System and method for cleaning noisy genetic data and determining chromosome copy number

Abstract

Disclosed herein is a system and method for increasing the fidelity of measured genetic data, for making allele calls, and for determining the state of aneuploidy, in one or a small set of cells, or from fragmentary DNA, where a limited quantity of genetic data is available. Poorly or incorrectly measured base pairs, missing alleles and missing regions are reconstructed using expected similarities between the target genome and the genome of genetically related individuals. In accordance with one embodiment, incomplete genetic data from an embryonic cell are reconstructed at a plurality of loci using the more complete genetic data from a larger sample of diploid cells from one or both parents, with or without haploid genetic data from one or both parents. In another embodiment, the chromosome copy number can be determined from the measured genetic data, with or without genetic information from one or both parents.

What is claimed: 
     
         1 . A method for measuring the amounts of fetal chromosome segments in a maternal blood sample, comprising:
 obtaining fetal and maternal chromosome segments from cell-free DNA in a maternal blood sample;   ligating at least one adapter to the chromosome segments;   performing clonal amplification of the amplified chromosome segments to generate clonally amplified chromosome segments; and   measuring the amounts of clonally amplified fetal chromosome segments by performing next generation sequencing, wherein the measuring comprises quantitative allele measurements performed irrespective of allele value.   
     
     
         2 . The method of  claim 1 , wherein the fetal chromosome segments map to chromosomes 13, 18, and/or 21. 
     
     
         3 . The method of  claim 2 , wherein the method further comprises detecting trisomy at chromosomes 13, 18, and/or 21. 
     
     
         4 . The method of  claim 1 , wherein the method further comprises comparing the measured amounts of fetal chromosome segments for a target chromosome from the maternal blood sample with measured amounts of fetal chromosome segments for the target chromosome from reference maternal blood samples that are disomic for the target chromosome. 
     
     
         5 . The method of  claim 1 , wherein the measuring comprises measurement of alleles having 100% penetrance. 
     
     
         6 . The method of  claim 1 , wherein the next generation sequencing is performed using sequencing-by-synthesis. 
     
     
         7 . The method of  claim 1 , wherein the clonally amplified maternal chromosome segments are measured along with the clonally amplified fetal chromosome segments by performing next generation sequencing. 
     
     
         8 . A method for measuring the amounts of fetal chromosome segments in a maternal blood sample, comprising:
 obtaining fetal and maternal chromosome segments from cell-free DNA of a maternal blood sample;   ligating at least one adapter to the chromosome segments;   performing clonal amplification of the amplified chromosome segments to generate clonally amplified chromosome segments;   measuring the amounts of clonally amplified fetal chromosome segments and the amounts of clonally amplified maternal chromosome segments by performing next generation sequencing, wherein the measuring comprises quantitative allele measurements performed irrespective of allele value and without prior knowledge of fetal genotype; and   comparing the measured amounts of clonally amplified maternal chromosome segments with the measured amounts of clonally amplified fetal chromosome segments.   
     
     
         9 . The method of  claim 8 , wherein the fetal chromosome segments map to chromosomes 13, 18, and/or 21. 
     
     
         10 . The method of  claim 9 , wherein the method further comprises detecting trisomy at chromosomes 13, 18, and/or 21. 
     
     
         11 . The method of  claim 8 , wherein the method further comprises comparing the measured amounts of fetal chromosome segments for a target chromosome from the maternal blood sample with measured amounts of fetal chromosome segments for the target chromosome from reference maternal blood samples that are disomic for the target chromosome. 
     
     
         12 . The method of  claim 8 , wherein the measuring comprises measurement of alleles having 100% penetrance. 
     
     
         13 . The method of  claim 8 , wherein the next generation sequencing is performed using sequencing-by-synthesis.