Early Detection Programme, CRUK Cambridge Cancer Centre, University of Cambridge, Cambridge, UK.
Department of Oncology, University of Cambridge, Cambridge, UK.
Nat Genet. 2021 Nov;53(11):1597-1605. doi: 10.1038/s41588-021-00957-1. Epub 2021 Nov 4.
Genetic alterations under positive selection in healthy tissues have implications for cancer risk. However, total levels of positive selection across the genome remain unknown. Passenger mutations are influenced by all driver mutations, regardless of type or location in the genome. Therefore, the total number of passengers can be used to estimate the total number of drivers-including unidentified drivers outside of cancer genes that are traditionally missed. Here we analyze the variant allele frequency spectrum of synonymous mutations from healthy blood and esophagus to quantify levels of missing positive selection. In blood, we find that only 30% of passengers can be explained by single-nucleotide variants in driver genes, suggesting high levels of positive selection for mutations elsewhere in the genome. In contrast, more than half of all passengers in the esophagus can be explained by just the two driver genes NOTCH1 and TP53, suggesting little positive selection elsewhere.
在健康组织中受到正选择作用的遗传改变会影响癌症风险。然而，整个基因组的正选择总水平尚不清楚。乘客突变受到所有驱动突变的影响，而不管它们在基因组中的类型或位置如何。因此，乘客总数可用于估计驱动突变的总数，包括传统上错过的癌症基因之外的未识别驱动突变。在这里，我们分析了来自健康血液和食管的同义突变的变异等位基因频率谱，以量化缺失的正选择水平。在血液中，我们发现只有 30%的乘客可以用驱动基因中的单核苷酸变异来解释，这表明基因组其他部位的突变受到高水平的正选择。相比之下，食管中超过一半的乘客可以仅用两个驱动基因 NOTCH1 和 TP53 来解释，这表明其他地方的正选择很少。
