System and method for cleaning noisy genetic data from target individuals using genetic data from genetically related individuals
First Claim
1. An ex vivo method for determining a number of copies of a chromosome or chromosome segment in the genome of a fetus, the method comprising:
- hybridizing polymerase chain reaction (PCR) probes to a plurality of at least 100 polymorphic loci on the chromosome or chromosome segment in a sample comprising DNA from the fetus and DNA from the mother of the fetus;
generating amplified products by PCR;
measuring an amount of the amplified products to obtain genetic data at the plurality of polymorphic loci on the chromosome or chromosome segment;
generating a set of one or more hypotheses specifying the number of copies of the chromosome or chromosome segment present in the genome of the fetus;
calculating a likelihood for each of the hypotheses based on a beta binomial distribution of expected and observed genetic data at the plurality of polymorphic loci; and
outputting the hypothesis with the highest probability based on Bayesian estimation, as an indication of the number of copies of the chromosome or chromosome segment in the genome of the fetus.
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Abstract
A system and method for determining the genetic data for one or a small set of cells, or from fragmentary DNA, where a limited quantity of genetic data is available, are disclosed. Genetic data for the target individual is acquired and amplified using known methods, and poorly measured base pairs, missing alleles and missing regions are reconstructed using expected similarities between the target genome and the genome of genetically related subjects. In accordance with one embodiment of the invention incomplete genetic data is acquired from embryonic cells, fetal cells, or cell-free fetal DNA isolated from the mother'"'"'s blood, and the incomplete genetic data is reconstructed using the more complete genetic data from a larger sample diploid cells from one or both parents, with or without genetic data from haploid cells from one or both parents, and/or genetic data taken from other related individuals.
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Citations
15 Claims
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1. An ex vivo method for determining a number of copies of a chromosome or chromosome segment in the genome of a fetus, the method comprising:
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hybridizing polymerase chain reaction (PCR) probes to a plurality of at least 100 polymorphic loci on the chromosome or chromosome segment in a sample comprising DNA from the fetus and DNA from the mother of the fetus; generating amplified products by PCR; measuring an amount of the amplified products to obtain genetic data at the plurality of polymorphic loci on the chromosome or chromosome segment; generating a set of one or more hypotheses specifying the number of copies of the chromosome or chromosome segment present in the genome of the fetus; calculating a likelihood for each of the hypotheses based on a beta binomial distribution of expected and observed genetic data at the plurality of polymorphic loci; and outputting the hypothesis with the highest probability based on Bayesian estimation, as an indication of the number of copies of the chromosome or chromosome segment in the genome of the fetus. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15)
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13. An ex vivo method for determining a number of copies of a chromosome or chromosome segment, the method comprising:
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hybridizing PCR probes to a plurality of at least 100 polymorphic loci on the chromosome or chromosome segment in the fetus in a sample comprising maternal DNA and fetal DNA; generating amplified products by PCR; measuring an amount of the amplified products to obtain genetic data at the plurality of polymorphic loci on the chromosome or chromosome segment; generating a set of one or more hypotheses specifying the number of copies of the chromosome or chromosome segment present in the genome of the fetus; calculating, on a computer, the data fit between the obtained genetic data comprising the amount of the amplified products at each locus and expected genetic data for the hypothesis comprising the expected amount of one or more of the alleles, based on a beta binomial distribution of expected and observed genetic data at the plurality of polymorphic loci; and outputting the hypothesis with the highest probability based on Bayesian estimation, as an indication of the number of copies of the chromosome or chromosome segment in the genome of the fetus.
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Specification