人类衰老的标志是分裂组织中克隆扩张挂毯的出现,在血液中作为克隆造血(CH)尤其明显。CH,与癌症风险和衰老相关的表型有关,通常源于一组已建立基因的体细胞突变。然而,大多数克隆缺乏已知的驱动程序。在这里,我们从英国生物银行的200,618个人中推断全血外显子组中的基因水平阳性选择。我们确定了17个额外的基因,ZBTB33,ZNF318,ZNF234,SPRED2,SH2B3,SRCAP,SIK3,SRSF1,CHEK2,CCDC115,CCL22,BAX,YLPM1,MYD88,MTA2,MAGEC3和IGLL5,在种群水平的阳性选择下,并在来自单细胞来源的造血集落的10,837个全基因组中验证了这种选择模式。这些基因突变的克隆的频率和大小随着年龄的增长而增长,与经典CH驱动器相当。它们与感染风险增加有关,死亡和血液恶性肿瘤,强调这些额外基因在衰老过程中的重要性。
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.