Insights into variation in meiosis from 31,228 human sperm genomes

Bell, Avery Davis; Mello, Curtis J.; Nemesh, James; Brumbaugh, Sara A.; Wysoker, Alec; McCarroll, Steven A.

doi:10.1038/s41586-020-2347-0

Cited by 83 publications

(146 citation statements)

References 76 publications

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“…Indeed, some of the first genetic surveys of human preimplantation embryos noted that certain patients appeared to be predisposed to generating embryos with complex forms of mosaic aneuploidy (i.e., “chaotic mosaicism”), independent of maternal age 78 . Similar observations have been noted with respect to oocyte and sperm aneuploidies of meiotic origin, including in recent studies 4,76 . These observations point to the possibility that inherited genetic variation influences the fidelity of meiosis and/or early embryonic mitosis, the latter controlled by maternal gene products deposited in the oocyte.…”

Section: Genetic Contributions and Pathways Associated With Aneuploidsupporting

confidence: 53%

“…78 Similar observations have been noted with respect to oocyte and sperm aneuploidies of meiotic origin, including in recent studies. 4,76 These observations point to the possibility that inherited genetic variation influences the fidelity of meiosis and/or early embryonic mitosis, the latter controlled by maternal gene products deposited in the oocyte.…”

Section: Genetic Contributions and Pathways Associated With Aneuplomentioning

confidence: 99%

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Origins and mechanisms leading to aneuploidy in human eggs

et al. 2021

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The gain or loss of a chromosome-or aneuploidy-acts as one of the major triggers for infertility and pregnancy loss in humans. These chromosomal abnormalities affect more than 40% of eggs in women at both ends of the age spectrum, that is, young girls as well as women of advancing maternal age. Recent studies in human oocytes and embryos using genomics, cytogenetics, and in silico modeling all provide new insight into the rates and potential genetic and cellular factors associated with aneuploidy at varying stages of development. Here, we review recent studies that are shedding light on potential molecular mechanisms of chromosome missegregation in oocytes and embryos across the entire female reproductive life span.

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Section: Genetic Contributions and Pathways Associated With Aneuploidsupporting

confidence: 53%

Section: Genetic Contributions and Pathways Associated With Aneuplomentioning

confidence: 99%

Origins and mechanisms leading to aneuploidy in human eggs

et al. 2021

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“…Consequently, spermatogonial stem cells, despite proliferating throughout reproductive life, do not appear to exhibit detectable clonal collapse or expansion, likely a reflection of cellular dynamics in the testicular stem cell niche. Single cell sequencing identified almost 3% of sperm with karyotype defects 34 , but the degree to which they contribute to risk of disease in offspring remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Temporal stability of human sperm mosaic mutations results in life-long threat of transmission to offspring

Yang

Breuss

et al. 2020

Preprint

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Every newborn harbors scores of new single nucleotide variants (SNVs) that may impact health and disease; the majority of these are contributed by the paternal germ cells. In some cases, these mutations are identifiable in a subset of the parents' cells-a phenomenon called mosaicism, which is capable of producing disease recurrence. Here, we provide a comprehensive analysis of male gonadal mosaic mutations, employing 300x whole genome sequencing (WGS) of blood and sperm in 17 healthy individuals, including assessment across multiple samples and age groups. Approximately 1 in 15 healthy males is predicted to harbor a transmissible, likely pathogenic exonic variant that is mosaic in his sperm. In general, only a third of sperm mosaic mutations were detectable in blood cells, all were remarkably stable over the course of months to years, and 23% were present in 5% or more of sperm cells. There was no evidence of age-dependent clonal expansion or collapse, as seen in hematopoiesis. Thus, despite the observed increase of mutations in offspring of men with advanced paternal age, detectable sperm mosaicism remains stable, represents a life-long transmission risk to offspring, and suggests a testis stem cell niche that prevents widespread clonality.

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“…Even for species with large genome sizes, we have seen multiple studies using single-sperm sequencing to examine the regulation of recombination events in mouse ( Hinch et al. 2019 ) and human ( Bell et al. 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Adaptive Divergence of Meiotic Recombination Rate in Ecological Speciation

Neupane

2020

Genome Biology and Evolution

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Theories predict that directional selection during adaptation to a novel habitat results in elevated meiotic recombination rate. Yet the lack of population-level recombination rate data leaves this hypothesis untested in natural populations. Here we examine the population-level recombination rate variation in two incipient ecological species, the microcrustacean Daphnia pulex (an ephemeral-pond species) and D. pulicaria (a permanent-lake species). The divergence of D. pulicaria from D. pulex involved habitat shifts from pond to lake habitats as well as strong local adaptation due to directional selection. Using a novel single-sperm genotyping approach, we estimated the male-specific recombination rate of two linkage groups in multiple populations of each species in common garden experiments and identified a significantly elevated recombination rate in D. pulicaria. Most importantly, population genetic analyses show that the divergence in recombination rate between these two species is most likely due to divergent selection in distinct ecological habitats rather than neutral evolution.

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Insights into variation in meiosis from 31,228 human sperm genomes

Cited by 83 publications

References 76 publications

Origins and mechanisms leading to aneuploidy in human eggs

Origins and mechanisms leading to aneuploidy in human eggs

Temporal stability of human sperm mosaic mutations results in life-long threat of transmission to offspring

Adaptive Divergence of Meiotic Recombination Rate in Ecological Speciation

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