Mutation in the germline is the ultimate source of genetic variation, but little is known about the influence of germline chromatin structure on mutational processes. Using ATAC-seq, we profile the open chromatin landscape of human spermatogonia, the most proliferative cell type of the germline, identifying transcription factor binding sites (TFBSs) and PRDM9 binding sites, a subset of which will initiate meiotic recombination. We observe an increase in rare structural variant (SV) breakpoints at PRDM9-bound sites, implicating meiotic recombination in the generation of structural variation. Many germline TFBSs, such as NRF1, are also associated with increased rates of SV breakpoints, apparently independent of recombination. Singleton short insertions (≥5 bp) are highly enriched at TFBSs, particularly at sites bound by testis active TFs, and their rates correlate with those of structural variant breakpoints. Short insertions often duplicate the TFBS motif, leading to clustering of motif sites near regulatory regions in this male-driven evolutionary process. Increased mutation loads at germline TFBSs disproportionately affect neural enhancers with activity in spermatogonia, potentially altering neurodevelopmental regulatory architecture. Local chromatin structure in spermatogonia is thus pervasive in shaping both evolution and disease.

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精原细胞的突变偏差影响人类基因组调控位点的解剖结构

种系突变是遗传变异的最终来源，但人们对种系染色质结构对突变过程的影响知之甚少。使用 ATAC-seq，我们分析了人类精原细胞（种系中增殖能力最强的细胞类型）的开放染色质景观，识别了转录因子结合位点 (TFBS) 和 PRDM9 结合位点，其中的一个子集将启动减数分裂重组。我们观察到 PRDM9 结合位点的罕见结构变异 (SV) 断点有所增加，这表明减数分裂重组参与了结构变异的产生。许多种系 TFBS，例如 NRF1，也与 SV 断点率增加相关，显然与重组无关。单例短插入（≥5 bp）在 TFBS 处高度富集，特别是在睾丸活性 TF 结合的位点，并且它们的发生率与结构变异断点的发生率相关。短插入通常会复制 TFBS 基序，导致在这个雄性驱动的进化过程中，基序位点在调控区域附近聚集。种系 TFBS 突变负荷的增加不成比例地影响精原细胞中具有活性的神经增强子，可能改变神经发育调节结构。因此，精原细胞中的局部染色质结构在进化和疾病的形成过程中普遍存在。