Assessment of risk of aneuploidy

Abstract

The present disclosure relates generally to methods and materials for use in detecting abnormalities of the number of whole chromosomes or chromosome regions (aneuploidy). It has particular utility for assessing the risk of aneuploidy of eggs (i.e., oocytes), fertilised eggs or embryos developed therefrom in the context of in vitro fertilisation.

1 . (canceled) 
     
     
         2 . A system for assessing centromeric heterozygosity of maternal meiotic origin in a human egg, the human egg comprising a first polar body (PB1), the first polar body comprising one or more PB1 chromosomes, the system comprising:
 (i) means for performing a nucleic acid detection assay to interrogate at least 25 biallelic SNPs flanking the centromeres of said one or more PB1 chromosomes, said SNPs located within 5 to 10 Mb of the centromere; and   (ii) a programmed storage device or medium comprising instructions assessing the presence or degree of centromeric heterozygosity (CH) for said one or more PB1 chromosomes, based on the results of the nucleic acid detection assay.   
     
     
         3 . The system of  claim 2 , wherein the means for SNP interrogation is a microarray. 
     
     
         4 . The system of  claim 2 , wherein the means for SNP interrogation is a sequencing platform. 
     
     
         5 . The system of  claim 2 , further comprising instructions for determining the risk that the human egg will give rise to an aneuploid fertilised egg or embryo following meiosis II,
 wherein the presence or a higher level of CH in the first polar body indicates a higher risk of said chromosomal aneuploidy in the corresponding fertilised egg or embryo developed therefrom compared to where an absence or lower level of CH is present in the first polar body.   
     
     
         6 . The system of  claim 2 , further comprising instructions for
 assessing the total number of crossovers in the PB1 chromosomes, based on the heterozygosity of some or all of the chromosomes of the first polar body of the egg, and   determining the risk that the human egg will give rise to an aneuploid fertilised egg or embryo, wherein a below average total number of crossovers determined in the PB1 chromosomes indicates a higher risk of aneuploidy, compared to where an average number of crossovers is determined in the PB1 chromosomes.   
     
     
         7 . The system of  claim 2  further comprising instructions for
 assessing the position of crossovers in said one or more of the PB1 chromosomes, based on the heterozygosity of one or more of the chromosomes of the first polar body of the egg, and 
 determining the risk that the human egg will give rise to an aneuploid fertilised egg or embryo, wherein a PB1 chromosome having only a single crossover proximal to the telomere or centromere indicates a higher risk of aneuploidy, compared to a PB1 chromosome having a plurality of medially distributed crossovers. 
 
     
     
         8 . The system of  claim 2  further comprising instructions for
 assessing the presence of structural defects in said one or more of the PB1 chromosomes, based on the heterozygosity of one or more of the chromosomes of the first polar body of the egg, and 
 determining the risk that the human egg will give rise to an aneuploid fertilised egg or embryo, wherein a PB1 chromosome showing a structural defect indicates a higher risk of aneuploidy. 
 
     
     
         9 . The system of  claim 8  wherein the structural defects are chromosomal or sub-chromosomal defects selected from: gains, losses, and duplications. 
     
     
         10 . The system of  claim 2  further comprising instructions for
 distinguishing (i) a polar body which contains a chromosome consisting of sister chromatids replicated from one of the homologous chromosomes from the mother, from (ii) a polar body wherein the chromosomes comprise two or more non-sister chromatids being collectively derived from both of the homologous maternal chromosomes, and 
 determining the risk that the human egg will give rise to an aneuploid fertilised egg or embryo, wherein (ii) indicates a higher risk of chromosomal aneuploidy of maternal meiotic origin in the corresponding egg. 
 
     
     
         11 . The system of  claim 2  further comprising instructions for assessing a plurality of different first polar bodies such as to grade the corresponding eggs, or fertilised eggs or embryos developed therefrom, according to their risk of possible chromosomal aneuploidy of maternal meiotic origin. 
     
     
         12 . The system of  claim 2  wherein the polar body is from a human female who has previously been diagnosed as having fertility problems or having or carrying an inheritable disease. 
     
     
         13 . The system of  claim 2  wherein the polar body is from a human female who is undergoing IVF treatment. 
     
     
         14 . The system of  claim 2  further comprising instructions for
 determining the risk of possible chromosomal aneuploidy of maternal meiotic origin, and 
 based on said risk of possible chromosomal aneuploidy, determining a likelihood of pregnancy in said human female. 
 
     
     
         15 . The system of  claim 2  wherein at least 5, 10, 15 or 20 chromosomes are assessed, or optionally all 23 chromosomes are assessed per polar body. 
     
     
         16 . The system of  claim 2  wherein centromeric heterozygosity is assessed for 2 or more of the human chromosomes selected from the group consisting of: X, 22, 21, 18, 16 and 13. 
     
     
         17 . The system of  claim 2  further comprising a means for whole genome amplification of said first polar body prior to said nucleic acid detection assay. 
     
     
         18 . The system of  claim 2  wherein said instructions for assessing the presence or degree of centromeric heterozygosity (CH) comprise:
 (i) phasing the SNPs of the maternal chromosomes; and 
 (ii) based on the SNP phasing from step (i), determining the presence of centromeric heterozygosity (CH) from any biallelic SNPs which are heterozygous maternal loci, but wherein said nucleic acid detection assay gives a homozygous call due to random allele dropout. 
 
     
     
         19 . The system of  claim 2  wherein equal to or at least 30, 40, 50, 75, 100, 200, 300, 400, 500 or more SNPs are interrogated flanking the centromere, wherein SNPs on both of the p and q arms of non-acrocentric chromosome are assessed. 
     
     
         20 . The system of  claim 2  wherein said instructions for assessing the presence or degree of centromeric heterozygosity (CH) comprises quantifying a proportion of heterozygous SNPs. 
     
     
         21 . The system of  claim 20 , further comprising instructions for comparing the proportion of heterozygous SNPs in the first polar body to a proportion of heterozygous SNPs in a maternal cell genotype, wherein the maternal cell genotype comprises at least 10, 15, 20, 25, 50, 100 or more heterozygous SNPs.