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WO 2015/164432 Al 29 October 2015 (29.10.2015) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/164432 Al 29 October 2015 (29.10.2015) P O P C T (51) International Patent Classification: mir; 201 Industrial Road, Suite 410, San Carlos, California C12Q 1/68 (2006.01) G06F 19/16 (201 1.01) 94070 (US). ZIMMERMAN, Bernhard; 201 Industrial Road, Suite 410, San Carlos, California 94070 (US). (21) International Application Number: PCT/US2015/026957 (74) Agents: MADDEN, Robert B. et al; P.O. Box 2938, Min neapolis, Minnesota 55402-0938 (US). (22) International Filing Date: 2 1 April 2015 (21 .04.2015) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (25) Language: English Filing AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (26) Publication Language: English BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (30) Priority Data: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 61/982,245 2 1 April 2014 (21.04.2014) US KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 61/987,407 1 May 2014 (01.05.2014) US MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, 62/066,5 14 2 1 October 20 14 (2 1.10.20 14) US PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 62/146,188 10 April 2015 (10.04.2015) US SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 62/147,377 14 April 2015 (14.04.2015) US TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 62/148,173 15 April 2015 (15.04.2015) US (84) Designated States (unless otherwise indicated, for every (71) Applicant: NATERA, INC. [US/US]; 201 Industrial kind of regional protection available): ARIPO (BW, GH, Road, Suite 410, San Carlos, California 94070 (US). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (72) Inventors: BABIARZ, Joshua; 201 Industrial Road, Suite TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, 410, San Carlos, California 94070 (US). CONSTANTIN, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, Tudor Pompiliu; 201 Industrial Road, Suite 410, San Car DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, los, California 94070 (US). EUBANK, Lane A.; 201 In LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, dustrial Road, Suite 410, San Carlos, California 94070 SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (US). GEMELOS, George; 201 Industrial Road, Suite GW, KM, ML, MR, NE, SN, TD, TG). 410, San Carlos, California 94070 (US). HILL, Matthew Published: Micah; 201 Industrial Road, Suite 410, San Carlos, Cali — with international search report (Art. 21(3)) fornia 94070 (US). KIRKIZLAR, Huseyin Eser; 201 In dustrial Road, Suite 410, San Carlos, California 94070 — before the expiration of the time limit for amending the (US). RABINOWITZ, Matthew; 201 Industrial Road, claims and to be republished in the event of receipt of Suite 410, San Carlos, California 94070 (US). amendments (Rule 48.2(h)) SAKARYA, Onur; 201 Industrial Road, Suite 410, San Carlos, California 94070 (US). SIGURJONSSON, Styr- (54) Title: DETECTING MUTATIONS AND PLOIDY IN CHROMOSOMAL SEGMENTS Figures 2 A and 20B (57) Abstract: The invention provides methods, systems, and computer readable medium for detecting ploidy of chromosome seg ments or entire chromosomes based on phasing of the alleles and determination of individual and joint probabilities and a best-fit model. In some aspects, the invention provides methods, systems, and computer readable medium for detecting cancer or a chromo - somal abnormality in a gestating fetus. The invention also provides methods for detecting circulating tumor nucleic acids based on the level of allelic imbalance present at the polymorphic loci found by ploidy determination. The invention also provides a method for detecting single nucleotide variants based on an estimation of amplification efficiency and error rate and a method for detecting single nucleotide variants based on a median variant allele frequency for a plurality of control samples from individuals. DETECTING MUTATIONS AND PLOIDY IN CHROMOSOMAL SEGMENTS CROSS-REFERENCE TO RELATED APPLICATIONS [001] This application claims the benefit of and priority to U.S. Provisional Application Ser. No. 61/982,245, filed April 21, 2014; U.S. Provisional Application Ser. No. 61/987,407, filed May 1, 2014; U.S. Provisional Application Ser. No. 62/066,514, filed October 21, 2014; U.S. Provisional Application Ser. No. 62/146,188, filed April 10, 2015; U.S. Provisional Application Ser. No. 62/147,377, filed April 14, 2015; U.S. Provisional Application Ser. No. 62/148,173, filed April 15, 2015, the entirety of these applications are hereby incorporated herein by reference for the teachings therein. FIELD OF THE INVENTION [002] The present invention generally relates to methods and systems for detecting ploidy of a chromosome segment, and methods and systems for detecting a single nucleotide variant. BACKGROUND OF THE INVENTION [003] Copy number variation (CNV) has been identified as a major cause of structural variation in the genome, involving both duplications and deletions of sequences that typically range in length from 1,000 base pairs ( 1 kb) to 20 megabases (mb). Deletions and duplications of chromosome segments or entire chromosomes are associated with a variety of conditions, such as susceptibility or resistance to disease. [004] CNVs are often assigned to one of two main categories, based on the length of the affected sequence. The first category includes copy number polymorphisms (CNPs), which are common in the general population, occurring with an overall frequency of greater than 1%. CNPs are typically small (most are less than 10 kilobases in length), and they are often enriched for genes that encode proteins important in drug detoxification and immunity. A subset of these CNPs is highly variable with respect to copy number. As a result, different human chromosomes can have a wide range of copy numbers (e.g., 2, 3, 4, 5, etc.) for a particular set of genes. CNPs associated with immune response genes have recently been associated with susceptibility to complex genetic diseases, including psoriasis, Crohn's disease, and glomerulonephritis. [005] The second class of CNVs includes relatively rare variants that are much longer than CNPs, ranging in size from hundreds of thousands of base pairs to over 1 million base pairs in length. In some cases, these CNVs may have arisen during production of the sperm or egg that gave rise to a particular individual, or they may have been passed down for only a few generations within a family. These large and rare structural variants have been observed disproportionately in subjects with mental retardation, developmental delay, schizophrenia, and autism. Their appearance in such subjects has led to speculation that large and rare CNVs may be more important in neurocognitive diseases than other forms of inherited mutations, including single nucleotide substitutions. [006] Gene copy number can be altered in cancer cells. For instance, duplication of Chrlp is common in breast cancer, and the EGFR copy number can be higher than normal in non-small cell lung cancer. Cancer is one of the leading causes of death; thus, early diagnosis and treatment of cancer is important, since it can improve the patient's outcome (such as by increasing the probability of remission and the duration of remission). Early diagnosis can also allow the patient to undergo fewer or less drastic treatment alternatives. Many of the current treatments that destroy cancerous cells also affect normal cells, resulting in a variety of possible side-effects, such as nausea, vomiting, low blood cell counts, increased risk of infection, hair loss, and ulcers in mucous membranes. Thus, early detection of cancer is desirable since it can reduce the amount and/or number of treatments (such as chemotherapeutic agents or radiation) needed to eliminate the cancer. [007] Copy number variation has also been associated with severe mental and physical handicaps, and idiopathic learning disability. Non-invasive prenatal testing (NIPT) using cell-free DNA (cfDNA) can be used to detect abnormalities, such as fetal trisomies 13, 18, and 21, triploidy, and sex chromosome aneuploidies. Subchromosomal microdeletions, which can also result in severe mental and physical handicaps, are more challenging to detect due to their smaller size. Eight of the microdeletion syndromes have an aggregate incidence of more than 1 in 1000, making them nearly as common as fetal autosomal trisomies. [008] In addition, a higher copy number of CCL3L1 has been associated with lower susceptibility to HIV infection, and a low copy number of FCGR3B (the CD 16 cell surface immunoglobulin receptor) can increase susceptibility to systemic lupus erythematosus and similar inflammatory autoimmune disorders. [009] Thus, improved methods are needed to detect deletions and duplications of chromosome segments or entire chromosomes. Preferably, these methods can be used to more accurately diagnose disease or an increased risk of disease, such as cancer or CNVs in a gestating fetus. SUMMARY OF THE INVENTION [0010] In illustrative embodiments, provided herein is a method for determining ploidy of a chromosomal segment in a sample of an individual. The method includes the following steps: a. receiving allele frequency data comprising the amount of each allele present in the sample at each loci in a set of polymorphic loci on the chromosomal segment; b. generating phased allelic information for the set of polymorphic loci by estimating the phase of the allele frequency data; c.
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