Caballero Madison, Koren Amnon
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.
Cell Genom. 2023 May 2;3(6):100305. doi: 10.1016/j.xgen.2023.100305. eCollection 2023 Jun 14.
Somatic mutations have important biological ramifications while exerting substantial rate, type, and genomic location heterogeneity. Yet, their sporadic occurrence makes them difficult to study at scale and across individuals. Lymphoblastoid cell lines (LCLs), a model system for human population and functional genomics, harbor large numbers of somatic mutations and have been extensively genotyped. By comparing 1,662 LCLs, we report that the mutational landscape of the genome varies across individuals in terms of the number of mutations, their genomic locations, and their spectra; this variation may itself be modulated by somatic acting mutations. Mutations attributed to the translesion DNA polymerase η follow two different modes of formation, with one mode accounting for the hypermutability of the inactive X chromosome. Nonetheless, the distribution of mutations along the inactive X chromosome appears to follow an epigenetic memory of the active form.
体细胞突变具有重要的生物学影响，同时在发生率、类型和基因组位置上存在显著的异质性。然而，它们的零星发生使得难以在大规模和跨个体水平上进行研究。淋巴母细胞系（LCLs）是人类群体和功能基因组学的模型系统，含有大量体细胞突变且已被广泛基因分型。通过比较1662个LCLs，我们报告基因组的突变格局在突变数量、基因组位置及其谱方面因个体而异；这种变异本身可能受体细胞作用突变的调节。归因于跨损伤DNA聚合酶η的突变遵循两种不同的形成模式，其中一种模式解释了失活X染色体的高突变性。尽管如此，突变沿失活X染色体的分布似乎遵循活性形式的表观遗传记忆。
