Rochman Nash D, Wolf Yuri I, Koonin Eugene V
National Center for Biotechnology Information, National Library of Medicine, Bethesda, MD, 20894, USA.
Commun Biol. 2020 Oct 2;3(1):551. doi: 10.1038/s42003-020-01276-7.
Driver mutations (DM) are the genetic impetus for most cancers. The DM are assumed to be deleterious in species evolution, being eliminated by purifying selection unless compensated by other mutations. We present deep phylogenies for 84 cancer driver genes and investigate the prevalence of 434 DM across gene-species trees. The DM are rare in species evolution, and 181 are completely absent, validating their negative fitness effect. The DM are more common in unicellular than in multicellular eukaryotes, suggesting a link between these mutations and cell proliferation control. 18 DM appear as the ancestral state in one or more major clades, including 3 among mammals. We identify within-gene, compensatory mutations for 98 DM and infer likely interactions between the DM and compensatory sites in protein structures. These findings elucidate the evolutionary status of DM and are expected to advance the understanding of the functions and evolution of oncogenes and tumor suppressors.
驱动突变（DM）是大多数癌症的遗传推动力。在物种进化中，驱动突变被认为是有害的，除非有其他突变进行补偿，否则会通过纯化选择被消除。我们展示了84个癌症驱动基因的深度系统发育树，并研究了434个驱动突变在基因-物种树上的普遍性。驱动突变在物种进化中很罕见，其中181个完全不存在，证实了它们对适应性的负面影响。驱动突变在单细胞真核生物中比在多细胞真核生物中更常见，这表明这些突变与细胞增殖控制之间存在联系。18个驱动突变在一个或多个主要分支中表现为祖先状态，其中包括3个在哺乳动物中的突变。我们识别出98个驱动突变的基因内补偿性突变，并推断出驱动突变与蛋白质结构中补偿位点之间可能的相互作用。这些发现阐明了驱动突变的进化状态，有望促进对癌基因和肿瘤抑制基因功能及进化的理解。
