An algorithm for determining the origin of trisomy and the positions of chiasmata from SNP genotype data

Abstract

Trisomy causes mental retardation, pregnancy loss, IVF failure, uniparental disomy and several other pathologies, and its accurate detection is thus clinically essential. Most trisomies arise at meiosis I and are associated with increasing maternal age and reduction or alteration in recombination patterns. Investigations into the relationship between trisomy and meiotic recombination have used short tandem repeat markers; however, this approach is limited by the resolution with which the position of crossovers can identified. As cytogenetics enters the post-genomic era, recent work has used array comparative genomic hybridisation (aCGH) to screen for trisomy of all 24 chromosomes, determining chromosome copy number by dosage analysis. However, aCGH has a fundamental drawback for studying the aetiology of trisomy since neither the parent and phase of origin nor uniparental disomy can be ascertained. The development of SNP microarrays has made it possible to analyse multiple loci for sequence variation, and the proprietary software provided can determine the presence of aneuploidy by algorithms based on fluorescence intensity. To the best of our knowledge, however, such software is not equipped to determine the phase of origin of the error or the position of any chiasmata. In this study, therefore, we present an algorithm to determine the parent of origin, the phase of origin and the location of chiasmata in a series of nine "trisomy triplets" (i.e. samples derived from father, mother and their trisomic foetus). Novel adaptations of well-established principles are applied along with a simple algorithm written in Microsoft Excel for visualisation of the results. Such analysis has a range of applications in preimplantation and prenatal diagnosis.

Chromosomal disorders and male infertility

“…In addition, qualitative analysis of SNP-based testing data may ultimately allow for analysis of parental haplotypes and, therefore, the detection of the parental origin of any chromosomal abnormalities. 120 This will be valuable in determining the true incidence of aneuploidy in sperm and its impact on aneuploidy in embryos.…”

Use of suboptimal sperm increases the risk of aneuploidy of the sex chromosomes in preimplantation blastocyst embryos

“…Human eggs only complete meiosis II after fertilization, so perhaps a (genetically) suboptimal sperm may impair subsequent segregation of maternal chromosome 18 more than any other. Some of these questions could be addressed in future studies by a molecular analysis of the phase and parent of origin of the aneuploidy; the ability to do this has recently been reported using single nucleotide polymorphism microarrays (20,21). Such an approach is not trivial, however, as it would require taking and sampling parental DNA.…”

“…Confined placental mosaicism (where cells derived from the TE differ in ploidy status compared with those derived from the ICM) is nonetheless a well-described phenomenon (18,24), with the errors of meiotic origin most likely leading to adverse clinical outcomes. Implementation of an approach that can distinguish not only parent but also phase of origin of the aneuploidy (20,21) would ultimately allow us to select against those embryos that arose as a result of fertilization with an aneuploid sperm.…”

The Role of Aneuploidy Screening in Human Preimplantation Embryos

“…Algorithms applied to SNP genotyping data, including Karyomapping can be applied for high resolution pinpointing of recombination points (Handyside et al 2010;Gabriel et al 2011a). Patterns of recombination across the genome can then be correlated with chromosome mal-segregation in meiosis in an attempt to find aberrant patterns that predispose to aneuploidy.…”