Human aging is marked by the emergence of a tapestry of clonal expansions in dividing tissues, particularly evident in blood as clonal hematopoiesis (CH). CH, linked to cancer risk and aging-related phenotypes, often stems from somatic mutations in a set of established genes. However, the majority of clones lack known drivers. Here we infer gene-level positive selection in whole blood exomes from 200,618 individuals in UK Biobank. We identify 17 additional genes, ZBTB33, ZNF318, ZNF234, SPRED2, SH2B3, SRCAP, SIK3, SRSF1, CHEK2, CCDC115, CCL22, BAX, YLPM1, MYD88, MTA2, MAGEC3 and IGLL5, under positive selection at a population level, and validate this selection pattern in 10,837 whole genomes from single-cell-derived hematopoietic colonies. Clones with mutations in these genes grow in frequency and size with age, comparable to classical CH drivers. They correlate with heightened risk of infection, death and hematological malignancy, highlighting the significance of these additional genes in the aging process.

人类衰老的标志是分裂组织中克隆扩张的出现，特别是在血液中明显的克隆造血（CH）。 CH 与癌症风险和衰老相关表型有关，通常源于一组已确定基因的体细胞突变。然而，大多数克隆缺乏已知的驱动程序。在这里，我们推断英国生物银行 200,618 名个体的全血外显子组中的基因水平正选择。我们在群体水平的正向选择下确定了 17 个额外基因：ZBTB33、ZNF318、ZNF234、SPRED2、SH2B3、SRCAP、SIK3、SRSF1、CHEK2、CCDC115、CCL22、BAX、YLPM1、MYD88、MTA2、MAGEC3和IGLL5，并进行验证这种选择模式存在于来自单细胞的造血集落的 10,837 个全基因组中。这些基因发生突变的克隆的频率和大小随着年龄的增长而增长，与经典的 CH 驱动因素相当。它们与感染、死亡和血液恶性肿瘤风险增加相关，凸显了这些额外基因在衰老过程中的重要性。