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.

健康组织中正选择下的遗传改变对癌症风险有影响。然而，整个基因组中阳性选择的总水平仍然未知。乘客突变受到所有驱动突变的影响，无论基因组中的类型或位置如何。因此，乘客总数可以用来估计司机的总数——包括传统上遗漏的癌症基因之外的身份不明的司机。在这里，我们分析来自健康血液和食道的同义突变的变异等位基因频谱，以量化缺失阳性选择的水平。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，这表明基因组中其他地方的突变存在高水平的阳性选择。相比之下，NOTCH1和TP53，表明其他地方几乎没有阳性选择。