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 is: 
     
         1 . A method for preparing a preparation of amplified DNA derived from a maternal blood sample or a fraction thereof useful for measuring the amounts of fetal chromosome segments on one or more chromosomes of interest and one or more reference chromosomes, the method comprising:
 (a) extracting cell-free DNA from the maternal blood sample or fraction thereof, wherein the cell-free DNA comprises fetal and maternal chromosome segments, and wherein the cell-free DNA comprises chromosome segments from the one or more chromosomes of interest and the one or more reference chromosomes;   (b) preparing a preparation of amplified DNA by (i) hybridizing the fetal and maternal chromosome segments with a plurality of target-specific probes and circularizing the hybridized probes by ligation, (ii) removing non-circularized probes by exonucleolysis, and (iii) amplifying the circularized probes; and   (c) analyzing the preparation of the amplified DNA by measuring the amounts of the chromosome segments, wherein the measuring is performed irrespective of allele value.   
     
     
         2 . The method of  claim 1 , wherein the measuring comprises measurement of alleles having 100% penetrance. 
     
     
         3 . The method of  claim 1 , wherein the measuring comprises quantitative measurements without making allele calls. 
     
     
         4 . The method of  claim 1 , wherein the measuring comprises labeling the amplification products with a detectable tag. 
     
     
         5 . The method of  claim 1 , wherein the measuring comprises hybridizing the amplification products with a fluorescent tag. 
     
     
         6 . The method of  claim 1 , wherein the measuring comprises measuring the amounts of chromosome segments from the one or more chromosomes of interest and the amounts of chromosome segments from the one or more reference chromosomes 
     
     
         7 . The method of  claim 1 , wherein the method further comprises comparing the measured amounts of chromosome segments for the one or more chromosomes of interest from the maternal blood sample with the measured amounts of chromosome segments for the one or more reference chromosomes. 
     
     
         8 . The method of  claim 1 , wherein the method further comprises comparing the measured amounts of chromosome segments for the one or more chromosomes of interest from the maternal blood sample with measured amounts of chromosome segments for the one or more chromosomes of interest from maternal blood samples that are disomic for the one or more chromosomes of interest. 
     
     
         9 . The method of  claim 1 , wherein the measured amounts of chromosome segments from each chromosome are combined into a single measurement for each chromosome. 
     
     
         10 . The method of  claim 1 , wherein the chromosome segments from the one or more chromosomes of interest map to chromosome 13, 18, and/or 21. 
     
     
         11 . A method for preparing a preparation of amplified DNA derived from a maternal blood sample or a fraction thereof useful for detecting aneuploidy of one or more chromosomes of interest in a fetus, the method comprising:
 (a) extracting cell-free DNA from the maternal blood sample or fraction thereof, wherein the cell-free DNA comprises fetal and maternal chromosome segments, and wherein the cell-free DNA comprises chromosome segments from the one or more chromosomes of interest and the one or more reference chromosomes;   (b) preparing a preparation of amplified DNA by (i) hybridizing the fetal and maternal chromosome segments with a plurality of target-specific probes and circularizing the hybridized probes by ligation, (ii) removing non-circularized probes by exonucleolysis, and (iii) amplifying the circularized probes; and   (c) analyzing the preparation of the amplified DNA by measuring the amounts of chromosome segments from the one or more chromosomes of interest and the amounts of chromosome segments from the one or more reference chromosomes, wherein the measuring is performed irrespective of allele value, and detecting aneuploidy of the one or more chromosomes of interest using the measured amounts of chromosome segments from the one or more chromosomes of interest and the measured amounts of chromosome segments from the one or more reference chromosomes.   
     
     
         12 . The method of  claim 11 , wherein the measuring comprises measurement of alleles having 100% penetrance. 
     
     
         13 . The method of  claim 11 , wherein the measuring comprises quantitative measurements without making allele calls. 
     
     
         14 . The method of  claim 11 , wherein the measuring comprises labeling the amplification products with a detectable tag. 
     
     
         15 . The method of  claim 11 , wherein the measuring comprises hybridizing the amplification products with a fluorescent tag. 
     
     
         16 . The method of  claim 11 , wherein the method further comprises comparing the measured amounts of chromosome segments for the one or more chromosomes of interest from the maternal blood sample with measured amounts of chromosome segments for the one or more chromosomes of interest from maternal blood samples that are disomic for the one or more chromosomes of interest. 
     
     
         17 . The method of  claim 11 , wherein the measured amounts of chromosome segments from each chromosome are combined into a single measurement for each chromosome. 
     
     
         18 . The method of  claim 11 , wherein the chromosome segments from the one or more chromosomes of interest map to chromosome 13, 18, and/or 21. 
     
     
         19 . The method of  claim 11 , wherein the method comprises detecting aneuploidy at chromosome 13, 18, and/or 21. 
     
     
         20 . The method of  claim 11 , wherein a statistical difference is detected by computing a standard deviation and/or a mean value for the measurement for each of the one or more chromosomes of interest and for each of the one or more reference chromosomes, and comparing the statistical difference to a threshold determined from normal samples.