Department of Genetics, Harvard Medical School, Boston, MA, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nature. 2020 Jul;583(7815):259-264. doi: 10.1038/s41586-020-2347-0. Epub 2020 Jun 3.
Meiosis, although essential for reproduction, is also variable and error-prone: rates of chromosome crossover vary among gametes, between the sexes, and among humans of the same sex, and chromosome missegregation leads to abnormal chromosome numbers (aneuploidy). To study diverse meiotic outcomes and how they covary across chromosomes, gametes and humans, we developed Sperm-seq, a way of simultaneously analysing the genomes of thousands of individual sperm. Here we analyse the genomes of 31,228 human gametes from 20 sperm donors, identifying 813,122 crossovers and 787 aneuploid chromosomes. Sperm donors had aneuploidy rates ranging from 0.01 to 0.05 aneuploidies per gamete; crossovers partially protected chromosomes from nondisjunction at the meiosis I cell division. Some chromosomes and donors underwent more-frequent nondisjunction during meiosis I, and others showed more meiosis II segregation failures. Sperm genomes also manifested many genomic anomalies that could not be explained by simple nondisjunction. Diverse recombination phenotypes-from crossover rates to crossover location and separation, a measure of crossover interference-covaried strongly across individuals and cells. Our results can be incorporated with earlier observations into a unified model in which a core mechanism, the variable physical compaction of meiotic chromosomes, generates interindividual and cell-to-cell variation in diverse meiotic phenotypes.
减数分裂虽然对生殖至关重要，但也具有变异性和易错性：染色体交叉互换率在配子、性别和同一性别之间的人类中各不相同，染色体错误分离导致异常染色体数量（非整倍体）。为了研究不同的减数分裂结果以及它们如何在染色体、配子和人类之间相互关联，我们开发了 Sperm-seq，这是一种同时分析数千个个体精子基因组的方法。在这里，我们分析了来自 20 名精子供体的 31228 个人类配子的基因组，鉴定出 813122 个交叉和 787 个非整倍体染色体。精子供体的非整倍体率范围为每配子 0.01 至 0.05 个非整倍体；交叉部分保护染色体在减数分裂 I 细胞分裂时不发生非分离。一些染色体和供体在减数分裂 I 中经历了更频繁的非分离，而其他染色体则显示出更多的减数分裂 II 分离失败。精子基因组还表现出许多无法用简单非分离解释的基因组异常。从交叉率到交叉位置和分离（衡量交叉干扰的指标）的各种重组表型，在个体和细胞之间强烈相关。我们的结果可以与早期的观察结果结合起来，形成一个统一的模型，其中核心机制是减数分裂染色体的可变物理紧缩，产生了个体间和细胞间不同减数分裂表型的变异性。
