Methods for Allele Calling and Ploidy Calling

Abstract

Disclosed herein is a system and method for making allele calls, and for determining the ploidy state, in one or a small set of cells, or where a limited quantity of genetic data is available. Poorly or incorrectly measured base pairs, missing alleles and missing regions are reconstructed and the haplotypes are determined using expected similarities between the target genome and the knowledge of the genomes of genetically related individuals. In one embodiment, incomplete genetic data from an embryonic cell are reconstructed at a plurality of loci using the genetic data from both parents, and possibly one or more sperm and/or sibling embryos. In another embodiment, the chromosome copy number can be determined using the same input data. In another embodiment, these determinations are made for embryo selection during IVF, for non-invasive prenatal diagnosis, or for making phenotypic predictions.

1 . A method for determining a ploidy state of at least one chromosome in a target individual, the method comprising:
 obtaining genetic data from the target individual and from one or more related individuals;   creating, on a computer, a set of at least one ploidy state hypothesis for each of the chromosomes of the target individual;   using one or more expert techniques to determine, on a computer, for each expert technique used, a statistical probability for each ploidy state hypothesis in the set, given the obtained genetic data, wherein at least one of the expert techniques makes use of parental contexts;   combining, on a computer, for each ploidy state hypothesis, the statistical probabilities as determined by the one or more expert techniques; and   determining, on a computer, the ploidy state for each of the chromosomes in the target individual based on the combined statistical probabilities of each of the ploidy state hypotheses.   
     
     
         2 . The method of  claim 1 , wherein the related individuals are selected from the group consisting of one or both parents of the target individual, one or more grandparents of the target individual, one or more siblings of the target individual, and combinations thereof. 
     
     
         3 . The method of  claim 1 , wherein the obtained genetic data comprises at least one of: single nucleotide polymorphisms measured from a genotyping array, DNA sequence data, and combinations thereof. 
     
     
         4 . The method of  claim 1 , wherein the target individual is an embryo, and the ploidy state determination is performed for the purpose of embryo selection during in vitro fertilization, where aneuploid embryos are deselected. 
     
     
         5 . The method of  claim 1 , wherein the target individual is a fetus, and the ploidy state determination is performed for the purpose of non-invasive prenatal diagnosis. 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 1 , wherein, for at least one of the expert techniques, determining the statistical probability for each of the ploidy state hypothesis involves comparing relationships between observed distributions of allele measurement data for a plurality of parental contexts. 
     
     
         9 . The method of  claim 1 , wherein the obtained genetic data is not phased, and wherein the related individuals comprise both parents of the target individual, and wherein the method further comprises:
 determining phased genetic data of both parents of the target individual using an informatics based method; and   determining phased genetic data of the target individual using an informatics based method.   
     
     
         10 . The method of  claim 1 , wherein the obtained genetic data comprises phased genetic data from one or both parents of the target individual. 
     
     
         11 . The method of  claim 1 , wherein at least one of the expert techniques is specific to a sex chromosome. 
     
     
         12 . The method of  claim 1 , wherein determining the ploidy state of each of the chromosomes in the target individual involves screening for a chromosomal condition selected from the group consisting of euploidy, nullsomy, monosomy, uniparental disomy, trisomy, matched copy error, unmatched copy error, tetrasomy, other aneuploidy, unbalanced translocation, deletions, insertions, mosaicism, and combinations thereof. 
     
     
         13 . A method for determining an allelic state in a set of alleles, in a target individual, and from one or both parents of the target individual, and optionally from one or more additional individuals related to the target individual, the method comprising:
 obtaining genetic data from the target individual, from the one or both parents of the target individual, and from any of the additional related individuals;   creating, on a computer, a set of at least one allelic hypothesis for the target individual, for the one or both parents of the target individual, and for any of the additional related individuals, where the allelic hypotheses describe possible allelic states in the set of alleles;   determining, on a computer, a statistical probability for each allelic hypothesis in the set of hypotheses given the obtained genetic data; and   determining, on a computer, the allelic state for each of the alleles in the set of alleles for the target individual, for the one or both parents of the target individual, and for any of the additional related individuals, based on the statistical probabilities of each of the allelic hypotheses.   
     
     
         14 . (canceled) 
     
     
         15 . The method of  claim 13 , wherein the target individual is an embryo, and the allelic state determination is performed for the purpose of embryo selection during in vitro fertilization, and where aneuploid embryos are deselected. 
     
     
         16 . The method of  claim 13 , wherein the allelic state determination is performed for the purpose of non-invasive prenatal diagnosis, and where the target individual is a fetus. 
     
     
         17 . (canceled) 
     
     
         18 . The method of  claim 13 , wherein determining the allelic state for each of the alleles in the set of alleles in an individual includes determining a phased genotype at the set of alleles for that individual. 
     
     
         19 . The method of  claim 13 , wherein the obtained genetic data includes single nucleotide polymorphisms measured from a genotyping array and also DNA sequence data. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 13 , wherein the method takes into account a possibility of DNA crossovers that may occur during meiosis. 
     
     
         22 . The method of  claim 13 , wherein the target individual is an embryo, and wherein determining the allelic state in the set of alleles of the target individual is performed to select at least one embryo for transfer in the context of IVF, and where the related individuals are selected from the group consisting of one or more embryos that are from the same parents, one or more sperm from the father, one or more siblings of the target individual, and combinations thereof. 
     
     
         23 . The method of  claim 13 , wherein the method is performed alongside or in conjunction with a method that determines a number of copies of a given chromosome segment present in the target individual, and where both methods use a same cell, or group of cells, from the target individual as a source of genetic data. 
     
     
         24 . A method for determining a ploidy state of at least one chromosome in a target individual, the method comprising:
 obtaining genetic data from the target individual, and from both parent of the target individual, and from one or more siblings of the target individual, wherein the genetic data includes data relating to at least one chromosome;   determining, on a computer, a ploidy state of the at least one chromosome in the target individual and in the one or more siblings of the target individual by using one or more expert techniques, wherein none of the expert techniques requires phased genetic data as input;   determining, on a computer, phased genetic data of the target individual, and of the parents of the target individual, and of the one or more siblings of the target individual, using an informatics based method, and the obtained genetic data from the target individual, and from the parents of the target individual, and from the one or more siblings of the target individual that were determined to be euploid at that chromosome; and   redetermining, on a computer, the ploidy state of the at least one chromosome of the target individual, using one or more expert techniques, at least one of which requires phased genetic data as input, and the determined phased genetic data of the target individual, and of the parents of the target individual, and of the one or more siblings of the target individual.   
     
     
         25 . The method of  claim 24 , wherein the determined ploidy state of the chromosome on the target individual is used to make a clinical decision about the target individual. 
     
     
         26 . (canceled)