麻省理工学院和哈佛大学的布罗德研究所Po-Ru Loh小组基于90万生物样本库参与者的DNA重复扩增研究启示。2026年1月7日出版的《自然》杂志发表了这项成果。

在这里，该研究团队分析了来自英国生物银行和该研究团队所有人研究计划的90多万参与者的DNA测序数据，这些研究计划以计算方法为主题，以识别、测量和从DNA重复不稳定性中学习。不同位点的重复序列在种系和血液中表现出广泛变化的组织特异性突变倾向。TCF4和ADGRE2中常见的重复等位基因在血液中显示出高的长度嵌合率，这表明大多数人类基因组包含随着年龄增长而扩展的重复元件。不稳定重复等位基因体细胞扩增程度的全基因组关联分析鉴定出29个位点，遗传变异增加了血液中一个或多个DNA重复扩增（P = 5 × 10^-8 ~ 2.5 × 10 ^-1438)。

这些基因修饰因子对重复不稳定性表现出强烈的集体效应：在一次重复中，多基因得分最高和最低的5%的个体之间的体细胞扩增率相差10倍。与其他DNA重复序列相比，几个DNA修复基因的修饰等位基因对TCF4重复序列的血液不稳定性表现出相反的影响。谷氨酰胺酶（GLS）基因5'非翻译区扩增重复序列与5期慢性肾病(优势比(OR) = 14.0（5.7-34.3, 95%可信区间（CI））和肝脏疾病（OR = 3.0 (1.5-5.9, 95% CI)）相关。这些结果指出了人类种群和整个人类寿命中DNA重复的复杂动态。

研究人员表示，串联DNA重复序列的扩增和收缩在人群和人体组织中产生遗传变异。一些扩增的重复序列与遗传性疾病有关，一些也在身体上不稳定。

附：英文原文

Title: Insights into DNA repeat expansions among 900,000 biobank participants

Author: Hujoel, Margaux L. A., Handsaker, Robert E., Tang, David, Kamitaki, Nolan, Mukamel, Ronen E., Rubinacci, Simone, Palamara, Pier Francesco, McCarroll, Steven A., Loh, Po-Ru

Issue&Volume: 2026-01-07

Abstract: Expansions and contractions of tandem DNA repeats generate genetic variation in human populations and in human tissues. Some expanded repeats cause inherited disorders and some are also somatically unstable1,2. Here we analysed DNA sequencing data from over 900,000 participants in the UK Biobank and the All of Us Research Program using computational approaches to recognize, measure and learn from DNA-repeat instability. Repeats at different loci exhibited widely variable tissue-specific propensities to mutate in the germline and blood. Common alleles of repeats in TCF4 and ADGRE2 exhibited high rates of length mosaicism in the blood, demonstrating that most human genomes contain repeat elements that expand as we age. Genome-wide association analyses of the extent of somatic expansion of unstable repeat alleles identified 29 loci at which inherited variants increased expansion of one or more DNA repeats in blood (P=5×108 to 2.5×101,438). These genetic modifiers exhibited strong collective effects on repeat instability: at one repeat, somatic expansion rates varied fourfold between individuals with the highest and lowest 5% of polygenic scores. Modifier alleles at several DNA-repair genes exhibited opposite effects on the blood instability of the TCF4 repeat compared with other DNA repeats. Expanded repeats in the 5′ untranslated region of the glutaminase (GLS) gene associated with stage 5 chronic kidney disease (odds ratio (OR)=14.0 (5.7–34.3, 95% confidence interval (CI))) and liver diseases (OR=3.0 (1.5–5.9, 95% CI)). These results point to complex dynamics of DNA repeats in human populations and across the human lifespan.

DOI: 10.1038/s41586-025-09886-z

Source: https://www.nature.com/articles/s41586-025-09886-z