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

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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.

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Abbreviations

IVF:

In-vitro fertilization

aCGH:

array comparative genomic hybridisation

SNP:

single nucleotide polymorphism

PCR:

polymerase chain reaction

STR:

short tandem repeat

WGA:

whole genome amplification

IGV:

integrative genomics viewer

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Acknowledgements

The authors are grateful to Julien Bauer, Emily Clemente, Christopher Reiter and Kerry Cliffe (Centre for Genomics, Department of Pathology, Cambridge University) for their technical expertise and their help with the bioinformatics. This work was supported by BBSRC Career Development Fellowship BB/E024211/1 awarded to DKG and NIH grant HD21341 to TJH. The algorithm is freely available by contacting the corresponding author.

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Correspondence to Darren K. Griffin.

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Responsible editor: Pat Heslop-Harrison

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Gabriel, A.S., Hassold, T.J., Thornhill, A.R. et al. An algorithm for determining the origin of trisomy and the positions of chiasmata from SNP genotype data. Chromosome Res 19, 155–163 (2011). https://doi.org/10.1007/s10577-010-9181-4

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  • DOI: https://doi.org/10.1007/s10577-010-9181-4

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