英国阿斯利康公司Slavé Petrovski团队报道了462666个英国生物样本库全基因组序列中端粒长度的遗传结构。2024年8月27日，《自然—遗传学》杂志在线发表了这项成果。

研究人员开发了一个联合端粒长度指标，结合了462666名英国生物样本库参与者的定量PCR和全基因组测序测量。该指标提高了SNP遗传率，表明它更好地捕捉了端粒长度的遗传调控。外显子范围的稀有变异和基因层面崩解关联研究鉴定出64个与端粒长度显著相关的变异和30个基因，包括ACD和RTEL1中的等位基因系列。

值得注意的是，这些基因中有16%已知是克隆性造血的驱动因素——一种与髓系癌症和几种非恶性疾病相关的年龄相关的体细胞嵌合现象。体细胞变异分析揭示了与端粒长度的基因特异性关联，包括SRSF2突变大克隆个体中的端粒延长，以及其他基因驱动的克隆扩展个体中的端粒缩短。总的来说，该研究发现表明稀有变异对端粒长度的影响较大，尤其是在与克隆性造血相关的基因中。

据悉，端粒保护染色体末端免受损伤，其长度与人类疾病和衰老有关。

附：英文原文

Title: Genetic architecture of telomere length in 462,666 UK Biobank whole-genome sequences

Author: Burren, Oliver S., Dhindsa, Ryan S., Deevi, Sri V. V., Wen, Sean, Nag, Abhishek, Mitchell, Jonathan, Hu, Fengyuan, Loesch, Douglas P., Smith, Katherine R., Razdan, Neetu, Olsson, Henric, Platt, Adam, Vitsios, Dimitrios, Wu, Qiang, Codd, Veryan, Nelson, Christopher P., Samani, Nilesh J., March, Ruth E., Wasilewski, Sebastian, Carss, Keren, Fabre, Margarete, Wang, Quanli, Pangalos, Menelas N., Petrovski, Slav

Issue&Volume: 2024-08-27

Abstract: Telomeres protect chromosome ends from damage and their length is linked with human disease and aging. We developed a joint telomere length metric, combining quantitative PCR and whole-genome sequencing measurements from 462,666 UK Biobank participants. This metric increased SNP heritability, suggesting that it better captures genetic regulation of telomere length. Exome-wide rare-variant and gene-level collapsing association studies identified 64 variants and 30 genes significantly associated with telomere length, including allelic series in ACD and RTEL1. Notably, 16% of these genes are known drivers of clonal hematopoiesis—an age-related somatic mosaicism associated with myeloid cancers and several nonmalignant diseases. Somatic variant analyses revealed gene-specific associations with telomere length, including lengthened telomeres in individuals with large SRSF2-mutant clones, compared with shortened telomeres in individuals with clonal expansions driven by other genes. Collectively, our findings demonstrate the impact of rare variants on telomere length, with larger effects observed among genes also associated with clonal hematopoiesis.

DOI: 10.1038/s41588-024-01884-7

Source: https://www.nature.com/articles/s41588-024-01884-7