Mechanisms of mosaicism, chimerism and uniparental disomy identified by single nucleotide polymorphism array analysis

TLDR

Mosaic aneuploidy and uniparental disomy arise from mitotic or meiotic events, differing in embryonic impact, co‑occurrence, and recurrence risk. The authors aimed to investigate the developmental mechanism and timing of chromosome aneuploidy mosaicism, UPD, and XX/XY chimerism using a genome‑wide SNP array. They applied a genome‑wide single‑nucleotide polymorphism array to analyze patients, enabling simultaneous evaluation of genomic alterations and mechanistic insights. The study identified 16 mitotically derived mosaic aneuploidies (including all monosomies and four rare trisomies) and five meiotically derived trisomies, three of which carried UPD, demonstrating that meiotic nondisjunction increases UPD risk; recombination patterns revealed meiotic origins, while UPD mechanisms included trisomy rescue, monosomy rescue, and mitotic mosaic segmental UPD, with a maternal UPD in an XX/XY chimeric case suggesting parthenogenesis; SNP array analysis thus enables simultaneous detection of genomic alterations and elucidation of aneuploidy and UPD mechanisms, informing selective pressures against full trisomy and recurrence risk estimates.

Abstract

Mosaic aneuploidy and uniparental disomy (UPD) arise from mitotic or meiotic events. There are differences between these mechanisms in terms of (i) impact on embryonic development; (ii) co-occurrence of mosaic trisomy and UPD and (iii) potential recurrence risks. We used a genome-wide single nucleotide polymorphism (SNP) array to study patients with chromosome aneuploidy mosaicism, UPD and one individual with XX/XY chimerism to gain insight into the developmental mechanism and timing of these events. Sixteen cases of mosaic aneuploidy originated mitotically, and these included four rare trisomies and all of the monosomies, consistent with the influence of selective factors. Five trisomies arose meiotically, and three of the five had UPD in the disomic cells, confirming increased risk for UPD in the case of meiotic non-disjunction. Evidence for the meiotic origin of aneuploidy and UPD was seen in the patterns of recombination visible during analysis with 1–3 crossovers per chromosome. The mechanisms of formation of the UPD included trisomy rescue, with and without concomitant trisomy, monosomy rescue, and mitotic formation of a mosaic segmental UPD. UPD was also identified in an XX/XY chimeric individual, with one cell line having complete maternal UPD consistent with a parthenogenetic origin. Utilization of SNP arrays allows simultaneous evaluation of genomic alterations and insights into aneuploidy and UPD mechanisms. Differentiation of mitotic and meiotic origins for aneuploidy and UPD supports existence of selective factors against full trisomy of some chromosomes in the early embryo and provides data for estimation of recurrence and disease mechanisms.