Signatures of replication timing, recombination, and sex in the spectrum of rare variants on the human X chromosome and autosomes
Signatures of replication timing, recombination, and sex in the spectrum of rare variants on the human X chromosome and autosomes
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DOI：
10.1073/pnas.1900714116
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发表时间：
2019-09-03
影响因子：
11.1
通讯作者：
Przeworski, Molly
中科院分区：
文献类型：
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作者：
Agarwal, Ipsita;Przeworski, Molly
人类生殖系突变的来源还知之甚少。部分困难在于突变很少发生，因此基于谱系的直接方法在可以检查的数量上仍然有限。为了解决这个问题，我们考虑了一个由13,860条人类X染色体和常染色体组成的数据集(基因组聚合数据库，gnomAD)中的低频变异的谱。X-常染色体的差异反映了生殖系的性别差异，并被广泛用于了解男性和女性的突变过程；较少人认识到的是，它们还反映了X和常染色体之间不同的染色体水平的生化特征。我们通过比较常染色体上多个基因组区段的突变谱以及X和常染色体之间的突变谱来梳理这些成分。在这样做的过程中，我们能够将特定的突变模式归因于复制时机和重组，并识别出男性和女性所产生的突变类型的差异。特别是，我们确定C>；G是X染色体上雄性减数分裂双链断裂的突变特征，这可能是由于后期修复造成的。我们的结果显示了生殖系中损伤和修复的生化过程如何与性别特有的生活史特征相互作用，以塑造X染色体和常染色体上的突变模式。
The sources of human germline mutations are poorly understood. Part of the difficulty is that mutations occur very rarely, and so direct pedigree-based approaches remain limited in the numbers that they can examine. To address this problem, we consider the spectrum of low-frequency variants in a dataset (Genome Aggregation Database, gnomAD) of 13,860 human X chromosomes and autosomes. X-autosome differences are reflective of germline sex differences and have been used extensively to learn about male versus female mutational processes; what is less appreciated is that they also reflect chromosome-level biochemical features that differ between the X and autosomes. We tease these components apart by comparing the mutation spectrum in multiple genomic compartments on the autosomes and between the X and autosomes. In so doing, we are able to ascribe specific mutation patterns to replication timing and recombination and to identify differences in the types of mutations that accrue in males and females. In particular, we identify C > G as a mutagenic signature of male meiotic double-strand breaks on the X, which may result from late repair. Our results show how biochemical processes of damage and repair in the germline interact with sex-specific life history traits to shape mutation patterns on both the X chromosome and autosomes.