Insights about variation in meiosis from tens of thousands of human sperm genomes
Bell, Avery Davis
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CitationBell, Avery Davis. 2019. Insights about variation in meiosis from tens of thousands of human sperm genomes. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractMeiosis is the specialized cell division that creates sperm and egg cells, and so is critical for reproduction. Even so, meiotic processes and outcomes are highly variable. For example, crossover rates and locations vary among individual humans, among gametes from the same individual, and between males and females. Meiosis is also error prone: chromosomes can fail to properly separate during this key cell division, leading to aneuploidy, the loss or gain of a chromosome in a gamete, which can cause miscarriage and morbidity. 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, generating chromosome-scale phased haplotypes for each donor, and identifying 813,122 crossovers, 787 aneuploid chromosomes, and unexpected genomic anomalies.
We found that diverse recombination phenotypes were surprisingly coordinated across individuals and individual sperm cells. 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 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 centromere-proximal regions. Variation in the physical compaction of chromosomes could help explain this coordination of meiotic variation at multiple levels.
Aneuploidy was evident in all sperm donors and all chromosomes. Individual sperm donors varied four-fold in the frequency of aneuploid sperm. The sex chromosomes were the most frequently aneuploid, followed by the acrocentric chromosomes and chromosomes 2 and 9. Chromosomes and individuals varied in their propensity for chromosome gains to occur during meiosis I or meiosis II. Aneuploid chromosomes gained in meiosis I had 35% fewer crossovers than corresponding non-aneuploid chromosomes.
By developing and applying a powerful new way of investigating meiosis via large-scale single-gamete sequencing, we have characterized variation in meiosis and relationships among meiotic phenotypes across and within individuals and cells at the interconnected levels of chromosomes, gametes, and individuals.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42013121
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