Abstract


OBJECTIVE: We have previously validated the FAST-SeqS technology for targeted next generation DNA sequencing-based detection of full chromosome and segmental aneuploidy in human embryos[1-2]. While not leveraged in those validations, we observed that the loci captured by FAST-SeqS include thousands of polymorphic sites. The relative representation of alleles at such sites can be used to derive information beyond segmental and full chromosome aneuploidy. view more

OBJECTIVE: We have previously validated the FAST-SeqS technology for targeted next generation DNA sequencing-based detection of full chromosome and segmental aneuploidy in human embryos[1-2]. While not leveraged in those validations, we observed that the loci captured by FAST-SeqS include thousands of polymorphic sites. The relative representation of alleles at such sites can be used to derive information beyond segmental and full chromosome aneuploidy. Here, we assessed the feasibility of using single nucleotide polymorphism (SNP) information captured by FAST-SeqS to detect uniparental isodisomy (UPD), familial relationships among samples, and polyploidy.
DESIGN: Technology development and feasibility assessment.
MATERIALS AND METHODS: First, to evaluate whether FAST-SeqS can detect UPD we ran cell line-derived samples containing isodisomic chromosomes through FAST-SeqS and assessed whether the captured SNP genotypes were consistent with the expected UPD. Next, to determine if FAST-SeqS can recapitulate expected familial relationships, samples from a 17-member multi-generation family were tested in replicate, the per-sample SNP genotypes were clustered, and the resulting dendogram was compared to the expected family tree. Finally, utilizing FAST-SeqS data for 200 embryo biopsies for which sex and autosome chromosome copy number calls were consistent with polyploidy (69,XXY; 69,XYY; 92,XXXY), we assessed the degree to which the observed allele fraction distributions at polymorphic loci supported such karyotypes.
RESULTS: We observed an abnormally low frequency (1.2% vs 62% for control samples) of heterozygous SNP calls within isodisomic chromosomes, providing a clear metric that could be utilized to call UPD. Similarly, clustering of familial samples based upon their FAST-SeqS-derived SNP genotypes accurately recapitulated the expected family tree. Finally, we found that for the majority (74.2%) of high quality embryo-biopsy samples for which sex chromosome copy number calls were consistent with polyploidy, the observed allele fraction distributions displayed characteristic multi-modal patterns that could readily be identified using an automated kernel fitting and peak finding strategy.
CONCLUSIONS: Collectively, our studies illustrate the feasibility of leveraging embryo-derived SNP information captured by FAST-SeqS to detect UPD, familial relationships among samples, and polyploidy, likely extending to karyotypes that are not currently detectable with most NGS-based technologies, including whole genome-amplified low-pass sequencing.

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