System and method for cleaning noisy genetic data from target individuals using genetic data from genetically related individuals

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.

What is claimed is: 
     
         1 . An ex vivo method for determining a number of copies of a chromosome of interest, or section of the chromosome, in the genome of a fetus, comprising;
 collecting a sample from the biological mother of the fetus comprising at least one fetal cell;   measuring genetic data from the fetal cell by determining the quantity of each allele at a plurality of loci in genetic material from the fetal cell, wherein the plurality of loci comprises single nucleotide polymorphisms;   collecting genetic material from one or both biological parents of the fetus;   measuring genetic data from the biological parent of the fetus by determining each allele at a plurality of the loci in genetic material from the biological parent;   creating on a computer, a plurality of hypotheses specifying the number of copies of the chromosome of interest or section of the chromosome of interest present in the genome of the fetus;   calculating, for each of the hypotheses, expected genetic data for the plurality of loci in the fetus from the measured genetic data from the biological parent;   comparing, on a computer, the expected genetic data for each of the hypotheses to the measured genetic data to determine a probability that each hypothesis is true;   ranking one or more of the hypotheses according to the probability that the hypothesis is true; and   selecting the hypothesis that is ranked the highest, thereby determining the number of copies of the chromosome of interest or the section of the chromosome of interest in the genome of the fetus.   
     
     
         2 . The method of  claim 1 , wherein the sample is a blood sample. 
     
     
         3 . The method of  claim 1 , wherein for each of the hypotheses that is compared (i) the probability distribution of the expected genetic data is compared to the measured genetic data or (ii) the probability distribution of the measured genetic data is compared to the expected genetic data to give a probability that the hypothesis is true. 
     
     
         4 . The method of  claim 1 , wherein a confidence is computed for the determination of the number of copies of the chromosome of interest or section of the chromosome of interest in the genome of the fetus. 
     
     
         5 . The method of  claim 1 , wherein the method further comprises using the determination of the number of copies of the chromosome of interest or section of the chromosome of interest to make a clinical decision about the fetus, wherein the clinical decision involves whether to terminate or not terminate a pregnancy. 
     
     
         6 . The method of  claim 1 , wherein the amount of genetic material from the fetus is selected from the group consisting of one cell, two cells, three cells, four cells, five cells, between six and ten cells, between eleven and twenty cells, from twenty to fifty cells, from one to ten picograms of DNA, from ten to one hundred picograms of DNA, and from one hundred to three hundred picograms of DNA 
     
     
         7 . The method of  claim 1 , where the method further comprises determining haplotypic genetic data of at least one of the biological parents of the fetus. 
     
     
         8 . The method of  claim 1 , wherein genetic data from the fetus has been measured using a tool or technique selected from the group consisting of the MOLECULAR INVERSION PROBES (MIPs) assay, circularizing probes, Genotyping Microarrays, the TAQMAN SNP Genotyping Assay, other hydrolysis probes, the ILLUMINA Genotyping System, other genotyping assays, Sanger DNA sequencing, pyrsequencing, other methods of DNA sequencing, other high through-put genotyping platforms, fluorescent in-situ hybridization (FISH), and combinations thereof. 
     
     
         9 . The method of  claim 1 , wherein the fetus's or biological parent's genetic material was found in substances selected from the group consisting of the biological parent's bulk diploid tissue, one or more diploid cells taken from the fetus or biological parent, one or more haploid cells taken from the biological parent, one or more embryos created from a gamete from the biological parent, one or more blastomeres taken from such an embryo, the biological parent's sperm, the biological parent's egg, the biological parent's polar body, extra-cellular genetic material found in the biological parent, extra-cellular genetic material from the biological parent found in maternal blood, extra-cellular genetic material from the biological parent found in maternal plasma, cells from the biological parent found in maternal blood, and combinations thereof. 
     
     
         10 . The method of  claim 1 , wherein the method further comprises a method for making allele calls at one or more loci of interest in the genome of the fetus, and wherein the genetic data of the fetus that is used in both the making of allele calls and the determining of the number of copies of the chromosome of interest or section of the chromosome of interest was obtained by analyzing the same sample of genetic material derived from the fetal cells obtained from maternal blood, and wherein the method for making allele calls comprises:
 creating, on a computer, a set of one or more hypotheses about which chromosome segment from which biological parent corresponds to the chromosome segment of the fetus that comprises the loci of interest;   using the genetic data of the fetus and the genetic data of one or both of the biological parents of the fetus to determine on a computer the probability of each of the hypotheses being true or false; and   using the probabilities associated with each hypothesis to determine the most likely actual allele identity of the fetus at the loci of interest.   
     
     
         11 . The method of  claim 1 , wherein the comparing step uses a technique selected from the group consisting of maximum a-posteriori estimation and Bayesian estimation to calculate either (a) the fit between (1) the measured genetic data from the fetus and (2) the probability distribution of the expected quantity of each allele at each of the plurality of loci in the fetus for a hypothesis, or (b) the fit between (1) the probability distribution of the measured genetic data from the fetus and (2) the expected quantity of each allele at each of the plurality of the loci in the fetus for the hypothesis. 
     
     
         12 . The method of  claim 1 , wherein the genetic data of the one or both biological parents is used to correct in silico one or more errors in the genetic data of the fetus selected from the group consisting of allele drop out errors, missing measurements, incorrect base pair measurements, and combinations thereof, wherein correcting the one or more errors comprises (i) using the genetic data of the one or both biological parents to generate a set of one or more possible alleles that the fetus could have inherited from the one or both biological parents, and (ii) using the set of possible alleles to correct one or more errors in the genetic data of the fetus by replacing an incorrect or missing measurement in the genetic data of the fetus with the corresponding genetic data from an allele from the one or both biological parents, and wherein using the genetic data of the one or both biological parents increases the confidence of the copy number determination in the fetus. 
     
     
         13 . The method of  claim 1 , wherein the measuring of the genetic material comprises measuring the number of DNA copies of the loci. 
     
     
         14 . The method of  claim 1 , wherein the loci comprise single nucleotide polymorphisms and the number of DNA copies of each allele of the loci is measured. 
     
     
         15 . The method of  claim 1 , wherein the expected genetic data for the fetus for each of the one or more hypotheses is determined, on a computer, using the measured genetic data of the fetus and the measured genetic data of the one or both biological parents. 
     
     
         16 . The method of  claim 1 , wherein the plurality of loci comprises non-polymorphic loci, and wherein measuring the quantity of each allele at each of the non-polymorphic loci comprises measuring a number of DNA copies associated with each of the non-polymorphic loci. 
     
     
         17 . An ex vivo method for determining a number of copies of a chromosome of interest, or section of the chromosome, in the genome of a fetus, comprising;
 collecting a maternal sample comprising at least one fetal cell,   obtaining measured genetic data from the sample by measuring the quantity of each allele at each of the plurality of loci in genetic material from the fetus, wherein the plurality of loci comprises single nucleotide polymorphisms, and wherein the plurality of loci comprises loci on the chromosome of interest or section of the chromosome of interest;   collecting genetic material from one or both biological parents of the fetus,   obtaining measured genetic data from the parental cells by determining the allele present at each of the plurality of loci in genetic material from the parent;   creating, on a computer, a plurality of hypotheses specifying the number of copies of the chromosome of interest or section of the chromosome of interest present in the genome of the fetus;   creating, on a computer, for each of the hypotheses, a probability distribution of the expected quantity of each allele at each of the plurality of loci in the fetus from the (i) the measured genetic data from the one biological parent and (ii) the probability of one or more crossovers that may have occurred during the formation of a gamete that contributed a copy of the chromosome or interest or section of the chromosome of interest to the fetus;   calculating, on a computer, a fit, for each of the hypotheses, between (1) the measured genetic data of the fetus and (2) the probability distribution of the expected quantity of each allele at each of the plurality of loci in the fetus for that hypothesis;   ranking one or more of the hypotheses according to the calculated fit; and   selecting the hypothesis that is ranked the highest, thereby determining the number of copies of the chromosome of interest or the section of the chromosome of interest in the genome of a fetus.   
     
     
         18 . The method of  claim 17 , wherein calculating the fit comprises using a technique selected from the group consisting of maximum a-posteriori estimation and Bayesian estimation to calculate the fit between (1) the measured genetic data from the fetus and (2) the probability distribution of the expected quantity of each allele at each of the plurality of loci in the fetus for the hypothesis. 
     
     
         19 . The method of  claim 17 , wherein the genetic data of the one or both biological parents is used to correct one or more errors in the genetic data of the fetus selected from the group consisting of allele drop out errors, missing measurements, incorrect base pair measurements, and combinations thereof, wherein correcting the one or more errors comprises (i) using the genetic data of the one or both biological parents to generate a set of one or more possible alleles that the fetus could have inherited from the one or both biological parents, and (ii) using the set of possible alleles to correct one or more errors in the genetic data of the fetus by replacing an incorrect or missing measurement in the genetic data of the fetus with the corresponding genetic data from an allele from the one or both biological parents, and wherein using the genetic data of the one or both biological parents increases the confidence of the copy number determination in the fetus. 
     
     
         20 . The method of  claim 17 , wherein the measuring of the genetic material comprises measuring the number of DNA copies of the loci. 
     
     
         21 . The method of  claim 17 , wherein the loci comprise single nucleotide polymorphisms and the number of DNA copies of each allele of the loci is measured. 
     
     
         22 . The method of  claim 17 , wherein the expected quantity of each allele at each of the plurality of loci in the fetus individual for each of the one or more hypotheses is determined, on a computer, using the measured genetic data of the fetus and the measured genetic data of the one or both biological parents. 
     
     
         23 . The method of  claim 17 , wherein the measured genetic material is amplified prior to being measured. 
     
     
         24 . The method of  claim 17 , wherein a confidence is computed for the determination of the number of copies of the chromosome of interest or section of the chromosome of interest in the genome of the fetus. 
     
     
         25 . The method of  claim 17 , wherein the method further comprises using the determination of the number of copies of the chromosome of interest or section of the chromosome of interest to make a clinical decision about the fetus, wherein the clinical decision involves whether to terminate or not terminate a pregnancy. 
     
     
         26 . The method of  claim 17 , wherein at least one of the fetus genetic data has been measured using a tool or technique selected from the group consisting of the MOLECULAR INVERSION PROBES (MIPs) assay, other circularizing probes, Genotyping Microarrays, the TAQMAN SNP Genotyping Assay, other hydrolysis probes, the ILLUMINA Genotyping System, other genotyping assays, Sanger DNA sequencing, pyrosequencing, other methods of DNA sequencing, other high through-put genotyping platforms, fluorescent in-situ hybridization (FISH), and combinations thereof. 
     
     
         27 . The method of  claim 17 , wherein the method further comprises a method for making allele calls at one or more loci of interest in the genome of the fetus, and wherein the genetic data of the fetus that is used in both the making of allele calls and the determining of the number of copies of the chromosome of interest or section of the chromosome of interest was obtained by analyzing the same sample of genetic material derived from the fetus, and wherein the method for making allele calls comprises:
 creating, on a computer, a set of one or more hypotheses about which chromosome segment from which biological parent corresponds to the chromosome segment of the fetus that comprises the loci of interest;   using the genetic data of the fetus and the genetic data of one or both of the biological parents of the fetus to determine, on a computer, the probability of each of the hypotheses being true or false; and   using the probabilities associated with each hypothesis to determine the most likely actual allele identity of the loci of interest in the genome of the fetus.   
     
     
         28 . An ex vivo method for determining a number of copies of a chromosome of interest, or section of the chromosome, in the genome of a fetus that makes use of the genetic data of a biological parent of the fetus, the method comprising:
 collecting a maternal sample comprising at least one fetal cell;   measuring genetic data from the fetal cell by determining the quantity of each allele at a plurality of loci in genetic material from the fetal cell, wherein the plurality of loci comprise single nucleotide polymorphisms;   collecting genetic material from a biological parent of the fetus;   measuring genetic data from one or both biological parents of the fetus by determining the identity of each allele at a plurality of the loci in genetic material from the biological parent;   creating, on a computer, a plurality of hypotheses specifying the number of copies of the chromosome of interest or section of the chromosome of interest present in the genome of the fetus;   calculating, on a computer, for each of the hypotheses, a probability distribution for expected genetic data of the fetus from the measured quantity of each allele at the loci;   calculating, on a computer, a fit, for each of the hypotheses, between (1) the measured genetic data and (2) the probability distribution for the expected genetic data of the fetus for that hypothesis;   ranking one or more of the hypotheses according to the calculated fit; and   selecting the hypothesis that is ranked the highest, thereby determining the number of copies of the chromosome of interest or the section of the chromosome of interest in the genome of the fetus.   
     
     
         29 . The method of  claim 28 , wherein the ranking step and the calculating the confidence step comprise applying, on a computer, a technique selected from the group consisting of maximum a-posteriori estimation and Bayesian estimation. 
     
     
         30 . The method of  claim 28 , wherein the calculating a probability distribution for the expected genetic data further comprises:
 determining the parameters of an error model from the measured genetic data, and   calculating a probability distribution for the expected genetic data from the measured genetic data and the determined parameters of the error model.