英国威康桑格研究所Jyoti Nangalia团队近期取得重要工作进展，他们通过对200618名个体全血中体细胞突变的分析，确定了普遍的阳性选择和克隆造血的新驱动因素。相关研究成果2024年5月14日在线发表于《自然—遗传学》杂志上。

据介绍，人类衰老的标志是分裂组织中出现了一系列克隆性扩增，尤其是在血液中表现为克隆性造血（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，大多数克隆都缺乏已知的驱动程序。

研究人员从英国生物库的200618个个体的全血外显子中推断出基因水平的阳性选择。研究人员在群体水平的正选择下鉴定了17个额外的基因，ZBTB33、ZNF318、ZNF234、SPRED2、SH2B3、SRCAP、SIK3、SRSF1、CHEK2、CCD115、CCL22、BAX、YLPM1、MYD88、MTA2、MAGEC3和IGLL5，并在来自单细胞来源的造血集落的10837个全基因组中验证了这种选择模式。这些基因突变的克隆在频率和大小上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的风险增加相关，突出了这些额外基因在衰老过程中的重要性。

附：英文原文

Title: Analysis of somatic mutations in whole blood from 200,618 individuals identifies pervasive positive selection and novel drivers of clonal hematopoiesis

Author: Bernstein, Nicholas, Spencer Chapman, Michael, Nyamondo, Kudzai, Chen, Zhenghao, Williams, Nicholas, Mitchell, Emily, Campbell, Peter J., Cohen, Robert L., Nangalia, Jyoti

Issue&Volume: 2024-05-14

Abstract: 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.

DOI: 10.1038/s41588-024-01755-1

Source: https://www.nature.com/articles/s41588-024-01755-1