Elucidation of de novo small insertion/deletion biology with parent-of-origin phasing.
Elucidation of de novo small insertion/deletion biology with parent-of-origin phasing.
复制标题
通过亲本定相阐明从头小插入/缺失生物学。
DOI：
10.1002/humu.23971
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发表时间：
2020
期刊：
影响因子：
3.9
通讯作者：
Gelb,BruceD
中科院分区：
文献类型：
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作者：
Seiden,AllisonH;Richter,Felix;Patel,Nihir;Rodriguez,OscarL;Deikus,Gintaras;Shah,Hardik;Smith,Melissa;Roberts,Amy;King,EileenC;Sebra,RobertP;Sharp,AndrewJ;Gelb,BruceD
从头插入/缺失(INDEL)发生的机制，如聚合酶滑移，在人类基因组中已经被假设，但没有很好地描述。我们实现了两个方法学上的改进，这两个改进被用来剖析内部突变。我们将从头开始的变异体分配给低覆盖率长读全基因组测序的起源亲本(即阶段化)，与短读测序(中位数分别为84%和23%)相比，实现了更好的阶段化。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分类为三个子类型。在三个不同分期方法的队列中(Ntrios= 540，所有队列)，我们观察到一个新出现的Indel亚型，即拷贝数变化(Ccc)，与父亲的年龄显著相关(p= 7.1 × 10−4)，但与母亲的年龄无关(p= .45)。我们在三个队列中复制了这种效应，而不进行新的阶段划分(ppaternal= 1.9 × 10−9，pmterial= .61；ntrios= 3,391，均为队列)。虽然这与精子发生过程中的聚合酶滑移是一致的，但由父亲年龄解释的差异百分比很低，我们没有观察到与复制时间的关联。这些结果表明，精子发生的特异性事件在ccc诱变中起着很小的作用，这在其他indel亚型和一般的母体年龄中都没有观察到。这些结果对进化论和疾病的INDELL建模具有重要意义。
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 (Ntrios= 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 (ppaternal= 1.9 × 10−9,pmaternal= .61;Ntrios= 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.