Novel companion diagnostic method

Abstract

The present invention relates to methods for the treatment and diagnosis of metabolic dysfunction-associated steatohepatitis (MASH), said methods comprising detecting the presence or absence of a somatic mutation in the DNA of one or more gene specified herein, wherein the presence of a somatic mutation in said one or more gene indicates that the subject has or is at risk of having MASH. Also provided is a method of detecting the presence or absence of a somatic mutation in a subject suspected of having or at risk of having metabolic dysfunction-associated steatohepatitis (MASH) comprising said steps. Methods of treatment herein further comprise administering to the subject an siRNA that inhibits expression of said one or more gene and / or administering a therapeutic intervention described herein if a somatic mutation is present in the DNA. dsRNA molecules comprising a sense strand and an antisense which comprise nucleotides of or nucleotides complementary to any mRNA sequence represented by sequences described herein.

Description

[0001] NOVEL COMPANION DIAGNOSTIC METHOD FIELD OF THE INVENTION The present invention relates to methods for the treatment and diagnosis of metabolic dysfunction-associated steatohepatitis (MASH), said methods comprising detecting the presence or absence of a somatic mutation in the DNA of one or more gene specified herein, wherein the presence of a somatic mutation in said one or more gene indicates that the subject has or is at risk of having MASH. Also provided is a method of detecting the presence or absence of a somatic mutation in a subject suspected of having or at risk of having metabolic dysfunction-associated steatohepatitis (MASH) comprising said steps. Methods of treatment herein further comprise administering to the subject an siRNA that inhibits expression of said one or more gene and / or administering a therapeutic intervention described herein if a somatic mutation is present in the DNA. dsRNA molecules comprising a sense strand and an antisense which comprise nucleotides of or nucleotides complementary to any mRNA sequence represented by sequences described herein. BACKGROUND OF THE INVENTION Metabolic dysfunction-associated steatohepatitis (MASH; also known as metabolic dysfunction-associated steatotic liver disease (MASLD) and non-alcoholic fatty liver disease (NAFLD)) is a chronic liver disease diagnosed with the excessive build up of fat in the liver (hepatic steatosis / sclerosing liver disease (SLD)) and at least one metabolic risk factor. Other terms, such as non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), are also used to described various stages and severities of MASH, with NAFL being less severe but still associated with cirrhosis, liver cancer, liver failure and cardiovascular disease. If alcohol consumption is involved, the term metabolic dysfunction and alcohol-associated liver disease (MetALD) is used, and this differs from alcohol-related liver disease (ALD) where alcohol is the main cause of the steatotic liver disease. Obesity and type 2 diabetes are strong risk factors for MASH, as are related conditions such as being overweight, older age and metabolic syndromes. While no noticeable symptoms may be present, MASH can cause various symptoms related to liver dysfunction, such as fatigue, malaise and dull right-upper-quadrant abdominal discomfort in its less severe forms / early stages, and severe liver function impairment, cirrhosis, liver failure and liver cancer in more severe / later stages of MASH. It is the most common liver disorder worldwide, with around 25% of all people affected. In particular, In the United States about 75 to 100 million people had MASH in 2017, and over 90% of obese, 60% of diabetic and up to 20% of normal weight people have it worldwide. MASH was the leading cause of chronic liver disease and the second most common reason for liver transplantation in both the US and Europe in 2017. There is therefore a need to develop diagnostic and prognostic methods to identify subjects who have or may be at risk of developing MASH, identifying them for suitable treatment. SUMMARY OF THE INVENTION According to a first aspect of the invention, there is provided a method of treating metabolic dysfunction-associated steatohepatitis (MASH) in a subject, the method comprising steps of: (i) isolating and purifying DNA from a sample obtained from the subject; (ii) detecting the presence or absence of a somatic mutation in the DNA of one or more gene selected from: fatty acid synthase (FASN); APOBEC1 complementation factor (A1CF); Krüppel-like factor 15 (KLF15); serotransferrin (TF); cytochrome P4502E1 (CYP2E1); cyclin-dependent kinase inhibitor 1B (CDKN1B); PCF11 cleavage and polyadenylation factor subunit (PCF11); ubiquitin-conjugating enzyme E2 D3 (UBE2D3); eukaryotic elongation factor 2 (EEF2); and serine protease hepsin (HPN), and (iii) administering to the subject an siRNA that inhibits expression of said one or more gene if a somatic mutation is present in the DNA. In a further aspect, there is provided a method of detecting the presence or absence of a somatic mutation in a subject suspected of having or at risk of having metabolic dysfunction- associated steatohepatitis (MASH), the method comprising the steps of: (i) isolating and purifying DNA from a sample obtained from the subject; and (ii) detecting the presence or absence of a somatic mutation in the DNA of one or more gene selected from: fatty acid synthase (FASN); APOBEC1 complementation factor (A1CF); Krüppel-like factor 15 (KLF15); serotransferrin (TF); cytochrome P4502E1 (CYP2E1); cyclin-dependent kinase inhibitor 1B (CDKN1B); PCF11 cleavage and polyadenylation factor subunit (PCF11); ubiquitin-conjugating enzyme E2 D3 (UBE2D3); eukaryotic elongation factor 2 (EEF2); and serine protease hepsin (HPN), and wherein the presence of a somatic mutation in said one or more gene indicates that the subject has or is at risk of having MASH. In some embodiments, the somatic mutation is one or more mutation selected from those listed in Table 1 herein. In further embodiments, the presence or absence of the somatic mutation is detected using sequencing and / or by PCR, such as quantitative and / or real-time PCR. In a yet further embodiment, the isolated and purified DNA is prepared for sequencing according to a method comprising the steps of: (i) fragmenting the DNA to generate fragmented nucleic acid molecules with blunt ends; (ii) introducing dideoxy nucleotides at internal nick sites present in the fragmented nucleic acid molecules with blunt ends and tailing to generate tailed nucleic acid fragments; and (iii) adding sequencing adapters to the tailed nucleic acid fragments to generate a nucleic acid library. In another aspect, there is provided a double stand RNA (dsRNA) molecule comprising a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand and / or the sense strand comprises at least 15 contiguous nucleotides of and differing by no more than 3 nucleotides from the nucleotide sequence of any mRNA sequence represented by the cDNA sequences set forth in Table 2 or set forth in any one of SEQ ID NOs: 1 to 59. In some embodiments, the antisense strand and / or the sense strand comprises at least 15 contiguous nucleotides complementary to and mismatching by no more than 3 nucleotides from the nucleotide sequence of any mRNA sequence represented by the cDNA sequences set forth in Table 2 or set forth in any one of SEQ ID NOs: 1 to 59. According to another aspect of the invention, there is provided a method of treating metabolic dysfunction-associated steatohepatitis (MASH) in a subject, the method comprising steps of: (i) isolating and purifying DNA from a sample obtained from the subject; (ii) detecting the presence or absence of a somatic mutation in the DNA of one or more gene selected from: fatty acid synthase (FASN); APOBEC1 complementation factor (A1CF); Krüppel-like factor 15 (KLF15); serotransferrin (TF); cytochrome P4502E1 (CYP2E1); cyclin-dependent kinase inhibitor 1B (CDKN1B); PCF11 cleavage and polyadenylation factor subunit (PCF11); ubiquitin-conjugating enzyme E2 D3 (UBE2D3); eukaryotic elongation factor 2 (EEF2); and serine protease hepsin (HPN), and (iii) administering to the subject a therapeutic intervention of Table 3 if a somatic mutation is present in the DNA of the specified gene. BRIEF DESCRIPTION OF THE FIGURES Figure 1: Schematic of fatty acid synthase protein with domains and the amino acid changes resulting from the herein identified somatic mutations in the FASN gene shown, from the indicated patient group and by the indicated sample preparation and analysis method. Figure 2: Schematic of APOBEC1 complementation factor protein with domains and the amino acid changes resulting from the herein identified somatic mutations in the A1CF gene shown, from the indicated patient group and by the indicated sample preparation and analysis method. Figure 3: Schematic of Krüppel-like factor 15 protein with domains and the amino acid changes resulting from the herein identified somatic mutations in the KLF15 gene shown, from the indicated patient group and by the indicated sample preparation and analysis method. Figure 4: Schematic of serotransferrin protein with domains and the amino acid changes resulting from the herein identified somatic mutations in the TF gene shown, from the indicated patient group and by the indicated sample preparation and analysis method. Figure 5: Schematic of cytochrome P4502E1 protein with domains and the amino acid changes resulting from the herein identified somatic mutations in the CYP2E1 gene shown, from the indicated patient group and by the indicated sample preparation and analysis method. Figure 6: Schematic of cyclin-dependent kinase inhibitor 1B protein with domains and the amino acid changes resulting from the herein identified somatic mutations in the CDKN1B gene shown, from the indicated patient group and by the indicated sample preparation and analysis method. Figure 7: Schematic of PCF11 cleavage and polyadenylation factor protein with domains and the amino acid changes resulting from the herein identified somatic mutations in the PCF11 gene shown, from the indicated patient group and by the indicated sample preparation and analysis method. Figure 8: Schematic of ubiquitin-conjugating enzyme E2 D3 protein with domains and the amino acid changes resulting from the herein identified somatic mutations in the UBE2D3 gene shown, from the indicated patient group and by the indicated sample preparation and analysis method. Figure 9: Schematic of eukaryotic elongation factor 2 protein with domains and the amino acid changes resulting from the herein identified somatic mutations in the EEF2 gene shown, from the indicated patient group and by the indicated sample preparation and analysis method. Figure 10: Schematic of serine protease hepsin protein with domains and the amino acid changes resulting from the herein identified somatic mutations in the HPN gene shown, from the indicated patient group and by the indicated sample preparation and analysis method. Figure 11: Histopathology of MASLD patients included in the study described in Example 1. A) Representative photomicrographs of H&E-stained liver sections from three patients included in the study. Arrows point to bridges offibrosis surrounding regenerative nodules. Stars indicate areas of lymphocyte infiltration. Segments refer to anatomical liver Coinaud segments. Scale bars 500µm. B) Overview of the sectioning approach used for processing samples. Figure 12: Number of coding mutations detected in whole-genome and exome sequencing of microbiopsies from 3 SLD patients. Number of substitution and indel mutations detected per microdissection within the callable exome region across whole genome (n=34) and exome (n=614) data. Shallow WGS (6-12x) data displayed for samples meeting the library concentration criteria for WGS (5ng / µL) but not for WES (10ng / µL), otherwise WES data displayed. Callable exome region was defined as sites within the bait capture panel with 5x coverage achieved in 90% of samples. Top panel shows mean sequencing coverage in each microdissection, coloured by sequencing platform. Donors are ordered by age. Mutations are coloured by impact on the coding sequence. Figure 13: Driver landscape across tissue histology in MASLD patient PD48372. On the left, a phylogenetic tree is displayed, with coloured branches representing distinct clones with driver mutations and lighter shades indicating subclonal variants. On the right, a visualisation of mutant clones overlaid on an H&E-stained liver tissue section, with clone colours matched to associated branches on the phylogenetic tree. Each dot signifies a microdissection, with solid black dots indicating microdissections harbouring a driver mutation. Surrounding the tissue image, pie chart-like disks illustrate the cell fraction, with the extent of filling within each disk indicating the proportion of mutant cells in the microdissection. Estimated clone boundaries are colour-highlighted. Figure 14: Driver landscape across tissue histology in MASLD patient PD48371. On the left, a phylogenetic tree is displayed, with coloured branches representing distinct clones with driver mutations and lighter shades indicating subclonal variants. On the right, a visualization of mutant clones overlaid on an H&E-stained liver tissue section, with clone colours matched to associated branches on the phylogenetic tree. Each dot signifies a microdissection, with solid black dots indicating microdissections harbouring a driver mutation. Surrounding the tissue image, pie chart-like disks illustrate the cell fraction, with the extent of filling within each disk indicating the proportion of mutant cells in the microdissection. Estimated clone boundaries are colour-highlighted. Figure 15: Driver landscape across tissue histology in MASLD patient PD48367. On the left, a phylogenetic tree is displayed, with coloured branches representing distinct clones with driver mutations and lighter shades indicating subclonal variants. On the right, a visualization of mutant clones overlaid on an H&E-stained liver tissue section, with clone colours matched to associated branches on the phylogenetic tree. Each dot signifies a microdissection, with solid black dots indicating microdissections harbouring a driver mutation. Surrounding the tissue image, pie chart-like disks illustrate the cell fraction, with the extent of filling within each disk indicating the proportion of mutant cells in the microdissection. Estimated clone boundaries are colour-highlighted. Figure 16: Histopathology of overweight and obese patients included in the study described in Example 7. Example photomicrographs of H&E-stained liver sections from nine patients included in the study. Numbers in the bottom right refer to NAS scores. Scale bars 250µm. DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the finding by the inventors of multiple novel mutations in certain genes associated with liver function in subjects with or at risk of metabolic dysfunction- associated steatohepatitis (MASH). These mutations have been identified according to the method described in WO 2022 / 112751, the sequencing library generation methods and computational analyses of which are hereby specifically incorporated by reference. Thus, according to a first aspect of the invention there is provided a method of treating metabolic dysfunction-associated steatohepatitis (MASH) in a subject, the method comprising the steps of: (i) isolating and purifying DNA from a sample obtained from the subject; (ii) detecting the presence or absence of a somatic mutation in the DNA of one or more gene selected from: fatty acid synthase (FASN); APOBEC1 complementation factor (A1CF); Krüppel-like factor 15 (KLF15); serotransferrin (TF); cytochrome P4502E1 (CYP2E1); cyclin-dependent kinase inhibitor 1B (CDKN1B); PCF11 cleavage and polyadenylation factor subunit (PCF11); ubiquitin-conjugating enzyme E2 D3 (UBE2D3); eukaryotic elongation factor 2 (EEF2); and serine protease hepsin (HPN), and (iii) administering to the subject an siRNA that inhibits expression of said one or more gene if a somatic mutation is present in the DNA. In a further aspect, there is provided a method of detecting the presence or absence of a somatic mutation in a subject suspected of having or at risk of having metabolic dysfunction- associated steatohepatitis (MASH), the method comprising the steps of: (i) isolating and purifying DNA from a sample obtained from the subject; and (ii) detecting the presence or absence of a somatic mutation in the DNA of one or more gene selected from: fatty acid synthase (FASN); APOBEC1 complementation factor (A1CF); Krüppel-like factor 15 (KLF15); serotransferrin (TF); cytochrome P4502E1 (CYP2E1); cyclin-dependent kinase inhibitor 1B (CDKN1B); PCF11 cleavage and polyadenylation factor subunit (PCF11); ubiquitin-conjugating enzyme E2 D3 (UBE2D3); eukaryotic elongation factor 2 (EEF2); and serine protease hepsin (HPN), and wherein the presence of a somatic mutation in said one or more gene indicates that the subject has or is at risk of having MASH. Metabolic dysfunction-associated steatohepatitis (MASH; also known as metabolic dysfunction-associated steatotic liver disease (MASLD) and non-alcoholic fatty liver disease (NAFLD)) is a chronic liver disease diagnosed with the excessive build up of fat in the liver (hepatic steatosis / sclerosing liver disease (SLD)) and at least one metabolic risk factor. Other terms, such as non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), are also used to described various stages and severities of MASH, with NAFL being less severe but still associated with cirrhosis, liver cancer, liver failure and cardiovascular disease. If alcohol consumption is involved, the term metabolic dysfunction and alcohol-associated liver disease (MetALD) is used, and this differs from alcohol-related liver disease (ALD) where alcohol is the main cause of the steatotic liver disease. Therefore, in certain embodiments the subject is suffering from and / or has been previously diagnosed with MASH. In further embodiments, the subject is suspected of having MASH. In yet further embodiments, the subject is at risk of MASH or at risk of developing MASH. In still further embodiments, the subject has, is at risk of having or is suspected as having SLD. Thus, provided herein are methods useful in the diagnosis and / or prognosis of MASH in a subject for identifying a suitable siRNA treatment for the subject, i.e. as a companion diagnostic. Presence of one or more of the herein described loss of function mutations indicates that the subject has, is at risk of having or is at risk of developing MASH. Absence of any of the herein described mutations indicates that the subject does not have, is not a risk of having or is not at risk of developing MASH. As will be appreciated, there is a desire to obtain samples for diagnosis / prognosis using minimally invasive methods. Thus, in one embodiment the sample is blood sample. In a further embodiment, the sample is a tissue biopsy. Such blood samples and tissue biopsies can be obtained from the subject using any well known and routine method in the art, and wherein the sample is a tissue biopsy may be obtained from the tissue or organ of particular interest relevant to the disease or disorder to be diagnosed. According to the present invention, the tissue biopsy may be a liver biopsy obtained from the subject. Obesity and type 2 diabetes are strong risk factors for MASH, as are related conditions such as being overweight, older age and metabolic syndromes. While no noticeable symptoms may be present, MASH can cause various symptoms related to liver dysfunction, such as fatigue, malaise and dull right-upper-quadrant abdominal discomfort in its less severe forms / early stages, and severe liver function impairment, cirrhosis, liver failure and liver cancer in more severe / later stages of MASH. It is the most common liver disorder worldwide, with around 25% of all people affected. In particular, In the United States about 75 to 100 million people had MASH in 2017, and over 90% of obese, 60% of diabetic and up to 20% of normal weight people have it worldwide. MASH was the leading cause of chronic liver disease and the second most common reason for liver transplantation in both the US and Europe in 2017. Thus, in still further embodiments the subject is obese and / or overweight. For example, the subject may be obese and / or overweight and be deemed at risk of / at risk of developing MASH due to their obesity / weight. In a further example, the subject may have MASH due to their obesity / weight. In other further embodiments, the subject has a metabolic condition. In yet further embodiments, the subject has type 2 diabetes. For example, the subject may be type 2 diabetic and thus be deemed at risk of / at risk of developing MASH. In further examples, the subject may have MASH due to their type 2 diabetes and / or a related metabolic condition. Isolating and purifying DNA from the sample obtained from the subject may be any well known method in the art. For example, following cell lysis (if required), the sample may be subjected to a salt precipitation of cell debris and removal, then precipitation / separation of the DNA may be performed by e.g. ethanol, phenol-chloroform or adsorption / binding to a substrate (such as beads or a column). In examples comprising bead adsorption / binding, such beads may be magnetic and / or paramagnetic, wherein after binding of the DNA the beads are subjected to a magnetic field and the supernatant removed, the beads washed and an elution buffer added to elute the DNA from the beads followed by resubjecting the beads to a magnetic field and removing the DNA-containing supernatant. Suitably, the method of DNA isolation and purification will be selected based on compatibility with the downstream method of detecting somatic mutations in step (ii) herein chosen by the skilled person. Detecting the Presence or Absence of Somatic Mutations Somatic mutations identified using the method described in WO 2022 / 112751 (referred to as nanorate sequencing (NanoSeq) therein) may be driver mutations of MASH, or non-driver mutations associated with the onset of disease (such as early in disease onset). The somatic mutations can be detected in single DNA molecules from a population of cells by NanoSeq due to its very low error rate (typically <5x10-9) and maintained independence of strands during duplex sequencing. The ability of NanoSeq to identify mutations in single molecules of DNA within a highly polyclonal disease sample also maximises the chances of sampling a different clone with each molecule, providing more information about disease. Thus, NanoSeq provides the ability to perform DNA sequencing with accurate single-molecule calling with error rates <5x10-9and with coverage across the whole genome for identifying mutation burden and mutation signatures or across the whole exome or large gene panels for driver mutation discovery. In addition, the total percentage of cells in the sample carrying a mutation in a given disease-related gene can be estimated. Therefore, in certain embodiments detecting step (ii) herein may comprise sequencing the isolated and purified DNA. Suitable methods of sequencing are well known to and will be readily recognised by the skilled person, and certain examples are described further herein. Alternatively, detecting step (ii) may comprise PCR, such as quantitative and / or real-time PCR. qPCR and real-time PCR are well known in the art and their use in the present method will be readily recognisable to the skilled person. For example, primers complementary to the mutated DNA sequence may be used such that a product (PCR) or signal (qPCR / real-time PCR) is generated when the mutation is present and no product or signal is generated in the absence of the mutation. Alternatively, primers complementary to the non-mutated DNA sequence may be used such that a product or signal is generated when the mutation is absent and no product or signal is generated in the presence of the mutation. In embodiments wherein detecting step (ii) comprises sequencing, said sequencing and generation of the nucleic acid library for sequencing may be by NanoSeq as described hereinbefore and in detail in WO 2022 / 112751. Thus, in some embodiments the isolated and purified DNA is prepared for sequencing according to a method comprising the steps of: (i) fragmenting the DNA to generate fragmented nucleic acid molecules with blunt ends; (ii) introducing dideoxy nucleotides at internal nick sites present in the fragmented nucleic acid molecules with blunt ends and tailing to generate tailed nucleic acid fragments; and (iii) adding sequencing adapters to the tailed nucleic acid fragments to generate a nucleic acid library. In one embodiment, fragmenting comprises using one or more blunt / non-cohesive end- generating endonucleases, thereby preventing the need for end-repair of the fragmented nucleic acid molecules. Such prevention of end-repair avoids the copying of an error present in a single strand in an overhang, which would thus appear as a mutation in both strands. Furthermore, removing the need for an end-repair step prevents possible extension by DNA polymerases from internal nicks. The terms “blunt end” and “non-cohesive end” may be used interchangeably herein and refer to ends of nucleic acid molecules at which both strands terminate in a base pair. This is in contrast to overhanging, cohesive or stick-ends which comprise unpaired nucleotides at the end of one strand. Using a blunt / non-cohesive end- generating endonuclease also prevents the need for the removal of overhangs from or trimming of the fragmented nucleic acid molecules using an exonuclease enzyme. Such repair or removal of overhangs is necessary when sonication or sticky end-generating enzymes are used. Avoiding the need for end-repair and the copying of 5’ overhangs to generate blunt- ended nucleic acid fragments, maintains the independence of each nucleic acid strand and avoids the introduction of double-stranded errors. In one embodiment, the blunt / non-cohesive end-generating endonuclease is a blunt / non- cohesive end-generating restriction endonuclease having a 4 base-pair recognition site. In a further embodiment, the blunt / non-cohesive end-generating endonuclease is a blunt / non- cohesive end-generating restriction endonuclease which is not impaired by overlapping CpG methylation. Such restriction endonucleases suitable for use in the methods described herein are well known in the art and would be easily recognised by the skilled person. Examples include AluI, HaeIII, HindII, SmaI and HpyCH4 (including subtypes thereof, such as HpyCH4III, HpyCH4IV or HpyCH4V). It will also be appreciated that, for the purpose of preparing a nucleic acid library for sequencing, restriction endonuclease enzymes yielding sufficient coverage of the whole genome to be sequenced are preferred. Thus, in one embodiment the blunt / non- cohesive end-generating restriction endonuclease is selected from one or both of: AluI and HpyCH4, such as HpyCH4III, HpyCH4IV or HpyCH4V. In alternative embodiments, fragmenting the nucleic acid composition comprises removing overhangs from fragmented nucleic acid molecules using one or more exonuclease enzyme to generate fragmented nucleic acid molecules with blunt ends. Thus, fragmenting may be separated into step (i a) which comprises initial fragmentation of the nucleic acid composition and step (i b) which comprises removal of overhangs to generate fragmented nucleic acid molecules with blunt ends. In some embodiments fragmenting the nucleic acid composition comprises mechanical fragmentation. In one embodiment, fragmenting the nucleic acid composition comprises sonication. Therefore, according to a further embodiment the isolated and purified DNA is prepared for sequencing according to a method comprising the steps of: (i a) fragmenting a nucleic acid composition by sonication to generate fragmented nucleic acid molecules; (i b) removing overhangs from the fragmented nucleic acid molecules using one or more exonuclease enzyme to generate fragmented nucleic acid molecules with blunt ends; (ii) introducing dideoxy nucleotides at internal nick sites present in the fragmented nucleic acid molecules and tailing to generate tailed nucleic acid fragments; and (iii) adding sequencing adaptors to the tailed nucleic acid fragments to generate a nucleic acid library. In other embodiments, fragmenting the nucleic acid composition comprises mechanical shearing. It will be readily appreciated that sonication and / or shearing of the nucleic acid composition which are sequence-independent, generate nucleic acid fragments representing complete coverage across the genome, including complete coverage of the nuclear genome, coding sequences and the mitochondrial genome. Trimming or removal of overhangs using exonuclease enzymes maintains the independence of each nucleic acid strand and any end- repair by copying 5’ overhangs, such as using a DNA polymerase, is avoided. In one embodiment, the one or more exonuclease enzyme is Mung Bean nuclease. Mung Bean nuclease is derived from the sprouts of the mung bean and removes nucleotides from single-stranded DNA and RNA in a step wise manner. It is therefore a specific nucleic acid exonuclease that degrades single-stranded extensions / overhangs from the ends of DNA and RNA while leaving double-stranded nucleic acid molecules intact. Following degradation of single-stranded extensions or overhangs, Mung Bean nuclease leaves blunt ends to which adaptors, such as sequencing adaptors, can be added by ligation. Preparation of the isolated and purified DNA for sequencing may comprise the step of introducing dideoxy nucleotides at internal nick sites present in the fragmented nucleic acid molecules with blunt ends and tailing the fragmented nucleic acid molecules to generate tailed nucleic acid fragments. The terms “nick” and “gap” may be used interchangeably herein to refer to the absence of a nucleotide at a position within one strand of the nucleic acid, positioned opposite a nucleotide on the other strand of the nucleic acid which is complementary to the nucleotide previously occupying the position represented by the nick / gap. As will be appreciated by the use of the term “internal”, such nicks / gaps are not found at the ends of the nucleic acid fragment and are found at least one nucleotide position in from either the 5’ or 3’ end of a nucleic acid strand. Introducing dideoxy nucleotides at internal nick sites prevents extension of the internal nick and blocks the extension by DNA polymerase, resulting in an unamplifiable nucleic acid strand. The failure to amplify one of the strands prevents obtaining duplex coverage (i.e. sequencing reads from both strands) for said nucleic acid fragment having a nick into which a dideoxy nucleotide has been incorporated. If the nucleic acid fragment is A-tailed, the dideoxy nucleotides will be dideoxy non-A nucleotides, such as ddBTPs. Alternatively, if the nucleic acid fragment is C-tailed, the dideoxy nucleotides will be dideoxy non-C nucleotides, such as ddDTP, if the nucleic acid fragment is G-tailed, the dideoxy nucleotides will be dideoxy non-G nucleotides, such as ddHTP, or if the nucleic acid fragment is T-tailed, the dideoxy nucleotides will be non-T nucleotides, such as ddVTP. Therefore, in one embodiment the dideoxy nucleotides are dideoxy non-A nucleotides, such as ddBTPs. According to this embodiment, the tailing of the fragmented nucleic acid molecules comprises A-tailing. In a further embodiment, the dideoxy nucleotides are dideoxy non-C nucleotides, such as ddDTP. According to this further embodiment, the tailing of the fragmented nucleic acid molecules comprises C-tailing. In another embodiment, the dideoxy nucleotides are dideoxy non-G nucleotides, such as ddHTP. According to this embodiment, the tailing of the fragmented nucleic acid molecules comprises G-tailing. In a still further embodiment, the dideoxy nucleotides are dideoxy non-T nucleotides, such as ddVTP. According to this further embodiment, the tailing of the fragmented nucleic acid molecules comprises T-tailing. Thus, in one embodiment, the tailing of the fragmented nucleic acid molecules comprises A-tailing and the dideoxy nucleotides introduced are dideoxy non-A nucleotides, such as ddBTPs. In another embodiment, the tailing of the fragmented nucleic acid molecules comprises C-tailing and the dideoxy nucleotides introduced are dideoxy non-C nucleotides, such as ddDTP. In a further embodiment, the tailing of the fragmented nucleic acid molecules comprises G-tailing and the dideoxy nucleotides introduced are dideoxy non-G nucleotides, such as ddHTP. In a yet further embodiment, the tailing of the fragmented nucleic acid molecules comprises T-tailing and the dideoxy nucleotides introduced are dideoxy non-T nucleotides, such as ddVTP. In order to generate a nucleic acid library for sequencing, sequencing adaptors are added to the tailed nucleic acid fragments. Such sequencing adaptors allow automated high throughput sequencing, such as next-generation sequencing (NGS). For example, such high throughput sequencing devices that are compatible with these adaptors include, but are not limited to Solexa (Illumina), the 454 System, and / or the ABI SOLiD. For example, the preparation of DNA for sequencing may include using universal primers in conjunction with poly-A tails. In one embodiment, the adaptors comprise Illumina sequencing adaptor sequences. The sequencing adaptors may comprise a barcode sequence (known as duplex sequencing adapters). Thus, in one embodiment the sequencing adaptors are duplex sequencing adaptors comprising a barcode sequence. Barcode sequences are necessary to identify copies from a single molecule when the read start and ends do not offer sufficient diversity as unique molecular identifiers (e.g. when using restriction enzyme digestion or deep sequencing). Therefore, the duplex sequencing adaptors may be barcoded. The presence of barcode sequences, such as 3 nucleotide barcode sequences, allows for the unique identification of sequencing reads originating from either of the strands of the nucleic acid composition and / or the identification of duplicate reads originating from PCR duplication during library preparation. Thus, in a further embodiment the barcode is unique to one strand of the nucleic acid composition. In a yet further embodiment, the barcoded duplex sequencing adaptors comprise nucleotide barcode sequences made up of several random nucleotides, such as a 3 to 8 nucleotide tag, e.g. a 3 nucleotide tag. These barcodes uniquely tag the end of nucleic acid fragments which would otherwise be indistinguishable when using blunt / non- cohesive end-generating restriction endonuclease enzymes which generate independent nucleic acid fragments having the same coordinates used for mapping during subsequent analysis of sequencing data or when sequencing a library to high depth. In contrast, the use of mechanical fragmentation and removal of overhangs using one or more exonuclease enzyme generates a wider diversity of breakpoints that can be used to distinguish copies from an original molecule of DNA. Such breakpoints can be used as unique molecular identifiers alone or in combination with a barcode in the duplex sequencing adapters. The nucleic acid library may be subject to selective enrichment in order to enrich one or more genomic region of interest prior to sequencing. Thus, in some embodiments the nucleic acid library for sequencing is selectively enriched for nucleic acids corresponding to one or more genomic region of interest to generate an enriched nucleic acid library. Examples of genomic regions of interest include, but are not limited to, specific genes or a panel of specific genes (e.g. a gene of particular interest or a panel of genes of particular interest, such as a panel of genes associated with liver function), coding sequences (CDSs; e.g. protein coding sequences), exonic sequences (including the whole exome) and intronic sequences. In one embodiment, the one or more genomic region of interest is one or more coding sequences (CDSs) of coding genes, such as protein coding sequences. In a further embodiment, the one or more genomic regions of interest are exonic sequences, such as the exome. Thus, in a particular embodiment the genomic region of interest is the entire / whole exome, which comprises all protein coding sequences (e.g. for the purpose of unbiased discovery of disease- associated coding mutations). In a yet further embodiment, the one or more genomic region of interest is one or more specific gene of interest. Such one or more gene of interest may be a single gene or a group / panel of genes (e.g. a group of genes known to be associated with liver function as described herein). Thus, in one embodiment the one or more genomic region of interest is a panel of genes associated with liver function. In a further embodiment, the genomic region of interest is one or more of the genes described herein. In order to selectively enrich one or more genomic region of interest, any suitable method known in the art may be used. For example, oligonucleotide probes having sequences which are complementary to the genomic region(s) of interest may be used. Such oligonucleotide probes therefore bind to sequences comprising the genomic region(s) of interest, allowing them to be enriched or isolated from sequences in the nucleic acid library which do not comprise the genomic region(s) of interest. In one embodiment, wherein a nucleic acid library for exome (e.g. whole-exome) sequencing is generated, selectively enriching nucleic acids corresponding to genomic regions of interest comprises using oligonucleotide probes which bind to the coding sequences (CDSs). Non-limiting examples of sets of oligonucleotide probes which bind to CDSs include the xGen Exome Research Panel from Integrated DNA Technologies (IDT), SureSelect probes from Agilent and the gene or exome enrichment panels from Twist Bioscience. Genes & Proteins in which Mutations are Detected In one embodiment, the gene is the FASN gene encoding the fatty acid synthase enzyme. Fatty acid synthase is a multi-enzyme protein that catalyses fatty acid synthesis, mainly the synthesis of palmitate from acetyl-CoA and malonyl-CoA. The mammalian protein is a homodimer of two identical protein subunits, in which three catalytic domains in the N-terminal region (-ketoacyl synthase (KS), malonyl / acetyltransferase (MAT), and dehydrase (DH)), are separated by a core region of 600 residues (known as the interdomain) from four C-terminal domains (enoyl reductase (ER), -ketoacyl reductase (KR), acyl carrier protein (ACP) and thioesterase (TE)). The dimer is formed by the interdomain region (Chirala, Jayakumar & Wakil (2001) PNAS, 98(6):3104-3108, doi: https: / / doi.org / 10.1073 / pnas.051635998; and Smith (1994) FASEB, 8(15):1248-1259, PMID: 8001737). Fatty acid synthase may be involved in the production of an endogenous ligand for the nuclear receptor PPARα, the target of the fibrate drugs for hyperlipidaemia (Chakravarthy et al. (2009) Cell, 138(3):476-488, doi: https: / / doi.org / 10.1016%2Fj.cell.2009.05.036), and is being investigated as a possible drug target for treating the metabolic syndrome (Wu et al. (2011) PNAS, 108(13):5378-5383, doi: https: / / doi.org / 10.1073%2Fpnas.1002588108). Orlistat which is a gastrointestinal lipase inhibitor also inhibits fatty acid synthase (Richardson et al. (2008) J. Med. Chem., 51(17):5285- 5296, doi: https: / / doi.org / 10.1021%2Fjm800321h). As demonstrated herein, the present inventors have identified many somatic mutations throughout the FASN gene leading to amino acid changes throughout the fatty acid synthase protein (see Table 1 and Figure 1). As shown in Figure 1, the identified loss of function mutations lead to amino acid changes in all protein domains. Mutations identified (see Table 1) include mutations to splice regulatory sites and splice recognition sites leading to changes in the splicing of FASN mRNA (labelled “Essential_Splice” in Table 1), missense mutations leading to the nonsynonymous change of a codon sequence to that for a different amino acid than in the wild type protein, mutations causing frameshifts (either by insertion or deletion), and single nucleotide variations (SNVs; also known as single nucleotide polymorphisms (SNPs); labelled as “no-SNV” in Table 1) and multi-nucleotide variations (labelled as “mnv” in Table 1). Thus, in some embodiments somatic mutation is in the DNA of the FASN gene and is selected from any one or more of those listed in Table 1. Mutations in the DNA of the FASN gene may be relative to ENSG00000169710 and / or the sequence located at chr17: 82,078,338-82,098,294, reverse strand (from Ensembl version ENSG00000169710.9, accessed: July 2024). In further embodiments, the somatic mutation causes an amino acid change in fatty acid synthase selected from any one or more of those listed in Table 1. Mutations in the fatty acid synthase protein may be relative to the amino acid sequence of UniProt ID: P49327 (checksum: 7A07171FEFA3287B, last updated: 2009- 11-24 v3, accessed: July 2024) and / or ENSP00000304592 (from Ensembl version ENSG00000169710.9, accessed July 2024). In a further embodiment, the gene is the A1CF gene encoding APOBEC1 complementation factor. APOBEC1 complementation factor has three non-identical RNA recognition motifs and belongs to the hnRNP R family of RNA-binding proteins (Henderson, Blanc & Davidson (2001) Biochim. Biophys. Acta., 1522(1):22-30, doi: 4781%2801%2900295-0). It has been proposed to function as an RNA-binding subunit that docks APOBEC1 to deaminate the upstream cytidine to a uracil in the mRNA of mammalian apolipoprotein B, and may also be involved in other RNA editing or processing events. Thus, APOBEC1 complementation factor in involved in the activity of apolipoprotein B which is the primary protein of LDL cholesterol particles. It is absolutely required for the formation of LDL particles and acts as a ligand for LDL receptors on various cell types. Apolipoprotein B is used as a risk factor of atherosclerotic cardiovascular disease (Behbodikhah et al. (2021) Metabolites, 11(10):690, doi: As demonstrated herein, the present inventors have identified many somatic mutations throughout the A1CF gene leading to amino acid changes throughout the APOBEC1 complementation factor protein (see Table 1 and Figure 2). As shown in Figure 2, the identified loss of function mutations lead to amino acid changes in all protein domains, with a slight increased proportion of mutations in the RRM2 domain. Mutations identified (see Table 1) include mutations to splice regulatory sites and splice recognition sites leading to changes in the splicing of A1CF mRNA, missense mutations leading to the nonsynonymous change of a codon sequence to that for a different amino acid than in the wild type protein, nonsense mutations leading to the introduction of a premature stop codon, mutations causing frameshifts (either by insertion or deletion), and single nucleotide variations (SNVs). Thus, in some embodiments somatic mutation is in the DNA of the A1CF gene and is selected from any one or more of those listed in Table 1. Mutations in the DNA of the A1CF gene may be relative to ENSG00000148584 and / or the sequence located at chr10: 50,799,409-50,885,675, reverse strand (from Ensembl version ENSG00000148584.16, accessed: July 2024). In further embodiments, the somatic mutation causes an amino acid change in APOBEC1 complementation factor selected from any one or more of those listed in Table 1. Mutations in the APOBEC1 complementation factor protein may be relative to the amino acid sequence of UniProt ID: Q9NQ94 (specifically Q9NQ94-1; checksum: AA5EF76BD8815807, last updated 2000-10-01 v1, accessed: July 2024) and related mapped potential isoform sequences, and / or ENSP00000363109 (from Ensembl version ENSG00000148584.16, accessed July 2024). In a further embodiment, the gene is the KLF15 gene encoding Krüppel-like factor 15. Krüppel-like factor 15 is a member of the Krüppel-like family of transcription factors, containing C2H2 zinc finger DNA-binding domains. The zinc finger domains bind to GC-rich regions of DNA and the C-terminus of the protein binds to the promoter and enhancer regions of genes. While many other Krüppel-like family proteins have N-terminal regions that bind to specific partners, Krüppel-like factor 15 has no defined protein interaction motifs (McConnell & Yang (2010) Physiological Reviews, 90(4):1337-1381, doi: https: / / doi.org / 10.1152%2Fphysrev. 00058.2009). Krüppel-like factor 15 has been identified as being involved in the upregulation of testosterone production (through a binding site in the HSD17B5 promoter), adipogenesis (resulting from overexpression of KLF15), the canonical Wnt pathway (through a binding site in the low-density lipoprotein receptor-related protein 5 gene; Li et al. (2010) BMC Genet., 11:12, doi: https: / / doi.org / 10.1186%2F1471-2156-11-12), activation of glucose transporter type 4 (GLUT4; through a binding site in the GLUT4 gene; Gray et al. (2002) J. Biol. Chem., 277(37):34322-34328, doi: fibrosis (KLF15 knock out mice subjected to aortic banding exhibited increased heart fibrosis), synergistic activation of the acetyl-CoA synthetase 2 (AceCS2) promoter with Sp1 transcription factor (KLF15 was upregulated leading to upregulated AceCS2 in fasting mice; Yamamoto et al. (2004) J Biol Chem, 279(17):16954-16962, doi: KLF15 is highly expressed in the liver, kidney, heart and skeletal muscle. As demonstrated herein, the present inventors have identified many somatic mutations throughout the KLF15 gene leading to amino acid changes throughout the Krüppel-like factor 15 protein (see Table 1 and Figure 3). As shown in Figure 3, the identified loss of function mutations lead to amino acid changes in all protein domains, with clusters of mutations in the zinc finger domains (particularly ZnF2). Mutations identified (see Table 1) include missense mutations leading to the nonsynonymous change of a codon sequence to that for a different amino acid than in the wild type protein, nonsense mutations leading to the introduction of a premature stop codon, mutations causing frameshifts (either by insertion or deletion), and single nucleotide variations (SNVs). Thus, in some embodiments somatic mutation is in the DNA of the KLF15 gene and is selected from any one or more of those listed in Table 1. Mutations in the DNA of the KLF15 gene may be relative to ENSG00000163884 and / or the sequence located at chr3: 126,342,635-126,357,408, reverse strand (from Ensembl version: ENSG00000163884.4, accessed: July 2024). In further embodiments, the somatic mutation causes an amino acid change in Krüppel-like factor 15 selected from any one or more of those listed in Table 1. Mutations in the Krüppel-like factor 15 protein may be relative to the amino acid sequence of UniProt ID: Q9UIH9 (checksum: 6335F85141BEB276, last updated 2000-05-01 v1, accessed: July 2024) and / or ENSP00000296233 (from Ensembl version: ENSG00000163884.4, accessed: July 2024). In a further embodiment, the gene is the TF gene encoding serotransferrin. Transferrins are glycoproteins which bind and mediate the transport of iron through blood plasma. They are mainly produced in the liver but are also produced by the brain. Transferrin levels are increased in iron deficiency anaemia – when plasma transferrin levels are high, there is a reciprocal decrease in percent transferrin iron saturation and a corresponding increase in total iron binding capacity (Miller (2013) Cold Spring Harbor Perspectives in Medicine, 3(7):a011866, doi: https: / / doi.org / 10.1101%2Fcshperspect.a011866). Altered transferrin levels are also associated with protein malnutrition and other metabolic diseases / disorders. As demonstrated herein, the present inventors have identified many somatic mutations throughout the TF gene leading to amino acid changes throughout the serotransferrin protein (see Table 1 and Figure 4). As shown in Figure 4, the identified loss of function mutations lead to amino acid changes in all protein domains. Mutations identified (see Table 1) include mutations to splice regulatory sites and splice recognition sites leading to changes in the splicing of TF mRNA, missense mutations leading to the nonsynonymous change of a codon sequence to that for a different amino acid than in the wild type protein, nonsense mutations leading to the introduction of a premature stop codon, mutations causing frameshifts (either by insertion or deletion), and single nucleotide variations (SNVs). Thus, in some embodiments somatic mutation is in the DNA of the TF gene and is selected from any one or more of those listed in Table 1. Mutations in the TF gene may be relative to ENSG00000091513 and / or the sequence located at chr3: 133,746,040-133,796,641, forward strand (from Ensembl version: ENSG00000091513.16, accessed: July 2024). In further embodiments, the somatic mutation causes an amino acid change in serotransferrin selected from any one or more of those listed in Table 1. Mutations in the serotransferrin protein may be relative to the amino acid sequence of UniProt ID: P02787 (checksum: 9A73BEAE8C567C79, last updated: 2022-12-14 v4, accessed: July 2024) and related mapped potential isoform sequences, and / or ENSP00000385834 (from Ensembl version: ENSG00000091513.16, accessed: July 2024). In a further embodiment, the gene is the CYP2E1 gene encoding cytochrome P4502E1. Cytochrome P4502E1 is a membrane protein highly expressed in the liver, where it is involved in the metabolism of many potentially toxic chemicals (Shimada et al. (1994) J. Pharmacol. & Experimental Therapeutics, 270(1):414-423, PMID: 8035341), the conversion of ethanol to acetaldehyde and acetate (together with alcohol dehydrogenase and aldehyde dehydrogenase; Hayashi, Watanabe & Kawajiri (1991) J. Biochem., 110(4):559-565, doi: https: / / doi.org / 10.1093%2Foxfordjournals.jbchem.a123619), as part of the conversion of acetyl-CoA to glucose, and the metabolism of endogenous fatty acids. Its involvement in the metabolism of fatty acids links its activity to diabetes and obesity (Porubsk, Meneely & Scott (2008) J Biol Chem, 283(48):33698-33707, doi: https: / / doi.org / 10.1074%2Fjbc.M805999200). As demonstrated herein, the present inventors have identified many somatic mutations throughout the CYP2E1 gene leading to amino acid changes throughout the cytochrome P450 2E1 protein (see Table 1 and Figure 5). As shown in Figure 5, the identified loss of function mutations lead to amino acid changes in all protein domains. Mutations identified (see Table 1) include mutations to splice regulatory sites and splice recognition sites leading to changes in the splicing of CYP2E1 mRNA, missense mutations leading to the nonsynonymous change of a codon sequence to that for a different amino acid than in the wild type protein, nonsense mutations leading to the introduction of a premature stop codon, mutations causing frameshifts (either by insertion or deletion), and single nucleotide variations (SNVs). Thus, in some embodiments somatic mutation is in the DNA of the CYP2E1 gene and is selected from any one or more of those listed in Table 1. Mutations in the DNA of the CYP2E1 gene may be relative to ENSG00000130649 and / or the sequence located at chr10: 133,520,406- 133,561,220, forward strand (from Ensembl version: ENSG00000130649.10, accessed: July 2024). In further embodiments, the somatic mutation causes an amino acid change in cytochrome P4502E1 selected from any one or more of those listed in Table 1. Mutations in the cytochrome P4502E1 protein may be relative to the amino acid sequence of UniProt ID: P05181 (checksum: ED0399E32A005644, last updated 1988-04-01 v1, accessed: July 2024) and related mapped potential isoform sequences, and / or ENSP00000252945 (from Ensembl version: ENSG00000130649.10, accessed: July 2024). In a further embodiment, the gene is the CDKN1B gene encoding cyclin-dependent kinase inhibitor 1B. Cyclin-dependent kinase inhibitor 1B belongs to the Cip / Kip family of cyclin dependent kinase inhibitor proteins and is involved in the control of the cell cycle by binding to and inhibiting cyclin D, cyclin E and cyclin A, as well as their active complexes cyclin E- CDK2, cyclin D-CDK4 and cyclin A-CDK2. Increased levels of cyclin-dependent kinase inhibitor 1B typically causes cells to arrest in the G1 phase of the cell cycle, thus it is considered a tumour repressor and in cancers cyclin-dependent kinase inhibitor 1B is often inactivated (Chu, Hengst & Slingerland (2008) Nat. Rev. Cancer, 8(4):253-267, doi: However, it is also involved in tissue regeneration with knockdown of CDKN1B expression in mice stimulating cochlear hair cell regeneration (Löwenheim et al. (1999) PNAS, 96(7):4084-4088, doi: https: / / doi.org / 10.1073% 2Fpnas.96.7.4084). As demonstrated herein, the present inventors have identified many somatic mutations throughout the CDKN1B gene leading to amino acid changes throughout the cyclin-dependent kinase inhibitor 1B protein (see Table 1 and Figure 6). As shown in Figure 6, the identified loss of function mutations lead to amino acid changes in all protein domains, although fewer are seen in the last exon of the gene as truncating mutations within this exon would still produce a functional protein product and they are therefore not loss of function. Mutations identified (see Table 1) include missense mutations leading to the nonsynonymous change of a codon sequence to that for a different amino acid than in the wild type protein, nonsense mutations leading to the introduction of a premature stop codon, mutations causing frameshifts (either by insertion or deletion), and single nucleotide variations (SNVs). Thus, in some embodiments somatic mutation is in the DNA of the CDKN1B gene and is selected from any one or more of those listed in Table 1. Mutations in the DNA of the CDKN1B gene may be relative to ENSG00000111276 and / or the sequence located at chr12: 12,685,498-12,722,369, forward strand (from Ensembl version: ENSG00000111276.12, accessed: July 2024). In further embodiments, the somatic mutation causes an amino acid change in cyclin-dependent kinase inhibitor 1B selected from any one or more of those listed in Table 1. Mutations in the cyclin-dependent kinase inhibitor 1B protein may be relative to the amino acid sequence of UniProt ID: P46527 (checksum: 1118D58901CDF3FC, last updated: 1995-11-01 v1, accessed: July 2024) and related mapped potential isoform sequences, and / or ENSP00000228872 (from Ensembl version: ENSG00000111276.12, accessed: July 2024). In further embodiments, the gene is the PCF11 gene encoding PCF11 cleavage and polyadenylation factor subunit protein. PCF11 cleavage and polyadenylation factor subunit forms part of the pre-mRNA cleavage factor IIm with CLP1. Cleavage factor IIm in involved in the processing of pre-mRNA to cleave and add polyadenylation at the 3’ end. The cleavage and polyadenylation specificity factor within it recognises the polyadenylation signal in pre- mRNA, providing sequence specificity (Schönemann et al. (2014) Genes & Development, 28(21):2381-2393, doi: https: / / doi.org / 10.1101%2Fgad.250985.114), and stalls RNA polymerase at the functional polyadenylation signal (Murphy, Doymaz & Kleiman (2021) Methods in Enzymology: MRNA 3' End Processing and Metabolism, vol.655: 265-290, doi: It is the first protein to bind to the signal region near the cleavage site of the pre-mRNA, to which the poly(A) tail will be added by polynucleotide adenylyltransferase. Following cleavage and polyadenylation, the mature mRNA is able to be exported into the cytoplasm of the cell for translation (Shi & Manley (2015) Genes & Development, 29(9):889-897, doi: https: / / doi.org / 10.1101%2Fgad.261974.115). Thus, the expression and activity of PCF11 cleavage and polyadenylation factor subunit are involved in general cellular gene expression regulation. As demonstrated herein, the present inventors have identified many somatic mutations throughout the PCF11 gene leading to amino acid changes throughout the PCF11 cleavage and polyadenylation factor subunit protein (see Table 1 and Figure 7). As shown in Figure 7, the identified loss of function mutations lead to amino acid changes in all protein domains, with a hotspot cluster seen around amino acid S590. Mutations identified (see Table 1) include mutations to splice regulatory sites and splice recognition sites leading to changes in the splicing of PCF11 mRNA, missense mutations leading to the nonsynonymous change of a codon sequence to that for a different amino acid than in the wild type protein, nonsense mutations leading to the introduction of a premature stop codon, mutations causing frameshifts (either by insertion or deletion), and single nucleotide variations (SNVs). Thus, in some embodiments somatic mutation is in the DNA of the PCF11 gene and is selected from any one or more of those listed in Table 1. Mutations in the DNA of the PCF11 gene may be relative to ENSG00000165494 and / or the sequence located at chr11: 83,156,988-83,187,451, forward strand (from Ensemble version: ENSG00000165494.12, accessed: July 2024). In further embodiments, the somatic mutation causes an amino acid change in PCF11 cleavage and polyadenylation factor subunit selected from any one or more of those listed in Table 1. Mutations in the PCF11 cleavage and polyadenylation factor subunit protein may be relative to the amino acid sequence of UniProt ID: O94913 (checksum: 0AEAE04D7CB4A34F, last updated 2007-10-23 v3, accessed: July 2024) and related mapped potential isoform sequences, and / or ENSP00000508500 (from Ensemble version: ENSG00000165494.12, accessed: July 2024). In further embodiments, the gene is the UBE2D3 gene encoding ubiquitin-conjugating enzyme E2 D3. Ubiquitin-conjugating enzyme E2 D3 is an E2 ubiquitin-conjugating enzyme, and works together with E1 ubiquitin-activating proteins to label proteins for degradation by E3 ubiquitin-protein ligases. It is thus involved in the general regulation of protein expression and activity, acting at the post-translational level. As demonstrated herein, the present inventors have identified many somatic mutations throughout the UBE2D3 gene leading to amino acid changes throughout the ubiquitin- conjugating enzyme E2 D3 protein (see Table 1 and Figure 8). As shown in Figure 8, the identified loss of function mutations lead to amino acid changes in all protein domains. Mutations identified (see Table 1) include mutations to splice regulatory sites and splice recognition sites leading to changes in the splicing of UBE2D3 mRNA, missense mutations leading to the nonsynonymous change of a codon sequence to that for a different amino acid than in the wild type protein, nonsense mutations leading to the introduction of a premature stop codon, mutations causing frameshifts (either by insertion or deletion), and single nucleotide variations (SNVs). Thus, in some embodiments somatic mutation is in the DNA of the UBE2D3 gene and is selected from any one or more of those listed in Table 1. Mutations in the DNA of the UBE2D3 gene may be relative to ENSG00000109332 and / or the sequence located at chr4: 102,794,383-102,868,896, reverse strand (from Ensembl version: ENSG00000109332.20, accessed: July 2024). In further embodiments, the somatic mutation causes an amino acid change in ubiquitin-conjugating enzyme E2 D3 selected from any one or more of those listed in Table 1. Mutations in the ubiquitin-conjugating enzyme E2 D3 protein may be relative to the amino acid sequence of UniProt ID: P61077 (checksum: ADD74A8A708EFEE3, last updated 2004-04-26 v1, accessed: July 2024) and all isoforms or mapped potential isoform sequences, and / or ENSP00000396901 (from Ensembl version: ENSG00000109332.20, accessed: July 2024). In further embodiments, the gene is the EEF2 gene encoding eukaryotic elongation factor 2. Eukaryotic elongation factor 2 is a member of the GTP-binding translation elongation factor family and is essential for protein synthesis, promoting GTP-dependent translocation of the ribosome (Entrez Gene ID 1938: EEF2 eukaryotic translation elongation factor 2 (human)). Eukaryotic elongation factor 2 is thus an essential component of cellular protein expression regulation and activity, acting at the translational level. As demonstrated herein, the present inventors have identified many somatic mutations throughout the EEF2 gene leading to amino acid changes throughout the eukaryotic elongation factor 2 protein (see Table 1 and Figure 9). As shown in Figure 9, the identified loss of function mutations lead to amino acid changes in all protein domains. Mutations identified (see Table 1) include mutations to splice regulatory sites and splice recognition sites leading to changes in the splicing of EEF2 mRNA, missense mutations leading to the nonsynonymous change of a codon sequence to that for a different amino acid than in the wild type protein, nonsense mutations leading to the introduction of a premature stop codon, mutations causing frameshifts (either by insertion or deletion), and single nucleotide variations (SNVs). Thus, in some embodiments somatic mutation is in the DNA of the EEF2 gene and is selected from any one or more of those listed in Table 1. Mutations in the DNA of the EEF2 gene may be relative to ENSG00000167658 and / or the sequence located at chr19: 3,976,056- 3,985,463, reverse strand (from Ensembl version: ENSG00000167658.16, accessed: July 2024). In further embodiments, the somatic mutation causes an amino acid change in eukaryotic elongation factor 2 selected from any one or more of those listed in Table 1. Mutations in the eukaryotic elongation factor 2 protein may be relative to the amino acid sequence of UniProt ID: P13639 (checksum: 78BD1710236C0D9C, last updated: 2007-01-23 v4, accessed: July 2024) and mapped potential isoform sequences, and / or ENSP00000307940 (from Ensembl version: ENSG00000167658.16, accessed: July 2024). In further embodiments, the gene is the HPN gene encoding serine protease hepsin. Serine protease hepsin is a membrane-bound serine protease highly expressed in the liver (Tsuji et al. (1991) J. Biol. Chem., 266(25):16948-16953, PMID: 1885621). It has been shown to activate prohepatocyte growth factor in the liver to enhance Met signalling, thereby regulating glucose, lipid and protein metabolism (Li et al. (2020) PNAS, 117(22):12359-12367, doi: https: / / doi.org / 10.1073 / pnas.1918445117). It also functions in non-hepatic tissues, including in adipose tissue and the kidney to regulate adipocyte differentiation and urinary protein processing respectively (Li et al. (2020) PNAS; and Brunati et al. (2015) eLife 4:e08887, doi: as well as in the inner ear to regulate auditory function and other tissues (such as in mouse blastocysts and embryos; Vu et al. (1997) J. Biol. Chem., 272(50):31315-31320, doi: and Camerer et al. (2010) Dev. Cell., 18(1):25-38, doi: https: / / doi.org / 10.1016 / j.devcel.2009.11.014). As demonstrated herein, the present inventors have identified many somatic mutations throughout the HPN gene leading to amino acid changes throughout the serine protease hepsin protein (see Table 1 and Figure 10). As shown in Figure 10, the identified loss of function mutations lead to amino acid changes in all protein domains, with clusters seen around amino acids P159 (cleavage site), F218-G233, L269-Y272 and L383-385. Mutations identified (see Table 1) include missense mutations leading to the nonsynonymous change of a codon sequence to that for a different amino acid than in the wild type protein, mutations causing frameshifts (either by insertion or deletion), and single nucleotide variations (SNVs). Thus, in some embodiments somatic mutation is in the DNA of the HPN gene and is selected from any one or more of those listed in Table 1. Mutations in the DNA of the HPN gene may be relative to ENSG00000105707 and / or the sequence located at chr19: 35,040,506- 35,066,573, forward strand (from Ensembl version: ENSG00000105707.15, accessed: July 2024). In further embodiments, the somatic mutation causes an amino acid change in serine protease hepsin selected from any one or more of those listed in Table 1. Mutations in the serine protease hepsin protein may be relative to the amino acid sequence of UniProt ID: P05981 (checksum: B2086FF661E551D7, last updated: 1988-11-01 v1, accessed: July 2024) and mapped potential isoform sequences, and / or ENSP00000500664 (from Ensembl version: ENSG00000105707.15, accessed: July 2024). Thus, in particular embodiments the somatic mutation is a loss of function mutation. Loss of function mutations can be in the form of: missense mutations which alter the protein structure and / or function by replacing one or more amino acid for different amino acids in the protein sequence (i.e. a nonsynonymous substitution), which may lead to the loss of protein function e.g. due to a change in a binding and / or active stie or alteration of protein structure essential for function; nonsense mutations which lead to the premature truncation of the protein by replacement of an amino acid coding codon with a stop codon, which may lead to incorrect folding resulting in degradation or may lead to loss of a protein domain required for function; mutation of a splice site (e.g. a splice recognition site) leading to altered splicing of the pre- mRNA, which may cause the removal of protein domains required for function, altered protein folding or structure which either is required for function or leads to degradation; mutation of a stop codon (a nonstop mutation / stop-loss variant) which remove the activity of a stop codon such that they are ‘read through’ and protein translation is not stopped when they are reached, which often lead to the loss of protein function due to extreme amino acid chain length and misfolding, or due to degradation often because of misfolding; single and multiple nucleotide variations (SNVs and MNVs, respectively) which can cause any of the beforementioned mutations; and frameshifts caused by insertions or deletions of one or more nucleotides (other than in multiples of three, which would not cause any frameshift), which can lead to the alteration of an amino acid sequence (as in missense mutations above) or the creation of otherwise hidden stop codons (as in nonsense mutations above). Thus, in some embodiments the somatic mutation is selected from one or more of: a missense mutation, a nonsense mutation, a mutation of an essential splice site, a mutation of a stop codon, a single or multiple nucleotide variation (SNV / MNV), and / or an insertion or deletion leading to a frameshift. As will be appreciated, some of the herein described somatic mutations may occur within the coding region of a gene (e.g. missense, nonsense, nonstop, insertion / deletion, SNV / MNV and frameshifts), while others may occur outside of coding regions of the gene, such as wherein the mutation is of a splice site and / or an insertion or deletion. Thus, in one embodiment the somatic mutation is located within a coding region of the gene. In a further embodiment, the somatic mutation is location within a non-coding region of the gene. Certain mutations described herein which comprise a change to multiple nucleotides (e.g. insertions / deletions and MNVs) may occur both within and outside of a coding region. Thus, in a yet further embodiment the somatic mutation may be located within a coding region and a non-coding region of the gene. In particular, the somatic mutation may be selected from any listed in Table 1 herein. Thus, in a particular embodiment the somatic mutation is one or more mutation selected from those listed in Table 1. As described herein and in Table 1 specifically, the somatic mutations may lead to an amino acid change in the protein product of the gene. Thus, in a further certain embodiment the somatic mutation causes one or more amino acid change selected from those listed in Table 1. As will be readily appreciated, the amino acid change is in the protein product produced from the gene containing the somatic mutation.

[0002] Table 1: Loss of Function Mutations Associated with MASH utated Amino Nucleotide Triplet Mutation plet Acid Change Codon Description don Change Change -1379-1380- - no-SNVinsfrshift AE245* G733T GAG>Nonsense TAG CA Y169H T505C TAC>Missense CAC -483-483- - no-SNVdelfrshift -217-218- - no-SNVinsfrshift CP64L C191T CCC>Missense CTC AY40H T118C TAT>Missense CAT GG36R G106A GGA>Missense AGA -104-104- - no-SNVdelfrshift AG10V G29T GGA>Missense GTA -854-867- - no-SNVdelfrshift TY591C A1772G TAT>Missense TGT AA D589N G1765A GAT>Missense AAT AA A583E C1748A GCA>Missense GAA CT575S A1723T ACC>Missense TCC AQ559K C1675A CAG>Missense AAG -1668-1668- - no-SNVdelfrshift A1CF ENSP0000 10 50809TCCCATACCTT -1 - - - - - 1628-1633- - no-SNVdelinframe CAA D530N G1588A GAT>Missense AAT -- 1586-1586- - no-SNVdelfrshift -- 1574-1575- - no-SNVdelfrshift -- 1539-1552- - no-SNVdelfrshift CAT - - - Essential_Splice -- 1449-1450- - no-SNVinsfrshift -- 1426-1426- - no-SNVdelfrshift CAA Q466K C1396A CAG>Missense AAG CAA Q466K C1396A CAG>Missense AAG -- 1387-1390- - no-SNVdelfrshift GAT - - - Essential_Splice -- 1307-1316- - no-SNVdelfrshift -- 1308-1311- - no-SNVdelfrshift AAG M434K T1301A ATG>Missense AAG -- 1272-1288- - no-SNVdelfrshift -- 1286-1287- - no-SNVinsfrshift ATC P427S C1279T CCT>Missense TCT A1CF ENSP0000 10 50813ATGTCATAGAA -1 - - - - - 1262-1273- - no-SNVdelinframe -- 1268-1269- - no-SNVinsfrshift ATG E419D A1257T GAA>Missense GAT -- 1223-1223- - no-SNVdelfrshift CAA Y401N T1201A TAT>Missense AAT -- 1196-1196- - no-SNVdelfrshift GCG G389A G1166C GGG>Missense GCG AGG M384R T1151G ATG>Missense AGG TGC Y383C A1148G TAC>Missense TGC -- 1135-1136- - no-SNVdelfrshift CTT P377L C1130T CCT>Missense CTT -- 1082-1082- - no-SNVdelfrshift ATC A344S G1030T GCT>Missense TCT AGT Y329* C987G TAC>Nonsense TAG CTG R276* C826T CGA>Nonsense TGA GAT A269D C806A GCT>Missense GAT GAA - - - Essential_Splice ATG G257C G769T GGT>Missense TGT ACT I247T T740C ATT>Missense ACT TCC T242P A724C ACC>Missense CCC A1CF ENSP0000 10 50828 T C -1 A G AAT AGT M227V A679G ATG>Missense GTG TAA E224K G670A GAA>Missense AAA GAG A195E C584A GCG>Missense GAG TGA H189D C565G CAT>Missense GAT -- 549-549- - no-SNVdelfrshift TGC F183C T548G TTC>Missense TGC -- 536-541- - no-SNVdelinframe CGG R179G C535G CGA>Missense GGA AGA N178D A532G AAC>Missense GAC TGA K175E A523G AAA>Missense GAA -- 499-499- - no-SNVdelfrshift GGC V166G T497G GTC>Missense GGC -- 478-479- - no-SNVmnv -- 453-464- - no-SNVdelinframe -- 448-449- - no-SNVdelfrshift -- 436-436- - no-SNVdelfrshift -- 425-425- - no-SNVdelfrshift CTG R137* C409T CGA>Nonsense TGA CTG R137* C409T CGA>Nonsense TGA CTG - - - Essential_Splice A1CF ENSP0000 10 50841 A T -1 T A ATG AAG Y119* T357A TAT>Nonsense TAAA CAG G80S G238A GGT>Missense AGTA TAT C76Y G227A TGT>Missense TATA TAA E69K G205A GAG>Missense AAGA CGG R65G C193G CGA>Missense GGAA CTG R65* C193T CGA>Nonsense TGAA CTC P64L C191T CCC>Missense CTCA - - 165-166- - no-SNVinsfrshiftA - - 68-80- - no-SNVdelfrshiftA AGT M1V A1G ATG>Missense GTGA - - 1576-1577- - no-SNVinsfrshiftA - - 1329-1347- - no-SNVdelfrshiftA AGG M384R T1151G ATG>Missense AGGA - - 1082-1082- - no-SNVdelfrshiftA CGG S274G A820G AGT>Missense GGTA TAC F273Y T818A TTC>Missense TACA TAA H189N C565A CAT>Missense AATA - - 425-425- - no-SNVdelfrshiftA CTG R137* C409T CGA>Nonsense TGA A1CF ENSP0000 10 50859 G A -1 C T GCG GTG R26C C76T CGC>Missense TGC CTA Q107* C319T CAG>Nonsense TAG CAC P114T C340A CCG>Missense ACG -- 52-61- - no-SNVdelfrshift -- 54-61- - no-SNVdelfrshift -- 56-56- - no-SNVdelfrshift -- 176-219- - no-SNVdelfrshift -- 290-291- - no-SNVdelfrshift -- 373-374- - no-SNVinsfrshift -- 409-409- - no-SNVdelfrshift -- 19-20- - no-SNVinsfrshift CGT P11R C32G CCT>Missense CGT TGG S12G A34G AGC>Missense GGC AAC S12N G35A AGC>Missense AAC -- 52-61- - no-SNVdelfrshift -- 54-61- - no-SNVdelfrshift GTA E22* G64T GAG>Nonsense TAG CDKN ENSP000012 12717 G T 1 G T GGA GTA E22* G64T GAG>Nonsense TAG CTA E39* G115T GAA>Nonsense TAA -- 125-126- - no-SNVdelfrshift CTG R43L G128T CGG>Missense CTG GTA E46* G136T GAG>Nonsense TAG GTA K47* A139T AAG>Nonsense TAG GTA K47* A139T AAG>Nonsense TAG -- 156-156- - no-SNVdelfrshift GTA E53* G157T GAA>Nonsense TAA ATA E54* G160T GAG>Nonsense TAG -- 166-167- - no-SNVinsfrshift -- 179-179- - no-SNVdelfrshift -- 189-189- - no-SNVdelfrshift -- 202-217- - no-SNVdelfrshift -- 205-208- - no-SNVdelfrshift -- 205-205- - no-SNVdelfrshift TAG W76* G227A TGG>Nonsense TAG ATA E78* G232T GAG>Nonsense TAG ATA R90I G269T AGA>Missense ATA -- 271-271- - no-SNVdelfrshift CDKN ENSP000012 12718 C A 1 C A CCC CAC P91H C272A CCC>Missense CAC CTC P91L C272T CCC>Missense CTC -- 278-279- - no-SNVinsfrshift -- 287-297- - no-SNVdelfrshift GCG V101A T302C GTG>Missense GCG GTA E105* G313T GAG>Nonsense TAG -- 329-339- - no-SNVdelfrshift -- 334-344- - no-SNVdelfrshift -- 338-354- - no-SNVdelfrshift -- 340-346- - no-SNVdelfrshift -- 356-356- - no-SNVdelfrshift -- 374-380- - no-SNVdelfrshift -- 375-376- - no-SNVdelfrshift -- 375-375- - no-SNVdelfrshift GCG E126A A377C GAG>Missense GCG -- 384-384- - no-SNVdelfrshift -- 409-409- - no-SNVdelfrshift -- 409-409- - no-SNVdelfrshift CDKN ENSP000012 12718 C T 1 C T CCA CTA Q141* C421T CAG>Nonsense TAG -- 457-457- - no-SNVdelfrshift -- 504-504- - no-SNVdelfrshift ATA E171* G511T GAA>Nonsense TAA CCT R196P G587C CGT>Missense CCT -- 54-61- - no-SNVdelfrshift GTC R19S G57T AGG>Missense AGT ATA E40* G118T GAG>Nonsense TAG GTA K47* A139T AAG>Nonsense TAG ATA E54* G160T GAG>Nonsense TAG TTA H67Y C199T CAC>Missense TAC -- 278-279- - no-SNVinsfrshift GTA E105* G313T GAG>Nonsense TAG -- 334-341- - no-SNVdelfrshift GGG A116G C347G GCG>Missense GGG -- 384-384- - no-SNVdelfrshift CAG P38Q C113A CCG>Missense CAG -- 921-922- - no-SNVinsfrshift -- 921-922- - no-SNVinsfrshift CAA Y426N T1276A TAT>Missense AAT -- 580-581- - no-SNVdelfrshift CYP2 ENSP000010 13353 C CT 1 - - - - - 921-922- - no-SNVinsfrshift AGA Y310D T928G TAT>Missense GAT -- 1209-1222- - no-SNVdelfrshift CAT F414I T1240A TTC>Missense ATC -- 1387-1388- - no-SNVinsfrshift TAT M1I G3A ATG>Missense ATA GAC S2T T4A TCT>Missense ACT GTC A3V C8T GCC>Missense GTC CTT L4F C10T CTC>Missense TTC CGC T7A A19G ACC>Missense GCC GTT V12L G34T GTG>Missense TTG GAG W13* G39A TGG>Nonsense TGA GAC A15T G43A GCC>Missense ACC GGC A15G C44G GCC>Missense GGC CAT L18M C52A CTG>Missense ATG ACG M22T T65C ATG>Missense ACG GAA W23* G69A TGG>Nonsense TGA GTT V26L G76T GTG>Missense TTG GGC P33A C97G CCC>Missense GCC GTC G35V G104T GGC>Missense GTC CYP2 ENSP000010 13352 C A 1 C A CCC CAC P36T C106A CCT>Missense ACT CGT P36R C107G CCT>Missense CGT CGT P36R C107G CCT>Missense CGT TAC F37L C111A TTC>Missense TTA TAC F37L C111A TTC>Missense TTA AGC N44S A131G AAC>Missense AGC -- 150-152- - no-SNVdelinframe -- 148-149- - no-SNVinsfrshift TGT I53V A157G ATT>Missense GTT TTC P54S C160T CCC>Missense TCC ATC T58I C173T ACC>Missense ATC CTG R59L G176T CGG>Missense CTG TGG F64L C192G TTC>Missense TTG GAC P66T C196A CCG>Missense ACG TAA F68L C204A TTC>Missense TTA CAC R76H G227A CGC>Missense CAC AAG M80K T239A ATG>Missense AAG GAG A89E C266A GCG>Missense GAG AGG K94R A281G AAG>Missense AGG TCC F97S T290C TTC>Missense TCC TAC A108T G322A GCG>Missense ACG CYP2 ENSP000010 13352 G A 1 G A GGG GAG G113R G337A GGA>Missense AGA CGT I115V A343G ATT>Missense GTT -- 345-350- - no-SNVdelinframe GTA D124Y G370T GAC>Missense TAC -- 375-375- - no-SNVdelfrshift GTG R127W C379T CGG>Missense TGG CAG R127Q G380A CGG>Missense CAG ATC T132I C395T ACC>Missense ATC -- 397-398- - no-SNVinsfrshift CAG R134Q G401A CGG>Missense CAG CTG Q141L A422T CAG>Missense CTG -- 459-459- - no-SNVdelfrshift CGG R159G A475G AGG>Missense GGG GAT - - - Essential_Splice -- 501-501- - no-SNVdelfrshift -- 499-500- - no-SNVinsfrshift AGC T169S C506G ACC>Missense AGC -- 513-516- - no-SNVdelfrshift GTG A175V C524T GCG>Missense GTG -- 549-549- - no-SNVdelfrshift -- 549-549- - no-SNVdelfrshift CYP2 ENSP000010 13353 C G 1 C G TCC TGC I183M C549G ATC>Missense ATG TAC F185Y T554A TTC>Missense TAC GGA H188D C562G CAT>Missense GAT -- 564-564- - no-SNVdelfrshift CGT H188R A563G CAT>Missense CGT -- 575-577- - no-SNVdelinframe -- 580-582- - no-SNVdelinframe -- 580-582- - no-SNVdelinframe -- 580-581- - no-SNVdelfrshift -- 580-581- - no-SNVdelfrshift -- 580-582- - no-SNVdelinframe -- 580-582- - no-SNVdelinframe -- 580-582- - no-SNVdelinframe -- 580-582- - no-SNVdelinframe -- 621-621- - no-SNVdelfrshift -- 621-621- - no-SNVdelfrshift TAC F207L C621A TTC>Missense TTA TAC F207L C621A TTC>Missense TTA TAC F207L C621A TTC>Missense TTA TGC P213A C637G CCC>Missense GCC GAC W214* G642A TGG>Nonsense TGA CYP2 ENSP000010 13353 C T 1 C T CCA CTA Q216* C646T CAG>Nonsense TAG -- 651-656- - no-SNVdelinframe AGT N219S A656G AAT>Missense AGT AGT N220K T660G AAT>Missense AAG -- 691-692- - no-SNVinsfrshift -- 692-693- - no-SNVinsfrshift GAC V235D T704A GTC>Missense GAC -- 706-707- - no-SNVdelfrshift -- 706-707- - no-SNVdelfrshift -- 708-710- - no-SNVdelinframe -- 712-717- - no-SNVdelinframe -- 726-727- - no-SNVdelfrshift -- 726-727- - no-SNVdelfrshift -- 726-727- - no-SNVdelfrshift -- 724-725- - no-SNVinsfrshift -- 726-727- - no-SNVdelfrshift -- 726-727- - no-SNVdelfrshift -- 726-727- - no-SNVdelfrshift -- 726-727- - no-SNVdelfrshift AGA K243R A728G AAA>Missense AGA -- 729-730- - no-SNVdelfrshift CYP2 ENSP000010 13353 AGAG A 1 - - 730-732- - no-SNVdelinframe -- 731-733- - no-SNVdelinframe TGT Y245C A734G TAT>Missense TGT TGT Y245C A734G TAT>Missense TGT -- 735-736- - no-SNVinsfrshift -- 744-757- - no-SNVdelfrshift -- 743-744- - no-SNVinsfrshift GAT V250M G748A GTG>Missense ATG -- 755-764- - no-SNVdelfrshift TTA Q255* C763T CAA>Nonsense TAA CTA N260Y A778T AAC>Missense TAC CGG R263G C787G CGG>Missense GGG CTG R263W C787T CGG>Missense TGG CTG R263L G788T CGG>Missense CTG -- 795-796- - no-SNVinsfrshift -- 876-893- - no-SNVdelinframe GTC A294V C881T GCC>Missense GTC CYP2 ENSP000010 13353 G A 1 G A CGA CAA D295N G883A GAC>Missense AAC TAT F297L C891A TTC>Missense TTA TAT F297L C891A TTC>Missense TTA TAC A299T G895A GCG>Missense ACG GTG A299V C896T GCG>Missense GTG GAG G300E G899A GGG>Missense GAG -- 921-922- - no-SNVinsfrshift -- 923-923- - no-SNVdelfrshift -- 921-922- - no-SNVinsfrshift -- 921-922- - no-SNVinsfrshift -- 921-922- - no-SNVinsfrshift -- 926-927- - no-SNVinsfrshift GAG G311E G932A GGG>Missense GAG TAT L315I C943A CTC>Missense ATC GCA - - - Essential_Splice GTC - - - Essential_Splice CAC L325H T974A CTC>Missense CAC CAA H326N C976A CAT>Missense AAT CAA H326N C976A CAT>Missense AAT TTA E327* G979T GAA>Nonsense TAA -- 982-983- - no-SNVinsfrshift CYP2 ENSP000010 13353AAATTGACAGA 1 - - - - - 984-999- - no-SNVdelfrshift ACT I329T T986C ATT>Missense ACT CGA P335R C1004G CCA>Missense CGA -- 1032-1033- - no-SNVinsfrshift CTC P348L C1043T CCC>Missense CTC CAA Y349N T1045A TAC>Missense AAC ACG M350T T1049C ATG>Missense ACG -- 1060-1061- - no-SNVinsfrshift GCG V354A T1061C GTG>Missense GCG TAA F360L C1080A TTC>Missense TTA CCC T362P A1084C ACC>Missense CCC CGC S366A T1096G TCC>Missense GCC -- 1118-1118- - no-SNVdelfrshift CTG R374* C1120T CGA>Nonsense TGA TGT I377M T1131G ATT>Missense ATG -- 1133-1137- - no-SNVdelfrshift -- 1140-1141- - no-SNVinsfrshift TGC Y381C A1142G TAC>Missense TGC CTT L382F C1144T CTC>Missense TTC CGT I383V A1147G ATC>Missense GTC CYP2 ENSP000010 13353 T C 1 T C ATC ACC I383T T1148C ATC>Missense ACC CTC P384L C1151T CCC>Missense CTC -- 1162-1163- - no-SNVinsfrshift -- 1165-1165- - no-SNVdelfrshift CTA P391L C1172T CCA>Missense CTA -- 1183-1184- - no-SNVinsfrshift -- 1183-1184- - no-SNVinsfrshift -- 1183-1184- - no-SNVinsfrshift -- 1189-1206- - no-SNVdelinframe -- 1213-1217- - no-SNVdelfrshift -- 1221-1224- - no-SNVdelfrshift -- 1223-1224- - no-SNVinsfrshift -- 1223-1224- - no-SNVinsfrshift GAT F409I T1225A TTT>Missense ATT TGA F409L T1227G TTT>Missense TTG CAT F414I T1240A TTC>Missense ATC -- 1239-1240- - no-SNVinsfrshift TAC F414L C1242A TTC>Missense TTA TAC F414L C1242A TTC>Missense TTA -- 1255-1256- - no-SNVinsfrshift CYP2 ENSP000010 13353 TC T 1 - - - - - 1263-1263- - no-SNVdelfrshift CCA Y426H T1276C TAT>Missense CAT -- 1275-1276- - no-SNVinsfrshift TAA F427L C1281A TTC>Missense TTA CTA P429L C1286T CCA>Missense CTA AAG G433R G1297A GGA>Missense AGA AAG G433R G1297A GGA>Missense AGA -- NA - no-SNV- - 1298-1304- - no-SNVdelfrshift -- 1298-1298- - no-SNVdelfrshift -- 1301-1310- - no-SNVdelfrshift AAT V436M G1306A GTG>Missense ATG TTG R444C C1330T CGC>Missense TGC -- 1337-1338- - no-SNVinsfrshift TGT L449V C1345G CTT>Missense GTT -- 1346-1353- - no-SNVdelfrshift TGT L449V C1345G CTT>Missense GTT -- 1348-1350- - no-SNVdelinframe TTT C452F G1355T TGT>Missense TTT -- 1359-1360- - no-SNVinsfrshift CYP2 ENSP000010 13353 ATT A 1 - - - - - 1361-1362- - no-SNVdelfrshift -- 1378-1380- - no-SNVdelinframe ATG K461M A1382T AAG>Missense ATG -- 1393-1407- - no-SNVdelinframe ACT I476T T1427C ATT>Missense ACT TTG G477W G1429T GGG>Missense TGG -- 1433-1445- - no-SNVdelfrshift -- 1459-1460- - no-SNVdelfrshift -- 1459-1460- - no-SNVdelfrshift -- 1459-1460- - no-SNVdelfrshift -- 1459-1460- - no-SNVdelfrshift -- 1459-1460- - no-SNVdelfrshift -- 1462-1463- - no-SNVdelfrshift -- 1462-1463- - no-SNVdelfrshift -- 1460-1461- - no-SNVinsfrshift -- 1460-1461- - no-SNVinsfrshift -- 1462-1463- - no-SNVdelfrshift -- 1462-1463- - no-SNVdelfrshift -- 1462-1463- - no-SNVdelfrshift CYP2 ENSP000010 13353 CTG C 1 - - - - - 1462-1463- - no-SNVdelfrshift -- 1460-1461- - no-SNVinsfrshift -- 1460-1461- - no-SNVinsfrshift TAT C488Y G1463A TGT>Missense TAT TTC P491S C1471T CCC>Missense TCC TAC P491T C1471A CCC>Missense ACC -- 1474-1482- - no-SNVdelinframe CTG R492C C1474T CGC>Missense TGC CAC R492H G1475A CGC>Missense CAC CAC R492H G1475A CGC>Missense CAC GTT V26L G76T GTG>Missense TTG -- 276-276- - no-SNVdelfrshift GAG G113R G337A GGA>Missense AGA TGC S129A T385G TCC>Missense GCC -- 509-511- - no-SNVdelinframe -- 580-582- - no-SNVdelinframe TAC F207L C621A TTC>Missense TTA GAC V235D T704A GTC>Missense GAC -- 724-725- - no-SNVinsfrshift -- 921-922- - no-SNVinsfrshift CYP2 ENSP000010 13353 C CTT 1 - - - - - 921-922- - no-SNVinsfrshift -- 936-954- - no-SNVdelfrshift ATC T362I C1085T ACC>Missense ATC CTC P369L C1106T CCC>Missense CTC -- 1223-1224- - no-SNVinsfrshift CGC H413R A1238G CAC>Missense CGC -- 1378-1380- - no-SNVdelinframe -- 1459-1460- - no-SNVdelfrshift CAC R492H G1475A CGC>Missense CAC ATG T804M C2411T ACG>Missense ATG GTT V762F G2284T GTT>Missense TTT CTA D703Y G2107T GAC>Missense TAC CGA K629E A1885G AAG>Missense GAG CGA K629E A1885G AAG>Missense GAG TTA M257I G771T ATG>Missense ATT GGT M257V A769G ATG>Missense GTG GTG E196V A587T GAG>Missense GTG GAC V187D T560A GTC>Missense GAC TGT F78L C234G TTC>Missense TTG GGC A26G C77G GCC>Missense GGC EEF2 ENSP0000 19 39766 G A -1 C T CCC CTC P831L C2492T CCC>Missense CTC GGA S828R C2484G AGC>Missense AGG GAC W817* G2451A TGG>Nonsense TGA ATG T804M C2411T ACG>Missense ATG AGG K766R A2297G AAG>Missense AGG GTG G761V G2282T GGG>Missense GTG GTC G758V G2273T GGC>Missense GTC ATC E742D G2226T GAG>Missense GAT -- 2198-2199- - no-SNVdelfrshift CTC R727L G2180T CGC>Missense CTC CTC A713S G2137T GCC>Missense TCC CTA D703Y G2107T GAC>Missense TAC GTT V680L G2038T GTG>Missense TTG GAT G668D G2003A GGT>Missense GAT GTT G668V G2003T GGT>Missense GTT CAG G656S G1966A GGC>Missense AGC -- 1939-1939- - no-SNVdelfrshift CAC R647H G1940A CGC>Missense CAC -- 1887-1901- - no-SNVdelinframe CTA E615* G1843T GAG>Nonsense TAG EEF2 ENSP0000 19 39780 C T -1 G A GGC GAC G612D G1835A GGC>Missense GAC TCC Y603S A1808C TAC>Missense TCC CAG R601Q G1802A CGG>Missense CAG -- 1762-1772- - no-SNVdelfrshift TCC C557S G1670C TGC>Missense TCC ATA K512N G1536T AAG>Missense AAT CAC S418T T1252A TCG>Missense ACG GAT V402M G1204A GTG>Missense ATG TGC Y373C A1118G TAC>Missense TGC GGC A364G C1091G GCC>Missense GGC CTT P361L C1082T CCT>Missense CTT CTC P359L C1076T CCC>Missense CTC CGC H357R A1070G CAC>Missense CGC -- 1057-1058- - no-SNVinsfrshift CTG Q352L A1055T CAG>Missense CTG GGT L351V T1051G TTG>Missense GTG CTG G347* G1039T GGA>Nonsense TGA CTG - - - Essential_Splice ACG E241D G723C GAG>Missense GAC AGG M231R T692G ATG>Missense AGG EEF2 ENSP0000 19 39823 C A -1 G T AGC ATC K226N G678T AAG>Missense AAT ATC K226N G678T AAG>Missense AAT ATC K226N G678T AAG>Missense AAT AGG K226R A677G AAG>Missense AGG GCG G220A G659C GGG>Missense GCG CAG G210S G628A GGT>Missense AGT CGT M204V A610G ATG>Missense GTG CGC T191A A571G ACC>Missense GCC ACC N186T A557C AAC>Missense ACC GTT L174F C520T CTC>Missense TTC GGT M160V A478G ATG>Missense GTG CTG R144L G431T CGG>Missense CTG CTA D110Y G328T GAC>Missense TAC CAC P106H C317A CCC>Missense CAC -- 288-288- - no-SNVdelfrshift CAC L81H T242A CTC>Missense CAC TGC Y79C A236G TAC>Missense TGC CGT F78V T232G TTC>Missense GTC -- 176-177- - no-SNVinsfrshift GTG G52V G155T GGG>Missense GTG CAG G52R G154A GGG>Missense AGG EEF2 ENSP0000 19 39842 G C -1 C G CCT CGT L39V C115G CTG>Missense GTG CTA H30Y C88T CAT>Missense TAT GAA D29N G85A GAC>Missense AAC GGC A26G C77G GCC>Missense GGC GCC S23P T67C TCT>Missense CCT GCC A646P G1936C GCC>Missense CCC CTC P359L C1076T CCC>Missense CTC TAC M340I G1020A ATG>Missense ATA -- 7443-7465- - no-SNVdelfrshift -- 7181-7187- - no-SNVdelfrshift -- 7167-7168- - no-SNVinsfrshift ACG K2354T A7061C AAG>Missense ACG TAA D2280N G6838A GAC>Missense AAC GAG G2252S G6754A GGC>Missense AGC GCC A2141P G6421C GCT>Missense CCT CCG S2081R A6241C AGT>Missense CGT -- 6135-6151- - no-SNVdelfrshift CTG P1882L C5645T CCG>Missense CTG FASN ENSP0000 17 82083 G T -1 C A TCG TAG S1874* C5621A TCG>Nonsense TAG TTG S1874L C5621T TCG>Missense TTG CAG W1634 T4900A TGG>Missense R AGG CTG R1574C C4720T CGC>Missense TGC TAC F1573L C4719A TTC>Missense TTA CTG R1515C C4543T CGC>Missense TGC GAC A1510T G4528A GCC>Missense ACC TCC F1395S T4184C TTC>Missense TCC -- 3747-3747- - no-SNVdelfrshift GTG G1018 G3052T GGG>Missense W TGG TAC F850L C2550A TTC>Missense TTA -- 2501-2503- - no-SNVdelinframe -- 1655-1655- - no-SNVdelfrshift CTT P431L C1292T CCT>Missense CTT -- 442-444- - no-SNVdelinframe -- 7481-7483- - no-SNVdelinframe -- 7170-7171- - no-SNVinsfrshift -- 4830-4831- - no-SNVinsfrshift TGT L1342V C4024G CTG>Missense GTG CGC S731A T2191G TCC>Missense GCC -- 793-794- - no-SNVinsfrshift FASN ENSP0000 17 82093 T C -1 A G CAT CGT I184V A550G ATC>Missense GTC -- 7481-7483- - no-SNVdelinframe -- 7481-7483- - no-SNVdelinframe -- 7481-7483- - no-SNVdelinframe CCA E2478Q G7432C GAG>Missense CAG CGG Q2466R A7397G CAG>Missense CGG TGC Y2462C A7385G TAC>Missense TGC ATG E2456D G7368T GAG>Missense GAT CTC R2447L G7340T CGC>Missense CTC -- 7270-7270- - no-SNVdelfrshift TAT F2423L C7269A TTC>Missense TTA TAC F2423Y T7268A TTC>Missense TAC -- 7181-7187- - no-SNVdelfrshift GGT F2375V T7123G TTC>Missense GTC -- 7096-7096- - no-SNVdelfrshift -- 7096-7096- - no-SNVdelfrshift GTG E2364V A7091T GAG>Missense GTG -- 7062-7069- - no-SNVdelfrshift -- 7055-7067- - no-SNVdelfrshift CCG L2355P T7064C CTG>Missense CCG FASN ENSP0000 17 82080 C A -1 G T CGG CTG R2352L G7055T CGG>Missense CTG -- 7054-7054- - no-SNVdelfrshift TTG S2340L C7019T TCG>Missense TTG TAG F2337L C7011A TTC>Missense TTA -- 6962-6973- - no-SNVdelinframe -- 6965-6966- - no-SNVmnv GAG C2312* C6936A TGC>Nonsense TGA -- 6908-6925- - no-SNVdelinframe CGC P2301R C6902G CCC>Missense CGC CGC L2264R T6791G CTC>Missense CGC -- 6688-6689- - no-SNVinsfrshift -- 6646-6646- - no-SNVdelfrshift -- 6547-6552- - no-SNVdelinframe -- 6533-6547- - no-SNVdelinframe CTC R2177L G6530T CGC>Missense CTC CAA D2139N G6415A GAC>Missense AAC CGG - - - Essential_Splice CGT M2088V A6262G ATG>Missense GTG FASN ENSP0000 17 82081 G A -1 C T CCA CTA Q2086* C6256T CAG>Nonsense TAG -- 6143-6143- - no-SNVdelfrshift -- 6135-6136- - no-SNVdelfrshift -- 6060-6062- - no-SNVdelinframe CCC S2020P T6058C TCC>Missense CCC GAT L2013M C6037A CTG>Missense ATG CTG R2007* C6019T CGA>Nonsense TGA GAA D2003N G6007A GAC>Missense AAC AAG D1990E C5970A GAC>Missense GAA TAC F1988L C5964A TTC>Missense TTA GAC G1978D G5933A GGC>Missense GAC -- 5795-5810- - no-SNVdelfrshift TAT S1916Y C5747A TCT>Missense TAT GGT I1905V A5713G ATA>Missense GTA TGG I1889M C5667G ATC>Missense ATG AGG K1885R A5654G AAG>Missense AGG -- 5632-5641- - no-SNVdelfrshift CAT F1880I T5638A TTC>Missense ATC TGG S1874W C5621G TCG>Missense TGG FASN ENSP0000 17 82083 C T -1 G A GGA GAA E1860K G5578A GAG>Missense AAG -- 5503-5504- - no-SNVmnv -- 5494-5494- - no-SNVdelfrshift TAC F1831L C5493A TTC>Missense TTA GAC A1816T G5446A GCC>Missense ACC -- 5435-5436- - no-SNVinsfrshift GCG W1811 T5431C TGG>Missense R CGG CAG R1808Q G5423A CGG>Missense CAG -- 5401-5403- - no-SNVdelinframe TAA F1800L C5400A TTC>Missense TTA TAC F1785L C5355A TTC>Missense TTA -- NA - no-SNVTGA Q1776E C5326G CAG>Missense GAG -- 5317-5325- - no-SNVdelinframe AGG H1763Q C5289G CAC>Missense CAG GGC V1744G T5231G GTC>Missense GGC ATT - - - Essential_Splice CGT F1720V T5158G TTC>Missense GTC GTT L1715F C5143T CTC>Missense TTC CAG R1705Q G5114A CGG>Missense CAG FASN ENSP0000 17 82083 C T -1 G A CGG CAG R1705Q G5114A CGG>Missense CAG -- 5092-5094- - no-SNVdelinframe -- 5092-5093- - no-SNVinsfrshift -- 5059-5064- - no-SNVdelinframe GTC A1684V C5051T GCC>Missense GTC GTC G1679V G5036T GGC>Missense GTC -- 5002-5016- - no-SNVdelinframe GAG G1663E G4988A GGG>Missense GAG TGC Y1652C A4955G TAC>Missense TGC -- 4915-4916- - no-SNVinsfrshift TAC F1632L C4896A TTC>Missense TTA GGC S1629A T4885G TCA>Missense GCA CCC S1625P T4873C TCT>Missense CCT GCG V1617A T4850C GTG>Missense GCG GGG R1612G C4834G CGT>Missense GGT CGA K1611E A4831G AAG>Missense GAG -- 4814-4814- - no-SNVdelfrshift GCA D1596H G4786C GAC>Missense CAC ACG M1577T T4730C ATG>Missense ACG -- 4713-4714- - no-SNVinsfrshift GT (SEQGTG W1546 G4638T TGG>Missense C TGT -- 4619-4620- - no-SNVinsfrshift ATC T1535I C4604T ACC>Missense ATC TAC F1517L C4551A TTC>Missense TTA TGC F1514L C4542G TTC>Missense TTG AAG N1504K C4512A AAC>Missense AAA -- 4462-4463- - no-SNVmnv AAC S1479N G4436A AGC>Missense AAC -- 4389-4390- - no-SNVdelfrshift -- 4383-4384- - no-SNVinsfrshift CTG R1461C C4381T CGC>Missense TGC GTT V1457L G4369T GTG>Missense TTG CAG R1439Q G4316A CGG>Missense CAG -- 4309-4313- - no-SNVdelfrshift TAC S1438Y C4313A TCC>Missense TAC TAT S1437Y C4310A TCT>Missense TAT -- 4303-4303- - no-SNVdelfrshift CGG S1421G A4261G AGC>Missense GGC -- 4243-4243- - no-SNVdelfrshift FASN ENSP0000 17 82085 G C -1 C G TCC TGC S1398C C4193G TCC>Missense TGC CAC R1387H G4160A CGC>Missense CAC TAG S1385* C4154A TCG>Nonsense TAG GAC P1365T C4093A CCG>Missense ACG CGT I1356V A4066G ATC>Missense GTC CAG R1349Q G4046A CGG>Missense CAG TGT L1342V C4024G CTG>Missense GTG -- 3967-3968- - no-SNVinsfrshift GTC G1308V G3923T GGC>Missense GTC ATC S1261I G3782T AGC>Missense ATC CAT V1232M G3694A GTG>Missense ATG AAG R1206K G3617A AGG>Missense AAG GCG E1197A A3590C GAG>Missense GCG CTG G1192 G3574T GGG>Missense W TGG -- 3545-3548- - no-SNVdelfrshift ACA Q1168H G3504C CAG>Missense CAC TAG M1159I G3477A ATG>Missense ATA ATG Q1146H G3438T CAG>Missense CAT GAA E1124K G3370A GAG>Missense AAG -- 3361-3366- - no-SNVdelinframe FASN ENSP0000 17 82087 G T -1 C A TCA TAA F1119L C3357A TTC>Missense TTA CC E1108D G3324C GAG>Missense GAC -3318-3319- - no-SNVdelfrshift TG Q1106L A3317T CAG>Missense CTG TG S1101L C3302T TCG>Missense TTG TG S1101L C3302T TCG>Missense TTG TA E1100* G3298T GAG>Nonsense TAG TC T1099S A3295T ACT>Missense TCT -3227-3232- - no-SNVdelinframe GC T1053A A3157G ACC>Missense GCC -3045-3051- - no-SNVdelfrshift TC S1012I G3035T AGC>Missense ATC AG Y1001* C3003A TAC>Nonsense TAA -2981-2982- - no-SNVinsfrshift -2971-2972- - no-SNVinsfrshift -2953-2953- - no-SNVdelfrshift GC L983R T2948G CTC>Missense CGC -2921-2922- - no-SNVinsfrshift -NA - no-SNV- 2842-2843- - no-SNVinsfrshift -2819-2836- - no-SNVdelinframe G (SEQ ID NO:CAG R936Q G2807A CGG>Missense CAG AGG K927R A2780G AAG>Missense AGG -- 2743-2744- - no-SNVinsfrshift GGT F914V T2740G TTT>Missense GTT -- 2723-2737- - no-SNVdelinframe -- 2657-2658- - no-SNVmnv CAC R883H G2648A CGC>Missense CAC GAA D877N G2629A GAC>Missense AAC CCC S868P T2602C TCC>Missense CCC GGC D865G A2594G GAC>Missense GGC GTC A859V C2576T GCC>Missense GTC -- 2554-2555- - no-SNVinsfrshift TAC F850L C2550A TTC>Missense TTA TAC F850L C2550A TTC>Missense TTA TAC F850L C2550A TTC>Missense TTA AAC S839N G2516A AGC>Missense AAC AAC S839N G2516A AGC>Missense AAC -- 2507-2508- - no-SNVinsfrshift -- 2501-2503- - no-SNVdelinframe FASN ENSP0000 17 82088GCC GCCGA 1 - - 2394-2407- - no-SNVdelfrshift CAG G799S G2395A GGC>Missense AGC TAC F796L C2388A TTC>Missense TTA -- 2359-2361- - no-SNVdelinframe -- 2351-2352- - no-SNVinsfrshift CTC P783L C2348T CCC>Missense CTC TGG I761M C2283G ATC>Missense ATG GGT I761V A2281G ATC>Missense GTC GCG W750R T2248C TGG>Missense CGG GTA E747* G2239T GAG>Nonsense TAG -- 2236-2236- - no-SNVdelfrshift TAC F745L C2235A TTC>Missense TTA -- 2212-2214- - no-SNVdelinframe GTC W722C G2166T TGG>Missense TGT CAG W712R T2134A TGG>Missense AGG CCG L694P T2081C CTG>Missense CCG -- 2032-2033- - no-SNVmnv CAG G678S G2032A GGC>Missense AGC GTA E663* G1987T GAG>Nonsense TAG -- 1936-1937- - no-SNVinsfrshift FASN ENSP0000 17 82089 C A -1 G T CGT CTT V638L G1912T GTG>Missense TTG GAC P617T C1849A CCG>Missense ACG CAC A590T G1768A GCC>Missense ACC CAC S581T T1741A TCC>Missense ACC -- 1641-1643- - no-SNVdelinframe CAA E543K G1627A GAG>Missense AAG GTT D524V A1571T GAT>Missense GTT -- 1541-1554- - no-SNVdelfrshift AGA Q502E C1504G CAG>Missense GAG GTT G474V G1421T GGT>Missense GTT CTT R468L G1403T CGT>Missense CTT CTG R468C C1402T CGT>Missense TGT ATC T463I C1388T ACC>Missense ATC GAA D447N G1339A GAC>Missense AAC GAC G441D G1322A GGC>Missense GAC ATC E439D G1317T GAG>Missense GAT ACC Q409H G1227C CAG>Missense CAC -- 1116-1116- - no-SNVdelfrshift GTT D371V A1112T GAT>Missense GTT TCG L370S T1109C TTG>Missense TCG FASN ENSP0000 17 82091 G T 1 C A TCC TAC F359L C1077A TTC>Missense TTA -1076-1076- - no-SNVdelfrshift -NA - no-SNVGAT - - - Essential_Splice TG R316C C946T CGC>Missense TGC AG G307S G919A GGC>Missense AGC TG Q278L A833T CAG>Missense CTG TG S275L C824T TCG>Missense TTG TC S237F C710T TCC>Missense TTC TA K235N G705T AAG>Missense AAT -660-661- - no-SNVinsfrshift -NA - no-SNVAG F215L C645A TTC>Missense TTA GCT F200L T598C TTC>Missense CTC GGG S177R C531G AGC>Missense AGG GAA Q169K C505A CAG>Missense AAG AA F150L C450A TTC>Missense TTA -442-444- - no-SNVdelinframe -435-438- - no-SNVdelfrshift CC F146S T437C TTC>Missense TCC CC F146S T437C TTC>Missense TCC FASN ENSP0000 17 82093 A G 1 T C TTC TCC F146S T437C TTC>Missense TCC TCC F146S T437C TTC>Missense TCC -- 416-424- - no-SNVdelinframe CAT V128M G382A GTG>Missense ATG AGT L127V C379G CTC>Missense GTC -- 352-352- - no-SNVdelfrshift GAA A72E C215A GCA>Missense GAA CTC P69L C206T CCC>Missense CTC TCC F64S T191C TTC>Missense TCC TCC F64S T191C TTC>Missense TCC GGC P48A C142G CCC>Missense GCC CCG W23R T67C TGG>Missense CGG GAA Q20K C58A CAG>Missense AAG GAT V4M G10A GTG>Missense ATG -- 7481-7483- - no-SNVdelinframe TGG F2337L C7011G TTC>Missense TTG TTG W1932L G5795T TGG>Missense TTG CGT H1832R A5495G CAT>Missense CGT GTC G1781V G5342T GGC>Missense GTC CTA Q1709* C5125T CAG>Nonsense TAG FASN ENSP0000 17 82083 G A -1 C T GCG GTG R1705 C5113T CGG>Missense W TGG -- 4356-4357- - no-SNVinsfrshift -- 4314-4315- - no-SNVdelfrshift TAT F1381L C4143A TTC>Missense TTA TTG S1101L C3302T TCG>Missense TTG -- 2743-2744- - no-SNVinsfrshift GCC V600A T1799C GTC>Missense GCC GTG G441C G1321T GGC>Missense TGC GTC A415V C1244T GCC>Missense GTC CTG R167W C499T CGG>Missense TGG CTG G195W G583T GGG>Missense TGG TGC I273M C819G ATC>Missense ATG ATC Q274H G822T CAG>Missense CAT CTC P159L C476T CCC>Missense CTC CGC L269R T806G CTC>Missense CGC CTG P50L C149T CCG>Missense CTG CGG P50R C149G CCG>Missense CGG GTG R80C C238T CGC>Missense TGC CTC R80L G239T CGC>Missense CTC GCG V106A T317C GTG>Missense GCG ATG T114M C341T ACG>Missense ATG HPN ENSP0000 19 35059 T G 1 T G TTC TGC F117C T350G TTC>Missense TGC TC P141L C422T CCC>Missense CTC GT I149V A445G ATC>Missense GTC AC C150Y G449A TGC>Missense TAC CG L158P T473C CTG>Missense CCG TC P159L C476T CCC>Missense CTC TC P159L C476T CCC>Missense CTC TC P159L C476T CCC>Missense CTC TC P159L C476T CCC>Missense CTC TA D161Y G481T GAC>Missense TAC TA D161Y G481T GAC>Missense TAC TT V164L G490T GTG>Missense TTG TG R167W C499T CGG>Missense TGG AG R167Q G500A CGG>Missense CAG AT S170R C510A AGC>Missense AGA TG L171F G513T TTG>Missense TTT TG L171F G513T TTG>Missense TTT TC G172V G515T GGC>Missense GTC TG R173W C517T CGG>Missense TGG GT F218C T653G TTT>Missense TGT TC A219S G655T GCC>Missense TCC HPN ENSP0000 19 35060 G T 1 G T TGC TTC A219S G655T GCC>Missense TCC GTC A219V C656T GCC>Missense GTC CAG G220S G658A GGT>Missense AGT CAG G220S G658A GGT>Missense AGT CTT V222L G664T GTG>Missense TTG GAC A223T G667A GCC>Missense ACC CTA Q224* C670T CAG>Nonsense TAG -- 676-677- - no-SNVmnv TTT S226F C677T TCT>Missense TTT CCG Q231P A692C CAG>Missense CCG GCG G233R G697C GGG>Missense CGG CTC P245L C734T CCC>Missense CTC CGC P245R C734G CCC>Missense CGC CGC L269R T806G CTC>Missense CGC CAC L269H T806A CTC>Missense CAC CGC L269R T806G CTC>Missense CGC CGC T270A A808G ACA>Missense GCA GGA E271G A812G GAA>Missense GGA GGA E271G A812G GAA>Missense GGA ACA Y272H T814C TAC>Missense CAC TGC Y272C A815G TAC>Missense TGC HPN ENSP0000 19 35065 T C 1 T C GTG GCG V293A T878C GTG>Missense GCG ATG T294M C881T ACG>Missense ATG GCC A306P G916C GCC>Missense CCC GGT D320G A959G GAT>Missense GGT TGT Y328C A983G TAT>Missense TGT TAG G380S G1138A GGC>Missense AGC CAG L383Q T1148A CTG>Missense CAG CAG L383Q T1148A CTG>Missense CAG GTC A384S G1150T GCC>Missense TCC CGG Q385R A1154G CAG>Missense CGG GGC D395G A1184G GAC>Missense GGC GTA W399C G1197T TGG>Missense TGT ACT I39T T116C ATT>Missense ACT CTT V222L G664T GTG>Missense TTG TTC A339S G1015T GCT>Missense TCT TAA D366N G1096A GAC>Missense AAC -- 1056-1057- - no-SNVmnv CGC P268R C803G CCC>Missense CGC -- 764-765- - no-SNVinsfrshift TAC P126T C376A CCT>Missense ACT GTG R407W C1219T CGG>Missense TGG S G C GCG G G R407W C1219T CGG>Missense TGG H403Y C1207T CAC>Missense TAC -1165-1167- - no-SNVdelinframe -1165-1167- - no-SNVdelinframe K389M A1166T AAG>Missense ATG K389* A1165T AAG>Nonsense TAG GC386R T1156C TGC>Missense CGC Y381* C1143A TAC>Nonsense TAA H375Q C1125G CAC>Missense CAG H371L A1112T CAC>Missense CTC GD366E C1098G GAC>Missense GAG GD366E C1098A GAC>Missense GAA D366N G1096A GAC>Missense AAC D366N G1096A GAC>Missense AAC D366N G1096A GAC>Missense AAC D366N G1096A GAC>Missense AAC F362Y T1085A TTC>Missense TAC R361S G1083T AGG>Missense AGT R361S G1083T AGG>Missense AGT W360* G1079A TGG>Nonsense TAG GG357S G1069A GGC>Missense AGC KLF15 ENSP0000 3 12635 G C 1 C G ACC AGC T354S C1061G ACC>Missense AGC TGG F351L C1053G TTC>Missense TTG TAG F351L C1053A TTC>Missense TTA CCT F351L T1051C TTC>Missense CTC ACC K349N G1047C AAG>Missense AAC TTA E348* G1042T GAG>Nonsense TAG CCC R343P G1028C CGC>Missense CCC CGC H341R A1022G CAC>Missense CGC GCA Y332H T994C TAC>Missense CAC GAA H321N C961A CAC>Missense AAC TGT L303V C907G CTC>Missense GTC CTG G302C G904T GGT>Missense TGT -- 869-878- - no-SNVdelfrshift -- 870-873- - no-SNVdelfrshift CTT P290L C869T CCT>Missense CTT ATC K289N G867T AAG>Missense AAT -- 826-827- - no-SNVdelfrshift TCA L272F G816C TTG>Missense TTC -- 783-790- - no-SNVdelfrshift GGG V263G T788G GTG>Missense GGG KLF15 ENSP0000 3 12635 C T -1 G A CGT CAT V263M G787A GTG>Missense ATG CTC A261S G781T GCA>Missense TCA CCG Q256P A767C CAG>Missense CCG GGT V248G T743G GTT>Missense GGT CAT P239H C716A CCT>Missense CAT CGT P239R C716G CCT>Missense CGT -- 707-711- - no-SNVdelfrshift -- 707-707- - no-SNVdelfrshift GAC G233D G698A GGC>Missense GAC -- 634-635- - no-SNVinsfrshift -- 616-630- - no-SNVdelinframe -- 591-605- - no-SNVdelinframe TTC A201S G601T GCA>Missense TCA TAC S193T T577A TCC>Missense ACC -- 559-573- - no-SNVdelinframe CGC L182R T545G CTC>Missense CGC -- 515-515- - no-SNVdelfrshift GGT D168G A503G GAT>Missense GGT KLF15 ENSP0000 3 12635 TGACTCCA T 1 - 462-468- - no-SNVdelfrshift CTT P154L C461T CCT>Missense CTT -432-436- - no-SNVdelfrshift GC T140A A418G ACC>Missense GCC -409-412- - no-SNVdelfrshift CTA Q138* C412T CAG>Nonsense TAG CTA E124* G370T GAG>Nonsense TAG CTA E124* G370T GAG>Nonsense TAG -332-350- - no-SNVdelfrshift -332-350- - no-SNVdelfrshift GTC A113V C338T GCC>Missense GTC CTC P107L C320T CCC>Missense CTC -318-318- - no-SNVdelfrshift GAG W105* G315A TGG>Nonsense TGA -307-307- - no-SNVdelfrshift -295-301- - no-SNVdelfrshift -289-290- - no-SNVinsfrshift -272-272- - no-SNVdelfrshift -238-238- - no-SNVdelfrshift KLF15 ENSP0000 3 12635 AG A 1 - - 238-238- - no-SNVdelfrshift -- 230-236- - no-SNVdelfrshift TAC F79L C237A TTC>Missense TTA TGC F79L C237G TTC>Missense TTG CTA E71* G211T GAG>Nonsense TAG -- 159-159- - no-SNVdelfrshift -- 159-159- - no-SNVdelfrshift -- 159-159- - no-SNVdelfrshift TGC S47C C140G TCC>Missense TGC -- 118-121- - no-SNVdelfrshift -- 97-97- - no-SNVdelfrshift -- 75-83- - no-SNVdelinframe CGG L26R T77G CTG>Missense CGG GAT G23D G68A GGT>Missense GAT CGG L22R T65G CTG>Missense CGG CAA P15Q C44A CCA>Missense CAA -- 33-34- - no-SNVdelfrshift -- 20-20- - no-SNVdelfrshift CGT M1V A1G ATG>Missense GTG GTG R407W C1219T CGG>Missense TGG CGC S397A T1189G TCC>Missense GCC -1165-1167- - no-SNVdelinframe AAG D366E C1098A GAC>Missense GAA GTC P356S C1066T CCA>Missense TCA TGG F351L C1053G TTC>Missense TTG TAG F351L C1053A TTC>Missense TTA -751-756- - no-SNVdelinframe CGT P239R C716G CCT>Missense CGT -515-515- - no-SNVdelfrshift CTA Q138* C412T CAG>Nonsense TAG CTA E124* G370T GAG>Nonsense TAG -353-353- - no-SNVdelfrshift -272-272- - no-SNVdelfrshift -238-238- - no-SNVdelfrshift ACG E41D A123C GAA>Missense GAC -1-13- - no-SNVdelfrshift ATG K106M A317T AAG>Missense ATG ACA K605T A1814C AAA>Missense ACA TAA L751* T2252A TTA>Nonsense TAA AGG Y1330* T3990G TAT>Nonsense TAG PCF11 ENSP0000 11 83182 TGCTATTAG T 1 - - 4396-4403- - no-SNVdelfrshift ACG K592T A1775C AAG>Missense ACG -- 2773-2773- - no-SNVdelfrshift ACA E3Q G7C GAG>Missense CAG -- 58-59- - no-SNVinsfrshift CGG P35R C104G CCG>Missense CGG CGA N38D A112G AAT>Missense GAT GGG E46G A137G GAG>Missense GGG ACG M74T T221C ATG>Missense ACG TAC A91T G271A GCC>Missense ACC ATA T99I C296T ACA>Missense ATA -- 313-313- - no-SNVdelfrshift -- 318-318- - no-SNVdelfrshift AGG K129R A386G AAG>Missense AGG -- 538-541- - no-SNVdelfrshift CCA Q195P A584C CAA>Missense CCA TTT L215F G645T TTG>Missense TTT TAA Q219K C655A CAG>Missense AAG GTA Q220* C658T CAG>Nonsense TAG ATA E228* G682T GAG>Nonsense TAG CAT L238H T713A CTT>Missense CAT CC L285F A855C TTA>Missense TTC CTG R295W C883T CGG>Missense TGG CAT R298H G893A CGT>Missense CAT CAG L299Q T896A CTG>Missense CAG AGA N300K C900G AAC>Missense AAG ATA K328N G984T AAG>Missense AAT -1031-1031- - no-SNVdelfrshift AG S364* C1091A TCG>Nonsense TAG -1151-1152- - no-SNVinsfrshift -1159-1159- - no-SNVdelfrshift -1190-1190- - no-SNVdelfrshift ACG M397T T1190C ATG>Missense ACG CGT H407R A1220G CAT>Missense CGT -1278-1279- - no-SNVinsfrshift AGT I449V A1345G ATC>Missense GTC ATA K456* A1366T AAA>Nonsense TAA GC T459A A1375G ACA>Missense GCA -1400-1401- - no-SNVdelfrshift -1400-1401- - no-SNVdelfrshift CGG Q467R A1400G CAG>Missense CGG -1401-1401- - no-SNVdelfrshift PCF11 ENSP0000 11 83166 A G 1 A G CAG CGG Q467R A1400G CAG>Missense CGG GG Q467R A1400G CAG>Missense CGG GG Q467R A1400G CAG>Missense CGG GG Q467R A1400G CAG>Missense CGG -1413-1413- - no-SNVdelfrshift AA R473K G1418A AGA>Missense AAA AC S487T T1459A TCT>Missense ACT CA I492T T1475C ATA>Missense ACA AA R498K G1493A AGA>Missense AAA TT D499V A1496T GAT>Missense GTT GT D499G A1496G GAT>Missense GGT TG R506W A1516T AGG>Missense TGG -1611-1612- - no-SNVmnv -1624-1625- - no-SNVdelfrshift TC A544S G1630T GCT>Missense TCT TA Q550* C1648T CAG>Nonsense TAG TG R557* C1669T CGA>Nonsense TGA CA E562A A1685C GAA>Missense GCA -1741-1742- - no-SNVinsfrshift GG N584K T1752G AAT>Missense AAG AT V585I G1753A GTA>Missense ATA PCF11 ENSP0000 11 83166 T C 1 T C GTA GCA V585A T1754C GTA>Missense GCA -1755-1759- - no-SNVdelfrshift -1757-1757- - no-SNVdelfrshift CC N587T A1760C AAC>Missense ACC -1766-1766- - no-SNVdelfrshift CG S590R A1768C AGT>Missense CGT CG S590R A1768C AGT>Missense CGT CG S590R A1768C AGT>Missense CGT CG S590R A1768C AGT>Missense CGT GG S590G A1768G AGT>Missense GGT -1770-1770- - no-SNVdelfrshift GT S590R T1770G AGT>Missense AGG GT S590R T1770G AGT>Missense AGG CG K592T A1775C AAG>Missense ACG CG K592T A1775C AAG>Missense ACG AC A594T G1780A GCC>Missense ACC CA K595N A1785C AAA>Missense AAC TT R596S A1788T AGA>Missense AGT -1792-1810- - no-SNVdelfrshift TT G600V G1799T GGT>Missense GTT C S G C G C GG GCA E602Q G1804C GAA>Missense CAA AGG S606G A1816G AGC>Missense GGC ATG R622M G1865T AGG>Missense ATG GTT W625C G1875T TGG>Missense TGT CGC P637A C1909G CCA>Missense GCA TCA L644S T1931C TTA>Missense TCA GGA A659G C1976G GCA>Missense GGA GCA - - - Essential_Splice TTA D681Y G2041T GAC>Missense TAC AGT D681E C2043G GAC>Missense GAG TCT V684L G2050C GTT>Missense CTT GGT L692V C2074G CTA>Missense GTA GTA Q703* C2107T CAG>Nonsense TAG AGT N708S A2123G AAT>Missense AGT AGT N739S A2216G AAT>Missense AGT -2225-2226- - no-SNVinsfrshift AGC T766A A2296G ACG>Missense GCG GCT D781A A2342C GAT>Missense GCT AGG D792E T2376G GAT>Missense GAG AGT I838V A2512G ATT>Missense GTT TTG R847W C2539T CGG>Missense TGG PCF11 ENSP0000 11 83168 C A 1 C A TCT TAT S859Y C2576A TCT>Missense TAT CGT H921R A2762G CAT>Missense CGT TTA D931Y G2791T GAT>Missense TAT CTA P937L C2810T CCA>Missense CTA ATA R942I G2825T AGA>Missense ATA -- 2866-2866- - no-SNVdelfrshift TGA S963* C2888G TCA>Nonsense TGA -- 2890-2891- - no-SNVinsfrshift GTG G971* G2911T GGA>Nonsense TGA TAA Q975K C2923A CAA>Missense AAA CGT L976R T2927G CTT>Missense CGT TCG G992R G2974C GGT>Missense CGT TGT I993V A2977G ATC>Missense GTC ATG R1030* A3088T AGA>Nonsense TGA -- 3099-3099- - no-SNVdelfrshift -- 3211-3212- - no-SNVinsfrshift GCT V1083A T3248C GTT>Missense GCT TTA Q1092* C3274T CAA>Nonsense TAA CGT H1099R A3296G CAT>Missense CGT ATG R1115* A3343T AGA>Nonsense TGA AGT N1118S A3353G AAT>Missense AGT PCF11 ENSP0000 11 83169 G T 1 G T TGA TTA E1125* G3373T GAA>Nonsense TAA CCA N1130H A3388C AAT>Missense CAT TCC F1152S T3455C TTC>Missense TCC TAC F1152L C3456A TTC>Missense TTA -- 3545-3545- - no-SNVdelfrshift AAA N1183K C3549A AAC>Missense AAA ACT I1215T T3644C ATT>Missense ACT -- NA - no-SNV- - 3877-3877- - no-SNVinsfrshift ATA E1305* G3913T GAG>Nonsense TAG AGT N1335S A4004G AAT>Missense AGT -- 4006-4006- - no-SNVdelfrshift -- 4027-4028- - no-SNVinsfrshift TTA H1361Y C4081T CAT>Missense TAT GCC W1364 G4092C TGG>Missense C TGC ACT E1393D A4179C GAA>Missense GAC ATG R1403 C4207T CGG>Missense W TGG AGA K1419R A4256G AAA>Missense AGA AGA K1427R A4280G AAA>Missense AGA TTA D1519Y G4555T GAC>Missense TAC ATC E1526D A4578T GAA>Missense GAT AAC A1533T G4597A GCT>Missense ACT TAT C1534Y G4601A TGT>Missense TAT -- 4624-4624- - no-SNVdelfrshift AGA T1551R C4652G ACA>Missense AGA CGA N38D A112G AAT>Missense GAT TAT F100Y T299A TTT>Missense TAT -- 313-313- - no-SNVdelfrshift -- 1031-1031- - no-SNVdelfrshift CGG Q467R A1400G CAG>Missense CGG CGG Q467R A1400G CAG>Missense CGG -- 1532-1533- - no-SNVinsfrshift -- 1611-1612- - no-SNVmnv -- 1757-1757- - no-SNVdelfrshift -- 1764-1770- - no-SNVdelfrshift ACG S590R A1768C AGT>Missense CGT ACG S590R A1768C AGT>Missense CGT GGC S593A T1777G TCT>Missense GCT -- 1792-1810- - no-SNVdelfrshift ACA D647H G1939C GAT>Missense CAT GTA Q703* C2107T CAG>Nonsense TAG PCF11 ENSP0000 11 83168 C A 1 C A TCG TAG R710S C2128A CGT>Missense AGT -2225-2226- - no-SNVinsfrshift AA - - - Essential_Splice CT E1393D A4179C GAA>Missense GAC -4649-4650- - no-SNVdelfrshift TA D52Y G154T GAT>Missense TAT TT C58F G173T TGT>Missense TTT CT V120L G358C GTG>Missense CTG GC F205C T614G TTC>Missense TGC AG F205L C615A TTC>Missense TTA -656-690- - no-SNVdelfrshift AC P325H C974A CCC>Missense CAC AC A398T G1192A GCC>Missense ACC TT - - - Essential_Splice AG L524Q T1571A CTG>Missense CAG -1732-1733- - no-SNVdelfrshift GC T586A A1756G ACC>Missense GCC AT V616I G1846A GTC>Missense ATC -1839-1840- - no-SNVinsfrshift TF ENSP0000 3 13374 G A 1 G A TGA TAA M1I G3A ATG>Missense ATA CGT L8V C22G CTG>Missense GTG GGC V10G T29G GTC>Missense GGC GTC A12V C35T GCC>Missense GTC GTC A12V C35T GCC>Missense GTC -39-40- - no-SNVinsfrshift CTC P21S C61T CCT>Missense TCT -67-68- - no-SNVdelfrshift -72-73- - no-SNVdelfrshift -72-73- - no-SNVdelfrshift TAC F41L C123A TTC>Missense TTA CTG R42C C124T CGC>Missense TGC -167-168- - no-SNVinsfrshift TTC C67F G200T TGC>Missense TTC GGT D77G A230G GAT>Missense GGT -273-273- - no-SNVdelfrshift TGC F103C T308G TTC>Missense TGC -323-323- - no-SNVdelfrshift GTT A116V C347T GCT>Missense GTT -360-362- - no-SNVdelinframe -360-362- - no-SNVdelinframe TF ENSP0000 3 13375 TGAA T 1 - - 360-362- - no-SNVdelinframe -- 360-362- - no-SNVdelinframe -- 360-362- - no-SNVdelinframe -- 360-362- - no-SNVdelinframe AGG K135R A404G AAG>Missense AGG TAC S136Y C407A TCC>Missense TAC GTT R143S G429T AGG>Missense AGT -- 447-447- - no-SNVdelfrshift CGT L165R T494G CTT>Missense CGT AGT N171S A512G AAT>Missense AGT ATG T184M C551T ACG>Missense ATG -- 558-561- - no-SNVdelfrshift -- 566-567- - no-SNVinsfrshift -- 604-607- - no-SNVdelfrshift -- 606-607- - no-SNVinsfrshift TGG F205L C615G TTC>Missense TTG TAG F205L C615A TTC>Missense TTA -- 635-635- - no-SNVdelfrshift TGT L214V C640G CTG>Missense GTG -- 665-666- - no-SNVinsfrshift S - - 675-686- - no-SNVdelinframe TTG S227L C680T TCG>Missense TTG TGT I229V A685G ATA>Missense GTA ACT F230L T688C TTT>Missense CTT -- 697-698- - no-SNVinsfrshift AGA N235K C705G AAC>Missense AAG GAA D248N G742A GAC>Missense AAC ATA D255Y G763T GAT>Missense TAT -- 765-765- - no-SNVdelfrshift AAT H261Q C783A CAC>Missense CAA -- 804-804- - no-SNVdelfrshift GGC A272G C815G GCC>Missense GGC TGT M275V A823G ATG>Missense GTG GTG G276C G826T GGC>Missense TGC GTC G277V G830T GGC>Missense GTC CGT L281V T841G TTG>Missense GTG -- 848-848- - no-SNVdelfrshift AAG - - - Essential_Splice -- 871-872- - no-SNVinsfrshift -- 881-882- - no-SNVinsfrshift S G G C CGA K295E A883G AAA>Missense GAA -883-884- - no-SNVinsfrshift -889-889- - no-SNVdelfrshift -889-892- - no-SNVdelfrshift AA F304L C912A TTC>Missense TTA -918-919- - no-SNVinsfrshift -963-964- - no-SNVinsfrshift -970-971- - no-SNVinsfrshift -970-971- - no-SNVinsfrshift AC P325H C974A CCC>Missense CAC AC P325H C974A CCC>Missense CAC GC T340A A1018G ACT>Missense GCT CG R346P G1037C CGG>Missense CCG -1048-1048- - no-SNVdelfrshift AA P354Q C1061A CCA>Missense CAA -1073-1075- - no-SNVdelinframe AA C358* C1074A TGC>Nonsense TGA CG K362T A1085C AAG>Missense ACG TG A365V C1094T GCG>Missense GTG GC L372R T1115G CTC>Missense CGC GT D375G A1124G GAT>Missense GGT - - 1150-1154- - no-SNVdelfrshift -- 1155-1156- - no-SNVdelfrshift -- 1155-1156- - no-SNVdelfrshift -- 1155-1156- - no-SNVdelfrshift -- 1155-1156- - no-SNVdelfrshift -- 1155-1156- - no-SNVdelfrshift -- 1155-1156- - no-SNVdelfrshift -- 1155-1156- - no-SNVdelfrshift -- 1155-1156- - no-SNVdelfrshift -- 1158-1159- - no-SNVdelfrshift -- 1158-1159- - no-SNVdelfrshift -- 1158-1159- - no-SNVdelfrshift -- 1163-1163- - no-SNVdelfrshift GGA A390G C1169G GCA>Missense GGA ATA E391D G1173T GAG>Missense GAT CTA E394* G1180T GAA>Nonsense TAA CAC A398T G1192A GCC>Missense ACC CAC A398T G1192A GCC>Missense ACC CAC A398T G1192A GCC>Missense ACC CAC A398T G1192A GCC>Missense ACC CAC A398T G1192A GCC>Missense ACC TF ENSP0000 3 13375 G A 1 G A CGC CAC A398T G1192A GCC>Missense ACC CAC A398T G1192A GCC>Missense ACC CAC A398T G1192A GCC>Missense ACC CAC A398T G1192A GCC>Missense ACC CAC A398T G1192A GCC>Missense ACC GTT D406V A1217T GAT>Missense GTT TGC Y416C A1247G TAC>Missense TGC -- 1252-1253- - no-SNVdelfrshift -- 1252-1253- - no-SNVinsfrshift TGC Y431C A1292G TAC>Missense TGC -- 1314-1315- - no-SNVmnv GTA D439Y G1315T GAT>Missense TAT GCT D439A A1316C GAT>Missense GCT AGC P441A C1321G CCA>Missense GCA ACA E442Q G1324C GAG>Missense CAG ATG G444W G1330T GGG>Missense TGG AAG G444R G1330A GGG>Missense AGG -- 1332-1335- - no-SNVdelfrshift GAG G444E G1331A GGG>Missense GAG -- 1356-1364- - no-SNVdelinframe TF ENSP0000 3 13376 AGCTT A 1 - 1363-1366- - no-SNVdelfrshift -1380-1392- - no-SNVdelfrshift -1387-1395- - no-SNVdelinframe K467E A1399G AAG>Missense GAG -1403-1403- - no-SNVdelfrshift G474V G1421T GGC>Missense GTC GW479G T1435G TGG>Missense GGG W479* G1437A TGG>Nonsense TGA P482L C1445T CCC>Missense CTC M483L A1447C ATG>Missense CTG G484S G1450A GGC>Missense AGC L486I C1456A CTC>Missense ATC -1492-1492- - no-SNVdelfrshift -1523-1524- - no-SNVdelfrshift -1538-1539- - no-SNVinsfrshift GC514G T1540G TGT>Missense GGT S520P T1558C TCA>Missense CCA S520P T1558C TCA>Missense CCA L522Q T1565A CTA>Missense CAA -1571-1572- - no-SNVdelfrshift TF ENSP0000 3 13376 CCAA C 1 - 1581-1583- - no-SNVdelinframe -1587-1588- - no-SNVinsfrshift -1593-1593- - no-SNVdelfrshift -1602-1602- - no-SNVdelfrshift CAG G535S G1603A GGC>Missense AGC -1615-1615- - no-SNVdelfrshift CAC A539T G1615A GCT>Missense ACT -NA - no-SNVGT L543V C1627G CTG>Missense GTG -1671-1672- - no-SNVinsfrshift CGC T561A A1681G ACT>Missense GCT -1681-1682- - no-SNVinsfrshift -1681-1682- - no-SNVinsfrshift GAA - - - Essential_Splice -1702-1702- - no-SNVdelfrshift ACG W569R T1705C TGG>Missense CGG GGT A570G C1709G GCT>Missense GGT AGT N574S A1721G AAT>Missense AGT -1722-1723- - no-SNVinsfrshift -1732-1733- - no-SNVdelfrshift -1732-1733- - no-SNVdelfrshift - 1732-1733- - no-SNVdelfrshift -1732-1733- - no-SNVdelfrshift -1732-1733- - no-SNVdelfrshift -1732-1733- - no-SNVdelfrshift -1732-1733- - no-SNVdelfrshift TY578C A1733G TAT>Missense TGT -1732-1733- - no-SNVinsfrshift GY578* T1734G TAT>Nonsense TAG E579* G1735T GAG>Nonsense TAG GL581Q T1742A CTG>Missense CAG C582F G1745T TGC>Missense TTC -1772-1772- - no-SNVdelfrshift GY593* T1779G TAT>Nonsense TAG -1796-1810- - no-SNVdelinframe GP602R C1805G CCG>Missense CGG -1808-1809- - no-SNVinsfrshift GH604Q C1812G CAC>Missense CAG CA605T G1813A GCT>Missense ACT CT608A A1822G ACA>Missense GCA GR609W C1825T CGG>Missense TGG S - - 1834-1834- - no-SNVdelfrshift -- 1834-1834- - no-SNVdelfrshift -- 1834-1834- - no-SNVdelfrshift -- 1836-1841- - no-SNVdelinframe -- 1839-1840- - no-SNVinsfrshift GAT A614D C1841A GCT>Missense GAT CAT V616I G1846A GTC>Missense ATC CAT V616I G1846A GTC>Missense ATC CAT V616I G1846A GTC>Missense ATC CAT V616I G1846A GTC>Missense ATC CAT V616I G1846A GTC>Missense ATC -- 1850-1859- - no-SNVdelfrshift CGC H617R A1850G CAC>Missense CGC -- 1853-1854- - no-SNVdelfrshift TGT I619M A1857G ATA>Missense ATG AAT L620I T1858A TTA>Missense ATA CAT R621H G1862A CGT>Missense CAT CGA Q622R A1865G CAA>Missense CGA CCG - - - Essential_Splice -- 1887-1889- - no-SNVdelinframe TF ENSP0000 3 13377 T TA 1 - - - - - 1891-1892- - no-SNVinsfrshift -- 1904-1904- - no-SNVdelfrshift GAG G636S G1906A GGC>Missense AGC TAT C639Y G1916A TGT>Missense TAT -- 1921-1921- - no-SNVdelfrshift CTG R642W C1924T CGG>Missense TGG CAG R642Q G1925A CGG>Missense CAG TAA F650L C1950A TTC>Missense TTA TAA F650L C1950A TTC>Missense TTA TAA H661N C1981A CAT>Missense AAT AGC N664S A1991G AAC>Missense AGC AGA T665R C1994G ACA>Missense AGA TGT Y666C A1997G TAT>Missense TGT -- 2003-2007- - no-SNVdelfrshift ACA Y669H T2005C TAC>Missense CAC -- 2009-2019- - no-SNVdelfrshift AAG G671R G2011A GGA>Missense AGA -- 2012-2022- - no-SNVdelfrshift -- 2013-2015- - no-SNVdelinframe TF ENSP0000 3 13377GAGAAGAATAG 1 - - 2013-2026- - no-SNVdelfrshift -- 2015-2018- - no-SNVdelfrshift -- 2022-2030- - no-SNVdelinframe -- 2025-2035- - no-SNVdelfrshift -- 2046-2047- - no-SNVinsfrshift TAC C684Y G2051A TGC>Missense TAC TTC S685F C2054T TCC>Missense TTC CGC L689R T2066G CTC>Missense CGC CCG L690P T2069C CTG>Missense CCG AAC A692T G2074A GCC>Missense ACC TTC C693F G2078T TGC>Missense TTC CGC T694A A2080G ACT>Missense GCT -- 2081-2084- - no-SNVdelfrshift -- 2080-2081- - no-SNVinsfrshift -- 2096-2096- - no-SNVdelfrshift -- 360-362- - no-SNVdelinframe -- 522-522- - no-SNVdelfrshift -- 1525-1525- - no-SNVdelfrshift -- 1732-1733- - no-SNVdelfrshift TF ENSP0000 3 13377 G T 1 G T TGA TTA E579* G1735T GAG>Nonsense TAG -- 1772-1772- - no-SNVdelfrshift AGG Y593* T1779G TAT>Nonsense TAG CGG R600G A1798G AGA>Missense GGA CAT V616I G1846A GTC>Missense ATC CTA H617Y C1849T CAC>Missense TAC TCG L670F A2010C TTA>Missense TTC -- 2096-2096- - no-SNVdelfrshift TGA K101E A301G AAA>Missense GAA -- 254-255- - no-SNVdelfrshift CGT F62V T184G TTC>Missense GTC CTC P61L C182T CCC>Missense CTC TGG S11G A31G AGT>Missense GGT TGC Y60C A179G TAC>Missense TGC ATA Q20* C58T CAA>Nonsense TAA -- 403-415- - no-SNVdelfrshift TTA K133* A397T AAG>Nonsense TAG -- 357-357- - no-SNVdelfrshift TAA S108* C323A TCA>Nonsense TAA TCA L104S T311C TTA>Missense TCA UBE2 ENSP00004 10279 G A -1 C T TCT TTT L103F C307T CTT>Missense TTT ATA T98I C293T ACA>Missense ATA TAT L89I C265A CTA>Missense ATA GAC C85* T255A TGT>Nonsense TGA ACT N77T A230C AAT>Missense ACT AGA N77D A229G AAT>Missense GAT AGG R72G A214G AGA>Missense GGA AGC T71A A211G ACA>Missense GCA GCT V67A T200C GTT>Missense GCT ATT - - - Essential_Splice GAC - - - Essential_Splice TGC Y60C A179G TAC>Missense TGC -- 150-152- - no-SNVdelinframe GAT G48D G143A GGT>Missense GAT GAC G47D G140A GGC>Missense GAC AAT - - - Essential_Splice GAG G39R G115A GGA>Missense AGA GCA - - - Essential_Splice AAT - - - Essential_Splice -- 83-83- - no-SNVdelfrshift GGA - - - Essential_Splice UBE2 ENSP00004 10279 A C 1 T G CTA CGA Y127D T379G TAT>Missense GAT AAA AGA N77D A229G AAT>Missense GAT TAC TGC Y60C A179G TAC>Missense TGC AAT AGT N41S A122G AAT>Missense AGT CAG CGG - - - Essential_Splice E ““ ng of each Ensembl gene ID as indicated.“ of each gene as indicated. “ ed position. “ 1”) of the indicated gene.“ resulting from the transcription of unmutated or mutated DNA sequence,r“ utated nucleotides, respectively, at the indicated positions are present.“ om the indicated nucleotide and transcribed mRNA mutation, relative to thea“ no acid is the final C-terminal amino acid in the produced protein.“ mRNA, resulting from transcription of the mutated DNA sequence, relative to th “ “““ ation. siRNA Therapeutics Therapeutic strategies involving RNA interference (RNAi) mechanisms are well known in the art. For example, small interfering RNAs (siRNAs; also known as silencing RNAs) reduce / prevent the translation of mRNAs to which they bind by promoting their degradation. siRNAs have complementary sequences to the mRNAs to which they bind, often to regions of the mRNA outside of the translated coding sequence (e.g. in the untranslated regions, including the 5’UTR and 3’UTR) but also sometimes within the translated region. They are short (usually 20-40 base pairs in length) double stranded RNA (dsRNA) sequences, with phosphorylated 5’ ends and hydroxylated 3’ ends with two overhanging nucleotides. Thus, “siRNA” and “dsRNA” may be used interchangeable herein. Natural endogenous siRNAs are produced from long double stranded RNAs and small hairpin RNAs by the Dicer endoribonuclease. Synthetic or exogenous siRNAs can be transfected into cells or administered by gene therapy techniques such as adeno-associated virus (AAV) or liposome delivery vectors. Suitable delivery methods and vectors are known in the art and will be readily recognised by the skilled person. The delivery method and / or vector may also be dependent on the chosen administration route as described further herein. After processing by Dicer (for naturally produced siRNAs) or introduction of synthetic / exogenous siRNA into cells, the siRNA is incorporated into the RNA-induced Silencing Complex (RISC; a multimeric nucleic acid- protein complex) in which it is unwound to form single stranded siRNA. The single stranded RNA that is part of the RISC is then used to scan for and bind complementary mRNA sequences. Upon recognition and binding, the siRNA induces cleavage of the mRNA molecule by proteins within RISC. Thus, by degrading recognised and bound mRNA, expression of the gene is reduced / silenced. In certain embodiments, the siRNA according to the methods herein is complementary in sequence to mRNAs generated from the genes described herein comprising the described somatic mutations. That is, the siRNA may have a sequence complementary to mRNAs of the mutated gene sequence but not the unmutated or wild type gene sequence. Thus, in one embodiment the siRNA administered to the subject herein comprises a sequence that is complementary to a region of the DNA comprising the somatic mutation. In a further embodiment, the siRNA comprises a sequence that is complementary to the mRNA sequence produced from a region of the DNA comprising the somatic mutation (e.g. any of the regions comprising mutations listed in Table 1). Thus, according to this embodiment the siRNA may have the sequence of the region of DNA comprising the somatic mutation. In another embodiment, the siRNA comprises a sequence that is complementary to a region of the mRNA sequence produced from the DNA comprising the somatic mutation (e.g. any of the somatic mutations listed in Table 1). In yet further embodiments, the siRNA comprises a sequence complementary to any of the mutated sequences listed in Table 1. In particular, the siRNA may be complementary to a region of an mRNA produced by any of the genes comprising somatic mutations as listed in Table 1, wherein the region of the mRNA comprises the mutation. In still further embodiments, the siRNA comprises a sequence complementary to the mutated mRNA sequence as listed in Table 1. In particular, the siRNA may be complementary to the region of the mRNA comprising the mutation as listed in Table 1. In alternative embodiments, the siRNA may have a sequence complementary to regions mRNAs of the herein described genes or regions of said genes which are unmutated. However, as will be readily appreciated, according to these embodiments the presence of the mutation must be detected in the DNA of the gene in order for a therapeutic effect to be achieved. Thus, in one embodiment the siRNA administered to the subject herein comprises a sequence that is complementary to a region of the DNA other than the region comprising the somatic mutation. In a further embodiment, the siRNA comprises a sequence that is complementary to the mRNA sequence produced from a region of the DNA other than the region comprising the somatic mutation. In another embodiment, the siRNA comprises a sequence that is complementary to a region of the mRNA sequence produced from the DNA comprising the somatic mutation (e.g. any of the somatic mutations listed in Table 1). For example, the siRNA may be complementary to a region of an mRNA produced by any of the genes comprising somatic mutations as listed in Table 1, wherein the region of the mRNA does not comprise the mutation. Administration of the siRNA may be systemically, e.g. enteral or parenteral, such as via intravenous infusion, or locally, such as directly into the tissue or organ affected by MASH, i.e. the liver, such as by topical administration. Suitable formulation of the siRNA for the chosen route of administration will be readily identified by the skilled person. In other embodiments, the siRNA may be administered singly or in combination with one or more therapeutic agent, such as those currently used as standard of care for MASH and / or for the control of obesity and / or diabetes as required by the subject. Such combined administration may be concurrently or sequentially as suitably determined by the skilled practitioner. In a further aspect of the invention, there is provided an siRNA molecule comprising a sequence complementary to an mRNA transcribed from any one of the genes comprising one or more somatic mutations as described herein. According to this aspect, the siRNA molecule has a sequence that is complementary to mRNAs transcribed from the mutated gene sequence but not from the unmutated or wild type gene sequence. Thus, in one embodiment the siRNA molecule comprises a sequence that is complementary to a region of the DNA comprising the somatic mutation. In a further embodiment, the siRNA molecule comprises a sequence that is complementary to a region of the mRNA sequence produced from the DNA comprising the somatic mutation (e.g. any of the somatic mutations listed in Table 1). Thus, according to this embodiment the siRNA may comprise the sequence of the region of the DNA comprising the somatic mutation (which will be understood to be complementary to the mRNA sequence). In yet further embodiments, the siRNA molecule comprises a sequence complementary to any of the mutated sequences listed in Table 1. In particular, the siRNA may be complementary to a region of an mRNA produced by any of the genes comprising somatic mutations as listed in Table 1, wherein the region of the mRNA comprises the mutation. In still further embodiments, the siRNA molecule comprises a sequence complementary to the mutated mRNA sequence as listed in Table 1. In particular, the siRNA may be complementary to the region of the mRNA comprising the mutation as listed in Table 1. Accordingly, in one aspect provided herein are double stranded ribonucleic acid (dsRNA) agents for inhibiting expression of one or more genes selected from fatty acid synthase (FASN), APOBEC1 complementation factor (A1CF), Krüppel-like factor 15 (KLF15), serotransferrin (TF), cytochrome P4502E1 (CYP2E1), cyclin-dependent kinase inhibitor 1B (CDKN1B), PCF11 cleavage and polyadenylation factor subunit (PCF11), ubiquitin- conjugating enzyme E2 D3 (UBE2D3), eukaryotic elongation factor 2 (EEF2); and / or serine protease hepsin (HPN), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises at least 15 (e.g.16, 17, 18, 19, 20, 21, 22 or 23) contiguous nucleotides of and differing by no more than 3 (e.g. 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any mRNA sequence represented by the cDNA sequences set forth in Table 2 or set forth in any one of SEQ ID NOs: 1 to 59. In some embodiments, the sense strand comprises at least 15 (e.g.16, 17, 18, 19, 20 or 21) contiguous nucleotides of and differing by no more than 3 (e.g.0, 1, 2 or 3) nucleotides from any nucleotide sequence of any mRNA sequence represented by the cDNA sequences set forth in Table 2 or set forth in any one of SEQ ID NOs: 1 to 59. In some embodiments, each of the antisense strand and the sense strand are not more than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16 or 15 nucleotides in length. In some embodiments, the antisense strand comprises from about 15 to 30, 16 to 30, 17 to 30, 18 to 30, 19 to 3020 to 30, 21 to 30, 22 to 30, 23 to 30, 24 to 30, 25 to 30, 36 to 30, 27 to 30, 28 to 30, 29 to 30, 19 to 20, 19 to 21, 19 to 22, 19 to 23, 19 to 24 or 19 to 25 nucleotides; and / or the sense strand comprises from about 15 to 30, 16 to 30, 17 to 30, 18 to 30, 19 to 30 20 to 30, 21 to 30, 22 to 30, 23 to 30, 24 to 30, 25 to 30, 36 to 30, 27 to 30, 28 to 30 to , 29 to 30, 19 to 20, 19 to 21, 19 to 22, 19 to 23, 19 to 24 or 19 to 25 nucleotides. In further embodiments, antisense strand comprises from about 19 to 23 nucleotides; and / or the sense strand comprises from about 19 to 23 nucleotides. In yet further embodiments, the antisense strand comprises or consists of about 23 nucleotides; and / or the sense strand comprises or consists of about 21 nucleotides. In some embodiments, the sense strand and / or the antisense strand comprises a 3′ and / or 5′ overhang of 1, 2 or 3 nucleotides. In further embodiments, the antisense strand comprises a 3′ overhang of 1, 2 or 3 nucleotides (e.g.2 nucleotides). In some embodiments, the double stranded region is from about 19 to 30, 19 to 29, 19 to 28, 19 to 27, 19 to 26, 19 to 25, 19 to 24, 19 to 23, 19 to 22, 19 to 20, 19 to 21, 23 to 30, 23 to 29, 23 to 28, 23 to 27, 23 to 26, 23 to 25, 23 to 24, 21 to 30, 21 to 29, 21 to 28, 21 to 27, 21 to 26, 21 to 25, 21 to 24, 21 to 23 or 21 to 22 nucleotide pairs in length. In further embodiments, the double stranded region is from about 19 to 23 or 19 to 21 nucleotide pairs in length. In yet further embodiments, the double stranded region is about 21 nucleotide pairs in length. In some embodiments, the sense strand and the antisense strand are part of a single nucleic acid molecule (e.g. wherein a hairpin loop is between the sense strand and the antisense strand of the single nucleic acid molecule. In alternative embodiments, the sense strand and the antisense strand are separate nucleic acid molecules (i.e. connected only through the double stranded region). In one aspect, provided herein are dsRNA molecules for inhibiting, reducing and / or preventing the expression of one or more genes selected from: fatty acid synthase (FASN), APOBEC1 complementation factor (A1CF), Krüppel-like factor 15 (KLF15), serotransferrin (TF), cytochrome P4502E1 (CYP2E1), cyclin-dependent kinase inhibitor 1B (CDKN1B), PCF11 cleavage and polyadenylation factor subunit (PCF11), ubiquitin-conjugating enzyme E2 D3 (UBE2D3), eukaryotic elongation factor 2 (EEF2); and / or serine protease hepsin (HPN), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, and wherein the antisense strand comprises at least 15 (e.g.16, 17, 18, 19, 20, 21, 22 or 23) contiguous nucleotides of and differing by no more than 3 (e.g.0, 1, 2 or 3) nucleotides from the nucleotide sequence of any mRNA sequence represented by the cDNA sequences set forth in Table 2 or set forth in any one of SEQ ID NOs: 1 to 59; and / or wherein the sense strand comprises at least 15 (e.g. 16, 17, 18, 19, 20, 21, 22 or 23) contiguous nucleotides of and differing by no more than 3 (e.g.0, 1, 2 or 3) nucleotides from the nucleotide sequence of any mRNA sequence represented by the cDNA sequences set forth in Table 2 or set forth in any one of SEQ ID NOs: 1 to 59. Thus, in further embodiments the dsRNA molecule comprises an antisense strand and / or a sense strand comprises at least 15 (e.g. 16, 17, 18, 19, 20, 21, 22 or 23) contiguous nucleotides complementary to and mismatching by no more than 3 (e.g. 0, 1, 2 or 3) nucleotides from the nucleotide sequence of any mRNA sequence represented by the cDNA sequences set forth in Table 2 or set forth in any one of SEQ ID NOs: 1 to 59. In some embodiments, the dsRNA comprises a targeting moiety, for example and without limitation GalNac. Suitable targeting moieties will be readily recognised by the skilled person and may be selected based on the target gene and, for example the cell type in which it is expressed. In a particular example of the present invention, the targeting moiety may recognise a marker of the liver, such as a marker expressed by a liver cell, thus targeting the dsRNA / siRNA to the liver and liver cells expressing the herein described genes. Non-siRNA Therapeutics According to another aspect of the invention, there is provided a method of treating metabolic dysfunction-associated steatohepatitis (MASH) in a subject, the method comprising steps of: (i) isolating and purifying DNA from a sample obtained from the subject; (ii) detecting the presence or absence of a somatic mutation in the DNA of one or more gene selected from: fatty acid synthase (FASN); APOBEC1 complementation factor (A1CF); Krüppel-like factor 15 (KLF15); serotransferrin (TF); cytochrome P4502E1 (CYP2E1); cyclin-dependent kinase inhibitor 1B (CDKN1B); PCF11 cleavage and polyadenylation factor subunit (PCF11); ubiquitin-conjugating enzyme E2 D3 (UBE2D3); eukaryotic elongation factor 2 (EEF2); and serine protease hepsin (HPN), and (iii) administering to the subject a therapeutic intervention of Table 3 if a somatic mutation is present in the DNA of the specified gene. Table 3: MASH Therapeutics / Interventions Thus, in some embodiments the method described herein may comprise administering a non- siRNA therapeutic. Suitable non-siRNA therapeutics for the treatment of MASH wherein the somatic mutation is located in the indicated gene are described herein. These include denifanstat, BI 99179, Cerulenin, orlipastat, orlistat, tetrahydrolipstatin, rifampicin / isoniazid / pyrazinamide and / or pyrazinamide wherein the mutation is present in the FASN gene; oligonucleotides as described in WO 2022 / 038211 (the sequences of which are specifically incorporated by reference) wherein the mutation is present in the A1CF gene; triptolide, ML264 and / or Tenovin-6 wherein the mutation is present in the KLF15 gene; pladienolide B, herboxidiene, THZ1 and / or SJ-1008066 wherein the mutation is present in the PCF11 gene; Q11, diallyl sulfide (DAS), PPC and / or fomepizole wherein the mutation is present in the CYP2E1 gene; toosendanin, A484954 and / or NH125 wherein the mutation is present in the EEF2 gene; bentiromide wherein the mutation is present in the HPN gene; and iron chelators, deferasirox, deferiprone, pyridoxal isonicotinoyl hydrazone, gallium nitrate, Dp44mT, ferristatin, transferrin aldifitox (Rec INN) an / d / or transferrin CRM-107 wherein the mutation is present in the serotransferrin (TF) gene. Wherein mutations are detected in multiple genes, the herein described non-siRNA therapeutics may be combined as appropriate, including with one or more siRNA therapeutic as described hereinbefore. It will be appreciated that references herein to a patient or subject relate equally to animals and humans and that the invention finds particular utility in veterinary treatment of any of the above mentioned diseases, disorders and conditions which are also present in said animals. Thus, in some embodiments the subject is a human subject. In other embodiments, the subject is a non-human animal, such as a non-human primate or a rodent. It will also be appreciated that references herein to “treatment” and “amelioration” include such terms as “prevention”, “reversal” and “suppression”. Such references include administration of the siRNA molecule as defined herein prior to the onset of MASH, e.g. wherein the subject is at risk of MASH. Administration of the siRNA as defined herein may also be anticipated after the onset of MASH (i.e. after the subject has been diagnosed with MASH according to the methods described herein), either before clinical presentation or after symptoms manifest. Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs. As may be used herein, the term “about” includes up to and including 10% greater and up to and including 10% lower than the value specified, suitably up to and including 5% greater and up to and including 5% lower than the value specified, especially the value specified. The term “between” as may be used herein includes the values of the specified boundaries. Throughout the specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations thereof such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not to the exclusion of any other integer, step, group of integers or group of steps. In addition, as used herein and the appended claims, the singular forms “a”, “an” and “the” include plural referents, and vice versa, unless the content clearly dictates otherwise. Thus, for example references to “a sample” may include two or more such samples and references to “an / a siRNA” and “an / a siRNA molecule” may include two or more such siRNAs. It will be understood that all embodiments described herein may be applied to all aspects of the invention and vice versa, and such combinations would be readily apparent from the description provided herein and to those skilled in the art. Other features and advantages of the present invention will be apparent from the description provided herein. It should be understood, however, that the description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications will become apparent to those skilled in the art.

[0003] Ta DetectedGeneFASN CGCCGCGCTTCAGCCTCCCGCTCCGCCGCGCTCCAGCCTCGCTCCAGCCATGGAGGAGGTGGTGATTGCCGGCATGTCCGGGAAGCTG CATCGGCGGTGTGGACATGGTCACGGACGATGACCGTCGCTGGA GCTGAAGGACCTGTCTAGGTTTGATGCCTCCTTCTTCGGAGTCCA TGCTGCTGGAAGTCACCTATGAAGCCATCGTGGACGGAGGCATC GGTGGGCGTGAGCGGCTCTGAGACCTCGGAGGCCCTGAGCCGAG CAGCGAGCGATGATGGCCAACCGGCTCTCCTTCTTCTTCGACTTC CAGCCTGATGGCCCTGCAGAACGCCTACCAGGCCATCCACAGCG CTGCTGAAGCCCAACACCTCCGTGCAGTTCTTGAGGCTGGGGAT CGGGGAATGGGTACTGCCGCTCGGAGGGTGTGGTGGCCGTCCT ACCATCCTGAACGCCGGCACCAATACAGATGGCTTCAAGGAGCAA CATCCGCTCGTTGTACCAGTCGGCCGGAGTGGCCCCTGAGTCATT GCGACCCCCAGGAGCTGAATGGCATCACCCGAGCCCTGTGCGCC CAACATGGGGCACCCGGAGCCAGCCTCGGGGCTGGCAGCCCTG CCCCCAACCTGCACTTCCATAGCCCCAACCCTGAGATCCCAGCGC GCCCGTCCGTGGCGGCAACGTGGGCATCAACTCCTTTGGCTTCGG AGCCGCCCCCCGCACCCGCCCCACATGCCACCCTGCCCCGTCTG AGCTGCTGGAGCAGGGCCTCCGGCACAGCCAGGACCTGGCTTTC CGCCATGCCCTTCCGTGGCTACGCTGTGCTGGGTGGTGAGCGCG CCCGCTCTGGTTCATCTGCTCTGGGATGGGCACACAGTGGCGCG GATTCCATCCTACGCTCCGATGAGGCTGTGAAGCCATTCGGCCT CCTTTGATGACATCGTCCATTCGTTTGTGAGCCTGACTGCCATCCA GGCCAGATGGCATCGTCGGCCACTCCCTGGGGGAGGTGGCCTGT TCCTCGCTGCCTACTGGAGGGGACAGTGCATCAAAGAAGCCCATC GGAGGAGTGTAAACAGCGCTGCCCCCCGGGCGTGGTGCCCGCCT CTCAGGCCCCGGTGTTTGAGTTCGTGGAGCAGCTGAGGAAGGAGGG CTTCCACTCCTACTTCATGGAGGCCATCGCACCCCCACTGCTGCAGG CAGCCCGCTGGCTCAGCACCTCTATCCCCGAGGCCCAGTGGCACAG CAACAACCTGGTGAGCCCTGTGCTGTTCCAGGAGGCCCTGTGGCAC CCACGCCCTGCTGCAGGCTGTCCTGAAGCGTGGCCTGAAGCCGAGC GACAACCTGGAGTTCTTCCTGGCCGGCATCGGCAGGCTGCACCTCTC TGTGGAGTTCCCAGCTCCCCGAGGAACTCCCCTCATCTCCCCACTCA GCCGCCGAGGACTTCCCCAACGGTTCAGGTTCCCCCTCAGCCGCCAT CTACCTGGTGGACCACACCCTCGACGGTCGCGTCCTCTTCCCCGCCA GCGCCCTGGGCCTGGGCGTCGAGCAGCTGCCTGTGGTGTTTGAGGA TGGGACAGTGTCCCTGGAGGTACGGCTCCTGGAGGCCTCCCGTGCC GGGAAGGTGTACCAGTGGGATGACCCTGACCCCAGGCTCTTCGACC CTCTTCCTGGCCCAGGCTGAAGTTTACAAGGAGCTGCGTCTGCGTGG GGCCAGCCTGGAAGGTGACTCGGGGAGGCTGCTGTGGAAGGATAAC ATCCTGGGCTCGGCCAAGCACGGCCTGTACCTGCCCACCCGTGTCAC GCTGTACACACTGCAGGACAAGGCCCAAGTGGCTGACGTGGTGGTG CCACATCTCCGGGCTCCACACTGAGTCGGCCCCGCGGCGGCAGCAG ACTCCCCACACGGAGGAGGGGTGCCTGTCTGAGCGCGCTGCCCTGC GCACTGCAGACCAAGGTGACCCAGCAGGGGCTGAAGATGGTGGTGC TCACAGCAGGAACTGCCCCGGCTGTTGTCGGCTGCCTGCAGGCTTCA TGCTGGCCCAGGAGAGGCCCAAGCTGCCAGAGGACCCTCTGCTCAG GGACACTGCCGTGGAGAACATGCCCAGCCTGAAGATGAAGGTGGTG ATCCCAGGCCTGCTCAGCCCCCATCCCCTGCTGCAGCTGAGCTACA GCCCAGGCCGAGCTGCAGCAGCACGACGTTGCCCAGGGCCAGTGG CGCCGACCTCCTGGTGTGCAACTGTGCTGTGGCTGCCCTCGGGGAC AGAGAAGGGGGCTTTCTGCTCCTGCACACACTGCTCCGGGGGCACC AGCCGCAGTATGGCCAGGGCATCCTGAGCCAGGACGCGTGGGAGAG GAAGAAGTCCTTCTACGGCTCCACGCTCTTCCTGTGCCGCCGGCCCA GATACCAGCTTCCGCTGGGTGGAGTCTCTGAAGGGCATCCTGGCTGA CAACTGTGCCACCTCGGGCGTGGTGGGCTTGGTGAACTGTCTCCGC GCTCTCCAACCTCAGCAGCACCTCCCACGTCCCGGAGGTGGACCCG CTGGTGATGAACGTCTACCGCGACGGGGCCTGGGGGGCTTTCCGC ACGGCACATGCCTTTGTGAGCACCCTCACCCGGGGGGACCTGTCCT AGCCCACCTGCCCTGGCGCCCAGCTCTGCACGGTCTACTACGCCTC CTGTCCCCTGATGCCATCCCAGGGAAGTGGACCTCCCAGGACAGCC GCAAGCGTGTGATGGGACTGGTGCCTGCCAAGGGCCTGGCCACCTC TCCAACTGGACGCTGGAGGAGGCGGCCTCGGTGCCTGTCGTCTACA GTGCGCCCCGGGGAGACGCTGCTCATCCACTCGGGCTCGGGCGGC GGCTGCCGCGTCTTCACCACCGTGGGGTCGGCTGAGAAGCGGGCG AGCTTCGCCAACTCCCGGGACACATCCTTCGAGCAGCATGTGCTGTG CTCCTTGGCGGAAGAGAAGCTGCAGGCCAGCGTGAGGTGCTTGGCT TTTCTCAGAACCACCCGCTCGGCATGGCTATCTTCCTGAAGAACGTG AGAGCAGTGCTGACTGGCGGGAGGTGTGGGCGCTTGTGCAGGCCG CGGTGTTCCATGGGGCCCAGGTGGAGGACGCCTTCCGCTACATGGC GCTTGCGGAGGAGCCGGAGGCAGTGCTGAAGGGGGCCAAACCCAA CCACAAGAGCTACATCATCGCTGGTGGTCTGGGTGGCTTCGGCCTGG AGCTCGTGTTGACTTCTCGCTCCGGGATCCGGACAGGCTACCAGGC AGGTGCAGGTGTCCACCAGCAACATCAGCTCACTGGAGGGGGCCCG TGGGCGGCGTCTTCAACCTGGCCGTGGTCTTGAGAGATGGCTTGCTG AAGCCCAAGTACAGCGGCACCCTGAACCTGGACAGGGTGACCCGAG CTCTGTGAGCTGCGGGCGTGGCAATGCGGGACAGAGCAACTACGG CGCCGGCACGAAGGCCTCCCAGGCCTGGCCGTGCAGTGGGGCGCC ACCAACGACACGATCGTCAGTGGCACGCTGCCCCAGCGCATGGCGT CCCACATGGTCCTGAGCAGCTTTGTGCTGGCTGAGAAGGCTGCGGC GGCCGTGGCACACATCCTGGGCATCCGCGACTTGGCTGCTGTCAAC CTCATGAGCGTGGAGGTGCGCCAGACGCTGGAGCGTGAGCTCAAC CTCCGGAAACTGCAGGAGCTGTCCTCAAAGGCGGATGAGGCCAGCG CCCAGCAGCAGACTCAGCTGAACCTGCGCTCCCTGCTGGTGAACCC AGCTCGGAGCGGCCCCTGTTCCTGGTGCACCCAATCGAGGGCTCC CCCCACCTATGGCCTGCAGTGCACCCGAGCTGCGCCCCTTGACA AGGCAGGTGCAGCCCGAGGGCCCCTACCGCGTGGCCGGCTACTC TGCAGGCCCAGCAGAGCCCAGCCCCCACCCACAACAGCCTCTTC CCAGAGCTACCGGGCAAAGCTGACCCCAGGCTGTGAGGCTGAGG ACGGACATGGAGCACAACAGGGTGCTGGAGGCGCTGCTGCCGCT CTGATCATCAAGAGCCACCAGGGCCTGGACCGCCAGGAGCTGAG CTGAGCAGTACACACCCAAGGCCAAGTACCATGGCAACGTGATGC CCTGGGCGCGGACTACAACCTCTCCCAGGTATGCGACGGGAAAG GCTGGAGGGCAGCGGCCTGGAGTCCATCATCAGCATCATCCACAG TAGGCCCGTGCCCCCGCCTGCCACCGGAGGTCACTCCACCATCC TTGAAGGGTCCTGCCGGTGGGACCCTGTCCGGCCCAGTGCCACTG CACCCACCCGCCGCCTCCCACGGCACCTCGGGGACACCAGAGCT GTGCCCGTGCCCGCAGGAACTGGGCTGGGCCTCGTGCGCCCGTG TTATTGCATTGCTGGTAGAGACCCCCAGGCCTGTCCACCCTGCCA CCCATTTCCCCGATGTCCCCTGCGGGCGCGGGCAGCCACCCAAGC CAGCCCGCTGAGTGGGGGGTCGTGGGCCAGTCCCCGAGGAGCTG GCGGCCCCCCGCACAGCCACCCGTGGGGTGCTGCCCTTATGCCC GTTTGTTTTTCAAGAAATGATTCAAATTGCTGCTTGGATTTTGAAATT TTTTTACACCAATTTGGTAAAAATGCTGCTCTCAGCCTCCCACAATTFASN CGCCCGCACCGCCGCCCGCGCCCTCACCAGAGCAGCCATGGAGGGTCGGAGAACTTGCAGGAGTTCTGGGACAACCTCATCGGCGGTGT GGGCTCTACGGCCTGCCCCGGCGGTCCGGCAAGCTGAAGGACCT AGCAGGCACACACGATGGACCCTCAGCTGCGGCTGCTGCTGGAAG GATTCACTCCGAGGAACACACACTGGCGTCTGGGTGGGCGTGAG GAGACACTCGTGGGCTACAGCATGGTGGGCTGCCAGCGAGCGAT GGCCCAGCATCGCACTGGACACAGCCTGCTCCTCCAGCCTGATGG TGCCGCCATCGTGGGGGGCATCAATGTCCTGCTGAAGCCGAGGGCACCTGCAAGGCCTTCGACACAGCGGGGAATGGGAGTCCCTGGCCCGGCGGGTGTACGCCACCATCCTGAACGCCCCTCAGGGGATATCCAGGAGCAGCTCATCCGCTCGTTG AGCCCACGGCACAGGCACCAAGGTGGGCGACCCCCAGG GCCGCTGCTCATCGGCTCCACCAAGTCCAACATGGGGCAGCTGTCCCTGGAGCACGGGCTCTGGGCCCCCAACCTGCACGGCTGCAGGTGGTGGACCAGCCCCTGCCCGTCCGTGGCTGCACATCATCCTGAGGCCCAACACGCAGCCGCCCCCCG CGGACGCACCCCTGAGGCCGTGCAGAAGCTGCTGGAGCGAACGACATCGCGGCTGTCCCCGCCACCGCCATGCCCTTGGTGCAGCAGGTGCCCGCTGGCGAGCGCCCGCTCTGGTT AGCCTCATGCGCCTGGACCGCTTCCGAGATTCCATCCTAAGCTGCTGCTGAGCACAGACGAGAGCACCTTTGATGACATTAGACCTGCTGAGCTGCATGGGGCTGAGGCCAGATGGCA CGGCTGCCTGTCCCAGGAGGAGGCCGTCCTCGCTGCCT CGCCATGGCAGCCGTGGGCTTGTCCTGGGAGGAGTGTAA AAGGACACAGTCACCATCTCGGGACCTCAGGCCCCGGTG GGAGGTGCGGACCGGCGGTATGGCCTTCCACTCCTACTTGTGATCCGGGAGCCGAAGCCACGTTCAGCCCGCTGGCTCGCACGTCCTCCGCCGAGTACAATGTCAACAACCTGGTGACGCGGTGGTGCTGGAGATCGCGCCCCACGCCCTGCTGCCCCCCTGATGAAGAAGGATCACAGGGACAACCTGGAGTTCCCAACCCCAATGCCTTGTTCCCACCTGTGGAGTTCCCAGC ACAGCCTGGCCTGGGACGTGCCGGCCGCCGAGGACTTC CACCAGCTCCGAGTCTCCTGACCACTACCTGGTGGACCAAGCATAGTGTGGAAGACGCTGGCCCGCGCCCTGGGCCTGACCAGGCCACCATCCTGCCCAAGACTGGGACAGTGTCCCAGAGAACGGCAACCTGGTAGTGAGTGGGAAGGTGTACCA GAAAGCCCCACCCCCAACCCCACGGAGCCCCTCTTCCTGGCCCAG CTACGGCCCTCATTTCCAGGGCATCCTGGAGGCCAGCCTGGAAGGAGCTTCATGGACACCATGCTGCAGATGTCCATCCTGGGCTCGGCATCCACATCGACCCTGCCACCCACAGGCAGAAGCTGTACACACTGC GTGGCTGAGGGTCACAGTGGCCGGAGGCGTCCACATCTCCGGGC GCAGGTGCCCATCCTGGAGAAGTTTTGCTTCACTCCCCACACGGA GAGCTGCAACTGTGCAAGGGGCTGGTGCAGGCACTGCAGACCAA CTGGATGGGGCCCAGATCCCCCGGGACCCCTCACAGCAGGAACTAACGGGAACCTGCAGCTGGAGCTGGCGCAGGTGCTGGCCCAGGA CTCCTGGACTCCCCGGCACTCAAGGCCTGCCTGGACACTGCCGTGCTGGCCACGGTCACCTGTATTCCCGCATCCCAGGCCTGCTCAGCCCCGCCACCCCCAGGCCCTGGAGGCTGCCCAGGCCGAGCTGCAGC CCCTGCCCCCAGCGCCCTGGGCAGCGCCGACCTCCTGGTGTGCATCTCAGCAACATGGTGGCTGCCCTGAGAGAAGGGGGCTTTCTGCT ATCGTGGCCTTCCTCACCTCCACTGAGCCGCAGTATGGCCAGGGCGGGTGTCGCTGCGCCTGGTGGGCCTGAAGAAGTCCTTCTACGGCTCAGCCCCATCTTCCTGCCGGTGGACGATACCAGCTTCCGCTGGGT CCCGGCCTGTGTGGCTGAAGGCCATCAACTGTGCCACCTCGGGCGCGGGAACCGCCTCCGGTGTGTGCTGCTCTCCAACCTCAGCAGCA ACTGCAGAAGGTGTTGCAGGGAGACCTGGTGATGAACGTCTACCGGAGGAGGACAAGCCTGAGGAGCCGACGGCACATGCCTTTGTGAGGTCTGCTCCTCGCTGCGCCATGCCCAGCCCACCTGCCCTGGCGCCCGACATCATGCTGGCCACTGGCAAGCTGTCCCCTGATGCCATCCCGAGTTCTCGGGCCGAGACGCCAGCGGCAAGCGTGTGATGGGACTGCACCGGACTTCCTCTGGGATGTGCCTTCCAACTGGACGCTGGAGGATACGCGCTGGTGGTGCGTGGGCGGGTGCGCCCCGGGGAGACGCT GCCATCGCCATCGCCCTCAGTCTGGGCTGCCGCGTCTTCACCACC GGTTCCCCCAGCTCGACAGCACCAGCTTCGCCAACTCCCGGGACAGAAGGGCGTTGACCTGGTCTTGAACTCCTTGGCGGAAGAGAAGCT GGAAATTGGCAAATTCGACCTTTCTCAGAACCACCCGCTCG ACTGGATGCGTTCTTCAACGAGAGCAGTGCTGACTGGCGGGGTACGGCCCCTCAAGTGCACGGTGTTCCATGGGGCCCAGGGCAAAGTCGTCGTGCAGGTGCTTGCGGAGGAGCCGGAGGCCAAGACCTTCTGCCCGGCCCACAAGAGCTACATCATCGCTGATACAGCGTGGGGTGCAGAAGCTCGTGTTGACTTCTCGCTTGGAGGCGCCAGGGCGTACAGGTGCAGGTGTCCACCAGCAGCGGCGCAGCTTGGGCCCGTGGGCGGCGTCTTCAACCTGGAGTTCTTCCAGGACGTCTGCAAGCCCAAGTACAGCGGCACC GACTACTTTGTGGTCTTCTCCTCTGTGAGCTGCGGGCGTGTGGAGCGTATCTGTGAGAAACGCCGGCACGAAGGCCTCCC TTTTGGTGGAGACGATGAGCACCAACGACACGATCGTCAGTGGACCTCTTCCTGAACCAGCCCCACATGGTCCTGAGCAGCT GCCAGCGGGACCTGGTGGAGGCCGTGGCACACATCCTGGCGGACCTGGGCCTGGACTCGCTCATGAGCGTGGAGGTGCG CGAGGTGCGGCAACTCACGCTCCGGAAACTGCAGGAGCTG CCCAAGGAGGATGGTCTGGCCCAGCAGCAGACTCAGCTGA TGCGGCTCAACTCCGTGCAGAGCTCGGAGCGGCCCCTGTTCCTGGCCTCCCGGCTCAGCATCCCCACCTATGGCCTGCAGT CCTACTACATCGACTGCATCAGGCAGGTGCAGCCCGAGGGCCTTTGAAATGTGCTCCCAGCTGCAGGCCCAGCAGAGCCCAACCTACGTACTGGCCTACACCCAGAGCTACCGGGCAAAGCT CTTCTTCGTGCAGCAGTTCACGGACATGGAGCACAACAGGTGTGGCAGCCGCCGTGGACCTGATCATCAAGAGCCACCAG TACTACAAGCTGCGTGCCGCTGAGCAGTACACACCCAAGGGTGGCGCCTACGGCGAGGACCTGGGCGCGGACTACAACCTGGGTGACCACCGCACGCTGCTGGAGGGCAGCGGCCTGGAG TGAGCGTGCGGGAGGGCTAGGCCCGTGCCCCCGCCTGCCCCCGCCATGCAACGGGATTGAAGGGTCCTGCCGGTGGGAC ATGTAGGTGTTAGGCATGTCCCACCCACCCGCCGCCTCCCACG GGTCTGTGAAGAGCCGGTGGTGCCCGTGCCCGCAGGAACTG TTCTGTGCTTGGATTTGCATATTTATTGCATTGCTGGTAGAGACC GTGGGTCCCGCACTCTGCCCCCATTTCCCCGATGTCCCCTGC CTCTCGGCCAGGCATTGGCTCAGCCCGCTGAGTGGGGGGTCG ACAGGGCCCGGCCACACCCAGCGGCCCCCCGCACAGCCACCC CCATGTTTGGTGTTTGTCTGTGTTTGTTTTTCAAGAAATGATTCA ACACGTCTGGACCCCGTTTCATTTTTACACCAATTTGGTAAAAAFASN GTCGGCGCCGGCCTAGAGGGAGCCAGAGAGACGGCAGCGGCGCCGCGCTCCAGCCTCGCTCTCCGCCGCCCGCACCGCCGCCC ATGTCCGGGAAGCTGCCAGAGTCGGAGAACTTGCAGGAGTTCT ATGACCGTCGCTGGAAGGCGGGGCTCTACGGCCTGCCCCGGC CTTCTTCGGAGTCCACCCCAAGCAGGCACACACGATGGACCCT TGGACGGAGGCATCAACCCAGATTCACTCCGAGGAACACACAC GGCCCTGAGCCGAGACCCCGAGACACTCGTGGGCTACAGCAT CTTCTTCTTCGACTTCAFASN GGTATGCGACGGGAAAGTATCCGTCCACGTCATCGAGGGTGACFASN CAGCCATGGAGGAGGTGGTGATTGCCGGCATGTCCGGGAAGCFASN TCCAGGGAGGGCCTCCTGTGGTGTGTGGCCATGGAGGAGGTGA1CF ACTCAGATAACAGTGCTGTGCCAAAAACCTGTGGATTTTCTCTAATAATCACTCTCAATGGAATCAAATCACAAATCCGGGGATGGAT TCCAGCGCACAGGATATAGCTTGGTCCAGGAAAATGGACAAAG CCTGAAAGGGGCTGTGAAATTTTTATTGGAAAACTTCCCCGAGA GTAAAATTTATGAAATGAGAATGATGATGGATTTTAATGGCAACA GAATGCAATCAAGCAACTTAATAATTATGAAATTAGAAAT TTTGTTGGGGGCATCCCAAAAACCAAAAAGAGAGAAGA ATCGTCTACCCAAGCGCTGCAGATAAAACCAAAAACCG GGCGAGGAGGAAACTGCTACCAGGAAGAATTCAGTTATGTTGATGAAGATACAATGTCTTCAGTGAAAATCCTATATG ATTCAACAATATCAAACCAGGTGCTGTGGAGAGGGTGAA GCAGTTGAGGCTATGAAAGCTTTAAATGGCAAGGTGCT GGACAGTTATGTTAGGTATACCCGAGGCACAGGTGGAA TTTATGATCCCACCACAACCTACCTTGGAGCTCCTGTCT AGCCACCAAAGGACATCTCAGCAACAGAGCCATTATCC GGCCGTGGCTATTTGGCATACACAGGCCTGGGTCGAGTTTTACCTGGGATGGAGCTCACCCCAATGAATCCTGTCA GATTTGTCAGAAAAATAACTGGGGACAGCCAGTGTACCA AAAATAACTATTCCTGCTCTAGCCAGCCAGAATCCTGCAGCAAAGACGTATGCAGCCGAATACACCCTGCAGACCCTGTGCTGCTGCTACTGCTTTCCCAGGATATGCTGTCCCTAACCCTTGGACAAGACTTAGCAGCATATACAACCTATGAGGT CTTCTGAAGATGCTTTTTTAAATTTAAGAATAAGACACACCCAATGATCATAAATAATATGTTTCCTAAAGAAATGCCTTTACGTTATTCTGAAATGAAATCAAATGTTAAAGAGCCTTTTCAGTCTTCCTGAGTGTTTGGGGAGTATGTTTACAAATCCTATGGAGCAGACCTGGGCAGTCAGTAATAATCAAGGGAAGTGATACACAAAGTCACAAAGAGGAAAAGGGAAGGGAGGATGATTGCAGGCCTGAGCTCATGAAAGACTGTCCAAGATTTTGTCACAGATCAGGATCTTCCTGTCCCCTGCAGCCCA AACAAATCCAGGCCCCATTGTTTATTCAGCTCATTAGTCC GCATGAAATGACCTTTTCTACTTTAAAATTTTTTGACTTGTAATATCATAAAAAAGTAAATCAGATATACAGAATATCATT GAGAGAAGTGCAGATTTGCTCTCATTTCTTTGATATTGTT TTAACTTGGGATTAGCTTTGCATTATCTAACCCATTTATTTTAAATAAGTATCAGGCAGCTTCACCATACCTGAGTCCTTTTGTCTTGAAAACTGTTTCAGACAATCAGCATGGGTGTTATTTACCAAATTCCCAAGTGAGGGGAGGGCAACGGTGCTACAAAACACGGAACAGAG TGCTTTGTTCAAACATAAATAATCTTAAGTCCAACACCAAATAC TACTAGAATTTTCATTTTTTAAAATCCCTTGGCCCTTAAAAAAATAATTTTGTCAACTCCTTAATGGAATTCTGTGATCAAAAAGCAGGAAGTACTTGTAACATTTCAGTTGTCCTAACTCCAATGAGATAACAGCTTTCTACTTTACATTTAGCGTCTAATATTTCCTAGGACAGTAGTTTAAATGCTAATGCCAATAACATATCTCATAAAATTTACACTAG TCCCTAGGTGATTTCAATGTGCACCTAGGTTTGGGAATTGCTAT TTTCACTTTTAGTAAATAGAAAAATGCAATTAAAAAATCATCTAATGAATTTAAATGTAACTTACGTAGGCTTCAAACTAACTCTAAAAA CAAATTTACACTCCCCTACAGATCTGCTTTTATTCTCAAAGACA ATTTCTACTGAGTCTAAAAAGCATTCCAAATTCTAGGAGCAAAA GTATTCTGGATGTCTTGTCAATGCAAATTAGGTTTGATTTAGAGGAATCTTTTTATGAGAAAAAATCATTATTCTGGATAAAGTCATAATAATACCAAAGTATTGAGAAAATTACCACTGGAACACCATCTCAA TAGGTAGAAGTGGTTTTGGTTTTTTTGCTAAAATTTTACTTTGTT TCATAGAAAGTGTTAATGTGTCTACCATGCCATATGTTTATTTTATAAGTTTAAAATTATTAAGACAACGGGCTTTTTTAAATTGCTGGTTAAGAAATTAGCACCTATATAATACCTTCATACCTTCTGCATCACTTTACAGAAAAAATTAAAATTTGTCACCCAACCAGGTGATAATATCTCTAAATTTTGGTAATTAATAGCTTATTGATAATTAAAATCAGC TTGGGTATCTATTTTCTTTCCTATAAAAGTGCTGCCTCTTCTCAAGCACCTTCAACTGCAACAAAATATAATTCTCCTAGATGACTAGG GGGAACAGCACCCGAAATGCTGCTAAAAAGCTACCTCATGTCATGCCTATAACCCCAGTACTTTGGGAGGCCAAGGCAGGAGGATT AGAGACTCCGCCTCTACAAAAAAAAAAAAAACAAATTTAATTTA CTTGGGAAGCTAAGGCAGGAGGATTGCTGGAGGCCTGGAGGGCCTGGGTGACAGAGCAAGACCCTGTCTCCAAAAAAGCAAAAAT TTAACTTTTTCATGATGGAATAGAAATTAAACTATAAGTATATACAGTATTTTTTAGAAAAAATGTTATTCTGATTGCATAGATTAGCAAATATTCTAAATGACCGTTTTATAATTCTGTCTTGGACAACTGGGCGCCATTTGTAGAATAAAGGGCAATCAAGTTAATATTCGGGGTAAA TTATTGAACAACTCTAACACTAAGATTTCCTAAAAGTAACTTACA ATTATTCTCTTCTTGCATTCATATAAAAGTTCCCAGGGGGAAGAGTATTGTAGATACACTTTCATATATTGTAAATACATCTGTTAAAGA TAAATATTTTTAAAAAGAAAATGTTAATAGGATAACTTAAGATTT ATATTCCTACCTGACGTGCAACCATTGTCAATCAGGTTTTGTTAAATCTTGAAAATGCTCTGAATTTTACTAGAACATATTCATAGAAAGT AGAAAAACAAAGTAAGTTGCGCTATAATGAGTGAAACTAAGGAA AATATTTAAGCTTTTTTTATTAAAGGAAAAATGGGTACAGAATAC TCCAACAATGTTTATACAGAAAATAGAATGCATAGGTTTAATATA ACTTTATGTGCCCCCAGTTCTCCTTGGTTTTGTAGGAAAGCTAA ATTTAGAAAGGGAAAATAACCTGAAAACCAAAATACCTCATTCATACCTCCCCCTTACAGACTTTTCTCCTATTTTGAGAGAGAAATTC TTGTCTAAGGGAATAGGAGATACCAAGAAACAGTATCTTTAAAA CAGCCCCATTCAGGGTTTACCAATGTCTCTCTGAGGTGACAAT TCCTTCTATAAATATTAACAATGATCCCTCTTATTTCCAAACGTGACACACACACACACCCCACCATCTTTATGGGTTGTTGTTGTTTTAAGCAGATAACAGCTTAAACTAAAGAGCCTAGCTACTTCTTTCTGTCCTCCTCTGAAATCTCCATCAATCCACTTTCTGTCCAACTATCT CCCTGGGCTGTGAGTCCTGAGTTCTGCCTTCATATGGCAGAGCACAAAAGATAGCTCTTGGGGACACTTGCTTGGTCTGTAGAGATC TTCTTCCTTGAGTTGAGTTACTTCTATCCCAAAACAGACAGGTCTTCTGCTTCACAAATTTGCTCCAACACTAATTCCCTTGCATTTGATCCTCACATCACGTCATATAAAGGTTTTATTATTTTTAATGGAAAAT TCCCTCCCTCTATTCTCTTCACTAACATTGGAAATTAAACAAGTT AGAATATATGATCAGCCTGTGTTTACTATGCACCTACTCTTATAC TTTAATTGGGGCACACAGTCCCATGGTCCATTCTGCATTTTTCA GAATTCTGAAAATAAATCAACTCTGTTCTAAACCTTAAGTTTCCA AAGGTGAATTTAACACTTCACCTATTATGGTTATTTAAGTAAAAT GCAAAAATAGAAGGAGAAAAAGGTTAGTTAGAGGTCCAGAAGG GATGTTAATGAGCAGGTACCTATACATTTTATTTACTTGAAAACA TATAAAATTTTAAAATCTATATCACAAGACTTAGACATGCCTTTC TTTTGAAACTTGGCATTTTCTTTATAATTCCTAAGATATCTTTGG TATCACTGGTTTAAATATTTAATGTAACCATTGGAATTTTTATTCT GCAATACAGCCCGATATTGTTATTCCCTATATCTTAATGAAAAGC AATCTCTTTCTTCTTTTCTTTTTTGTTATTATTTTTATTTATGTGAA TAAAAAGTGTGCATAAAGCACTTATTTTTGTACTTTAGTACAATG TACACCATTCACTTGTTGGGAAAATAATCTTTGGTTTGGAAGAT GAGAGACAATGCAATATTGTATAATTCCTGGATGATGCAATTGT TCAAA1 ATTCGCCATAATCAAGGAAACCTTTTCCGGGTGGGGATCTCTGGATAATCACTCTCAATGGAATCAAATCACAAATCCGGGGATGGA GTCCAGCGCACAGGATATAGCTTGGTCCAGGAAAATGGACAAA CCCTGAAAGGGGCTGTGAAATTTTTATTGGAAAACTTCCCCGAG GTAAAATTTATGAAATGAGAATGATGATGGATTTTAATGGCAAC GCCAAGAATGCAATCAAGCAACTTAATAATTATGAAATTAGAAA CGATTATTTGTTGGGGGCATCCCAAAAACCAAAAAGAGAGAAG GATGTCATCGTCTACCCAAGCGCTGCAGATAAAACCAAAAACC TGCCATGGCGAGGAGGAAACTGCTACCAGGAAGAATTCAGTTA TAGAAGTTGATGAAGATACAATGTCTTCAGTGAAAATCCTATAT AAAGGAATTCAACAATATCAAACCAGGTGCTGTGGAGAGGGTGA GAAGATGCAGTTGAGGCTATGAAAGCTTTAAATGGCAAGGTGCT CAAGGACAGTTATGTTAGGTATACCCGAGGCACAGGTGGAA AAGTTTATGATCCCACCACAACCTACCTTGGAGCTCCTGTCT CCCAGCCACCAAAGGACATCTCAGCAACAGAGCCATTATCC GGCGGCCGTGGCTATTTGGCATACACAGGCCTGGGTCGAG ACATTTTACCTGGGATGGAGCTCACCCCAATGAATCCTGTCA AGAGATTTGTCAGAAAAATAACTGGGGACAGCCAGTGTACCAGTACAAAATAACTATTCCTGCTCTAGCCAGCCAGAATCCTGCAGAAGCAAAGACGTATGCAGCCGAATACACCCTGCAGACCCTGTGCTGCTGCTGCTACTGCTTTCCCAGGATATGCTGTCCCTAATAACCCTTGGACAAGACTTAGCAGCATATACAACCTATGAGGT CACCTTCTGAAGATGCTTTTTTAAATTTAAGAATAAGACACAC CCCCAATGATCATAAATAATATGTTTCCTAAAGAAATGCCTTTAGAACGTTATTCTGAAATGAAATCAAATGTTAAAGAGCCTTTTTTCCAGTCTTCCTGAGTGTTTGGGGAGTATGTTTACAAATCCTGGGATGGAGCAGACCTGGGCAGTCAGTAATAATCAAGGGAATTTGTGATACACAAAGTCACAAAGAGGAAAAGGGAAGGGAGGGGCATGATTGCAGGCCTGAGCTCATGAAAGACTGTCCAAGATCGATTTGTCACAGATCAGGATCTTCCTGTCCCCTGCAGCCCA TAAAACAAATCCAGGCCCCATTGTTTATTCAGCTCATTAGTCC CCAGCATGAAATGACCTTTTCTACTTTAAAATTTTTTGACTTGACCTAATATCATAAAAAAGTAAATCAGATATACAGAATATCATT AAAGAGAGAAGTGCAGATTTGCTCTCATTTCTTTGATATTGTT AACTTGGGATTAGCTTTGCATTATCTAACCCATTTATTTTAAA AGTATCAGGCAGCTTCACCATACCTGAGTCCTTTTGTCTTGA ACTGTTTCAGACAATCAGCATGGGTGTTATTTACCAAATTCCCAGTGAGGGGAGGGCAACGGTGCTACAAAACACGGAACAGAGGCTTTGTTCAAACATAAATAATCTTAAGTCCAACACCAAATACACTAGAATTTTCATTTTTTAAAATCCCTTGGCCCTTAAAAAAAT TTTTGTCAACTCCTTAATGGAATTCTGTGATCAAAAAGCAGG GTACTTGTAACATTTCAGTTGTCCTAACTCCAATGAGATAACA TTTCTACTTTACATTTAGCGTCTAATATTTCCTAGGACAGTAG TAAATGCTAATGCCAATAACATATCTCATAAAATTTACACTAGCCCTAGGTGATTTCAATGTGCACCTAGGTTTGGGAATTGCTAT TCACTTTTAGTAAATAGAAAAATGCAATTAAAAAATCATCTAAGAATTTAAATGTAACTTACGTAGGCTTCAAACTAACTCTAAAAAAAATTTACACTCCCCTACAGATCTGCTTTTATTCTCAAAGACA TTCTACTGAGTCTAAAAAGCATTCCAAATTCTAGGAGCAAAATATTCTGGATGTCTTGTCAATGCAAATTAGGTTTGATTTAGAG ATCTTTTTATGAGAAAAAATCATTATTCTGGATAAAGTCATAAT TACCAAAGTATTGAGAAAATTACCACTGGAACACCATCTCAA GGTAGAAGTGGTTTTGGTTTTTTTGCTAAAATTTTACTTTGTT CATAGAAAGTGTTAATGTGTCTACCATGCCATATGTTTATTTT AAGTTTAAAATTATTAAGACAACGGGCTTTTTTAAATTGCTGG AAGAAATTAGCACCTATATAATACCTTCATACCTTCTGCATCA TTACAGAAAAAATTAAAATTTGTCACCCAACCAGGTGATAATA TCTAAATTTTGGTAATTAATAGCTTATTGATAATTAAAATCAGC GGGTATCTATTTTCTTTCCTATAAAAGTGCTGCCTCTTCTCAA ACCTTCAACTGCAACAAAATATAATTCTCCTAGATGACTAGG GGAACAGCACCCGAAATGCTGCTAAAAAGCTACCTCATGTCA CCTATAACCCCAGTACTTTGGGAGGCCAAGGCAGGAGGATT GAGACTCCGCCTCTACAAAAAAAAAAAAAACAAATTTAATTTATTGGGAAGCTAAGGCAGGAGGATTGCTGGAGGCCTGGAGGG TGGGTGACAGAGCAAGACCCTGTCTCCAAAAAAGCAAAAATTAACTTTTTCATGATGGAATAGAAATTAAACTATAAGTATATAC TATTTTTTAGAAAAAATGTTATTCTGATTGCATAGATTAGCAA ATTCTAAATGACCGTTTTATAATTCTGTCTTGGACAACTGGGC CATTTGTAGAATAAAGGGCAATCAAGTTAATATTCGGGGTAAATATTGAACAACTCTAACACTAAGATTTCCTAAAAGTAACTTACA GATTATTCTCTTCTTGCATTCATATAAAAGTTCCCAGGGGGAAGAGTATTGTAGATACACTTTCATATATTGTAAATACATCTGTTAAAGAATAAATATTTTTAAAAAGAAAATGTTAATAGGATAACTTAAGATTT ATATTCCTACCTGACGTGCAACCATTGTCAATCAGGTTTTGTTAAATCTTGAAAATGCTCTGAATTTTACTAGAACATATTCATAGAAAGTTAGAAAAACAAAGTAAGTTGCGCTATAATGAGTGAAACTAAGGAA AATATTTAAGCTTTTTTTATTAAAGGAAAAATGGGTACAGAATACGTCCAACAATGTTTATACAGAAAATAGAATGCATAGGTTTAATATA ACTTTATGTGCCCCCAGTTCTCCTTGGTTTTGTAGGAAAGCTAAAATTTAGAAAGGGAAAATAACCTGAAAACCAAAATACCTCATTCATACCTCCCCCTTACAGACTTTTCTCCTATTTTGAGAGAGAAATTCTTTGTCTAAGGGAATAGGAGATACCAAGAAACAGTATCTTTAAAATCAGCCCCATTCAGGGTTTACCAATGTCTCTCTGAGGTGACAATGTCCTTCTATAAATATTAACAATGATCCCTCTTATTTCCAAACGTG ACACACACACACACCCCACCATCTTTATGGGTTGTTGTTGTTTTAAGCAGATAACAGCTTAAACTAAAGAGCCTAGCTACTTCTTTCTGTCCTCCTCTGAAATCTCCATCAATCCACTTTCTGTCCAACTATCTCCCCTGGGCTGTGAGTCCTGAGTTCTGCCTTCATATGGCAGAGCACAAAAGATAGCTCTTGGGGACACTTGCTTGGTCTGTAGAGATC TTCTTCCTTGAGTTGAGTTACTTCTATCCCAAAACAGACAGGTCT TCTGCTTCACAAATTTGCTCCAACACTAATTCCCTTGCATTTGAT CCTCACATCACGTCATATAAAGGTTTTATTATTTTTAATGGAAAAT TCCCTCCCTCTATTCTCTTCACTAACATTGGAAATTAAACAAGTT AGAATATATGATCAGCCTGTGTTTACTATGCACCTACTCTTATAC TTTAATTGGGGCACACAGTCCCATGGTCCATTCTGCATTTTTCAAGAATTCTGAAAATAAATCAACTCTGTTCTAAACCTTAAGTTTCCAAAAGGTGAATTTAACACTTCACCTATTATGGTTATTTAAGTAAAATTGCAAAAATAGAAGGAGAAAAAGGTTAGTTAGAGGTCCAGAAGG GATGTTAATGAGCAGGTACCTATACATTTTATTTACTTGAAAACA TGTTTATAAAATTTTAAAATCTATATCACAAGACTTAGACATGCCTTTC TTTATTTTGAAACTTGGCATTTTCTTTATAATTCCTAAGATATCTTTGG CATTATCACTGGTTTAAATATTTAATGTAACCATTGGAATTTTTATTCT ACTGCAATACAGCCCGATATTGTTATTCCCTATATCTTAATGAAAAGC TAACAATCTCTTTCTTCTTTTCTTTTTTGTTATTATTTTTATTTATGTGAA GTATTAAAAAGTGTGCATAAAGCACTTATTTTTGTACTTTAGTACAATG AAATTACACCATTCACTTGTTGGGAAAATAATCTTTGGTTTGGAAGAT AAATGAGAGACAATGCAATATTGTATAATTCCTGGATGATGCAATTGT ATTATCAAA1CF TGAATTCGCCATAATCAAGGAAACCTTTTCCGGGTGGGGATCTCTGGATTTTCTCTACAAAAATTATCATGACTGTTATCTTTTTGATGGAAAA AGAAGACTGTAGACTTTGCCTTCAAAGAGTGAGCAACCCTAATTAACC ACAAATCCGGGGATGGATTGAGCGGCACTCAGAAGGAAGCAGCCC CCAGGAATTTAGAGGTTCCTATAGATGGAAGCAGTGTGTCTGGGCA TTCCTGGCCTCAAAAAAGGAAATAATGCTTTGCAGTCCATCATTTTGC GGTGGCCCTCCACCTGGTTGGGATGCTGCACCCCCTGAAAGGGGC GAGGATGAGCTTATACCATTATGTGAAAAAATCGGTAAAATTTATGA GATATGCATTTGTAACATTTTCAAATAAAGTGGAAGCCAAGAATGCAA CTCTTAGGGGTTTGTGCCAGTGTGGACAACTGCCGATTATTTGTTGG TCGGAGATGAAAAAGGTTACTGAAGGTGTTGTCGATGTCATCGTCTA GCCTTCGTGGAGTATGAGAGTCATCGAGCAGCTGCCATGGCGAGGA TGGTATTGCAGTAGACTGGGCAGAGCCAGAAGTAGAAGTTGATGAA TCTTATGCTGTCTACCTCTGAAGAGATGATTGAAAAGGAATTCAACAA CGAGACTATGCTTTTGTGCACTTCAGTAACCGAGAAGATGCAGTTGA TCCCCCATTGAAGTCACCCTAGCAAAACCAGTGGACAAGGACAGTTA CATGCTGCAAGGAGAGTATACCTACTCTTTGGGCCAAGTTTATGATC CCCCAGACCTATGCAGCAATTCCCAGTCTTCATTTCCCAGCCACCA TTCTGTTAGAGAAATTTACATGAATGTACCTGTAGGGGCTGCGGGAG GCCTGGGTCGAGGATACCAGGTCAAAGGAGACAAAAGAGAAGA ATGAATCCTGTCACATTAAAACCCCAAGGAATTAAACTCGCTCCC AGCCAGTGTACCAGCTGCACTCTGCTATTGGACAAGACCAAAGA CCAGAATCCTGCAATCCACCCTTTCACACCTCCAAAGCTGAGTG CCTGCAGACCCTGGGCATCCCCACTGATGGAGGCGATGGCACC ATGCTGTCCCTAATGCAACTGCACCCGTGTCTGCAGCCCAGCTC CAACCTATGAGGTCTACCCAACTTTTGCAGTGACTGCCCGAGGG GAATAAGACACACAAAACTCTATTAAAAAAAAAAAAGAAATAAACA1CF AATTCGCCATAATCAAGGAAACCTTTTCCGGGTGGGGATCTCTGTTTTCTCTACAAAAATTATCATGACTGTTATCTTTTTGATGGAAAA AGACTGTAGACTTTGCCTTCAAAGAGTGAGCAACCCTAATTAACC AAATCCGGGGATGGATTGAGCGGCACTCAGAAGGAAGCAGCCC AGGAAAATGGACAAAGAAAATATGGTGGCCCTCCACCTGGTTGG GAAAACTTCCCCGAGACCTTTTTGAGGATGAGCTTATACCATTAT GATTTTAATGGCAACAATAGAGGATATGCATTTGTAACATTTTCA ATTATGAAATTAGAAATGGGCGCCTCTTAGGGGTTTGTGCCAGTG CAAAAAGAGAGAAGAAATCTTATCGGAGATGAAAAAGGTTACTG TAAAACCAAAAACCGAGGCTTTGCCTTCGTGGAGTATGAGAGTC GAAGAATTCAGTTATGGGGACATGGTATTGCAGTAGACTGGGCA TGAAAATCCTATATGTAAGAAATCTTATGCTGTCTACCTCTGAAG TGTGGAGAGGGTGAAGAAAATTCGAGACTATGCTTTTGTGCACTT AATGGCAAGGTGCTGGATGGTTCCCCCATTGAAGTCACCCTAGC GGCACAGGTGGAAGGGGCACCATGCTGCAAGGAGAGTATACCT GGAGCTCCTGTCTTCTATGCCCCCCAGACCTATGCAGCAATTCC AGAGCCATTATCCGAGCCCCTTCTGTTAGAGGGGCTGCGGGAG GCCTGGGTCGAGGATACCAGGTCAAAGGAGACAAAAGAGAAGA ATGAATCCTGTCACATTAAAACCCCAAGGAATTAAACTCGCTCCC CAGCCAGTGTACCAGCTGCACTCTGCTATTGGACAAGACCAAAGA GCCAGAATCCTGCAATCCACCCTTTCACACCTCCAAAGCTGAGTG CCCTGCAGACCCTGGGCATCCCCACTGATGGAGGCGATGGCACC TATGCTGTCCCTAATGCAACTGCACCCGTGTCTGCAGCCCAGCTC ACAACCTATGAGGTCTACCCAACTTTTGCAGTGACTGCCCGAGGG AGAATAAGACACACAAAACTCTATTAAAAAAAAAAAAGAAATAAAC TAAAGAAATGCCTTTCCAGAGACTGTATAGCTTATACCAATTATAGA1CF GAATTCGCCATAATCAAGGAAACCTTTTCCGGGTGGGGATCTCTGCTGATAATCACTCTCAATGGAATCAAATCACAAATCCGGGGATGGA GGTCCAGCGCACAGGATATAGCTTGGTCCAGGAATTTAGAGGTTC GCCAGAAGCGAGCATGAGCACAGCAATTCCTGGCCTCAAAAAAGG GAAAAGGAAAATGGACAAAGAAAATATGGTGGCCCTCCACCTGGT ATTGGAAAACTTCCCCGAGACCTTTTTGAGGATGAGCTTATACCAT GATGGATTTTAATGGCAACAATAGAGGATATGCATTTGTAACATTT AATAATTATGAAATTAGAAATGGGCGCCTCTTAGGGGTTTGTGCCA AAACCAAAAAGAGAGAAGAAATCTTATCGGAGATGAAAAAGGTTA CAGATAAAACCAAAAACCGAGGCTTTGCCTTCGTGGAGTATGAGA CCAGGAAGAATTCAGTTATGGGGACATGGTATTGCAGTAGACTGG TCAGTGAAAATCCTATATGTAAGAAATCTTATGCTGTCTACCTCTG GTGCTGTGGAGAGGGTGAAGAAAATTCGAGACTATGCTTTTGTGC CTTTAAATGGCAAGGTGCTGGATGGTTCCCCCATTGAAGTCACCC CCCGAGGCACAGGTGGAAGGGGCACCATGCTGCAAGGAGAGTAT ACCTTGGAGCTCCTGTCTTCTATGCCCCCCAGACCTATGCAGCAA GCAACAGAGCCATTATCCGAGCCCCTTCTGTTAGAGGGGCTGCGG ACAGGCCTGGGTCGAGGATACCAGGTCAAAGGAGACAAAAGAGA CCCAATGAATCCTGTCACATTAAAACCCCAAGGAATTAAACTCGCT GGACAGCCAGTGTACCAGCTGCACTCTGCTATTGGACAAGACCAA GCCAGAATCCTGCAATCCACCCTTTCACACCTCCAAAGCTGA CCCTGCAGACCCTGGGCATCCCCACTGATGGAGGCGATGGC TATGCTGTCCCTAATGCAACTGCACCCGTGTCTGCAGCCCAG ACAACCTATGAGGTCTACCCAACTTTTGCAGTGACTGCCCGA AGAATAAGACACACAAAACTCTATTAAAAAAAAAAAAGAAATA TAAAGAAATGCCTTTCCAGAGACTGTATAGCTTATACCAATTAA1CF AGCAACCCTAATTAACCTGATTTTTTGCTGATAATCACTCTCAAAGAAGGAAGCAGCCCTCCGCGCACTGGTCCAGCGCACAGG GCAGTGTGTCTGGGCACATGCCCAGAGCCAGAAGCGAGCAT GCAGTCCATCATTTTGCAAACTTTGCTGGAAAAGGAAAATGGA CCCCCTGAAAGGGGCTGTGAAATTTTTATTGGAAAACTTCCC TCGGTAAAATTTATGAAATGAGAATGATGATGGATTTTAATGG GAAGCCAAGAATGCAATCAAGCAACTTAATAATTATGAAATTA TGCCGATTATTTGTTGGGGGCATCCCAAAAACCAAAAAGAGA GTCGATGTCATCGTCTACCCAAGCGCTGCAGATAAAACCAAA GCTGCCATGGCGAGGAGGAAACTGCTACCAGGAAGAATTCA AAGTAGAAGTTGATGAAGATACAATGTCTTCAGTGAAAATCCT GAAAAGGAATTCAACAATATCAAACCAGGTGCTGTGGAGAGG GAGAAGATGCAGTTGAGGCTATGAAAGCTTTAAATGGCAAG GTGGACAAGGACAGTTATGTTAGGTATACCCGAGGCACAGG GGGCCAAGTTTATGATCCCACCACAACCTACCTTGGAGCTCC TCATTTCCCAGCCACCAAAGGACATCTCAGCAACAGAGCCATT ACTGGGCGGCCGTGGCTATTTGGCATACACAGGCCTGGGTC ATGACATTTTACCTGGGATGGAGCTCACCCCAATGAATCCTG AGAAGAGATTTGTCAGAAAAATAACTGGGGACAGCCAGTGTA CTTGTACAAAATAACTATTCCTGCTCTAGCCAGCCAGAATCCT GATGAAGCAAAGACGTATGCAGCCGAATACACCCTGCAGACC GCTACTGCTGCTGCTGCTGCTACTGCTTTCCCAGGATATGCTGTCCC CAAGCGGTAACCCTTGGACAAGACTTAGCAGCATATACAACCTATGA GGATATGGCACCTTCTGAAGATGCTTTTTTAAATTTAAGAATAAGACA TAACTCGGTCCCCAATGATCAA1CF AATTACTCAGTGAGCAACCCTAATTAACCTGATTTTTTGCTGATAATCATGAGCGGCACTCAGAAGGAAGCAGCCCTCCGCGCACTGGTCCAGCG AAATATGGTGGCCCTCCACCTGGTTGGGATGCTGCACCCCCTGAAA CCTTTTTGAGGATGAGCTTATACCATTATGTGAAAAAATCGGTAAAATT TAGAGGATATGCATTTGTAACATTTTCAAATAAAGTGGAAGCCAAGAA GGCGCCTCTTAGGGGTTTGTGCCAGTGTGGACAACTGCCGATTATTT TCTTATCGGAGATGAAAAAGGTTACTGAAGGTGTTGTCGATGTCATC GCTTTGCCTTCGTGGAGTATGAGAGTCATCGAGCAGCTGCCATGGC GGACATGGTATTGCAGTAGACTGGGCAGAGCCAGAAGTAGAAGTTG AGAAATCTTATGCTGTCTACCTCTGAAGAGATGATTGAAAAGGAATTC AAATTCGAGACTATGCTTTTGTGCACTTCAGTAACCGAGAAGATGCA ATGGTTCCCCCATTGAAGTCACCCTAGCAAAACCAGTGGACAAGGAC GGCACCATGCTGCAAGGAGAGTATACCTACTCTTTGGGCCAAGTTTAT ATGCCCCCCAGACCTATGCAGCAATTCCCAGTCTTCATTTCCCAGCC CCCCTTCTGTTAGAGAAATTTACATGAATGTACCTGTAGGGGCTGCG TACACAGGCCTGGGTCGAGGATACCAGGTCAAAGGAGACAAAAGAG CACCCCAATGAATCCTGTCACATTAAAACCCCAAGGAATTAAACTCGC GGGGACAGCCAGTGTACCAGCTGCACTCTGCTATTGGACAAGACCA TAGCCAGCCAGAATCCTGCAATCCACCCTTTCACACCTCCAAAGCTG AATACACCCTGCAGACCCTGGGCATCCCCACTGATGGAGGCGATGG CCAGGATATGCTGTCCCTAATGCAACTGCACCCGTGTCTGCAGCCCA GCATATACAACCTATGAGGTCTACCCAACTTTTGCAGTGACTGCCCG AAATTTAAGAATAAGACACACAAAACTCTATTAAAAAAAAAAAAGAAAT TCCTAAAGAAATGCCTTTCCAGAGACTGTATAGCTTATACCAATTKLF TCGAGCCAGCGCAGGACCCGCGGCTCGGCCCCCGGCCGCCGCCCCGGCCGCAGGACCGCCGGGGCCTGGCCGCCGGTCCGGCGTG TGGTGGACCACTTACTTCCAGTGGACGAGAACTTCTCGTCGCCA CGGCGGGCATATCACATGCTGCCCTCACCCGTCTCTGAAGATGA CTCTCAAGCCCTCTGCTCCTGCTATGGTGGAGGCCTGGGCACCG CCACGCTGGGCAGTGGCGGGGGCAGCGGCAGTAGCATTGGGGC GCAGCGGCCCCTGTGAAGGGGGAGCATTTCTGCTTGCCCGAGTT GCCTACCCTGGAGGAGATTGAAGAGTTTCTGGAGGAGAACATGG GACTTGGATGCCTGCAGCCAGCTCTCAGCTGGGCCACACAAGAG CCCCTCCACCAGGTGGTGCCAGTGCAGGAGGTGCCCAGGGCCC TGCTGCAGATCCAGCCCGTGCCTGTGAAGCAGGAATCGGGCACA GGTTGCCCAGCTCCTGGTCAACATCCAGGGGCAGACCTTCGCAC CCTCCAAGTTTGTGCGCATTGCCCCTGTGCCCATTGCCGCCAAG TCTCCTCATGGGCCAGAAGTTCCCCAAGAACCCAGCCGCAGAAC GATGTACACCAAAAGCAGCCACCTCAAGGCCCACCTGCGCCGGC TGCGGCTGGAGGTTCTCGCGCTCTGACGAGCTGTCGCGGCACAG GTGCGAGAAGAAGTTCGCGCGGAGCGACCACCTCTCCAAGCAC GCGCTCCGTGAACTGAAAGCGCCCTGAACCCCAGCCTGTCCGTC ATTTATTTGCCTCCTCCAGAGGGACATGGCAATGTTACCAGCCCA AACCGCTGCCTTTCTCGGGAGTACTTAGAGCCTCGAACCCGCGT CAGGCCTTCGTGCCTTCGTGCCTTCGTGCCTTCCCGCGGTGGCC GGGACCTGGCCCTTCTCCCACTGGGCTCCCCCATCCTGGGCCA GTTTTGAAATGTTGGGTTTCCAGAGAGAGTCATGCTGGAGGAGAA AGGGTGGCTTTGTCTAAGATGCCTGCTCAGCATGATCACCAGAGG GGGGGGGGGGGGCAGGACCGGGCCGCTGGGCCCTCATGTGG GTGCATGTGCTTGAGTTAAATGTGCAGGGCAGACAGAGCCAGAA CCAGACAAATCCAGACACCAGCCTTTAGGGTGGCCTTGGGAGGA GAGCCTCCCAACCCTGATTTAGAAATGCATTCCTTATTTTGTCTAGA ACATCCTATGAATGTATGTAAATAAACTGTACATAGGTCCATCCACA GAAATTTAAAAAAATCTATGAAGCTGGTGTACATATGTTACAATTAC CCAATAAAAAGAAAAAGAACTCACATF GCACCCGGAAGATGAGGCTCGCCGTGGGAGCCCTGCTGGTCTGCTGTGAGATGGTGTGCAGTGTCGGAGCATGAGGCCACTAAGTGCCA TGGTCCCAGTGTTGCTTGTGTGAAGAAAGCCTCCTACCTTGATTG CACTGGATGCAGGTTTGGTGTATGATGCTTACCTGGCTCCCAATA GAGGATCCACAGACTTTCTATTATGCTGTTGCTGTGGTGAAGAAGG TCCTGCCACACGGGTCTAGGCAGGTCCGCTGGGTGGAACATCCCC CCTCTTGAGAAAGCAGTGGCCAATTTCTTCTCGGGCAGCTGTGCC ACTGTGTCCAGGGTGTGGCTGCTCCACCCTTAACCAATACTTCGG GGGATGTGGCCTTTGTCAAGCACTCGACTATATTTGAGAACTTGGC TGGACAACACCCGGAAGCCGGTAGATGAATACAAGGACTGCCACT ATGGGCGGCAAGGAGGACTTGATCTGGGAGCTTCTCAACCAGGC ACTATTCAGCTCTCCTCATGGGAAGGACCTGCTGTTTAAGGACTCT CAAGATGTACCTGGGCTATGAGTATGTCACTGCCATCCGGAATCTA GCAAGCCTGTGAAGTGGTGTGCGCTGAGCCACCACGAGAGGCTCA GAGTGTGTATCAGCAGAGACCACCGAAGACTGCATCGCCAAGATC GTTTGTCTACATAGCGGGCAAGTGTGGTCTGGTGCCTGTCTTGGC AGAGGCAGGGTATTTTGCTATAGCAGTGGTGAAGAAATCAGCTTC GCCATACGGCAGTTGGCAGAACCGCTGGCTGGAACATCCCCATGG AATTTTTCAGTGAAGGTTGTGCCCCTGGGTCTAAGAAAGACTCCAG GTGAACCCAACAACAAAGAGGGATACTACGGCTACACAGGCGCTTT AACACCAGACTGTCCCACAGAACACTGGGGGAAAAAACCCTGATC TGTGCCTTGATGGTACCAGGAAACCTGTGGAGGAGTATGCGAACT ACGGAAAGATAAGGAAGCTTGCGTCCACAAGATATTACGTCAACAG ACTTTTGTTTGTTCCGGTCGGAAACCAAGGACCTTCTGTTCAGACATATGAAAAATACTTAGGAGAAGAATATGTCAAGGCTGTTGGTA CACTTTCCGTAGACCTTAAAATCTCAGAGGTAGGGCTGCCACCATGGTTTCACTGGCCCAAGTGGTTTGTGCTAACCACGTCTGTCTTCATTATTATTGATTTTATATTTCAAAAACTCCATTCTTTCCTAAATATTTGCAACTGAGCCCTTCCTTCTCAGCTCAAGATTCGTCTGGTCTTT ACAGTTCAAGGAGACATCTTTTCTAAAAGGGTCTGCGTGATCATTCGCGTGCGTGTGTCATGCTAAGGAAGGGGCAAGAAGGAGGATG AAAGACTACAGAAGACTTACCTTTATTTGGTATTTTAAATGAATTCGAAACACTGACATCTTTTTTGCTGAAAAGCATTCCCTGAGCTTGA CCAGCTTCCTGTAAGGTGGAGGCTGACTTTTCTGTCTCACTTATT TTACCTGAATGTACCCTGGCAAAAGTCACCGTCTACCTGCCAAC TGCAGTTGATAAAGTTGACCACTCCCTCCTCCTTGGAACTCTTTTTACCTCTCTCTGTTCATTTGTAGTCTTCACTGTGGGCTCATCCTAC TTGATCTGGTCAGTGCTCCTCTCACTTTGCAGGCCCTCCTTCAGTCCCCAGCCTCCAGCAGTATCCCTGCACTTATACATCCTACTACCT CCAACAAATCAAAAATTGAAGTGATCATCCTGTTCTTCTCTCTCTAGCTGAAGACCTGGTCATCTACCCAATCACATAAGCCATAAATAGTCCAGCGTCACCAAGTTCTGTTGATTTTGCTTTCTAAATAACTTCA TTATACTCAAATACAGAAGTGCAGATAAGGGGTATCTGGACACAAGGACTCTGGGTCCACTTTGCAGTCCAGACCTGATATGGACCGTCTGCCTTATTTAATATTAACCTAAACTTACCCCAAATCCTATAACTCTGGGACGCAGTCTGTCTCATTGCAATGGATCAATAAACCTAATT GGGCTAAAACAAAAATATTCAACATCCATTCTTAATTATTAAATTA TTATATACATGTAAACAAAAGCTAATACATACCTAATGATGAAGAA GATTACTATCTATCTTATTTTACAGTGTTTTAGAACAGGTGGCCA TGCCAAAATTACTTTTATTTGTAAGTGATTATACACCTAGGAAATCAGTGGTTCATGCCTATAATCCCAGCATTTTGGGAGGCTGAGGTG CCAACATGGCGAAACCCCATCTCTTCTAAAAATACAAAAATTAGC GGCTGAAGCATGAGAAGTGCTTGATCCTGGGAGGCAGAGGTT CAGAGCAAGACTCTGTCTGGAAAATAATAAAAATAATAATAATGGGAGGCCAAGTCGGGCGGATCACCTGAGGTCAGGAGTTCGATAAAAATTAGCCGGGCGTAGTGGTGCATGCCTGTAATCCCAGGAGGCAGAAGTTGTGGTGAGCCGAGATCGCACCATTGCACTAAAATAATAATAATAATAAATAAAGTGGTAAAAGTGGTAAGATATTCTTTTATACAAATAATAGTGAGTTAGGACAATAATAATTAAC ATTTAAACCACACTTATCAAAGTAAAAAATAATGTAAAGAAGAAATTCTCCCTAAATTAATCAATATACAATTTTTTAACTTGACAAA GAAAAATTCTGATGAGAGTGGAAGAGCTCTTCCAGCTGTTAA TTTGGCTATCACATCAAAAGCCCAGGCCACAAAAGCAAAAATAAAGACAACAAGCAACAAAATGAAATGGCAACCTATGGATTGG GATAAAGAACTCATACAACTCAATAGCAGGAAAACAAATGATCGAAGAAAAATGGCCAAGATGGATATGAAAAGGTGTTCAACATCCTAGATAATAATAGGATGACTATTATCAAAAAGTCAAAAGATAT TGTGCATTGTTGGTGAGAATGTACAGCCATTGTGGAAAACAGTCCAACAATCCCTCTTTAGGGGATATACACAAATAAAATGAGATA ATTGCAGCCAATATAGGGAAGCAACCTAAATGCCTGTTGAAGAATGGAATATTATTCAGCCCTAAAAAGAATATCTTGCCATTTGC AGATACAGAAAGAAAAATATTACACGATTTCACTCACATGGGGAAACCTGAGGTGGAGGAGGGTGGAGAGATGTAGGTCAGAGGA CCTGTAATCCCAGGACTTTGGGAGGCAGAGGTGGGCAGATTAAAACCCCATCTCTGCAAAAAAAAAAAAAAAAACAAAAAAAACCACACACACACAAAAAAAATTAGCGAGGAGTGCTGGTGCCCAC GGTCGAGGCTGCAGTGAGCAGTGATTTGATCGTGCCACTGCA AACCAAGTAGCAGATATGCATGATGAACAAGCCTAGAGATCTA TATTTGGGATTCCTCCTTCACTGTAGTAATCTTTTTTTAACTATGAAGCTTATTTTAAAAAATGAAATGTATAATGATGACTGGAAAG AGATATTAAATGCAAATGAGAATTTATTACATGATAAAGCTGG GTTTAGAAGCAGAGTAGCTGAAAATTTTGGCGCAGAAGAAAATC AACGTATAAAGGTTTAAATATAAAATTAAAATCGTAAAAACAATTAATTCCACAAACCTAGTAGCAATTAAGGAAAATATTAATTTCAGATCAAAATGTGAAGATTTTTAAGAAAGAACAAAGGGCTAATCTATATTT CGCGGACAGCTCTGCTGGGCCCTCCAGGCCCTCCGCCCGGTAATTTCTTGAAGCAGCGGCGAACCACTTTTCCTCCCCGACCTGCCCGAAGCTTCTGCTGAGCCGCCTGGACGCAGCGCCCCTGGGTGCCAACGCCGCGGAGGCCACCAGCGGGTGCAGAGGGCCAGGAAGGAGCCGAGCAGATCCGGGTCTTCGGGTGGCCGCAATGTCCCAAGTCCTTAATGGGCCCAGAAGGTGAGGGGAGTCCGGCAATGAGTTCTACCAGACGCTGGTGCTGGAAAAGAGAAGTGTAAGAATAAC GGAAGATTACTGGCTGTTTATAGAAGGCCCGTGTATATCCTATG AACATTTGCTACATCGAGCCGTTCTAGGTGTAAAGAGGTTGTGAATTTGTTAAAAAAATAATAATAATAATAATAATAATAATAATAATAA GTTGTTAGACCACCTCTGGAAGTGACAGCAGGAGCCACACATCTGGATCTAGGTTGCACGCTCCTTATGAGACTCTAATAATGCCTGCTACCTTCCATGGAAAAATTGCCTTCCGTGAAACCATTCCCTGGTGCAGAAGACCTGAGAAGGAAGAGAGGACAGTTCTGTGCCACAC TGTGTGTGCATTTTATTTCTCACGACTGTATATGTAGTTAACAATGGCCAGCCGCCCCGTCCGGGAGGGAGGTGGGGGGGTCAGCCCGCCTCTGCCCGGCCGCCCCTACTGGGAAGTGAGGAGCCCCTCT GTCAGCCCCCCGCCCGGCCAGCCGCCCTGTCCGGGAGGGAGCTGGGAGGTGAGGGGCGCCTCTGCCCGGCCGCCCCTACTGGG GGAGGGAGGTGGGGGGGTCGGCCCCCCGCCCGACCAGCCGCCGGCCAGCCGCCCTGTCCGGGAGGGAGGTGGGGGTGTCAGCCGGGGGTCAGCCCCCCGCCCGGCCAGCCGCCCCGTCCGGGAGCCCCGTCCGGGAGGTGAGGGGCGCCTCTGCCCGGCTGCCCCT GTCCGGGAGGGAGAGTGGGGGGTCAGCCCCCCCCCGCCCGGCAGCCACCACCCGGTCTGGGAGGTGTGCCCAACAGCTCATTGA AAAGGCGGGAAAGGCGGGGAAAAGATTGAGAAATCGGATGGTTG CATTTTGTTCTGCACTAAGAAAAATTCCTCTGTCTTGGGATCCTGT CATGTGCTGTGTCCACTCAGGGTTAAATGGATTAAGGGCGGTGCA TCGTTAAGAGTCATCGCCAATCCCTAATCTCAAGTAATCAGGGACA AAACCAGAGACCTTTGTTCACTTGTTTATCTGCTGACCTTCCCTCC AAACACCCAAGAATTATCAATAAAAAAATAAATTAAAAAAAAAAAAATGTTCTGAAATGCCTATGTTAAAATTAGAGATAGTAAAATAACACATTGGTTGGGGGGGGTGGCCAAACCACCTGTTAATAATACACATTGT GTGTAAGAGCTCTATGCCAATGTGCTTATAGTGAGGCAAGGTTAA GTATATTGTGGATCTAAAGGACAAATGAGTCCTGACTTTACATCTAAAGTAGTTAGTAAACTAATATATTTTGTACATTTCGTTTTAAGATTCCCAGTGGGTTGATGGAGATGGGAAGGTGTAGGCCAGAATGTTCATA TTTATTCAAGACTTCTGTGCATATAGTGGACGAATTAACTTCTTAC TGTATGTTAAGTGTAGAGGTAGTAAAATATCACCTTGTAAATATCTTGAATTGTGAAGCCACCTCTGTAAGCAGTATAGTACTGTCTATACTTG GTAATATGCTAGTGTGTTCATACTTGGACATTTCACTTGCCATTTTT TACATAATGGACAAATGAGTCCTAATTTTGCAACATTTGGTCTCTATAAAATTAGCACATTTTGCACACTTTGTATTGAAATTCATAGGAAAGGCCATCTCTAAGCGTTACACATGCCTGTACCTGTCCACTGGATTGAGTCAAAATTGTCATATTTAGAAGATACCTCCGATTATAGCCACTGAT AAAGTTATATGAAATATCTGGTCTCTCTAGATAGTTAGAAATGCTTTAAATAGCTTTTAAAAACTGATGGGAAATACTGTGTTTGCAAGTGG TCAGTTGAGGAAGGTGAGAGGGAAGAAATTACAAAAGATGTTTTGTATGTTAAATGCATTGCAAGTAACTTTGCTATACTACATATTGTGTTCTCTAGATACTAAAGAGGTTGCCAATGTATGACAAAAATAGTAAAGACTATCTTCTGAAAACGACTTTTGGAAGTGAAATGATAACATCAACCTGCAGAGGAGCTGGAAGAAATGAAGGATTCTAGATCAGAATATTCC ATTCAACCCTACTGATGCAAGAGAATAGGGTCTGGAGGCAGGAAAAATGGAAACACATCAGCTATGACAGGACATATACTCTCCAACAGAG GGGCGTACATCAAGTAAATGACTAGGGTGTATACTAAGTAAATG ATACCAAGTAACCAATGGAAACCTTGAGAGGGTATTTAAACCCG GCCTTCTCCCACCCTGTGGAGCGTACTTTCATTTCATAAATCTCT CAATTCTTGGTTCAATATGCCCAGAACCTGGACACCCTCCACTG GTTTGGGATTTTTCATCTTTTCTTTTCCACTCCATACAGGGGAAT GGTGGGCAGCGCCTAAACACGGAGGCAACCGCAGGTTTCTGGG TGGTCCCTGATTCCTATGTGTGGCGCAGCTCAGGGCAAACTTGACCCTACTTGACTGGCTAAGGACAAAAGAAGCCTACTCAGCTTCC CAGGAAGCATGGGATAATGTGGCCTTATCAAATTATAAGGATGC ACAATTGCCTCTGGAGGGAAAATATGCAAAGCGGCACTGGTGC CCCCAAAGGGGGATTCCCCAGGGGATCCTCCAGACTTCAACCTGTACTAAGCCCTCCTTAGAATTTTCTCTTGCAGTTGCAATACTGTTTGGGAAAGCGGGATGCAGTTGCATGTATCCAGGCTTTGGTGCTGCTCCTTTGGTGCTGTTTGACCCCAGTGTTCTTTCGAGTCTGGGG TACCTGAAATAATAGTTCACAGCCTTCATTGGATTGCTTATTGGG GTTAGGGTTCCAAGGTAAAAGCTATTGAATCTTCATTTGTGTGTG ATGTTGTGTTTTGGCATATAAGTAAAAGAGCACTCATAAATTAAGATAACTTTCCTAAACAGGCTAGTTTTAAAATTATTGGTGAAGTAAAGGGTTTTATATTTGTCTCTGCTAGATATTTTGAGGTGTTAGGGTTTAACGATCTCGTTTGCGTTTTTTTTTTTTTTTTTTTTTTTTTTTTTGACTGGCAAAAATACGTATGTATTAACTTTGAGGCTCTTACTTAGGTTTATAACTGACTTTAAAAGATAGTGTCTAACATTTCGGTTTACAGAG GTGAATGGGACAAATGTTTTAGATAAGCTTTTTGTGTAAAGTCTTAATTAGAAAGGTTGTGATATGGGGAAATATGTTTCTAAAATTGTGGATTTCTAGCTTTTTAGCGTTTCACTAAAGTTTTAGGTTACTAAGGGCCAGAAAGTTTGTGTTATTAGTGAGAAAAAGAATAATTTAGAAGTTTATGAAACAATGTAGTAAGGAACCAGTAAGTAGAGGAGAACGAT AGAGAATTGGAGATATTTGGCTAATTAACATTTTCATAGTGAAAGTGCATCGGCAGTTTGGCAATTCCTTTTTACTATAGTTAAGCATGA CATTGCTTCACACTGTTTACTGTTTTGTGTGGATAGTGCTGGCATTGCACAGGATGTATGGTGATATTGGTGAACTTAAGGATACTGA GGGCCCTAGGTAAACACTGTAGCCTCCAGGGTAGATTGAGAATTTTCATTTGTTTGCCATTTATTCTCCTCTGGCTTTGCTTGTGTAAAGGCTTTTATTTGGTTCTGTGAATAGTTATTTTGTTCCCTATGC AGGCTACCTTTGTCAGGCTGGCAGGAATTGATGGAGCACACC TTAAGTGTGTTGAGTATATTTTCATAAACAGAATTTGAGTCATAT GAATATTCTTAATTCATGGCAATGTGTTTGTTTGCATATAGTCAAACCTGGCATACTGGCAAAAGGGTAAGAATTTCTTACCAGCCA AGTAAAAGTCACTGTTTATCTCCTCTGTAAAGTTTTGATTAATAT GGTGTGCTTTGTGTCTTTCTGTATTGTTTTGTCATAAAGAGGGGCTGTTCAAGACACACCAGCAGACTGGTCAGTCATGTCTTTGG CAGTGGCAGCCTGGGTTTAGGGTTCAATTCCTGGCTTAGGGA GTGTACTATAAAAGAGCATTAATTAATTAGCTTAATAATAATAA GCCTTCTATTTACTTCATGTAACTTAAGTAATCTTTGGGAAATA AATGTAAATATTTAGTCTAAATTATGCAGGTCAGATATTAGATTTAAATTGCTCAATTTATTTTGGAGCATTAGATTCTAGATAAGGCCT AAGGTTATAAAGAAAGGAGATTTTATATAAGAAAGGATCTTATAAAGAGGGATGTTTAGGACAAGTTAGAAAGTCAAAGCATGTCGT TTATGCAAGAAATATACAATTTAACGGTGATTAGACCTCCTAAACCTGCTTTACAGCTCGGTAAGGCCTGAGACACGTGGAGTCAGAGACTCCACAACTAATATATAATTAAAATCCTTAACTTACCAAAGTTGTAAGTGAGACTACTGAAGCAACAGTTTTACATGCAAGTTACG CATGGGAATGTAGATTTTTTTTTCTGTCTAAAGGGTTAAAGGATGAAGATTTATAAAAATTAATATTGTAAAAAATTATGTGTGTGAAC ATTGAACATCAAAATAAAAGCACAAACAGGGTTTTCTTAAAGCAGTTTATGAGAATCTCACCTTATGGTCAAACGGATTAAGATTGGATAATAGCACACTAATGCAAGGGTGAAATTTGGCTTTCTCTCTTG GTTTGCCTTTTGAATAAACTACCCCCCCACCAAAAAAAAGGAA CTATCAACATGGAAAGGTTTTTGCCTTTTAAAACATTTTTGAGATTTCATAATGTCAAGTGTTTTAAATCTTTAACATATTTAATAG CTCTAACTTTGAGATGCTGCAGAGGGCCCCTGAAGCATCCAGAAGCATTGTCAAAAAGAAAAAAATTTAATCTTCTTCAGGTTATTTTCTAAAATTCCAATATGTCTGAGTATATGCTATCAATCATAACCTTGTCAATTGTGTTTTTAACTATAACTATTTAAAGTCATTTCCAAGCATGCAAAGTCCTAGAATATGGTGTCTTTTAGGAGATTCGGTTTCTAATAAGTTTAGAATTATATCATTTGAACTGGGTAAGAGCTAACCCAAGTAGAACAAAAATTAATTAAATACCAAGAAAATTTTAGATATAAAATTTGAATAAACTCCATCATTTAAATCAAATTGGGGAAACAACTGGTATTCAAGAGGATATGAGTCTAATGTTAA TTCCTAAGTCGTTAAAGCTTTTGTTAGTAAAATTTCTGCATTACTTGATGTGGTGACTTATAAATTGCTAAAATAGTTTATAACCAAT CATCCAGTCACCTGATAGGCCATTTAAACATTTTATAGAGGGAAAAGCTTTCCCATGCAAGAGGGCTGATGTTATAACACTAAGT TGGTTCACTGAGGACAATCAACTCCTTCACAACCTAGAAACTCCATCCACACTACAGCAAAACTTCTGGACTTTGAACTTTGGG ACTGTACACCCATTGGAACCCTTAAGGTAAAGCTAACCAGGGCTTTTCCCAAGATCATGAATCAAGACTTCTCTATTATCATGAAGAATAGAAGTGGAAAAAGGATCTGTTGTGTACAATTATGGG TTTTTCCATGATTTGGAATAAAAGAGGCAAATGTATCCCTCAT ATAGACTAAATTATCTTAAGAAAGTTATGCTAAATAATAGAGT GCCTATGGAGAAAACATCAGGTATTATAGAGATTCAGTTGTA TAGCTCATTGTTTAATCTATTTGAGTTTAGGAGGTTTGGTTTATATTATCCTCCTGATAGTCATAATAATAGTCTCCCTGGTGTGCTAGAATGTCAAATGGCCTCTCTTCAACTGGAATGACAAGAGCATGTGCTGAGTCCAAAAGCCCAAAGTGTTGGTAACTGAGAGT GTGAGAACCTGACCAAAAAAGTGGAATTTTTTTTTTTTTTTTTCAGTGGCACGATCTCGGCTCACTGCAAGCTCCACTTCCCGG CTGGGACTACAGGCACCTGCCACCACGCCCGGCTAATTTTTTTGTATTT GGTCTCGATCTCCTAACCTCATGATCTGCCCACCTCGGCCTCCCAAAG CAAAAAGGGGAATTTTTTTTAAACAAAATTATGGGAGGTCATTTTTTTGT AAACCAAAACGGAGTCACGTATGCCAAGACCTTAAGGAAACACATAG CCTACAAATCTCTATAACAAACATTCCTGACAGCATAGATATCCACCCC TCTCGCCAAAAGACCATCAAGCTTCAGATGATCATGCAACAAAAGTTT CCCTGCCTTCACTAGAAAGAGCAGAGCAGGACTTCTGTGATCCTCAAT TACAAAAGAAAGACCATCGGCCCCTCCACCTCCCATAAAGATTTATGG AGGGTCTGTAGGCAAGGAATATAAGGCAGATGCATGCTCACTTCCTA AAATGTCTTCTGTATTTACATAGGGCATACACTGAGTAACCAATGGAA ACCGGGCTATTGAGCCCCTATGCTCAAGCCCTCTGCCACCCTGTGGA TTCATF CCGCACCCGGAAGATGAGGCTCGCCGTGGGAGCCCTGCTGGTCTGCTGGATGCAGGTTTGGTGTATGATGCTTACCTGGCTCCCAATAACCTGA ATCCACAGACTTTCTATTATGCTGTTGCTGTGGTGAAGAAGGATAGTG GCCACACGGGTCTAGGCAGGTCCGCTGGGTGGAACATCCCCATAGG CTTGAGAAAGCAGTGGCCAATTTCTTCTCGGGCAGCTGTGCCCCTTGT GTGTCCAGGGTGTGGCTGCTCCACCCTTAACCAATACTTCGGCTACTC ATGTGGCCTTTGTCAAGCACTCGACTATATTTGAGAACTTGGCAAACAA CAACACCCGGAAGCCGGTAGATGAATACAAGGACTGCCACTTF CTGCAGCCCTGGAGTCAGGAGCAGAGCCCCCCGGCTCCCAGCCCGCCAATGGCTGCATTGTGCTTCATGTCCCTTCCCATCAACATTTCTGTGCT GAAAATGAGGGCTGTGTCTGGCTGTCCCTGATAAAACTGTGAGATGG GAGTTTCCGCGACCATATGAAAAGCGTCATTCCATCCGATGGTCCCAG ATCAGGGCCATTGCGGCAAACGAAGCGGATGCTGTGACACTGGATG CCTGAAGCCTGTGGTGGCAGAGTTCTATGGGTCAAAAGAGGATCCAC CYP2ECATGTCTGCCCTCGGAGTCACCGTGGCCCTGCTGGTGTGGGCGGCCTTC1 AGCAGCTGGAATCTGCCCCCAGGCCCTTTCCCGCTTCCCATCATCGGGAA TCCTTCACCCGGTTGGCCCAGCGCTTCGGGCCGGTGTTCACGCTGTACGT ACAAGGCGGTGAAGGAAGCGCTGCTGGACTACAAGGACGAGTTCTCGGG GGACAGGGGAATCATTTTTAATAATGGACCTACCTGGAAGGACATCCGGC TGGGGAAACAGGGCAATGAGAGCCGGATCCAGAGGGAGGCCCACTTCCT CTTTCGACCCCACCTTCCTCATCGGCTGCGCGCCCTGCAACGTCATAGCC ATGAGAAGTTTCTAAGGCTGATGTATTTGTTTAATGAGAACTTCCACCTACT CCCAGCTTTCTACACTACTTGCCTGGAAGCCACAGAAAAGTCATAAAAAAT GTGAAGGAGCACCATCAATCTCTGGACCCCAACTGTCCCCGGGACCTCAC GCACAGTGCAGAGCGCTTGTACACAATGGACGGTATCACCGTGACTGTGG GCACAACTCTGAGATATGGGCTCCTGATTCTCATGAAATACCCTGAGATCG TTGGGCCAAGCCGAATCCCTGCCATCAAGGATAGGCAAGAGATGCCCTAC ATCACCCTCGTGCCCTCCAACCTGCCCCATGAAGCAACCCGAGACACCAT CGTAGTGCCAACTCTGGACTCTGTTTTGTATGACAACCAAGAATTTCCTGAT AAAATGGAAAGTTCAAGTACAGTGACTATTTCAAGCCATTTTCCACAGGAA TGGAGTTGTTTCTTTTGTTGTGTGCCATTTTGCAGCATTTTAATTTGAAGCC ATACATATTGGGTTTGGCTGTATCCCACCACGTTACAAACTCTGTGTCATT CCCCCCGCTTTCAAACAAGTTTTCAAATTGTTTGAGGTCAGGATTTCTCAA TAAATATTTTCCCAGAATATAAATAAATCATCACATGATTATTTTAACTATA CYP2EGCAGCTCAGCGTGCGGGCAGAGCCGGCTGACAGGAGACAGGACACAGCA1 CGTTCCTGCACCAGCGTGGCTTGCCCTTTGGACGCGGCGAGTTAACTTGA TTCTGGCCCCATTCATGTGGCAGGTGGTGATTCAGGATTGTCTCCCGGGC CCTCGGAGTCACCGTGGCCCTGCTGGTGTGGGCGGCCTTCCTCCTGCTG GAATCTGCCCCCAGGCCCTTTCCCGCTTCCCATCATCGGGAACCTCTTCCA CGGTTGGCCCAGCGCTTCGGGCCGGTGTTCACGCTGTACGTGGGCTCGC GTGAAGGAAGCGCTGCTGGACTACAAGGACGAGTTCTCGGGCAGAGGCGA GAATCATTTTTAATAATGGACCTACCTGGAAGGACATCCGGCGGTTTTCCCT ATGAGAGCCGGATCCAGAGGGAGGCCCACTTCCTGCTGGAAGCA CTCATCGGCTGCGCGCCCTGCAACGTCATAGCCGACATCCTCTT CTGATGTATTTGTTTAATGAGAACTTCCACCTACTCAGCACTCCCT CTTGCCTGGAAGCCACAGAAAAGTCATAAAAAATGTGGCTGAAGT ATCTCTGGACCCCAACTGTCCCCGGGACCTCACCGACTGCCTGC TTGTACACAATGGACGGTATCACCGTGACTGTGGCCGACCTGTTC GGGCTCCTGATTCTCATGAAATACCCTGAGATCGAAGAGAAGCTC CCTGCCATCAAGGATAGGCAAGAGATGCCCTACATGGATGCTGT CAACCTGCCCCATGAAGCAACCCGAGACACCATTTTCAGAGGATA CTCTGTTTTGTATGACAACCAAGAATTTCCTGATCCAGAAAAGTTT ACAGTGACTATTTCAAGCCATTTTCCACAGGAAAACGAGTGTGTG TGTGTGCCATTTTGCAGCATTTTAATTTGAAGCCTCTCGTTGACCC CTGTATCCCACCACGTTACAAACTCTGTGTCATTCCCCGCTCATGA GTTTTCAAATTGTTTGAGGTCAGGATTTCTCAAACTGATTCCTTTC TAAATAAATCATCACATGATTATTTTAACTAT CYP2GTTGGAATTGAAGAATATTCCCAAGTCCTTCACCCGGGAATCATTT1 CCCTGACCACCCTCCGGAACTATGGGATGGGGAAACAGGGCAAT AGCACTCAGGAAGACCCAAGGCCAGCCTTTCGACCCCACCTTCC TCTTCCGCAAGCATTTTGACTACAATGATGAGAAGTTTCTAAGGC TCCCTGGCTCCAGCTTTACAATAATTTTCCCAGCTTTCTACACTAC GAAGTAAAAGAGTATGTGTCTGAAAGGGTGAAGGAGCACCATCAA CTGCTCGTGGAAATGGAGAAGGAAAAGCACAGTGCAGAGCGCTT GTTCTTTGCGGGGACAGAGACCACCAGCACAACTCTGAGATATG AGCTCCATGAAGAAATTGACAGGGTGATTGGGCCAAGCCGAATCC CTGTGGTGCATGAGATTCAGCGGTTCATCACCCTCGTGCCCTCC GGATACCTCATCCCCAAGGGCACAGTCGTAGTGCCAACTCTGGA AAGTTTAAGCCAGAACACTTCCTGAATGAAAATGGAAAGTTCAAGT GTGTGCTGGAGAAGGCCTGGCT CYGTTGGAATTGAAGAATATTCCCAAGTCCTTCACCCGGGCCAGCCT1 GTCATAGCCGACATCCTCTTCCGCAAGCATTTTGACTACAATGAT CCACCTACTCAGCACTCCCTGGCTCCAGCTTTACAATAATTTTCC ATAAAAAATGTGGCTGAAGTAAAAGAGTATGTGTCTGAAAGGGT GGACCTCACCGACTGCCTGCTCGTGGAAATGGAGAAGGAAAAGC TGACTGTGGCCGACCTGTTCTTTGCGGGGACAGAGACCACCAGC CTGAGATCGAAGAGAAGCTCCATGAAGAAATTGACAGGGTGATT ATGCCCTACATGGATGCTGTGGTGCATGAGATTCAGCGGTTCAT AGACACCATTTTCAGAGGATACCTCATCCCCAAGGGCACAGTCG ATTTCCTGATCCAGAAAAGTTTAAGCCAGAACACTTCCTGAATGA CCACAGGAAAACGAGTGTGTGCTGGAGAAGGCCTGGCT CYCCCTGTGAGGCACAGACTCTCCAGGGCACGCGGGTCCCGCCTG1 TTCCGATGTTGAATTTTCCTTCTGGCCCCATTCATGTGGCAGGTG AGCGGCACCATGTCTGCCCTCGGAGTCACCGTGGCCCTGCTGG AGGTGCACAGCAGCTGGAATCTGCCCCCAGGCCCTTTCCCGCT ATTCCCAAGTCCTTCACCCGGTTGGCCCAGCGCTTCGGGCCGGT GCACGGCTACAAGGCGGTGAA CDTAAAAAAAGGGGGCTCGTCTTTTCGGGGTGTTTTTCTCCCCCTCB CGGCAAGGTTTGGAGAGCGGCTGGGTTCGCGGGACCCGCGGG TCCGCTTGCCTGGTCCCCTCTCCTCTCCGCCCTCCCGCTCGCCA GCTTCCCCGCAGCCCCTGCGCGCTCCTAGAGCTCGGGCCGTGG CTGGGCTTCCGAGAGGGGTTCGGGCTGCGTAGGGGCGCTTTGT TCGTGCAGACCCGGGAGAAAGATGTCAAACGTGCGAGTGTCTAA CGGAGCACCCCAAGCCCTCGGCCTGCAGGAACCTCTTCGGCCC CTGCAGAGACATGGAAGAGGCGAGCCAGCGCAAGTGGAATTTC GGCAAGAGGTGGAGAAGGGCAGCTTGCCCGAGTTCTACTACAG CGCAGGAGAGCCAGGATGTCAGCGGGAGCCGCCCGGCGGCGC GGTGGACCCAAAGACTGATCCGTCGGACAGCCAGACGGGGTTA CCGACGATTCTTCTACTCAAAACAAAAGAGCCAACAGAACAGAAGA AGCAGACGCCCAAGAAGCCTGGCCTCAGAAGACGTCAAACGTAAA CATCACTGCTTGATGAAGCAAGGAAGATATACATGAAAATTTTAAAA AGCACTGAAAAACAACAACACAATAACACTAAAATTTTAGGCACTCT GCAATTAGGTTTTTCCTTATTTGCTTCATTGTACTACCTGTGTATATA GAGGGCAGGGTGGGGCTGAGGAACTGACGTGGAGCGGGGTATGA ACTTGCATGAAGAGAAGCAATTTTGGGGAAGGGTTTGAATTGTTTTC TCATTTAAAAAAATCACAAAAATTTGAACACTGGCTAAAGATAATTG CTGGTGATCTCCCAAGCTATCTAAAGTTTGTTAGATAGCTGCATGT CCTCCCCAGTCTCTCTTAAAGTTGGAATTTACCAGTTAATTACTCAG CCGAGGTGCTTGGGAGTTTTGAATGTTAAGAATTGACCATCTGCTTT TTCGGGCTGTGTAAACACAGTCAAAATAATTCTAAATCCCTCGATATT ATTTTTTAATTTAAAGCTTACTCTGTCCATTTATCCACAGGAAAGTGT GTAGGATAAGTGAAATGGATACTACATCTTTAAACAGTATTTCATTG CATAACTCTGTAAAAACACTGAAAAATTATACTAACTTATTTATGTTAA GCATGTTTTGTGCATTTGTAAATGCTGTGTTGGGTAGAATAGGTTTT TGCATACTGAGCCAAGTATAATTTTTTGTAATGTGTGAAAAAGATGC CCATAGCTA CDKNACTAAAAAAAGGGGGCTCGTCTTTTCGGGGTGTTTTTCTCCCCCTCB GCCGGCAAGGTTTGGAGAGCGGCTGGGTTCGCGGGACCCGCGGG TCTCCGCTTGCCTGGTCCCCTCTCCTCTCCGCCCTCCCGCTCGCCA GGCTTCCCCGCAGCCCCTGCGCGCTCCTAGAGCTCGGGCCGTGG CGCTGGGCTTCCGAGAGGGGTTCGGGCTGCGTAGGGGCGCTTTGT GGTCGTGCAGACCCGGGAGAAAGATGTCAAACGTGCGAGTGTCTAA GGCGGAGCACCCCAAGCCCTCGGCCTGCAGGAACCTCTTCGGCCC CACTGCAGAGACATGGAAGAGGCGAGCCAGCGCAAGTGGAATTTC GTGGCAAGAGGTGGAGAAGGGCAGCTTGCCCGAGTTCTACTACAG GGCGCAGGAGAGCCAGGATGTCAGCGGGAGCCGCCCGGCGGCGC GGACCCAAAGACTGATCCGTCGGACAGCCAGACGGGGTTAGATTCTTCTACTCAAAACAAAAGAGCCAACAGAACAGAAGAACGCCCAAGAAGCCTGGCCTCAGAAGACGTCAAACGTAAACGGGGCCTTCAGACCTCACGATACCTGATCTTACTGGTTGC GAGGTCAAAAAAGTAGCAATGGGGAAGGCTGGGGATACG CTGTTGACCAGAGCAGCTACTTGTAACCCAGGCCCCATCGGGAGCAATAGGTTCTTTGCCCATCCGAACAAGAACTAGGGTAGCTTGAGTCGGTAACAGATTTTGAGCCATACATGGAAAAAGTAGAAATTGCTCATCTTTGGTTATGCAAGGGATTAGAGAT TCACTTTCCCTGTTGTCTCCTAAGTTTGGAGAGAGAAGGAAAGTTTCTACAGAATTTCTGGTAACACTGAAGTTGCAAAGCAGGCCAGTGTATGCTAATTGTGCCGTAACAGGGTGATTTGGATTAGGTCAGCCCAGCACAAAGGAAGTGGAGATTTTTCCATGC CCCAGATAACCAACATGGGTTGGTTATTCATAATAAACTAC TCTTTATTTTCTAAAGCACACACGTAGTTTAGCATATGAGGCTTTAAAATAACAGGGATTAAGGTGAGATTCAGGTTTGTTGTGTACAAAACGGCACTATAGAACCTCCATTTTACAGCACCATAT ATGCGCAGCCCTTGTTGGTTTGTGACTTGTGGCCTAGCTCATGTTCTGACATGCAATGAGGCATTTGTAGGATTTAGTAATAT AAGTATTCATGAGTATTTTCTGCATATGAATCAGGAATTAGA TATAATTTTTATTCCCAATCATTTTTCAAATTTAGAAAGTTTA AAATTTTTACCCGTAAGTATTACAGTTTCCTAATTATCCTATT TCAGCCTCTGCACTAATGACATTTTGGGCCGAATAATTCTGCCTGGCCTCTCACACTAGATGCCAGCAGTATCCTCCTCCCC CTGTGGGGCGGGGGCAACATTGCCTACTGTTAAGAACTACATCCAGTTAAGAGAATGTTAGGTGGAGATGACTATAGTCAT AAATAATTCCTGTACTCTACTGGTAACGTTAATCTAGTGCT ATGTTTCCTTGTTTATCAGATACATCACTGCTTGATGAAGC CATGGAATGGACATCCTGTATAAGCACTGAAAAACAACAAC AAAAGCGTTGGATGTAGCATTATGCAATTAGGTTTTTCCTTATTAGCACATAAACTTTGGGGAAGGGAGGGCAGGGTGGGGCTG TACAGCAAGTAGATAAATATTTGACTTGCATGAAGAGAAGCA CCCTTTCAGAGACAGCTGATACTTCATTTAAAAAAATCACAAGAAGTTTATTCTCATTTGGGAGATCTGGTGATCTCCCAAGCTA AACAGAAACCTATCCTCACTGCCCTCCCCAGTCTCTCTTAAACCAGGTAGTTTGGGGCAAAAATCCGAGGTGCTTGGGAGTTTTAAATTTTCTCATTTTCTTTTCACTTCGGGCTGTGTAAACACAGTAACTTCACATTAAAAAATGAAATATTTTTTAATTTAAAGCTTAGTTCATGTAGAGAAAAGCACACTTGTAGGATAAGTGAAATGG ACCATTTGAAGTGTACCTGTGTACATAACTCTGTAAAAACACTTAGACAATATACAAGCCAAAGTGGCATGTTTTGTGCATTTGTA GGGAGCCCTAGCCTGGAGCGGATGGACGCCAGGCAGGCGGGTGGACCACGAAGAGTTAACCCGGGACTTGGAGAAGCACTGATTTTCAGAATCACAAACCCCTAGAGGGCAAGTACGAGTGG CCCCCGCGGCCCCCCAAAGGTGCCTGCAAGGTGCCGGCGCTTTAATTGGGGCTCCGGCTAACTCTGAGGACACGCATTTGGGCGGAGCAATGCGCAGGAATAAGGAAGCGACCTGCAACCGA ATTTTAAAAATACATATCGCTGACTTCATGGAATGGACATCCT GGCACTCTTAAATGATCTGCCTCTAAAAGCGTTGGATGTAGCGTGTATATAGTTTTTACCTTTTATGTAGCACATAAACTTTGGGGGGGTATGAAGAGCTTGCTTTGATTTACAGCAAGTAGATAAA AATTGTTTTCTTTAAAGATGTACGGAGCACCCCAAGCCCTCGGCCTGCAGGAACCTCTTCGGCCTGCAGAGACATGGAAGAGGCGAGCCAGCGCAAGTGGAATTAAACAAAAGAGCCAACAGAACAGAAGAAAATGTTTCAGACGG TGGCCTCAGAAGACGTCAAACGTAAACAGCTCGAATTAAGA GCAAGGAAGATATACATGAAAATTTTAAAAATACATATCGCTGACT ACACAATAACACTAAAATTTTAGGCACTCTTAAATGATCTGCCTCT ATTTGCTTCATTGTACTACCTGTGTATATAGTPCF11 TGGAGCCGCCACTGCCGCCGCCATTTTGTGTCTGTGGAGAAAGCGAGACGGCGGCGTTTCATACCCGAGGTTCCCCCTGTGTCGTC AGCCGCGAGAGAGCCGGGGAGAGGAAGAGGAGTCGGAAGGGA GACCTCGGAGGGGGGCCGCGGCGCAATGTCAGAGCAGACGCC TGTCGGGATTATCAGTCATCGCTCGAAGACCTGACCTTCAATAGC ACCTGCCCTTCGCCAAGGAGATCGTCTCTCTCATCGAGGCCCA TACCTTATGGATTCTATTGTGAAAAACGTTGGAAGAGAGTATCTC GTTTGAAAAGGTGGATGAAAATACTAGGAAAAGTTTATTTAAGTTA TGCCCTGGATGTCAGAGTCAATTCATTAGATCCTGCTTGGCCTAT GTGAATCCTAAATTTTTAAATAAATCGCCCGAGGAGCCTTCAACA CAATTGTTCCTGATATACAAAAGAATCTTACACAAGAACAACTAA ACTTCAGCAGAAAAAGCTGGAGCTTGAGCTAGAGCAAGCTAAGG CAATTTAGGTCCTGGATCTGCACCATCCAAATTACATGTTTCACA GTGCAATCTGAGAAAAGCCGTCCAGGACCATCCTTACAAATTCA ATAAGCCAACATTCTCATGGAAAAGATCAGAGTCACAGGAAAGA GTAAAACTATACCCTCTGAAAAACTAAATTCATCCAAGCAAGAAA CCAATTAGATTCTAAATCGAAATCGAAATCGAAATCACCCTCACCT AGAATCGGAAAGTATGAGGTTGTCTGATATGAACAAGAGAGATC AGATGATGATGTGAAAGAGAAGAGAAAAACTGCAGAAAAAAAGG TGGAAGTAGAAATAAAATCATAAATGGCATTGTACAAAAACAGGA GGGAGATCGAGTACTAGAAAGCGATCAAGATCTCGATCACCCAA AGGCGGTCACCCAAACGAAGGCAAAGAAGTATGTCTCCAACATC CAGTCACATATGGAAGAGTTTACACCACCTTCTAGGGAAGACAG AGGCGAATGAAAAAGACTGAAGAGGAGCGACCACAAGAAACTAC AATGTAGAAAACTGGCAAAGTTCCAAGTCTGCCAAAAGATGGAA GTAAACCTCCTCATCTGAGGCATAGGGAGAGCTGGTCCATCGATTAAGTGTAGATGCCAATCTTCAGATTCCTAAA ACGTTTAGCATCTGGTGAAATTACACAGGATGACTTCCAAACATAGATGCAATGTACGGGATAGTCCTACAGAAGA AACCTACTATGAACATAAAGCAAAACTGAAAAGGACAC TTGACTACCCTTTGACTGATGCCTTGTTGTCTGGAATACACAGTTTGACAGAAAAGAACAATTTAGTGAAAGAGCATTCACCCCATGAGGGCCGGAGAAGACATGACGAGCAAATCGTTTTCCACTTAAGCGACCTCGATATGAAGATTCAG ACAAATCAGCGACTTACAGCTTTAGCTGAAGACAGACAACGAAGATGATTTTTGAAGGACCCAATAAATTAAGCCGTCACCAGGACAAATGGGGGGAGGAGGCCCTTTGAGA TTGAAGGTCCTCCAGGACCAGTGGGGACACCTCTGCG GAAGGTTCCCCTGGTCTGAGGTTTGAGGGATCTCCAGTGAGGTTTGAGGGACATCGTGGTCAACCTGTGGGTGG TTTGATAATCCCCGAGGTCAGCCTGTAGGTGGACTTAG GGACCTCATGGTCAGCCAGGAGGTGGAATCAGATTTGCCCATGGTCAGTCAGTAGCTGGTCTGAGATTTGAGGGAGTCAGCCAGGGGTTGGTATCAGGTTTGAAGGCCCTTTA GAGGTGGCCTGAGAATTGAAGGGCCTCTGGGTCAAG CCAGGTCAGCCGTCACTCTTGCCAAGATTTGATGGATAGGCCCTCAGAGGTTTGATGGACCACCTGGACAGCAG ACATCAGCAAGCATCAAGGTTTGATATTCCTCTTGGTCGTATCTTTCAATCAGACTGGTCCATATAATGATCCACCT TGAACAAATATTTGATTCACCTCAAGGACCAAATTTTAA GAGCTTCTGGACACTATTTTGATGAAAAAAATCTTCAGAGGAAATATTCAGGCATCTCAACAGGTTCTGAGTGGTGCATCCACAAAATCCTGGATTTGTTCAGAATCCTTCAGG TAAATGAATTGTTTTCAAAATTGCTAAAAACAGGAATTC GTAACTGCTCAGCCTCCCCCTGAAGAGGAGGAAGATCAAA GAATTGAAACAACGTTATGACAGTGTTATAAATCGACTGTAC ACAGACAGATGTTTATGCAGATCATTTGGACTGGCATTATC TAGACGTTGGTACTACAGTTTAACAGACTGGATAGAATTTGA GAAAAGGTGCATGAAGAAGTTGTGCTCAAAACTCAAGAGGC GGAGCAGTTGAGAGTTGTGAAATCTGTCAAGAACAATTTGA GCTATTAGAGTAGATGGAAAGATTTATCATCCATCATGTTAT AGCAAGACACCAGTTGAAAACCCCTTGAATATTATGTTGAA GTTAAGGAAGAACGAATTGATACACCACCAGCTTGTACAGA ACAGTCGAGTCAGTTTAAATAAAATGAGAAAGGTATGTTTTT TTTTATGTATATATAGACATATCTATATAAATTGTCTGGCTGA ATTTGCATTTCCTACTGCCTGCAGAGTTTCAGGTGCTTGTTG GTATGTGTAAAAATGTACGATTTTTCACTGTGCAACTGTAAA GCACACCATCAAATAGTTTCTGTACTTTTTATTGGGTAAAAA CCTCCCACTGATTAAAGAAGCAAGTTTGAGGTTTCATCCTTC GAAAAGCCAGATTTTGAAAAAATTTTAAAGATAAAATAGGAC GTATAGAGAACCATCCAGATGTTCACTTTTGAAAATATCTAA ACAATTAACAAATATATTTAAGTACTAAAGGTGATTTTTTTTT ATTTCTATTTTAAGTAACGGGAATCTGTAAGAATGTTTGCTT ACACCATGAGATGTTAATATTCATACATGTAATAAATAGAATPCF CCGGGGGCGGGGCTCGTGACGTTGCCGGGACAGCCAATCCCCCTCCCCTAGTTCATTTCGCACGACGCAGCGGTTGGGAA TTTGTGTCTGTGGAGAAAGAAGCTTCTGTGGCGGCTGGAAG GGTTCCCCCTGTGTCGTCCCCCATCCCCCCTCCGCGGTCA AAGAGGAGTCGGAAGGGAGGCGGGGTATCCAGAGCGGCT CAATGTCAGAGCAGACGCCGGCCGAGGCCGGTGCTGCGG AAGACCTGACCTTCAATAGCAAGCCGCACATCAATATGCTG TCTCTCTCATCGAGGCCCAAACCGCCAAGGCTCCTTCCTC CGTTGGAAGAGAGTATCTCACTGCCTTTACTAAAAATCTAG GGAAAAGTTTATTTAAGTTACGTTCTACATGGGATGAAATAATTAGATCCTGCTTGGCCTATTAAACCTCTACCCCCCAATGT GCCCGAGGAGCCTTCAACACCTGGTACAGTGGTCAGTTCCTCTTACACAAGAACAACTAATAAGGCAGCAGTTACTGGCAA GAGCTAGAGCAAGCTAAGGCACAGTTGGCAGTTTCTCTTA TCCAAATTACATGTTTCACAGATTCCCCCTATGGCAGTTAAGGACCATCCTTACAAATTCAGGATTTAAAAGGAACTAACCGGATCAGAGTCACAGGAAAGAATTTCTAATGAACACATTAAACAAATTCATCCAAGCAAGAAAAAAGTAAATCAGGTGAAAAAATAATCGAAATCACCCTCACCTTTGAAAAACAAATTATCTCACA GATATGAACAAGAGAGATCCAAGATTAAAAAAACATCTTCA AAAACTGCAGAAAAAAAGGATAAAGATGAGCACATGAAGTC GCATTGTACAAAAACAGGATACAATAACAGAAGAGTCAGAA CAAGATCTCGATCACCCAAGTCTAGGTCACCAATTATACAT GAAGTATGTCTCCAACATCGACACCTAAAGCTGGAAAGATTCACCTTCTAGGGAAGACAGAAATGCTAAGAGAAGTACTAAA AGCGACCACAAGAAACTACAAATCAGCATTCTACAAAGTCAAGTCTGCCAAAAGATGGAAATCTGGTTGGGAAGAAAATAAA GCATAGGGAGAGCTGGTCAAGCACTAAAGGAATTTTATCACCAATCTTCAGATTCCTAAAGAGTTAACTCTTGCAAGCAAAAG TTACACAGGATGACTTCCTTGTTGTTGTGCATCAAATTCGACTCCATTCAATGATCGTTTTCCACTTAAGCGACCTCGATATGGCCGGCCTGGATACAAATCAGCGACTTACAGCTTTAGCTGAAGAGATGGCCCAACGAAGATGATTTTTGAAGGACCCAATAA GGTTTGATGGGTCACCAGGACAAATGGGGGGAGGAGGCCGTCCTTTGAGATTTGAAGGTCCTCCAGGACCAGTGGGGACAGGTTTTCGGTTTGAAGGTTCCCCTGGTCTGAGGTTTGAGGG CTGTGGGTGGTCTGAGGTTTGAGGGACATCGTGGTCAACCTG GGTGGACTTAGATTTGATAATCCCCGAGGTCAGCCTGTAGGTCGATTAGGTTTGATGGACCTCATGGTCAGCCAGGAGGTGGAAT GGTTTGAGGGCCCCCATGGTCAGTCAGTAGCTGGTCTGAGAT AGGGTCCACATGGTCAGCCAGGGGTTGGTATCAGGTTTGAAG CCTTCTGTACCAGGAGGTGGCCTGAGAATTGAAGGGCCTCTGGTTTGATGGGCAGCCAGGTCAGCCGTCACTCTTGCCAAGATTTTCCTGGTCAGCCAGGCCCTCAGAGGTTTGATGGACCACCTGG TGATGGTCCACAACATCAGCAAGCATCAAGGTTTGATATTCCTAGGCTTGAATCAGTATCTTTCAATCAGACTGGTCCATATAATGA GTTCCAAAGACATGAACAAATATTTGATTCACCTCAAGGACCA AATCCACTTAACAGAGCTTCTGGACACTATTTTGATGAAAAAAATCCAATGACAGTAGGAAATATTCAGGCATCTCAACAGGTTCTGGTTTTTACCAGTTCATCCACAAAATCCTGGATTTGTTCAGAATC GTCAGGTGGATGTAAATGAATTGTTTTCAAAATTGCTAAAAACAGTAAGTGAAGTAACTGCTCAGCCTCCCCCTGAAGAGGAGGAA CAGTTGAAGAATTGAAACAACGTTATGACAGTGTTATAAATCGTACAACATCACAGACAGATGTTTATGCAGATCATTTGGACTGG GTCACTCATAGACGTTGGTACTACAGTTTAACAGACTGGATAG CAGTTTTTTGAAAAGGTGCATGAAGAAGTTGTGCTCAAAACTCGGACCAGCTGGAGCAGTTGAGAGTTGTGAAATCTGTCAAGAACTTGAAAAATGCTATTAGAGTAGATGGAAAGATTTATCATCCATCCCATCTCCCAGCAAGACACCAGTTGAAAACCCCTTGAATATTA GTCCCAAAGTTAAGGAAGAACGAATTGATACACCACCAGCTTGAAAATGACACAGTCGAGTCAGTTTAAATAAAATGAGAAAGGTA AAGAATTTTTTTATGTATATATAGACATATCTATATAAATTGTCT ATTTTAGTATTTGCATTTCCTACTGCCTGCAGAGTTTCAGGTGAATGAAATTGTATGTGTAAAAATGTACGATTTTTCACTGTGCAATAATATTTATGCACACCATCAAATAGTTTCTGTACTTTTTATTGG TTTCTAGTAGCCTCCCACTGATTAAAGAAGCAAGTTTGAGGTTTC TTTCTCAAATAGAAAAGCCAGATTTTGAAAAAATTTTAAAGATAAACACATCTCCAGGTATAGAGAACCATCCAGATGTTCACTTTTGAAAA ATGCCATCAAACAATTAACAAATATATTTAAGTACTAAAGGTGATTAGATGAACATATTTCTATTTTAAGTAACGGGAATCTGTAAGAATGT CTTAGATGGACACCATGAGATGTTAATATTCATACATGTAATAAAGAAAAGCTTTAGAATGTGACTTTCTTGTTGTCTTTCATCTGTTTTTT AGACAGGTTAGTCTTTTCTGCCATTTATTGGAGATAGGCATATAA TAGCACTTTCTACATGTATTTTCTCTGGTATTCACATCTAATAACTCCACTCACTTTAAAATTTTTATAAGAATTTGAACGTGGCTTTGTTTCCAAATTGATTGTTAGGATAGAAATAAGCACACCAAACTACTGGA GTCTTGGAGGATAACCAGGAGTGGAGTCCATACTGATGGGAAGATACTTTTGTGTTTTCAAAAATTGACTTCTTATGGTTAAAACTCAGTGAAATGGAGTCTCACTACGTAGTCCAGGCTGGTTTCGAATTCCTGGGGATTACAGGCATGAGCCACGTGCCCAGCCTTTATTTTTAAGTA CTGATGACCAGAGCAGCCACTAGAAATTTTAAACAGGGTGACAT GAATACAATTTTAGAGATTGCTAAATCCAGAGAGGTCCAGTGGGAGCTGAACTTACGTATATGAACACTGCCATAGGAACTGAGGTCTG TCTGGGGAAACCACCATAGCTTTTATCAAATGCTTAAAGGTATGG TCAACGGTATCCACATGGAGAAGAGGGTCAAGGATGGGGGAACAACCAGCAATGGGAAAATTTTTTTTTTTCTTTTTTTGAGACAGTCTT CGGCTCAGTGCAGTGGCACAATCTCGGCTCACTGCAACCTCTG GTAGCTGGGATTACAGGTGCCCGCCACCACGCCTGGCTAATTTT GCTGGTCTCGAACTCCTGACCTTAAGTGATCTGCCCGTCTTGGC AATTTCAATGGACGAGGTAGTCAACAAAATGAAGTCAAGAAAATAGCTGAGTATGGGTGCGAGCTGGAGCCGCCACTGCCGCCGCCATTTTGTGTCTGTGGAGACCGCGAGACGGCGGCGTTTCATACCCGAGGTTCCCCCTGTGTC GGAGCCGCGAGAGAGCCGGGGAGAGGAAGAGGAGTCGGAAG CGGACCTCGGAGGGGGGCCGCGGCGCAATGTCAGAGCAGACCCTGTCGGGATTATCAGTCATCGCTCGAAGACCTGACCTTCAAT GAACCTGCCCTTCGCCAAGGAGATCGTCTCTCTCATCGAGGC TGTACCTTATGGATTCTATTGTGAAAAACGTTGGAAGAGAGTATGTGTTTGAAAAGGTGGATGAAAATACTAGGAAAAGTTTATTTAAGTATGCCCTGGATGTCAGAGTCAATTCATTAGATCCTGCTTGGCC TGTGAATCCTAAATTTTTAAATAAATCGCCCGAGGAGCCTTCAACCAATTGTTCCTGATATACAAAAGAATCTTACACAAGAACAACTAACTTCAGCAGAAAAAGCTGGAGCTTGAGCTAGAGCAAGCTAACCAATTTAGGTCCTGGATCTGCACCATCCAAATTACATGTTTCATGTGCAATCTGAGAAAAGCCGTCCAGGACCATCCTTACAAATTC ATAAGCCAACATTCTCATGGAAAAGATCAGAGTCACAGGAAAGGTAAAACTATACCCTCTGAAAAACTAAATTCATCCAAGCAAGAACCAATTAGATTCTAAATCGAAATCGAAATCGAAATCACCCTCACCAGAATCGGAAAGTATGAGGTTGTCTGATATGAACAAGAGAGATCGATGATGATGTGAAAGAGAAGAGAAAAACTGCAGAAAAAAAGG GGAAGTAGAAATAAAATCATAAATGGCATTGTACAAAAACAGGA GGAGATCGAGTACTAGAAAGCGATCAAGATCTCGATCACCCAAGGCGGTCACCCAAACGAAGGCAAAGAAGTATGTCTCCAACATC AGTCACATATGGAAGAGTTTACACCACCTTCTAGGGAAGACAGGGCGAATGAAAAAGACTGAAGAGGAGCGACCACAAGAAACTAC ATGTAGAAAACTGGCAAAGTTCCAAGTCTGCCAAAAGATGGAAAACATAGTAAACCTCCTCATCTGAGGCATAGGGAGAGCTGGTC AACAGCATCGATTAAGTGTAGATGCCAATCTTCAGATTCCTAAAGAGTGAACGTTTAGCATCTGGTGAAATTACACAGGATGACTTCCAAGGTAAACATAGATGCAATGTACGGGATAGTCCTACAGAAGA TGAATTAACCTACTATGAACATAAAGCAAAACTGAAAAGGACAC ATATTTTTGACTACCCTTTGACTGATGCCTTGTTGTCTGGAATA TGGAGCACAGTTTGACAGAAAAGAACAATTTAGTGAAAGAGCA AATCTTTCACCCCATGAGGGCCGGAGAAGACATGACGAGCAA CAATGATCGTTTTCCACTTAAGCGACCTCGATATGAAGATTCAG CTGGATACAAATCAGCGACTTACAGCTTTAGCTGAAGACAGAC GGCCCAACGAAGATGATTTTTGAAGGACCCAATAAATTAAGCC GATGGGTCACCAGGACAAATGGGGGGAGGAGGCCCTTTGAGA GAGATTTGAAGGTCCTCCAGGACCAGTGGGGACACCTCTGCG GGTTTGAAGGTTCCCCTGGTCTGAGGTTTGAGGGATCTCCAGPCF1 GCCGCCGCCATTTTGTGTCTGTGGAGAAAGAAGCTTCTGTGGCTTTCATACCCGAGGTTCCCCCTGTGTCGTCCCCCATCCCCCCT CCGGGGAGAGGAAGAGGAGTCGGAAGGGAGGCGGGGTATCC GGCCGCGGCGCAATGTCAGAGCAGACGCCGGCCGAGGCCG GTCATCGCTCGAAGACCTGACCTTCAATAGCAAGCCGCACAT CCAAGGAGATCGTCTCTCTCATCGAGGCCCAAACCGCCAAGG CTATTGTGAAAAACGTTGGAAGAGAGTATCTCACTGCCTTTACT GATGAAAATACTAGGAAAAGTTTATTTAAGTTACGTTCTACATG CAGAGTCAATTCATTAGATCCTGCTTGGCCTATTAAACCTCTAC TTTTAAATAAATCGCCCGAGGAGCCTTCAACACCTGGTACAGT TATACAAAAGAATCTTACACAAGAACAACTAATAAGGCAGCAG AAGCTGGAGCTTGAGCTAGAGCAAGCTAAGGCACAGTTGGCA GGATCTGCACCATCCAAATTACATGTTTCACAGATTCCCCCTAT AAAGCCGTCCAGGACCATCCTTACAAATTCAGGATTTAAAAGG CTCATGGAAAAGATCAGAGTCACAGGAAAGAATTTCTAATGAAC TCTGAAAAACTAAATTCATCCAAGCAAGAAAAAAGTAAATCAGG ATCGAAATCGAAATCGAAATCACCCTCACCTTTGAAAAACAAAT TGAGGTTGTCTGATATGAACAAGAGAGATCCAAGATTAAAAAA AAGAGAAGAGAAAAACTGCAGAAAAAAAGGATAAAGATGAGCA AAATAAAATCATAAATGGCATTGTACAAAAACAGGATACAATAACAGAA AGTACTAGAAAGCGATCAAGATCTCGATCACCCAAGTCTAGGTCACC CCCAAACGAAGGCAAAGAAGTATGTCTCCAACATCGACACCTAAAGC TATGGAAGAGTTTACACCACCTTCTAGGGAAGACAGAAATGCTAAGAG GAAAAAGACTGAAGAGGAGCGACCACAAGAAACTACAAATCAGCATTC AAACTGGCAAAGTTCCAAGTCTGCCAAAAGATGGAAATCTGGTTGGGA AAACCTCCTCATCTGAGGCATAGGGAGAGCTGGTCAAGCACTAAAGG CGATTAAGTGTAGATGCCAATCTTCAGATTCCTAAAGAGTTAACTCTT GTTTAGCATCTGGTGAAATTACACAGGATGACTTCCTTGTTGTTGTGC GCGAGAAGAGCAGAGATCTCCATTCAATGATCGTTTTCCACTTAAGCG AGTCCAGCATCAAGATTCGCCGGCCTGGATACAAATCAGCGACTTACA GTAGGCCATCAGTAGCAAGAGATGGCCCAACGAAGATGATTTTTGAA CCPCF TTACCTGCTTGGTTCTGAGTGGTGTTGCTCAGCCAGTAGCTTTTGGTCTGGATTTGTTCAGAATCCTTCAGGAGCCCTCCCTAAGGCATATCCTGA CAAAATTGCTAAAAACAGGAATTCTCAAATTGTCCCAAACTGATTCAG CCCTGAAGAGGAGGAAGATCAAAATGAAGATCAAGATGTTCCAGATC GACAGTGTTATAAATCGACTGTACACTGGTATTCAGTGTTACTCTTGT CAGATCATTTGGACTGGCATTATCGGCAAAATAGAACTGAAAAGGATG TTTAACAGACTGGATAGAATTTGAGGAGATAGCTGATCTGGAAGAACPCF TTGTGTCTGTGGAGAAAGAAGCTTCTGTGGCGGCTGGAAGTGGACGGGTTCCCCCTGTGTCGTCCCCCATCCCCCCTCCGCGGTCAGCATGTG AAGAGGAGTCGGAAGGGAGGCGGGGTATCCAGAGCGGCTTCAGCTT CAATGTCAGAGCAGACGCCGGCCGAGGCCGGTGCTGCGGGGGCCCG AGACCTGACCTTCAATAGCAAGCCGCACATCAATATGCTGACCATTCT CTCTCTCATCGAGGCCCAAACCGCCAAGGTGGATGAAAATACTAGGA ATTCCCTTTGAAGAAACTTTATGCCCTGGATGTCAGAGTCAATTCATTA UBE2DTGCGCGTGAGCCCCGTAGGGCCGGGGAGGCACCAGCTGCCGCGCGG3 CCGGCCCCTCTGCGCCTGTGTCTGGCAGAGCTGGTGTGAGACGAGACA GCCGGACCTTTGAGCATACACCGAGAGAGTGAGGAGCCAGACGACAA ACTTAGTGATTTGGCCCGTGACCCTCCAGCACAATGTTCTGCAGGTCCA ATGGGACCTAATGACAGCCCATATCAAGGCGGTGTATTCTTTTTGACAA AGGTTGCATTTACAACAAGAATTTATCATCCAAATATTAACAGTAATGGC CCTGCTTTAACAATTTCTAAAGTTCTTTTATCCATTTGTTCACTGCTATGT TGCACGGATCTATAAAACAGACAGAGATAAGTACAACAGAATATCTCGG AAAGTCAGAATAACCTGCATTATAGCTGGAATAAACTTTAAATTACTGTT GACCTCATCTTTTTTAATTTTATTTTTTGTTTACCTCCCTCCATTCATTCA TGGACAATAACTGCTTTTAGAAACTGTAAAGTAGTTACAAGAGAACAGTT CATGTGTATTATGTGGCCAATGTCTTCACTCTAACTTGGTTATGAGACTA CATCTGAGGGGGAGGGAGATGGATGCTCAGTTGTCACATCAAAGGATA CTTCCACTGTTAGAGATTTGAGGTTACATGATATGCTTTATGCTCATAAC TCAGCAGAACAGAAAATGTGATGTATTTTATGCATGTCAATAAAGGAAT GTCAAACACCCTTTGTATTCCAAAATAGGGTCTCAAACATTTTGTAATTT AATCTATCTTCCAATACACTGTTTAATATAGCACTGAATAAATGATGCAAG AGTAATTGATTTATTTTTCTTCAATAAAGTTGCATAAACCAATGAGTTAGC AAATGCAAAGCTGTTTTTTGTATATACTGTTGGGATTTGCTTCATTGTTTG ATTTTGCCATGTTCAGTTAAAGTGCACAGTCTGTTACAGGTTGACACATT GGATAGTGTAGCTTTAATGTGCTGCACATGATACTGGCAGCCCTAGAGT TGTGTTTATGGAGTTTAAGAAATTTATTTTCCAGGTGCAGCCCCTGTCTA GAAAAAAAACAACATGGGAGTAATAATGGGTCAAAATTTGCAAAATAAAG TGAAGTGACTTATCTATGTGGGATATTGAGTATCCATTGAAATGGATTT CAGATATCATTTCAGGTGACTTAACATGAATGAATAAAAGTCAATGCTATT CTGATTTAACTTCTGTAGTAACAAGGGCATTACCATTCTTCACCTTTCCT ATTTTGTTCACTGCTTTATTTCTTAAAGTTCTAGCACATCTGTGACT AATCTTATTCCTTGTCTGCACACACATGTGGAAAGCTAGAAATAAA GACATGATTTATTGACTTAAGGTTCTTCTCTAAACTGGAAGTGAAA AATCATTTCATTGGGGAAAAAACCAGCTACGCAGTTTTTCCAATGA CAGGGTAGATGTCATACTGCATAACTTTTTTGGATTCAAATTATGA AACTGCTCTTTGGCTCTATTTTCAAAATTACTTCTGAGATGCATAT AAAGCCAAACATGAGTGTAAGACACTTTTATGAAACACGGTGGAT ACCCTTAGGTATTTACGGAGATGACTTCTTTGATTGTCATAACAAT TTTATACATCATTTCATTTGTTGCTTCTAAGGGAATAAGCCATAGA AACCAACATTTTTGAATGTATGGACACTGGACATGAGATATGTACA CCACTCCACCCAGTAATTTGACATTACTAGTGCCATGTATAGGACC TCCTAAATCTTTTAATGCATAAACCGAATTAGGGTCCAGTTGGCC TTCCTGGGCGAGTTTGCAATGTGATAATCAGATTTTTTAAAACTGA ATGAACCACAGTTAACTAGTGGTCTCAGGGGTAGTGAAACACTCA AGTTGAAGTATACTTAAGGTACTGATCATGCTGTGTTAGTAATTTG CATAACAAAACTGTTAATGATTGTTGATTACACTTTTAAGTGAATTT CTAATAGTGACATCTGCATAAGACTTGTAATAGCTGAAGTTAATTG ACA UBGTGGGGCTGGATCGCGCAGCGGCTGCTTCCTTTACCTTCCTCCC3 GGGTTTCCGCCACTCGTTCACCCTCCCCCCAGCTCATGATCCTCC AGTAAGAAGGTGCTGTTCCGAGAAGAAGGAAAAGGGCTTGACAC GGCTTCGGCCTCACATCGGTCTTGTGCTCGGGACGGCGGCGTTG TTAAACTTGTAGCCACCACCTCCGCTCTTCCCGTCACCCTCGCCC GGCTTTGCCACGCCACCCCACCCACCCCGGATCGCGGCTGTCTT GCGAGTGCTGATCTGCTCCGTTTTTGCAAAAGGCGCCTGTGTCTG CCGGGATAATCAAGAGTTTTGGCCGGACCTTTGAGCATACACCGA CTGAAACGGATTAATAAGGAACTTAGTGATTTGGCCCGTGACCCT TTTCATTGGCAAGCCACAATTATGGGACCTAATGACAGCCCATAT CAAACCACCTAAGGTTGCATTTACAACAAGAATTTACACAGTGGTCGCCTGCTTTAACAATTTCTAAAGTTC GTGCCAGAGATTGCACGGATCTATAAAACAGACAG TGATGCTACCTTAAAGTCAGAATAACCTGCATTATA GCTCCCCTATCAGACCTCATCTTTTTTAATTTTATTTTTCTTCCAGCTTTGGACAATAACTGCTTTTAGAAAC AAAAAAATGGAGCATGTGTATTATGTGGCCAATGTATGCTGAAGAAATCATCTGAGGGGGAGGGAGATGATTCTTGTTTAAGCCTTCCACTGTTAGAGATTTGAG TTGAATTTATAGCATCAGCAGAACAGAAAATGTGAT ATGGAAATTGGAAGTCAAACACCCTTTGTATTCCAAGGAGCTATTAGTTAATCTATCTTCCAATACACTGTTT TAATAGCTCTGCTAGTAATTGATTTATTTTTCTTCAAAAACAATCTTTTGTAAATGCAAAGCTGTTTTTTGTATTCGAAAGAGTGAATATTTTGCCATGTTCAGTTAAAGATTAATAAGCTATTTGGATAGTGTAGCTTTAATGTGC CAGCAGTTTTGAAATGTGTTTATGGAGTTTAAGAAATACACTTGACAGCTGAAAAAAAACAACATGGGAGTA TCATGAGGCTGTGTTGAAGTGACTTATCTATGTGGGCATTTAAATGCAACAGATATCATTTCAGGTGACTTATGCTATCTGTGCCACTGATTTAACTTCTGTAGTAACATTTTTCCTGTTTATTTTGATTTTGTTCACTGCTTTATTTGCTTACACTTACGTGCAATCTTATTCCTTGTCTGCCATTTTAATATGTAGTTTGGACATGATTTATTGACTT TGGCTTTGTTAATTCTGTAATCATTTCATTGGGGAA TGCTTAAAACGGCTCCTTCAGGGTAGATGTCATAC GCTCCACAAGGTAAGAAAAACTGCTCTTTGGCTCT TAGGCATATCACTTCTTGAAAGCCAAACATGAGTG CCTTTATAGCCTTAGACAACCCTTAGGTATTTACGG TGTATCTTTGACTTGATGCTTTATACATCATTTCATTT ACAGTAAAGTACCTGGAAAACCAACATTTTTGAATGT AGAATTTGCCCTCTTTGCCCCACTCCACCCAGTAATTT TTTGACTATGTCTTTGTATTTCCTAAATCTTTTAATGCA AAATGACTCAGTTTGTTTTTCCTGGGCGAGTTTGCAA TGTACTCACATTTTAAAGTATGAACCACAGTTAACTAG TTGTTTGTTGAAATGGCTTAGTTGAAGTATACTTAAGG AGCCATGTTTTGTGTTGGCATAACAAAACTGTTAATG GCAAGTCACTAAATATTGTCTAATAGTGACATCTGCAT TAAAGTCTGTGTTTAAAG UBEGACCCTCCAGCACAATGTTCTGCAGGTCCAGTTGGG3 CCATATCAAGGCGGTGTATTCTTTTTGACAATTCATTT AATTTATCATCCAAATATTAACAGTAATGGCAGCATTT AAGTTCTTTTATCCATTTGTTCACTGCTATGTGATCCAA GACAGAGATAAGTACAACAGAATATCTCGGGAATGGA TTATAGCTGGAATAAACTTTAAATTACTGTTCCTTTTTT TATTTTTTGTTTACCTCCCTCCATTCATTCACATGCTC GAAACTGTAAAGTAGTTACAAGAGAACAGTTGCCCAA AATGTCTTCACTCTAACTTGGTTATGAGACTAAAACCA GATGGATGCTCAGTTGTCACATCAAAGGATACAGCAT GAGGTTACATGATATGCTTTATGCTCATAACTGATGT TGATGTATTTTATGCATGTCAATAAAGGAATGACCTG CCAAAATAGGGTCTCAAACATTTTGTAATTTTCATTTA GTTTAATATAGCACTGAATAAATGATGCAAGTTGTCA TTCAATAAAGTTGCATAAACCAATGAGTTAGCTGCCT TGTATATACTGTTGGGATTTGCTTCATTGTTTGACATC AAAGTGCACAGTCTGTTACAGGTTGACACATTGCTTG GTGCTGCACATGATACTGGCAGCCCTAGAGTTCATA AAATTTATTTTCCAGGTGCAGCCCCTGTCTAACTG GTAATAATGGGTCAAAATTTGCAAAATAAAGTACT TGGGATATTGAGTATCCATTGAAATGGATTTGTTC CTTAACATGAATGAATAAAAGTCAATGCTATTGGA TAACAAGGGCATTACCATTCTTCACCTTTCCTAATT TTATTTCTTAAAGTTCTAGCACATCTGTGACTCCTC CTGCACACACATGTGGAAAGCTAGAAATAAATGTT ACTTAAGGTTCTTCTCTAAACTGGAAGTGAAATGC GGAAAAAACCAGCTACGCAGTTTTTCCAATGAGTG ATACTGCATAACTTTTTTGGATTCAAATTATGAATG CTCTATTTTCAAAATTACTTCTGAGATGCATATAGT AGTGTAAGACACTTTTATGAAACACGGTGGATCCC ACGGAGATGACTTCTTTGATTGTCATAACAATTAG CATTTGTTGCTTCTAAGGGAATAAGCCATAGAGGC ATGTATGGACACTGGACATGAGATATGTACAATG AATTTGACATTACTAGTGCCATGTATAGGACCCAA ATGCATAAACCGAATTAGGGTCCAGTTGGCCTGTT TGCAATGTGATAATCAGATTTTTTAAAACTGATTAA ACTAGTGGTCTCAGGGGTAGTGAAACACTCACTTT TAAGGTACTGATCATGCTGTGTTAGTAATTTGGGC TAATGATTGTTGATTACACTTTTAAGTGAATTTGTC TGCATAAGACTTGTAATAGCTGAAGTTAATTGAGC UATTTCCTTCCTTTTCCCGGCCGCACCTTTGGACAG3 CCCCTTGCCTTTCTTTGCCCTAGTGACGCCGGTA CCCCGCACCCACCCCTTTCTCCTACGCCTCTTCCT GCCACCACCTCCGCTCTTCCCGTCACCCTCGCCCC GCCACCCCACCCACCCCGGATCGCGGCTGTCTTA TCTGCTCCGTTTTTGCAAAAGGCGCCTGTGTCTGG AAGAGTTTTGGCCGGACCTTTGAGCATACACCGAG AATAAGGAACTTAGTGATTTGGCCCGTGACCCTC GCCACAATTATGGGACCTAATGACAGCCCATATC AACCACCTAAGGTTGCATTTACAACAAGAATTTAT CAGTGGTCGCCTGCTTTAACAATTTCTAAAGTTCT GCCAGAGATTGCACGGATCTATAAAACAGACAGA GTAGGGTACAACAGAATATCTCGGGAATGGACTC GCTGGAATAAACTTTAAATTACTGTTCCTTTTTTGAT TTGTTTACCTCCCTCCATTCATTCACATGCTCATCT GTAAAGTAGTTACAAGAGAACAGTTGCCCAAGACT TCACTCTAACTTGGTTATGAGACTAAAACCATTCC TGCTCAGTTGTCACATCAAAGGATACAGCATTATT ACATGATATGCTTTATGCTCATAACTGATGTGGCT ATTTTATGCATGTCAATAAAGGAATGACCTGTTCTT TAGGGTCTCAAACATTTTGTAATTTTCATTTAAATTG ATAGCACTGAATAAATGATGCAAGTTGTCAATGGA AGTTGCATAAACCAATGAGTTAGCTGCCTGGATTA CTGTTGGGATTTGCTTCATTGTTTGACATCAAATGA CAGTCTGTTACAGGTTGACACATTGCTTGACCTG ACATGATACTGGCAGCCCTAGAGTTCATAGATGG ATTTTCCAGGTGCAGCCCCTGTCTAACTGAAATTT AATGGGTCAAAATTTGCAAAATAAAGTACTGTTTTG UGATCGCGCAGCGGCTGCTTCCTTTACCTTCCTCCC3 ACTCGTTCACCCTCCCCCCAGCTCATGATCCTCC GCTGTTCCGAGAAGAAGGAAAAGGGCTTGACAC TCACATCGGTCTTGTGCTCGGGACGGCGGCGTTG GTGTGAGACGAGACAATCCTGCCCCGCCGCCGG GGAGCCAGACGACAAGCACACACTATGGCGCTGA TGTTCTGCAGGTCCAGTTGGGGATGATATGTTTC TGTATTCTTTTTGACAATTCATTTTCCTACAGACTA TATTAACAGTAATGGCAGCATTTGTCTCGATATTC TTTGTTCACTGCTATGTGATCCAAACCCAGATGAC ACAACAGAATATCTCGGGAATGGACTCAGAAGTAT AAACTTTAAATTACTGTTCCTTTTTTGATTTTCTTAT CTCCCTCCATTCATTCACATGCTCATCTGAGAAGA GTTACAAGAGAACAGTTGCCCAAGACTCAGAATTT ACTTGGTTATGAGACTAAAACCATTCCTCACTGCT TGTCACATCAAAGGATACAGCATTATTCTAGCAGC TGCTTTATGCTCATAACTGATGTGGCTGGAGAATT ATGTCAATAAAGGAATGACCTGTTCTTGTTCTACA CAAACATTTTGTAATTTTCATTTAAATTGTTAGGAG TGAATAAATGATGCAAGTTGTCAATGGATGAGTGA TAAACCAATGAGTTAGCTGCCTGGATTAATCAGTA GATTTGCTTCATTGTTTGACATCAAATGATGATGTA GTTACAGGTTGACACATTGCTTGACCTGATTTATGC CTGGCAGCCCTAGAGTTCATAGATGGACTTTTGG GGTGCAGCCCCTGTCTAACTGAAATTTCTCTTCAC AAAATTTGCAAAATAAAGTACTGTTTTGGTGTGGG ATCCATTGAAATGGATTTGTTCAGCCATTTACATTA ATAAAAGTCAATGCTATTGGA UBE2DCGCCCCAGTTCGAGCCGGTGCCTTACTGCGTCTC3 AAAACTGCTCTTAAGTCATTGCAGAGCTACCGCTT GCGCCTGTGTCTGGCAGAGCTGGTGTGAGACGA TGAGCATACACCGAGAGAGTGAGGAGCCAGACG TGGCCCGTGACCCTCCAGCACAATGTTCTGCAGG ATGACAGCCCATATCAAGGCGGTGTATTCTTTTTG ACAACAAGAATTTATCATCCAAATATTAACAGTAAT AATTTCTAAAGTTCTTTTATCCATTTGTTCACTGCT TATAAAACAGACAGAGATAAGTACAACAGAATATC TAACCTGCATTATAGCTGGAATAAACTTTAAATTA TTTTTTAATTTTATTTTTTGTTTACCTCCCTCCATTC CTGCTTTTAGAAACTGTAAAGTAGTTACAAGAGAA ATGTGGCCAATGTCTTCACTCTAACTTGGTTATGA GGGAGGGAGATGGATGCTCAGTTGTCACATCAAA TAGAGATTTGAGGTTACATGATATGCTTTATGCTC CAGAAAATGTGATGTATTTTATGCATGTCAATAAAG CTTTGTATTCCAAAATAGGGTCTCAAACATTTTGTA CAATACACTGTTTAATATAGCACTGAATAAATGATG TTATTTTTCTTCAATAAAGTTGCATAAACCAATGAGT CTGTTTTTTGTATATACTGTTGGGATTTGCTTCATT GTTCAGTTAAAGTGCACAGTCTGTTACAGGTTGAC GCTTTAATGTGCTGCACATGATACTGGCAGCCCTA GAGTTTAAGAAATTTATTTTCCAGGTGCAGCCCCT AACATGGGAGTAATAATGGGTCAAAATTTGCAAAA TTATCTATGTGGGATATTGAGTATCCATTGAAATG TTCAGGTGACTTAACATGAATGAATAAAAGTCAAT UBE2DCCGTAGGGCCGGGGAGGCACCAGCTGCCGCGC3 GGCCGGGAAGTTAAACTTGTAGCCACCACCTCCG GGCTGTTGGTGGCTTTGCCACGCCACCCCACCCA GGGGCCTGTGCGAGTGCTGATCTGCTCCGTTTTT GCCCCGCCGCCGGGATAATCAAGAGTTTTGGCC ACACTATGGCGCTGAAACGGATTAATAAGGAACTT GGGATGATATGTTTCATTGGCAAGCCACAATTATG TTTTCCTACAGACTACCCCTTCAAACCACCTAAGG TTTGTCTCGATATTCTAAGATCACAGTGGTCGCCT CAAACCCAGATGACCCCCTAGTGCCAGAGATTGC GGACTCAGAAGTATGCCATGTGATGCTACCTTAAA TTTTGATTTTCTTATCCGGCTGCTCCCCTATCAGAC CTCATCTGAGAAGACTTAAGTTCTTCCAG UBE2DGCCCTCCTCTTGGGCCTTTAACGTCTGTAGATGCT3 TGCTTTCTAACCGAAAGTGCCTTTCAAAAGCGCCT GGATAATCAAGAGTTTTGGCCGGACCTTTGAGCAT AAACGGATTAATAAGGAACTTAGTGATTTGGCCCG ATTGGCAAGCCACAATTATGGGACCTAATGACAG CCCCTTCAAACCACCTAAGGTTGCATTTACAACAA TAAGATCACAGTGGTCGCCTGCTTTAACAATTTCT CCCCTAGTGCCAGAGATTGCACGGATCTATAAAA GCCATGTGATGCTACCTTAAAGTCAGAATAACCT TCCGGCTGCTCCCCTATCAGACCTCATCTTTTTTA UBE2DCCCAGCTCATGATCCTCCTCCCTCCCCCGCCCTCC3 GCTGGTGTGAGACGAGACAATCCTGCCCCGCCGC TGAGGAGCCAGACGACAAGCACACACTATGGCGC CAATGTTCTGCAGGTCCAGTTGGGGATGATATGT GGTGTATTCTTTTTGACAATTCATTTTCCTACAGAC AATATTAACAGTAATGGCAGCATTTGTCTCGATAT CATTTGTTCACTGCTATGTGATCCAAACCCAGATG GTACAACAGAATATCTCGGGAATGGACTCAGAAGT ATAAACTTTAAATTACTGTTCCTTTTTTGATTTTCTT ACCTCCCTCCATTCATTCACATG UBE2DGATGTAAAAGGCATTCTGGAAGCTCCCTTTTCCTTT3 ATTTGGCCCGTGACCCTCCAGCACAATGTTCTGCA CTAATGACAGCCCATATCAAGGCGGTGTATTCTTTT TTACAACAAGAATTTATCATCCAAATATTAACAGTA ACAATTTCTAAAGTTCTTTTATCCATTTGTTCACTG TCTATAAAACAGACAGAGATAAGTACAACAGAATA AATAACCTGCATTATAGCTGGAATAAACTTTAAAT TCTTTTTTAATTTTATTTTTTGTTTACCTCCCTCCAT UBE2DCTCGGAATCTCGTGTGAAGGTGGCCCTCCTCTTG3 GCGATGAGATAAGCATGTGAGAATGCTTTCTAACC CAATGTTCTGCAGGTCCAGTTGGGGATGATATGT GGTGTATTCTTTTTGACAATTCATTTTCCTACAGAC AATATTAACAGTAATGGCAGCATTTGTCTCGATAT CATTTGTTCACTGCTATGTGATCCAAACCCAGATG GTACAACAGAATATCTCGGGAATGGACTCAGAAGT ATAAACTTTAAATTACTGT UBE2DAAGTCATTGCAGAGCTACCGCTTCGGTTAGCCAG3 TTAAACTTGTAGCCACCACCTCCGCTCTTCCCGT TGGCTTTGCCACGCCACCCCACCCACCCCGGATC GCGAGTGCTGATCTGCTCCGTTTTTGCAAAAGGC GCCGGGATAATCAAGAGTTTTGGCCGGACCTTTGA GCTGAAACGGATTAATAAGGAACTTAGTGATTTGG GTTTCATTGGCAAGCCACAATTATGGGACCTAATG UBE2DAGGCTCTTTCCGGCATCTCCTTTCGTAATAATGTG3 TAAGATCCTCTGCTCAAAACTTACCTAAATTCAAA GTTGTTGCACAATCGAAGAGGGTGGAGTGTTTAC TGTGGAGTGTCGGAACTTAGTGATTTGGCCCGTG TGGCAAGCCACAATTATGGGACCTAATGACAGCC CCTTCAAACCACCTAAGGTTGCATTTACAACAAGA AGATCACAGTGGTCGCCTGCTTTAACAATTTCTAAA UBE2DACGAAGTTCTCGCGAGAGTCGTCTCCTCGATACC3 CACTCGGCCCCGGACGTGGGAAGCAAGCCGTCTG CTGATCCGCGGCGGTGAAGAGGCGCCTGTGTCTG CAAGAGTTTTGGCCGGACCTTTGAGCATACACCGA TTAATAAGGAACTTAGTGATTTGGCCCGTGACCCT AGCCACAATTATGGGACCTAATGACAGCCCATAT AAACCACCTAAGGTTGCATTTACAACAAGAATTTA UBE2DTCCTTTCGTAATAATGAACTTAGTGATTTGGCCCG3 ATTGGCAAGCCACAATTATGGGACCTAATGACAG CCCCTTCAAACCACCTAAGGTTGCATTTACAACAA TAAGATCACAGTGGTCGCCTGCTTTAACAATTTCT CCCCTAGTGCCAGAGATTGCACGGATCTATAAAA GCCATGTGATGCTACCTTAAAGTCAGAATAACCT TCCGGCTGCTCCCCTA UBE2DGGGTGGAGTGTTTACAGCTAACTTGAAAAAAATGT3 GTGATTTGGCCCGTGACCCTCCAGCACAATGTTCT GACCTAATGACAGCCCATATCAAGGCGGTGTATTC GCATTTACAACAAGAATTTATCATCCAAATATTAAC TTTAACAATTTCTAAAGTTCTTTTATCCATTTGTTCA GGATCTATAAAACAGACAGAGATAAGTACAACAGA CAGAATAACCTGCATT UBE2DGGAAAGCTAATAGGGTGGAGTGTTTACAGCTAACT3 GTCGGAACTTAGTGATTTGGCCCGTGACCCTCCA CACAATTATGGGACCTAATGACAGCCCATATCAA CCACCTAAGGTTGCATTTACAACAAGAATTTATCA GTGGTCGCCTGCTTTAACAATTTCTAAAGTTCTTTT CAGAGATTGCACGGATCTATAAAACAGACAGAGAT CTACCTTAAAGTCA UBE2DCCTTTAACGTCTGTAGATGCTGGAGACCAGCAGAA3 AGTGCCTTTCAAAAAGCTGGTGTGAGACGAGACA CATACACCGAGAGAGTGAGGAGCCAGACGACAA CCGTGACCCTCCAGCACAATGTTCTGCAGGTCCA CAGCCCATATCAAGGCGGTGTATTCTTTTTGACAA CAAGAATTTATCATCCAAATATTAACAGTAATGGC UBE2DGGAAAGCTAATGAACTTAGTGATTTGGCCCGTGAC3 GCAAGCCACAATTATGGGACCTAATGACAGCCCA TTCAAACCACCTAAGGTTGCATTTACAACAAGAAT ATCACAGTGGTCGCCTGCTTTAACAATTTCTAAAG TAGTGCCAGAGATTGCACGGATCTATAAAACAGA TGTGATGCTACCTTAAAGTCAGAATAACCTGCATTEEF2 TTCTACCTGGGAGAATCCACCGCCATCCGCCACCCCAACATCCGCAACATGTCTGTCATCGCCCACGT CATCATCGCCTCGGCCCGGGCCGGGGAGACACG TCAACTGCCATCTCCCTCTTCTACGAGCTCTCGGA ATCAACCTCATTGACTCCCCCGGGCATGTCGACTT GGTGGTGGACTGCGTGTCAGGCGTGTGCGTGCAGCTGATGATGAACAAGATGGACCGCGCCCTGCTGG GGAGAACGTGAACGTCATCATCTCCACCTACGGCGGTACCGTGGGCTTTGGGTCTGGCCTCCACGGGT CGCCAAGGGGGAGGGCCAGTTGGGGCCTGCCGAGTACTTTGACCCAGCCAACGGCAAGTTCAGCAAGTTGATCCTGGACCCCATCTTCAAGGTGTTTGATGCG CATCAAACTGGACAGCGAGGACAAGGACAAAGAA GACGCCTTGTTGCAGATGATCACCATCCACCTGCGGCCCCCGGACGACGAGGCTGCCATGGGCATTAA CAACCTCCGACAAAGGTCGGTTCTACGCCTTTGG GGGCCCAACTATACCCCTGGGAAGAAGGAGGACTGGAGCCCATCGAGGATGTGCCTTGTGGGAACATCACCACCTTCGAGCACGCGCACAACATGCGGGTG ACCCGGCTGACCTGCCCAAGCTGGTGGAGGGGCAGTCGGGAGAGCATATCATCGCGGGCGCCGGCGACATCCCCATCAAGAAATCTGACCCGGTCGTCTCGT CCCCAACAAGCACAACCGGCTGTACATGAAGGCG TCCGCCCGTCAGGAGCTCAAGCAGCGGGCGCGCTGGTGCTTTGGGCCCGACGGCACCGGCCCCAACACAGTGTGGTGGCCGGCTTCCAGTGGGCCACCAAG CACGACGTCACCCTGCACGCCGACGCCATCCACC GTGTGCTGACCGCCCAGCCACGCCTCATGGAGCC TACGGGGTTTTGAACAGGAAGCGGGGCCACGTGTATCTGCCCGTCAACGAGTCCTTTGGCTTCACCGCTGACCACTGGCAGATCCTGCCCGGAGACCCCTTCGAAGGGCCTGAAAGAAGGCATCCCTGCCCTGGACA GGGGACTCGCAGCACCCACAGCACCACGTCCTC TGAGAGGTTTCTGGGGCCCGCTGCGTGCCATCA GGAGGCAGCAGACACGCCCTCTTAGTAGGGACTTTTTCCATTTCTTCAGAGGGAAACTCAGATGTCCAAATGGCTTTTGCCCCAGAAAGGGGAAAGGAACACGC GCACCTCCAGCTGTACTAGTGCCATTGGAATAATACGGCTGTACATGAAGGCGCGGCCCTTCCCCGACGTCCATTTCTTCAGAGGGAAACTCAGATGTCCAAACGGCTTTTGCCCCAGAAAGGGGAAAGGAACACGCG CACCTCCAGCTGTACTAGTGCCATTGGAATAATAA AGGCCGCCCGCTGCTGCGGGGCCACCATGCTCCGCCCCCACCTGCTGGACCCCAGGGTCCCACCCTGGCAGAAGGAGGGTGGCCGGACTGTGCCATGCTGC CAGCCATCGGGGCGGCATCCTGGGCCATTGTGG CTCTGCGGACGCTCGGCTCATGGTCTTTGACAAG GTAGCCGGACTCAGCTGCGAGGAGATGGGCTTC AATGGCACGTCGGGCTTCTTCTGTGTGGACGAGGATTGCCCCAGAGGCCGTTTCTTGGCCGCCATCTG CCGGGACACCAGCTTGGGCCGGTGGCCGTGGCA TCCGGGGACTGGGTGCTGACAGCCGCCCACTGCGCCGTGGCCCAGGCCTCTCCCCACGGTCTGCAGCACCCCAACAGCGAGGAGAACAGCAACGATATTGCGTGTGCCTCCCAGCTGCCGGCCAGGCCCTGGTGGGCCAACAGGCCGGGGTACTCCAGGAGGCTCGAGT AGATCAAGCCCAAGATGTTCTGTGCTGGCTACCCGTGTGAGGACAGCATCTCTCGGACGCCACGTTGGAAGCCAGGCGTCTACACCAAAGTCAGTGACTTCC GGTGACCCAGCTCTGACCGGTGGCTTCTCGCTG GCCTAGGATGGGACGTTTTTCTTCTTGGGCCCGGGCGGGCCCACTCAGCCCCGAGACCACCCAACCTC TAGGTGCCCCTGATGACGGGATGCTCTTTAAATAAGCCTGGCCTAGCAGGCCCCACGCCACCGCCTCTGTGGAGACTGACCCGACCCCGGCACTACCTCGAG ACTCACAGTTCCAGCCCTGAGGACAGGGGTTCCCGGGACCTGAAGAGGGGGCACTATGACGTCCCCCC CCCAGTCCTTTCCTCCCCAGACCCAGGAGTTCCACCTCCTTTCCCAAGACTTATGATTTCAGGTCCTCA TCAGGCATGGGGGTCCCCATCCCTGCAAATCCAG CAATCTGCGTCCGTGATCACGGCGTGCTCTGGCC CGCCAGGACTGGGCTGGGCTGGGCTCCCCCAGGGTCAGCCAGGGAATCATTAACAAGAGGCAGTGACA AGGTGGCAGCTCTCACTGCGGGGACCCTGCTACT AGGAGTGACCAGGAGCCGCTGTACCCAGTGCAGACGTGGCGGCTGCTGTGCTCCTCGCGCTCCAACG TGACCCACTCCGAGCTGGACGTGCGAACGGCGGCCCACACCCAGAGGCTGCTGGAGGTCATCTCCGTGGCCGCAGGAAGCTGCCCGTGGACCGCATCGTG CGCTATGATGGAGCACACCTCTGTGGGGGATCCCGGAACCGGGTCCTGTCCCGATGGCGAGTGTTTG AGGCTGTGGTCTACCACGGGGGCTATCTTCCCTT CTCTCCAGTCCCCTGCCCCTCACAGAATACATCCTCTGTACCGTGACGGGCTGGGGCAACACGCAGTACAGCAATGATGTCTGCAATGGCGCTGACTTCTATG CATTGATGCCTGCCAGGGCGACAGCGGTGGTCC GGCATTGTGAGTTGGGGCACTGGCTGTGCCCTG ATCTTCCAGGCCATAAAGACTCACTCCGAAGCCAG CAGGGCCCGAGGTGATCCCGGTGGTGGGATCCAC CAAGGACACCCTCCCTCCAGGGTCCTCTCTTCCA ACCCCCATGTAAATATTGTTCTGCTGTCTGGGACT TTTTGATTHPN GGCCGCCCGCTGCTGCGGGGCCACCATGCTCCTCCCCCACCTGCTGGACCCCAGGGTAAGGACAAG CCCCCACCCAGCCTAATGCCCACCTCCTAATAGAG CCTAGGTGTTCTGTCCTGCTCTTCCTTCAGACTCA CAGGCCCCTCCTCCCTCATACTAGGGAGTCCTGG CTCCTCCCTCAAACCGGGATCCTCAGTCCCCTGCT CCCCCGCTGCTGGTCAGACACTGACCCCATCCTT CCCAGTCCCTACAGCCTGCCTGGATGGACGCCTG GCCTCCCCGTCCATCTCCTCACAGGTCCCACCCT CGCAGAAGGAGGGTGGCCGGACTGTGCCATGCTG ACAGCCATCGGGGCGGCATCCTGGGCCATTGTG GCTCTGCGGACGCTCGGCTCATGGTCTTTGACAA GGTAGCCGGACTCAGCTGCGAGGAGATGGGCTT CAATGGCACGTCGGGCTTCTTCTGTGTGGACGAG GATTGCCCCAGAGGCCGTTTCTTGGCCGCCATCT GCCGGGACACCAGCTTGGGCCGGTGGCCGTGGC CTCCGGGGACTGGGTGCTGACAGCCGCCCACTG TGCCGTGGCCCAGGCCTCTCCCCACGGTCTGCAG GACCCCAACAGCGAGGAGAACAGCAACGATATTG TGTGTGCCTCCCAGCTGCCGGCCAGGCCCTGGTG GGCCAACAGGCCGGGGTACTCCAGGAGGCTCGAG CAGATCAAGCCCAAGATGTTCTGTGCTGGCTACC TGTGTGAGGACAGCATCTCTCGGACGCCACGTTG GAAGCCAGGCGTCTACACCAAAGTCAGTGACTTCATGGTGACCCAGCTCTGACCGGTGGCTTCTCGCT GGCCTAGGATGGGACGTTTTTCTTCTTGGGCCCGGGCGGGCCCACTCAGCCCCGAGACCACCCAACC TCTAGGTGCCCCTGATGACGGGATGCTCTTTAAATGCCTGGCCTAGCAGGCCCCACGCCACCGCCTCTGTGGAGACTGACCCGACCCCGGCACTACCTCGAG GTCAGCCAGGGAATCATTAACAAGAGGCAGTGAC AAGGTGGCAGCTCTCACTGCGGGGACCCTGCTAC CAGGAGTGACCAGGAGCCGCTGTACCCAGTGCAGACGTGGCGGCTGCTGTGCTCCTCGCGCTCCAAC CTGACCCACTCCGAGCTGGACGTGCGAACGGCG CCCCACACCCAGAGGCTGCTGGAGGTCATCTCCG TGGCCGCAGGAAGCTGCCCGTGGACCGCATCGTTTCGCTATGATGGAGCACACCTCTGTGGGGGATCGCGGAACCGGGTCCTGTCCCGATGGCGAGTGTTTGCAGGCTGTGGTCTACCACGGGGGCTATCTTCCCT CCTCTCCAGTCCCCTGCCCCTCACAGAATACATC ATCTGTACCGTGACGGGCTGGGGCAACACGCAGT CAGCAATGATGTCTGCAATGGCGCTGACTTCTAT GCATTGATGCCTGCCAGGGCGACAGCGGTGGTC TGGCATTGTGAGTTGGGGCACTGGCTGTGCCCTGATCTTCCAGGCCATAAAGACTCACTCCGAAGCCAGCAGGGCCCGAGGTGATCCCGGTGGTGGGATCCAC CAAGGACACCCTCCCTCCAGGGTCCTCTCTTCCAACCCCCATGTAAATATTGTTCTGCTGTCTGGGACT TTTTGATT HPN GAGACTGACCCGACCCCGGCACTACCTCGAGGCCAGCCAGGGAATCATTAACAAGAGGCAGTGACAT CTTTGACAAGACGGAAGGGACGTGGCGGCTGCT GATGGGCTTCCTCAGGCGGAACCGGGTCCTGTCC CTGCAGCTGGGGGTGCAGGCTGTGGTCTACCACG ATATTGCCCTGGTCCACCTCTCCAGTCCCCTGCCC TGGTGGATGGCAAGATCTGTACCGTGACGGGCT CTCGAGTCCCCATAATCAGCAATGATGTCTGCAAT GCTACCCCGAGGGTGGCATTGATGCCTGCCAGGG CGTTGGCGGCTGTGTGGCATTGTGAGTTGGGGC GACTTCCGGGAGTGGATCTTCCAGGCCATAAAGAC CGCTGCGCAGCCTCCAGGGCCCGAGGTGATCCC CCCGGTCCACAGGTCCAAGGACACCCTCCCTCCA AACCTCACCCTCCTGACCCCCATGTAAATATTGTT TAAATAATAAAHPN GCTCCTGCCCAGGCCTGGAGACTGACCCGACCCTCTGCGTCCGTGATCACGGCGTGCTCTGGCCAAG CAGGACTGGGCTGGGCTGGGCTCCCCCAGGCCC GCCAGGGAATCATTAACAAGAGGCAGTGACATGG TGGCAGCTCTCACTGCGGGGACCCTGCTACTTCT GAGTGACCAGGAGCCGCTGTACCCAGTGCAGGTC TGGCGGCTGCTGTGCTCCTCGCGCT CLAUSES A set of clauses defining the invention, its aspects and embodiments is as follows: 1. A method of treating metabolic dysfunction-associated steatohepatitis (MASH) in a subject, the method comprising steps of: (i) isolating and purifying DNA from a sample obtained from the subject; (ii) detecting the presence or absence of a somatic mutation in the DNA of one or more gene selected from: fatty acid synthase (FASN); APOBEC1 complementation factor (A1CF); Krüppel-like factor 15 (KLF15); serotransferrin (TF) cytochrome P4502E1 (CYP2E1); cyclin-dependent kinase inhibitor 1B (CDKN1B) PCF11 cleavage and polyadenylation factor subunit (PCF11); ubiquitin-conjugating enzyme E2 D3 (UBE2D3); eukaryotic elongation factor 2 (EEF2); and / or serine protease hepsin (HPN), and (iii) administering to the subject an siRNA that inhibits expression of said one or more gene if a somatic mutation is present in the DNA. 2. A method of detecting the presence or absence of a somatic mutation in a subject suspected of having or at risk of having metabolic dysfunction-associated steatohepatitis (MASH), the method comprising the steps of: (i) isolating and purifying DNA from a sample obtained from the subject; and (ii) detecting the presence or absence of a somatic mutation in the DNA of one or more gene selected from: fatty acid synthase (FASN); APOBEC1 complementation factor (A1CF); Krüppel-like factor 15 (KLF15); serotransferrin (TF) cytochrome P4502E1 (CYP2E1); cyclin-dependent kinase inhibitor 1B (CDKN1B) PCF11 cleavage and polyadenylation factor subunit (PCF11); ubiquitin-conjugating enzyme E2 D3 (UBE2D3); eukaryotic elongation factor 2 (EEF2); and / or serine protease hepsin (HPN), and wherein the presence of a somatic mutation in said one or more gene indicates that the subject has or is at risk of having MASH. 3. The method of clause 1 or clause 2, wherein the somatic mutation is a loss of function mutation. 4. The method of any one of clauses 1 to 3, wherein the somatic mutation is selected from one or more of: a missense mutation, a nonsense mutation, a mutation of an essential splice site, a mutation of a stop codon, and / or a no-SNV mutation. 5. The method of any one of clauses 1 to 4, wherein the somatic mutation is located within a coding region and / or within a non-coding region of the gene. 6. The method of any one of clauses 1 to 5, wherein the somatic mutation is one or more mutation selected from those listed in Table 1. 7. The method of any one of clauses 1 to 6, wherein the somatic mutation causes one or more amino acid change selected from those listed in Table 1. 8. The method of any one of clauses 1 to 7, wherein the somatic mutation is in the DNA of the FASN gene and is selected from any one or more of:

[0004] 9. The method of any one of clauses 1 to 8, wherein the somatic mutation causes anamino acid change in fatty acid synthase selected from any one or more of: 10. The method of any one of clauses 1 to 7, wherein the somatic mutation is in the DNA of the A1CF gene and is selected from any one or more of: 11. The method of any one of clauses 1 to 7 or clause 10, wherein the somatic mutation causes an amino acid change in APOBEC1 complementation factor selected from any one or more of: 12. The method of any one of clauses 1 to 7, wherein the somatic mutation is in the DNA of the KLF15 gene and is selected from any one or more of: 13. The method of any one of clauses 1 to 7 or clause 12, wherein the somatic mutation causes an amino acid change in Krüppel-like factor 15 selected from any one or more of: 14. The method of any one of clauses 1 to 7, wherein the somatic mutation is in the DNA of the TF gene and is selected from any one or more of: 15. The method of any one of clauses 1 to 7 or clause 14, wherein the somatic mutation causes an amino acid change in serotransferrin selected from any one or more of: 16. The method of any one of clauses 1 to 7, wherein the somatic mutation is in the DNA of the CYP2E1 gene and is selected from any one or more of: 17. The method of any one of clauses 1 to 7 or clause 16, wherein the somatic mutation causes an amino acid change in cytochrome P4502E1 selected from any one or more of: 18. The method of any one of clauses 1 to 7, wherein the somatic mutation is in the DNA of the CDKN1B gene and is selected from any one or more of: 19. The method of any one of clauses 1 to 7 or clause 18, wherein the somatic mutation causes an amino acid change in cyclin-dependent kinase inhibitor 1B selected from any one or more of: 20. The method of any one of clauses 1 to 7, wherein the somatic mutation is in the DNA of the PCF11 gene and is selected from any one or more of: 21. The method of any one of clauses 1 to 7 or clause 20, wherein the somatic mutation causes an amino acid change in PCF11 cleavage and polyadenylation factor subunit selected from any one or more of: 22. The method of any one of clauses 1 to 7, wherein the somatic mutation is in the DNA of the UBE2D3 gene and is selected from any one or more of: 23. The method of any one of clauses 1 to 7 or clause 22, wherein the somatic mutation causes an amino acid change in ubiquitin-conjugating enzyme E2 D3 selected from any one or more of: 24. The method of any one of clauses 1 to 7, wherein the somatic mutation is in the DNA of the EEF2 gene and is selected from any one or more of: 25. The method of any one of clauses 1 to 7 or clause 24, wherein the somatic mutation causes an amino acid change in eukaryotic elongation factor 2 selected from any one or more of: 26. The method of any one of clauses 1 to 7, wherein the somatic mutation is in the DNA of the HPN gene and is selected from any one or more of: 27. The method of any one of clauses 1 to 7 or clause 26, wherein the somatic mutation causes an amino acid change in serine protease hepsin selected from any one or more of: 28. The method of any one of clauses 1 to 27, wherein the presence or absence of the somatic mutation is detected using sequencing and / or by PCR, such as quantitative and / or real-time PCR. 29. The method of clause 28, wherein the isolated and purified DNA is prepared for sequencing according to a method comprising the steps of: (i) fragmenting the DNA to generate fragmented nucleic acid molecules with blunt ends; (ii) introducing dideoxy nucleotides at internal nick sites present in the fragmented nucleic acid molecules with blunt ends and tailing to generate tailed nucleic acid fragments; and (iii) adding sequencing adapters to the tailed nucleic acid fragments to generate a nucleic acid library. 30. The method of clause 29, wherein fragmenting in step (i) comprises using one or more blunt / non-cohesive end-generating endonucleases, thereby preventing the need for end- repair of the fragmented nucleic acid molecules. 31. The method of clause 30, wherein the blunt / non-cohesive end-generating endonuclease is a blunt / non-cohesive end-generating restriction endonuclease having a 4 base-pair recognition site and / or which is not impaired by overlapping CpG methylation, such as an endonuclease is selected from one or both of: AluI and HpyCH4. 32. The method of clause 31, wherein the HpyCH4 endonuclease is HpyCH4III, HpyCH4IV or HpyCH4V. 33. The method of any one of clauses 29 to 32, wherein fragmenting in step (i) comprises removing overhangs from the fragmented nucleic acid molecules using one or more exonuclease enzyme to generate fragmented nucleic acid molecules with blunt ends. 34. The method of clause 33, wherein fragmenting in step (i) comprises mechanical fragmentation, such as sonication. 35. The method of clause 28, clause 33 or clause 34, wherein the isolated and purified DNA is prepared for sequencing according to a method comprising the steps of: (i a) fragmenting the DNA by sonication to generate fragmented nucleic acid molecules; (i b) removing overhangs from the fragmented nucleic acid molecules using one or more exonuclease enzyme to generate fragmented nucleic acid molecules with blunt ends; (ii) introducing dideoxy nucleotides at internal nick sites present in the fragmented nucleic acid molecules with blunt ends and tailing to generate tailed nucleic acid fragments; and (iii) adding sequencing adapters to the tailed nucleic acid fragments to generate a nucleic acid library. 36. The method of any one of clauses 33 to 35, wherein the one or more exonuclease enzyme is Mung Bean nuclease. 37. The method of any one of clauses 29 to 35, wherein introducing dideoxy nucleotides at internal nick sites in step (ii) prevents extension of the internal nick and results in an unamplifiable nucleic acid strand. 38. The method of any one of clauses 29 to 37, wherein: (i) the dideoxy nucleotides introduced in step (ii) are dideoxy non-A nucleotides, such as ddBTPs, and optionally the tailing of the fragmented nucleic acid molecules in step (ii) comprises A-tailing; or (ii) the dideoxy nucleotides introduced in step (ii) are dideoxy non-C nucleotides, such as ddDTP, and optionally the tailing of the fragmented nucleic acid molecules in step (ii) comprises C-tailing; or (iii) the dideoxy nucleotides introduced in step (ii) are dideoxy non-G nucleotides, such as ddHTP, and optionally the tailing of the fragmented nucleic acid molecules in step (ii) comprises G-tailing; or (iv) the dideoxy nucleotides introduced in step (ii) are dideoxy non-T nucleotides, such as ddVTP, and optionally the tailing of the fragmented nucleic acid molecules in step (ii) comprises T-tailing. 39. The method of any one of clauses 1 to 38, wherein the sample is blood or a tissue biopsy. 40. The method of clause 1 or any of clauses 3 to 39, wherein the siRNA comprises a sequence that is complementary to a region of the DNA comprising the somatic mutation. 41. The method of clause 1 or any of clauses 3 to 39, wherein the siRNA comprises a sequence that is complementary to a region of an mRNA produced from the DNA comprising the somatic mutation, wherein the region of the mRNA comprises the mutation. 42. A double stand RNA (dsRNA) molecule comprising a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand and / or the sense strand comprises at least 15 contiguous nucleotides of and differing by no more than 3 nucleotides from the nucleotide sequence of any mRNA sequence represented by the cDNA sequences set forth in Table 2 or set forth in any one of SEQ ID NOs: 1 to 59. 43. The dsRNA molecule of clause 42, for inhibiting, reducing and / or preventing the expression of one or more gene selected from: fatty acid synthase (FASN); APOBEC1 complementation factor (A1CF); Krüppel-like factor 15 (KLF15); serotransferrin (TF); cytochrome P4502E1 (CYP2E1); cyclin-dependent kinase inhibitor 1B (CDKN1B); PCF11 cleavage and polyadenylation factor subunit (PCF11); ubiquitin-conjugating enzyme E2 D3 (UBE2D3); eukaryotic elongation factor 2 (EEF2); and / or serine protease hepsin (HPN). 44. The dsRNA molecule of clause 42 or clause 43, wherein the antisense strand comprises at least 15 contiguous nucleotides complementary to and mismatching by no more than 3 nucleotides from the nucleotide sequence of any mRNA sequence represented by the cDNA sequences set forth in Table 2 or set forth in any one of SEQ ID NOs: 1 to 59. 45. The dsRNA molecule of any one of clauses 42 to 44, wherein the sense strand comprises at least 15 contiguous nucleotides complementary to and mismatching by no more than 3 nucleotides from the nucleotide sequence of any mRNA sequence represented by the cDNA sequences set forth in Table 2 or set forth in any one of SEQ ID NOs: 1 to 59. 46. The dsRNA molecule of any one of clauses 42 to 45, comprising a targeting moiety. 47. The dsRNA molecule of clause 46, wherein the targeting moiety is GalNac. 48. The dsRNA molecule of clause 46 or clause 47, wherein the targeting moiety recognises a marker of the liver, such as a marker expressed by a liver cell. 49. A method of treating metabolic dysfunction-associated steatohepatitis (MASH) in a subject, the method comprising steps of: (i) isolating and purifying DNA from a sample obtained from the subject; (ii) detecting the presence or absence of a somatic mutation in the DNA of one or more gene selected from: fatty acid synthase (FASN); APOBEC1 complementation factor (A1CF); Krüppel-like factor 15 (KLF15); serotransferrin (TF); cytochrome P4502E1 (CYP2E1); cyclin-dependent kinase inhibitor 1B (CDKN1B); PCF11 cleavage and polyadenylation factor subunit (PCF11); ubiquitin-conjugating enzyme E2 D3 (UBE2D3); eukaryotic elongation factor 2 (EEF2); and serine protease hepsin (HPN), and (iii) administering to the subject a therapeutic intervention of Table 3 if a somatic mutation is present in the DNA of the specified gene. 50. The method of any one of clauses 1 to 41 or clause 49, wherein the mutation is present in the FASN gene and the therapeutic intervention is selected from any one or more of: denifanstat; BI 99179; cerulenin; orlipastat; orlistat; tetrahydrolipstatin; rifampicin / isoniazid / pyrazinamide; and / or pyrazinamide. 51. The method of any one of clauses 1 to 41, clause 49 or clause 50, wherein the mutation is present in the A1CF gene and the therapeutic intervention is selected from any one or more of the oligonucleotides described in WO 2022 / 038211. 52. The method of any one of clauses 1 to 41 or clauses 49 to 51, wherein the mutation is present in the KLF15 gene and the therapeutic intervention is selected from any one or more of: triptolide; ML264; and / or Tenovin-6. 53. The method of any one of clauses 1 to 41 or clauses 49 to 52, wherein the mutation is present in the PCF11 gene and the therapeutic intervention is selected from any one or more of: pladienolide B; herboxidiene; THZ1; and / or SJ-1008066. 54. The method of any one of clauses 1 to 41 or clauses 49 to 53, wherein the mutation is present in the CYP2E1 gene and the therapeutic intervention is selected from any one or more of: Q11; diallyl sulfide (DAS); PPC; and / or fomepizole. 55. The method of any one of clauses 1 to 41 or clauses 49 to 54, wherein the mutation is present in the EEF2 gene and the therapeutic intervention is selected from any one or more of: toosendanin; A484954; and / or NH125. 56. The method of any one of clauses 1 to 41 or clauses 49 to 55, wherein the mutation is present in the HPN gene and the therapeutic intervention is selected from bentiromide. 57. The method of any one of clauses 1 to 41 or clauses 49 to 56, wherein the mutation is present in the TF gene and the therapeutic intervention is selected from any one or more of: iron chelators: deferasirox, deferiprone, pyridoxal isonicotinoyl hydrazone, gallium nitrate, Dp44mT; ferristatin; transferrin aldifitox (Rec INN); and / or transferrin CRM-107. 58. The method of any one of clauses 1 to 41 or clauses 49 to 57, wherein the one or more therapeutic interventions are used in combination, optionally in combination with an siRNA and / or a dsRNA. 59. The method of clause 58, wherein the siRNA and / or dsRNA is as defined in any one or clauses 40 to 48. The invention will now be described using the following, non-limiting examples: EXAMPLES Example 1: The Driver Mutation Landscape in Liver Cirrhosis Patient Selection & Experimental Design 4 to 8 multi-regional biopsies were collected from three patients, chosen for their similar sample collection dates (July-September 2019) to ensure optimal RNA integrity. All three patients had been diagnosed with MASLD and were undergoing transplant for liver failure. Neither was diagnosed with liver cancer. Histopathology was characteristic of end-stage chronic liver disease, with severefibrosis or cirrhosis and minimal steatosis (Figure 11A and Table 3). For two patients, previously identified to possess multiple independent clones within the CIDEB and FOXO1 mutations (Ng et al. (2021) Nature, 568:473-478, doi: https: / / doi.org / 10.1038 / s41586-021-03974-6), biopsies were selected exhibiting the highest load of driver mutations. For the third patient, lacking prior sequencing data, all eight Couinaud segments were sampled to increase the chances of capturing clones harbouring mutations of interest. Table 3: Demographic Details of MASLD Patients For each biopsy, 20 tissue sections totalling 290µm in thickness were obtained, as necessitated by the diverse methodologies employed for a thorough phenotypic characterization of mutant clones. To ensure the consistency of clones phenotyped across the entire depth of the tissue, genomic analyses were performed on slices from both extremities of the z-stack. Specifically, two sections for laser-capture microdissection were prepared: one from the top and the other from the bottom end of the section series, adjacent to regions analysed using VISIUM technology (see Figure 11B). Since driver mutations were previously shown to affect parenchymal tissue, exclusively regenerative nodules were isolated, avoiding fibrotic bands or other features. 24 microdissections per tissue slice were collected, out of which 12-15 were submitted for whole genome sequencing (WGS) to facilitate reconstruction of clonal structures and phylogenetic trees. The remaining samples were sent for whole exome sequencing (WES) to achieve optimal sampling density for inferring clone boundaries. Sequencing criteria required a minimum library concentration of 10 ng / µL for exome sequencing and 5 ng / µL for whole genome sequencing, with 27-48 microdissections per biopsy meeting those requirements. Altogether 669 samples were submitted for sequencing: 375 for dual whole-genome and exome sequencing, 264 for exome sequencing and 30 for whole genome sequencing. Median coverage of 23x for WGS and 55x on-target coverage for WES was achieved. Results Between 3 and 126 coding mutations were detected per microdissection (median=20.5, mean=27.7; Figure 12). The mutation burden varied considerably between and within donors, in accordance with previously published observations (Brunner et al. (2019) Nature, 574:538- 542, doi: The youngest donor (51 y) exhibited the lowest burden of coding mutations (median = 14). In contrast, the older donors showed higher burdens, with medians of 24 and 51 coding mutations per microdissection, respectively (Figure 12). To test whether extending the sample size would allow for detection of novel driver genes, the genome and exome calls were combined with whole genome data published in Ng et al. (2021). The combined dataset comprised 35 donors: 5 healthy, 10 ALD and 20 MASLD cases. The dNdScv algorithm (Martincorena et al. (2017) Cell, 171(5): 1029-1041, doi: https: / / doi.org / 10.1016%2Fj.cell.2017.09.042) was utilised to assess the ratio of non- synonymous to synonymous mutations (dN / dS) across all liver microdissections, while correcting for regional and context-dependent variation in mutation rates. Reassuringly, running the statistical model on the mutation list confirmed 6 driver genes previously identified in SLD by Ng et al. (2021): ALB , FOXO1 (q < 2x10-16), CIDEB (q < 2x10-16), GPAM (q = 4x10-13), ACVR2A (q < 2x10-16) and TNRC6B (q = 3x10-5). Additionally, the analysis revealed 6 novel genes significantly under positive selection after correction for multiple hypothesis testing (qglobal cv < 0.1) : INSR (q = 0.002), CHD4 (q = 0.047), FASN (q = 2x10-4), TF (q = 0.06), EEF2 (q = 0.055) and A1CF (q = 0.076). Prior to the present study, it is believe that none of these genes has been reported in hepatocellular carcinoma (HCC), implying that they may confer a selective advantage without promoting carcinogenesis. Additional evidence from the Pan-Cancer Analysis of Whole Genomes (PCAWG) dataset supports this conclusion, with less than 2% of liver tumours harbouring mutations in the identified genes. Mutation patterns in certain of these genes were then investigated individually, and are presented in Examples 2-6 herein. Example 2: Mutations in A1CF 10 mutations were detected in the Apobec1 complementation factor (A1CF) gene, a member of the hnRNP family of RNA-binding proteins. A strong excess of indels (dN / dS = 32.13) and nonsense (dN / dS = 8.22) mutations were observed, and a moderate excess of missense (dN / dS = 4.52) mutations, suggesting the likely effect of these mutations is loss of protein function. The distribution of mutations within the gene did not exhibit pronounced clustering. However, a significant proportion, specifically 6 out of 10, impacted known functional domains, notably the RNA recognition motifs and the dsRNA binding domain (Figure 2). The remainder localise to the N-terminal region, upstream of the RNA recognition motifs. Initially identified as a mediator of site-specific cytidine to uridine deamination in apolipoprotein B (APOB) mRNA, recent evidence challenges the indispensable role of A1CF in this process, and suggests broader implications in RNA editing and processing activities (Mehta et al. (2000) Mol. Cell. Biol., 20(5):1846-1854, doi: https: / / doi.org / 10.1128 / mcb.20.5.1846- 1854.2000; Snyder et al. (2017) RNA, 23(4):457-465, doi: https: / / doi.org / 10.1261 / rna.058818.116; and Blanc et al. (2019) RNA, 25(1):70-81, doi: https: / / doi.org / 10.1261 / rna.068395.118). This includes an important role in defining a hepatic splicing signature (Nikolaou et al. (2019) Cell Reports, 29:283-300, doi: https: / / doi.org / 10.1016 / j.celrep.2019.08.100). Notably, A1CF deletion in mice enhances glucose tolerance and confers resistance to steatosis and obesity, while its overexpression exacerbates hepatic conditions, leading to steatosis,fibrosis, and hepatocellular carcinoma (HCC) (Nikolaou et al. (2019); Blanc et al. (2021)). Furthermore, a missense variant in A1CF (G398S, rs41274050) correlates with elevated triglyceride levels in humans, emphasising its potential role in lipid metabolism (Liu et al. (2017) Nature Genetics, 49:1758-1766, doi: https: / / doi.org / 10.1038 / ng.3977; and de Vries et al. (2019) Am. J. Epidemiol., 188(6):1033-1054, doi: https: / / doi.org / 10.1093 / aje / kwz005). Collectively, existing evidence suggest that somatic loss- of-function mutations in A1CF may represent another adaptation to mitigate lipid-induced toxicity, with potential benefits at both cellular and organismal levels. Example 3: Mutations in FASN Another gene with strong signs of positive selection was FASN, which encodes fatty acid synthase – an enzyme catalysing the last step in fatty acid biosynthesis. FASN orchestrates the rate-limiting step of the reaction, controlling the rate of hepatic de novo lipogenesis. In the present analysis, 25 non-synonymous mutations were detected within this extensive gene, which spans 2511 amino acids, marked by a significantly elevated dN / dS ratio for indels (dN / dS = 27.9). Given the involvement of FASN in a pathway associated with steatotic liver disease, loss-of-function mutations in this gene could act as driver mutations. However, there was no clear clustering observed in the distribution of mutations (Figure 1) and the statistical significance is driven exclusively by indels (Table 1), whereas typically loss-of-function mutations under positive selection would include nonsense and essential splice mutations. Example 4: Mutations in TF One of the other significantly positively selected gene in dN / dS analysis was TF. Transferrin, encoded by the TF gene, is a glycoprotein synthesised in the liver and secreted into the bloodstream. The gene exhibited a prominent excess of indels compared to other mutation types (dN / dS = 17.1, Table 1). This mutation profile may arise from a replication-transcription machinery conflict, and has been previously documented in TF during liver cancer development (Helleday, Eshtad & Nik-Zainal (2014) Nat. Rev. Genet., 15(9):585-598, doi: https: / / doi.org / 10.1038 / nrg3729; Letouzé et al. (2017) Cancer Cell, 23(6):739-752, doi: https: / / doi.org / 10.1016 / j.ccr.2013.04.018; and Dietlein et al. (2022) Science, 376(6589), doi: Example 5: Mutations in EEF2 EF2, encoding Eukaryotic translation elongation factor 2, was another gene detected to be under significant positive selection, with 11 missense mutations (dN / dS = 10). By contrast to TF, EEF2 exhibits low tissue specificity, and no indels were detected in the gene (Table 1). Missense mutations were generally distributed evenly throughout the gene, with the exception of one residue which was affected twice, in two different donors, hinting at a potential hotspot site: M257. EEF2 is an essential component for the elongation phase of translation, and experimental downregulation in mouse liver models has demonstrated a consequent global decrease in protein synthesis (Dever and Green (2012) Cold Spring. Harb. Perspect. Biol., 4(7):a013706, doi: https: / / doi.org / 10.1101 / cshperspect.a013706; and Gerashchenko et al. (2020) Sci. Rep., 10(15473), doi: https: / / doi.org / 10.1038 / s41598-020-72399-4). Considering intensive demands on hepatocytes for protein production, modifications in EEF2 may present a selective advantage. By potentially reducing the protein synthesis workload, these alterations could help alleviate the burden on cells particularly strained in the setting of steatotic liver disease. Example 6: Mapping of Mutant Clones onto Tissue Sections Previous work from Brunner et al. (2019) revealed that regenerative nodules in liver cirrhosis are largely clonal or oligoclonal. This assumption was important to facilitate mapping of clone boundaries onto tissue sections. By applying a beta-binomial mixture model to assess clonality across microdissections, a median dominant clone variant allele fraction (VAF) of 0.34 was found herein, supporting a high degree of clonality. The majority of variants in driver genes had VAFs between 0.2 and 0.5, and there was no evidence of loss-of-heterozygosity (LOH) events, suggesting their heterozygosity in the major clone. Next, the N-dimensional Dirichlet Process (NDP) algorithm was applied to cluster mutations based on their variant allele frequency (VAF). This analysis enabled determination of the clonal composition of each microdissection and elucidate the phylogenetic relationships between clones within and between microbiopsies. Utilizing the clonal structures identified by NDP and their corresponding prevalence data from each microdissection, phylogenetic trees were constructed and projected them onto tissue histology (Figures 13-15). As previously observed by Brunner et al. (2019), the data herein showed extensive sharing between microdissections within the same nodule, but phylogenetic relatedness was rare between nodules separated by bands offibrosis. Notably, driver mutations were primarily located in the phylogenetic trees’ trunks, exhibiting mutant cell fractions as high as 100% in micro- biopsies. The pattern of clonal architecture persisted across z-stacked sections, guiding the manual demarcation of driver clone boundaries (Figures 13-15). Several criteria were incorporated for this delineation: inclusion of microbiopsies sharing the mutant clone, exclusion of samples with low VAF (0.1) to avoid boundary ambiguities or contamination, consideration of exome- sequencing samples supporting mutations of interest, and, where sufficient evidence was available, extension of boundaries to encompass entire nodules. Example 7: Driver Mutations in Preliminary Stages of Steatotic Liver Disease Exome sequencing was then applied to microbiopsies from obese individuals, a population at risk for developing steatotic liver disease. The aim was to explore whether the driver mutations identified in end-stage disease are also detectable in the disease’s nascent stages. This comparative approach seeks to identify shared somatic mutation profiles between early and end-stage steatotic liver disease and to assess the potential of these mutations as biomarkers for disease progression or targets for therapeutic intervention. Description of Obese Cohorts 9 post-mortem liver samples were obtained from individuals with BMI of at least 26, with three overweight and six obese donors (Table 4). All died of causes unrelated to liver disease – stroke, anoxia or head trauma. Based on histopathology review, the donors had minimal, mild or moderatefibrosis (Kleiner scores 1-3) and moderate steatosis scores, characteristic of early stage disease. Representative histopathology images can be seen in Figure 16.

[0005] Table 4: Demographic Details of Overweight and Obese Patients One tissue section was taken per patient and 24 microdissections per sample collected. Similarly to cirrhotic samples, parenchymal features were isolated, avoiding blood vessels or biliary ducts. As previously, the driver landscape was focussed on. All 233 microdissections were submitted for sequencing, passing library concentration requirements (greater than 10 ng / µL) for exome sequencing. A median coverage of 77x was achieved. Following variant filtering, 23,528 total mutations were identified in the cohort, a mean of 106 per sample. Between 3 and 110 coding mutations per microdissection were detected. A discernible variation in mutation burden across donors was noted, with no apparent correlation to age. This observation could be attributed to a narrow age spectrum (50-67), combined with a diverse sample encompassing both smokers and non-smokers, and varied mutagenic exposures. The mean variant allele frequency (VAF) of the mutations detected across the samples was 0.21, with a median VAF of 0.20. This suggests that the detected mutations predominantly originate from oligoclonal cell populations within each biopsy. Analysis of the major clone’s VAF across the samples revealed that in the majority (148 out of 222), the major clone constituted less than 40% of the cells in a biopsy (VAF < 0.2), highlighting the subclonal complexity within these microdissections. However, there is a wide variation across the samples, with some samples approaching a VAF of 0.4, suggesting the presence of dominant clones in a subset of the samples. The clonality also varied between donors, with one donor showing the most polyclonal landscape (median estimated VAF of the major clone was 0.11), and another having more clonal tissue (median estimated VAF = 0.25). Mutation patterns in certain of these genes were then investigated individually, and are presented in Example 8 herein. Example 8: Mutations in CYP2E1 and CDKN1B A high frequency of indels in CYP2E1 was observed, a gene encoding cytochrome P4502E1 (dN / dS = 215 for indels). Cytochrome P450 monooxygenase is involved in the metabolism of fatty acids and xenobiotics, and is a liver-specific gene with previously recognized excess of mutation events in liver cancer (Dietlein et al. (2022) Science, 376(6589):eabg5601, doi: CDKN1B, a gene not previously reported in steatotic liver disease, stood out for its pronounced excess of indels, with a dN / dS ratio exceeding 1300 (Table 1). The gene encodes cyclin- dependent kinase inhibitor 1B, also known as p27. The primary function of CDKN1B as a cell cycle inhibitor protein is to prevent or suppress cell division.7 frameshift indel mutations were observed in the gene. Intriguingly, three of these variants co-localised at consecutive residues D17, A18 and R19 (Figure 6), which appeared in three distinct microdissections from one donor. Manual inspection of supporting reads in the Jbrowse genome browser did not reveal any discrepancies, affirming the authenticity and independence of these events. This locus may be particularly prone to indel accumulation, potentially due to a DNA sequence that predisposes DNA polymerase to stalling, thereby escalating the risk of replication-transcription collision events. The same donor also presented with three indels in CYP2E1 and two in a further gene, suggesting a pronounced indel-driven mutational process in this individual’s genome. While the accumulation of indels in CDKN1B is intriguing, the gene’s broad expression across tissues suggests that the earlier proposed mutational process, characterised by indel accumulation in highly expressed, tissue-specific genes, may not fully explain the observed mutations (Karlsson et al. (2021) Sci. Adv., 7(31):eabh2169, doi: https: / / doi.org / 10.1126 / Alternatively, the presence of these indels may reflect positive selection, particularly given CDKN1B’s role as a tumour suppressor. While CDKN1B is not mutated in human cancers, it is frequently down-regulated and its reduced expression is associated with a poorer prognosis in liver cancer, amongst others (Chu, Hengst & Slingerland (2008) Nat. Rev. Cancer, 8(253-267, doi: https: / / doi.org / 10.1038 / nrc2347). The frameshift indel variants in CDKN1B may compromise its inhibitory role in the cell cycle, potentially facilitating clonal expansion through increased cell proliferation.

Claims

CLAIMS 1. A method of treating metabolic dysfunction-associated steatohepatitis (MASH) in a subject, the method comprising the steps of: (i) isolating and purifying DNA from a sample obtained from the subject; (ii) detecting the presence or absence of a somatic mutation in the DNA of one or more gene selected from: fatty acid synthase (FASN); APOBEC1 complementation factor (A1CF); Krüppel-like factor 15 (KLF15); serotransferrin (TF); cytochrome P4502E1 (CYP2E1); cyclin-dependent kinase inhibitor 1B (CDKN1B); PCF11 cleavage and polyadenylation factor subunit (PCF11); ubiquitin-conjugating enzyme E2 D3 (UBE2D3); eukaryotic elongation factor 2 (EEF2); and / or serine protease hepsin (HPN), and (iii) administering to the subject an siRNA that inhibits expression of said one or more gene if a somatic mutation is present in the DNA.

2. A method of detecting the presence or absence of a somatic mutation in a subject suspected of having or at risk of having metabolic dysfunction-associated steatohepatitis (MASH), the method comprising the steps of: (i) isolating and purifying DNA from a sample obtained from the subject; and (ii) detecting the presence or absence of a somatic mutation in the DNA of one or more gene selected from: fatty acid synthase (FASN); APOBEC1 complementation factor (A1CF); Krüppel-like factor 15 (KLF15); serotransferrin (TF); cytochrome P4502E1 (CYP2E1); cyclin-dependent kinase inhibitor 1B (CDKN1B); PCF11 cleavage and polyadenylation factor subunit (PCF11); ubiquitin-conjugating enzyme E2 D3 (UBE2D3); eukaryotic elongation factor 2 (EEF2); and / or serine protease hepsin (HPN), andwherein the presence of a somatic mutation in said one or more gene indicates that the subject has or is at risk of having MASH.

3. The method of claim 1 or claim 2, wherein the somatic mutation is a loss of function mutation.

4. The method of any one of claims 1 to 3, wherein the somatic mutation is selected from one or more of: a missense mutation, a nonsense mutation, a mutation of an essential splice site, a mutation of a stop codon, a single or multiple nucleotide variation (SNV / MNV), and / or an insertion or deletion leading to a frameshift.

5. The method of any one of claims 1 to 4, wherein the somatic mutation is located within a coding region and / or within a non-coding region of the gene.

6. The method of any one of claims 1 to 5, wherein the somatic mutation is one or more mutation selected from those listed in Table 1.

7. The method of any one of claims 1 to 6, wherein the somatic mutation causes one or more amino acid change selected from those listed in Table 1.

8. The method of any one of claims 1 to 7, wherein the presence or absence of the somatic mutation is detected using sequencing and / or by PCR, such as quantitative and / or real-time PCR.

9. The method of claim 8, wherein the isolated and purified DNA is prepared for sequencing according to a method comprising the steps of: (i) fragmenting the DNA to generate fragmented nucleic acid molecules with blunt ends; (ii) introducing dideoxy nucleotides at internal nick sites present in the fragmented nucleic acid molecules with blunt ends and tailing to generate tailed nucleic acid fragments; and (iii) adding sequencing adapters to the tailed nucleic acid fragments to generate a nucleic acid library.

10. The method of claim 9, wherein fragmenting in step (i) comprises using one or more blunt / non-cohesive end-generating endonucleases, thereby preventing the need for end- repair of the fragmented nucleic acid molecules,optionally wherein the blunt / non-cohesive end-generating endonuclease is a blunt / non-cohesive end-generating restriction endonuclease having a 4 base-pair recognition site and / or which is not impaired by overlapping CpG methylation, such as an endonuclease is selected from one or both of: AluI and HpyCH4.

11. The method of claim 9, wherein fragmenting in step (i) comprises removing overhangs from the fragmented nucleic acid molecules using one or more exonuclease enzyme to generate fragmented nucleic acid molecules with blunt ends, optionally wherein fragmenting in step (i) comprises mechanical fragmentation, such as sonication.

12. The method of claim 11, wherein the one or more exonuclease enzyme is Mung Bean nuclease.

13. The method of any one of claims 9 to 12, wherein introducing dideoxy nucleotides at internal nick sites in step (ii) prevents extension of the internal nick and results in an unamplifiable nucleic acid strand, and / or wherein: (i) the dideoxy nucleotides introduced in step (ii) are dideoxy non-A nucleotides, such as ddBTPs, and optionally the tailing of the fragmented nucleic acid molecules in step (ii) comprises A-tailing; or (ii) the dideoxy nucleotides introduced in step (ii) are dideoxy non-C nucleotides, such as ddDTP, and optionally the tailing of the fragmented nucleic acid molecules in step (ii) comprises C-tailing; or (iii) the dideoxy nucleotides introduced in step (ii) are dideoxy non-G nucleotides, such as ddHTP, and optionally the tailing of the fragmented nucleic acid molecules in step (ii) comprises G-tailing; or (iv) the dideoxy nucleotides introduced in step (ii) are dideoxy non-T nucleotides, such as ddVTP, and optionally the tailing of the fragmented nucleic acid molecules in step (ii) comprises T-tailing.

14. The method of any one of claims 1 to 13, wherein the sample is blood or a tissue biopsy.

15. The method of claim 1 or any of claims 3 to 14, wherein the siRNA comprises a sequence that is complementary to a region of the DNA comprising the somatic mutation,or comprises a sequence that is complementary to a region of an mRNA produced from the DNA comprising the somatic mutation, wherein the region of the mRNA comprises the mutation.

16. A double stand RNA (dsRNA) molecule comprising a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand and / or the sense strand comprises at least 15 contiguous nucleotides of and differing by no more than 3 nucleotides from the nucleotide sequence of any mRNA sequence represented by the cDNA sequences set forth in Table 2 or set forth in any one of SEQ ID NOs: 1 to 59.

17. The dsRNA molecule of claim 16, for inhibiting, reducing and / or preventing the expression of one or more gene selected from: fatty acid synthase (FASN); APOBEC1 complementation factor (A1CF); Krüppel-like factor 15 (KLF15); serotransferrin (TF); cytochrome P4502E1 (CYP2E1); cyclin-dependent kinase inhibitor 1B (CDKN1B); PCF11 cleavage and polyadenylation factor subunit (PCF11); ubiquitin-conjugating enzyme E2 D3 (UBE2D3); eukaryotic elongation factor 2 (EEF2); and / or serine protease hepsin (HPN).

18. The dsRNA molecule of claim 16 or claim 17, wherein the antisense strand and / or the sense strand comprises at least 15 contiguous nucleotides complementary to and mismatching by no more than 3 nucleotides from the nucleotide sequence of any mRNA sequence represented by the cDNA sequences set forth in Table 2 or set forth in any one of SEQ ID NOs: 1 to 59.

19. The dsRNA molecule of any one of claims 16 to 18, comprising a targeting moiety.

20. A method of treating metabolic dysfunction-associated steatohepatitis (MASH) in a subject, the method comprising steps of: (i) isolating and purifying DNA from a sample obtained from the subject; (ii) detecting the presence or absence of a somatic mutation in the DNA of one or more gene selected from: fatty acid synthase (FASN);APOBEC1 complementation factor (A1CF); Krüppel-like factor 15 (KLF15); serotransferrin (TF); cytochrome P4502E1 (CYP2E1); cyclin-dependent kinase inhibitor 1B (CDKN1B); PCF11 cleavage and polyadenylation factor subunit (PCF11); ubiquitin-conjugating enzyme E2 D3 (UBE2D3); eukaryotic elongation factor 2 (EEF2); and serine protease hepsin (HPN), and (iii) administering to the subject a therapeutic intervention of Table 3 if a somatic mutation is present in the DNA of the specified gene.

Images