276S+L281V+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501N+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N+L530R; V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500V+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V500V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S501E; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+D525L+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G526T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N527H+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K+L530R; M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501E+L530R; V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499L+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A472I+L530R; V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+N527H; V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497P; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V498I; V45L+A79C+L149R+S173Y+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N+R483V; V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T+L530R; M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A79C+L149R+G187K+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H+D470T+L530R; V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L+D470T+R483V; V45L+Q61R+A79C+L149R+V258P+A276S+A364G+S388K; V45L+A79C+L149R+N168G+V258P+A276S+A364G+S388K; V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A79C+L149R+T215V+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V500T; V45L+A79C+L149R+V258P+A276S+A286S+A364G+S388K; V45L+A79C+L149R+H219V+V258P+A276S+A364G+S388K; V45L+A79C+L149R+A170S+V258P+A276S+A364G+S388K; V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T; V45L+A79C+L149R+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T+R483V; V45L+A93T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499Y; V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N; V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468L+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366I+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S473G; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T+R483V; D11E+V45L+A79C+L149R+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N529T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T; V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A79C+L149R+V258P+A276S+A286E+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+G503L; V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T; V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S528H; V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496R; V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T; D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S473K; V45L+A79C+L149R+T180Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K+D470T+R483V; V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+N260H+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+G187S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N474G; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501N; V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R+D470T; V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T; V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+G187S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N; V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A79C+L149R+H219I+V258P+A276S+A364G+S388K; V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366V+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R+D470T+R483V; V45N+A79C+L149R+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496Q; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q+D470T+R483V; V45L+A79C+L149R+V258P+A276S+V350L+A364G+S388K; V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366I+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+G526T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L484S; V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499L; V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T+L530R; V45L+A79C+D113T+L149R+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+D525L; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V498I; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L+D470T; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S528H+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476D+R483V; D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501E; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A; V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S; V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+I469T+D470T+R483V; V45L+A79C+N127D+L149R+V258P+A276S+A364G+S388K; D9E+V45L+A79C+L149R+V258P+A276S+A364G+S388K; V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T; V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N529T+L530R; V45L+A79C+L149R+W250Y+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V497P; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N527H; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496Q; V45L+A117S+L149R+N168G+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476N+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477V+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478N+R483V; V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K+D470T+R483V; M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H+D470T+R483V; V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497P; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V498I; V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T+L530R; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375V+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470A+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477K+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496E; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496R; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+A499L; V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T; V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T; V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468S+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G503L+L530R; V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+S501E; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+N529T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+S501N; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S481S+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478P+R483V; D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V497P+L530R; V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K+D470T+R483V; V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+N527H; V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T; V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H+D470T+R483V; V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496E; V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+H219I+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A79C+L149R+N163H+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+A499Y; V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V500T; V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G526T; V45L+C60L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+C69L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497D; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A+L530R; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+D525L; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N; V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H+D470T; V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T+L530R; V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476D; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N+R483V; V45L+C60A+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D+D470T; A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+T70R+A117S+L149R+S214Q+C243L+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478N; V45L+C60S+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K+D470T+R483V; V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K+D470T; D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G; V45L+C69A+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+T70R+A117S+L149R+C161S+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+S282N+A364G+S388K+D470T; V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473G; V45L+T70R+D95N+A117S+L149R+S214Q+V258P+A276S+L356M+H358D+A364G+S388K; D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476N; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394D+D470T; V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G503L; V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478P; V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K+D470T; V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+C69V+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+D525L; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496R; V45L+A117S+N127D+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+A499Y; V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480L; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L+D470T; V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N529T; V45L+C60V+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497E; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478N; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; M28P+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470V+R483V; V45L+A117S+L149R+S214Y+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477K; V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K; V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+T215I+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496E; V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+W495I; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V498I; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470K+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V500V; D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+A170S+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477V; A25W+V45L+A79C+L149R+S214E+V258P+A276S+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q; V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496Q; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375A+S388K+G394A+D470T+R483V; V45L+A117S+L149R+D192E+S214Q+V258P+A276S+H358D+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A472L; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A499Y; V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q385C+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T480N; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V497P; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+A499L; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S501N; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375S+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L+D470T+R483V; V45L+A79C+S92D+L149R+V258P+A276S+A364G+S388K; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540A; V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A; V45L+C69S+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V498I; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G; V45L+A117S+L149R+S214Q+H219I+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+N163H+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+L149R+S214Q+V258P+A276S+H358D+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K; V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D; A25W+V45L+A79C+L149R+V258P+A276S+A364G; V45L+L149R+S214Q+V258P+A276S+A286E+A364G+S388K; V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K; V45L+A117S+L149R+D192E+S214Q+V258P+A276S+H358D+A364G; V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K; V45L+L149R+S214Q+T215I+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N476D; V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+T215K+V258P+A276S+A364G+S388K+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478P; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S481A; A25W+V45L+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+D470T+R483V; V45L+A79C+L149R+V258P+A276S+L281V+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V500T; V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K; V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375L+S388K+G394A+D470T+R483V; V45L+L149R+A170S+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K+D470T; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470V+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V500V; V45L+Q61K+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+L149R+N168G+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A79C+D95D+L149R+V258P+A276S+A364G+S388K; V45L+Q77E+A79C+L149R+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497W; V45L+L149R+S214Q+V258P+A276S+S282N+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S481S; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V500T; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540L; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C522S; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+W495S; V45L+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K; V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497W; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540S; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396S+D470T+R483V; V45L+T70R+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N474G; V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Q496Q; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V+D470T; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S501E; A25W+V45L+L149R+S214E+V258P+A276S+A364G; V45L+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K; V45L+L149R+G187K+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N476N; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473K; V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K; C40L+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Q496E; A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+L149R+V258P+A276S+L281V+H358T+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A; V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H; M28P+V45L+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T480L; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K; V45L+A93S+L149R+A252S+H334D; C40A+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; V45L+L149R+G187L+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K; V45L+L149R+S214Q+V258P+A276S+A286S+A364G+S388K; V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L; V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K; D9E+V45L+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Y391V; V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394D; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S473G; V45L+A79C+L149R+V258P+A276S+H358T+A364G+S388K; V45L+L149R+S214Q+V258P+A276Q+A364G+S388K; A25W+V45L+L149R+S214E+V258P+A276S+H358T+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T480N; D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K; C40S+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; C40V+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; A25W+V45L+L149R+S214E+V258P+A276S+A286E+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A499L; A25W+V45L+Q61K+L149R+S214E+V258P+A276S+A364G; V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K; A25W+V45L+L149R+V258P+A276S+H358T+A364G+S388K; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+W495E; A25W+V45L+A79C+L149R+V258P+A276S; V45L+L149R+S214Q+V258P+A276S+V350L+A364G+S388K; D11E+V45L+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+L149R+H219I+V258P+A276S+H358T+A364G+S388K; V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396V+D470T+R483V; V45N+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K; V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K; V45L+S92D+L149R+S214Q+V258P+A276S+A364G+S388K; V45L+L149R+V258P+A276S+H358T+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+L478P; V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S481A; V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K; A25W+V45L+L149R+T211H+S214E+V258P+A276S+A364G; A25W+V45L+L149R+S214E+H219V+V258P+A276S+A364G; V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+...

Claims

1. A xylanase variant of a parent xylanase comprising a substitution at one or more positions corresponding to positions 45, 149, 364, 258, 276 and 388 of SEQ ID NO:1, wherein the xylanase variant has xylanase activity and has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO:

1.

2. 2. The xylanase variant of claim 1, which has increased thermostability compared to the xylanase of SEQ ID NO:

1.

3. 3. The xylanase variant of claim 1 or 2, wherein the increased thermostability is measured using TSA as an increased melting point of at least 0.5°C, at least 1°C, at least 1.5°C, at least 2°C, at least 2.5°C, at least 3°C, at least 3.5°C, at least 4.0°C, at least 4.5°C or at least 5°C.

4. 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 387, 388, 389, 390, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 4. The xylanase variant of any one of claims 1 to 3, further comprising substitutions at one or more positions corresponding to positions 89, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530 and 540.

5. The following substitutions are made at positions corresponding to positions in SEQ ID NO: 1: D9, D11, A18, S19, A20, A24, A25, M28, C40, V45, C60, Q61, C69, T70, Q77, A79, S92, A93, D95, D113, A117, N127, L149, C161, N163, N168, A170, S173, T180, G187, S190, D192, T211, S214, T215, H219, V234, W250, A252, V 258, N260, A276, L281, S282, A286, Q314, H334, A340, V350, N355, L356, H358, A3 64, T366, C375, Q384, Q385, Y386, S388, S389, Y391, V393, G394, N395, C396, D44 6, R459, C468, I469, D470, L471, A472, A472, S473, S473, N474, N476, T477, L478 , T480, S481, R483, L484, W495, Q496, V497, V498, A499, V500, S501, G503, C522, D525, G526, N527, S528, N529, L530 and C540.

6. The following substitutions were made at positions corresponding to positions in SEQ ID NO: 1: D9E, D11E, A18V, S19T, A20H, A20P, A24H, A24K, A25W, M28P, C40A, C40L, C40S, C40V, C60A, C60L, C60S, C60V, Q61K, Q61R, C69A, C69L, C69S, C69V, T70R, Q77E, A79C, S92D, S92N, A93S, A93T, D95N, D113T, A117C, A117S, N127D, C161L, C161S, C161V, N163H, N168G, A170S, S173 Y, T180Q, G187K, G187L, G187S, S190E, D192E, T211H, S214E, S214Q, S214Y , T215I, T215K, T215V, H219I, H219V, V234P, C243L, C243S, C243V, W250Y, A252S, N260H, L281V, S282N, A286E, A286S, Q314A, H334D, A340G, V350L, N 355G, L356M, H358D, H358T, T366I, T366V, C375A, C375L, C375S, C375V, Q38 4A, Q385C, Y386G, S389H, S389V, Y391V, V393H, V393R, G394A, G394D, G394 Q, N395D, C396A, C396L, C396A, C396S, C396V, D446T, R459V, C468A, C468L , C468S, C468V, I469T, D470A, D470K, D470T, D470V, L471R, A472I, A472L, S473G, S473K, N474G, N476D, N476N, T477K, T477V, L478N, L478P, T480L, T4 6. The xylanase variant of claim 5, comprising one or more of the following: 80N, S481A, R483V, L484D, L484K, L484S, W495E, W495I, W495S, Q496E, Q496W, Q496R, V497D, V497E, V497P, V497W, V498I, A499L, A499Y, V500T, S501E, S501N, G503L, C522A, C522S, C522V, D525L, G526T, N527H, S528H, N529T, L530R, C540A, C540L, C540S and C540V.

7. A method for producing a xylanase variant according to any one of claims 1 to 6, comprising culturing a host cell under conditions conducive to the production of said polypeptide, and further comprising recovering said polypeptide.

8. A method for obtaining a xylanase variant, comprising: (a) introducing substitutions into a parent xylanase at one or more positions corresponding to positions 45, 149, 364, 258, 276 and 388 of SEQ ID NO: 1, wherein the xylanase variant has xylanase activity and has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%, but less than 100%, sequence identity to SEQ ID NO: 1; and (b) optionally recovering the xylanase variant.

9. A composition comprising the xylanase variant according to any one of claims 1 to 6.

10. 10. A method for increasing starch and / or gluten yield from maize kernels in a wet-milling process, the method comprising contacting maize kernels or a fraction of said maize kernels, in particular a fiber-rich fraction, with an effective amount of a xylanase variant according to any one of claims 1 to 6 and optionally one or more hydrolytic enzymes.

11. a) soaking the corn kernels in water to form soaked kernels; b) milling the soaked grain to produce milled grain; c) separating the germ from the milled kernels to produce a corn kernel mass containing fiber, starch, and gluten; d) subjecting the corn kernel mass to a fiber washing procedure to separate starch and gluten from the fiber; 11. The method according to claim 10, wherein at least a xylanase variant according to any one of claims 1 to 6 is present / added before or during step d).

12. e) separating the starch from the gluten; and optionally, f) washing the starch; The method of claim 11 further comprising:

13. 13. The method of any one of claims 10 to 12, wherein the one or more hydrolytic enzymes comprise one or more cellulases.

14. 14. The method of claim 13, wherein the cellulase comprises one or more enzymes selected from the group consisting of endoglucanases (EGs) and cellobiohydrolases (CBHs).

15. Use of a xylanase variant according to any one of claims 1 to 6 in a method for increasing starch and / or gluten yield from maize kernels in a wet milling process.

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