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

Abstract

Meiosis, while critical for reproduction, is also highly variable and error prone: crossover rates 10 vary among humans and individual gametes, and chromosome nondisjunction leads to aneuploidy, a leading cause of miscarriage. To study variation in meiotic outcomes within and across individuals, we developed a way to sequence many individual sperm genomes at once.We used this method to sequence the genomes of 31,228 gametes from 20 sperm donors, identifying 813,122 crossovers, 787 aneuploid chromosomes, and unexpected genomic 15 anomalies. Different sperm donors varied four-fold in the frequency of aneuploid sperm, and aneuploid chromosomes gained in meiosis I had 36% fewer crossovers than corresponding nonaneuploid chromosomes. Diverse recombination phenotypes were surprisingly coordinated: donors with high average crossover rates also made a larger fraction of their crossovers in centromere-proximal regions and placed their crossovers closer together. These same 20 relationships were also evident in the variation among individual gametes from the same donor: sperm with more crossovers tended to have made crossovers closer together and in centromereproximal regions. Variation in the physical compaction of chromosomes could help explain this coordination of meiotic variation across chromosomes, gametes, and individuals. 485We thank Giulio Genovese for suggestions on analyses, Evan Macosko for advice on technology development, and other members of the McCarroll lab, including

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

“…A companion protocol for generating single-sperm libraries using the methods presented here is available via Protocol Exchange 48 . Custom scripts (available via Zenodo 49 ) are referenced by name in the sections describing analyses they perform. Recombination and aneuploidy data generated via the described methods are also publicly available 50 .…”

Inference and effects of barcode multiplets in droplet-based single-cell assays

“…Until then, we suggest that inferences regarding rare cell events should be corroborated across multiple channels or technologies to validate interpretation. Moreover, we acknowledge contexts where multiplets can be used to benchmark features of droplet-based assays as have been recently described 16 .…”

Crossover interference and sex-specific genetic maps shape identical by descent sharing in close relatives

“…Another source of crossover events is switches between ancestral populations within an admixed individual's genome, but lacking information about which ancestor produced each crossover, the resulting admixture-based maps are also sex averaged [21]. Lastly, recent work on sequencing and resolving crossovers in single oocytes [22,23] and sperm cells [24][25][26][27] provide information on sex-specific crossover properties and can be used to construct sex-specific maps.…”