The mechanisms underlying de novo insertion/deletion (indel) genesis, such as polymerase slippage, have been hypothesized but not well characterized in the human genome. We implemented two methodological improvements, which were leveraged to dissect indel mutagenesis. We assigned de novo variants to parent‐of‐origin (i.e., phasing) with low‐coverage long‐read whole‐genome sequencing, achieving better phasing compared to short‐read sequencing (medians of 84% and 23%, respectively). We then wrote an application programming interface to classify indels into three subtypes according to sequence context. Across three cohorts with different phasing methods (N_trios = 540, all cohorts), we observed that one de novo indel subtype, change in copy count (CCC), was significantly correlated with father's (p = 7.1 × 10⁻⁴) but not mother's (p = .45) age at conception. We replicated this effect in three cohorts without de novo phasing (p_paternal = 1.9 × 10⁻⁹, p_maternal = .61; N_trios = 3,391, all cohorts). Although this is consistent with polymerase slippage during spermatogenesis, the percentage of variance explained by paternal age was low, and we did not observe an association with replication timing. These results suggest that spermatogenesis‐specific events have a minor role in CCC indel mutagenesis, one not observed for other indel subtypes nor for maternal age in general. These results have implications for indel modeling in evolution and disease.

中文翻译：

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从原发阶段进行阐明从头开始的小插入/缺失生物学。

已经假设了从头插入/缺失（indel）发生的基础机制，例如聚合酶滑移，但在人类基因组中并未得到很好的表征。我们实施了两种方法上的改进，这些改进被用于剖析插入缺失诱变。我们使用低覆盖率的长读全基因组测序将从头变异体指定为产地来源（即定相），与短读序列（中位数分别为84％和23％）相比，实现了更好的定相。然后，我们编写了一个应用程序编程接口，根据序列上下文将indel分为三个子类型。在采用不同阶段方法的三个队列中（N _trios  = 540，所有队列），我们观察到一种新的indel亚型，即拷贝数变化（CCC）与父亲的（p  = 7.1×10 ^-4），而不是母亲 在受孕时的年龄（p = .45）。我们在没有重新定相的三个队列中复制了这种效果（p_父亲 = 1.9×10 ^-9，p_母亲 = 0.61；N个_三重奏 = 3,391，所有同类群组）。尽管这与精子发生过程中聚合酶的滑移相一致，但由父亲年龄解释的变异百分数很低，而且我们没有观察到与复制时机的关联。这些结果表明，精子发生特异的事件在CCC插入缺失诱变中作用较小，其他插入缺失亚型和一般产妇年龄均未观察到。这些结果对进化和疾病中的indel建模有影响。