澳大利亚新南威尔士大学Daniel G. MacArthur等合作在研究中取得进展。他们揭示了串联重复变异对免疫细胞类型特异性基因表达的影响。2026年10月28日出版的《自然》杂志发表了这项成果。

串联重复（TRs）是人类基因组中高度多态的重复序列，是基因表达的重要调控因子，但由于准确基因分型和分析存在挑战，其研究仍不充分。在此，研究人员从两个队列的1,925名个体中超过540万份血液来源细胞生成了全基因组和单细胞RNA测序数据，并进行荟萃分析，以表征超过170万个TR位点的变异对免疫细胞类型特异性基因表达的影响。研究人员鉴定出超过69,000个单细胞表达数量性状位点，其中30.7%对28种免疫细胞类型中的1种具有特异性，并利用细胞状态推断揭示了动态调控效应。来自922名个体超过340万个细胞核的匹配单细胞转座酶可及染色质高通量测序图谱，为近三分之一与表达相关的TRs鉴定出染色质可及性数量性状位点，支持其对顺式调控架构的协调作用。精细定位表明，1,490个TRs是6.1%的受检基因中基因表达的候选因果驱动因素，共定位分析凸显出超过200个基因，其中TRs可能介导与免疫和血液学性状的遗传关联。总之，这些结果提供了人类免疫系统中TR介导调控的全基因组多组学视角，确立TRs作为细胞类型特异性调控变异和复杂性状架构的关键贡献者。

附：英文原文

Title: Tandem repeat variation shapes immune cell type-specific gene expression

Author: Tanudisastro, Hope A., Cuomo, Anna S. E., Weisburd, Ben, Welland, Matthew, Spenceley, Eleanor, Franklin, Michael, Xue, Angli, Huang, Hao Lawrence, Bowen, Blake, Fan, Jianan, Dong, Oscar A., Henry, Albert, Allen, Peter C., Wing, Kristof, Tang, Owen, Gray, Michael, Reis, Andre L. M., Margoliash, Jonathan, Kurtas, Nehir E., Pullin, Jeffrey M., Lee, Arthur S., Brand, Harrison, Harper, Michael, Bobowik, Katalina, Silk, Michael, Miniter, Amy, Marshall, John, Bakiris, Vivian, Madala, Bindu Swapna, Uren, Caitlin, Bartie, Caitlin, McCloy, Rachael A., Senabouth, Anne, Dashnow, Harriet, Fearnley, Liam, Martin-Trujillo, Alejandro, Dolzhenko, Egor, Qiao, Zhen, Grieve, Stuart M., Nguyen, Tung, Ben-David, Eyal, Chen, Ling, Farh, Kyle Kai-How, Talkowski, Michael E., Alexander, Stephen I., Siggs, Owen M., Gruenschloss, Leonhard

Issue&Volume: 2026-10-28

Abstract: Tandem repeats (TRs)—highly polymorphic, repetitive sequences across the human genome—are important regulators of gene expression but remain underexplored due to challenges in accurate genotyping and analysis1. Here we generate whole-genome and single-cell RNA sequencing from more than 5.4million blood-derived cells across 1,925 individuals in two cohorts2, and perform meta-analysis to characterize the impact of variation in more than 1.7million TR loci on immune cell type-specific gene expression. We identify more than 69,000 single-cell expression quantitative trait loci, 30.7% of which are specific to 1 of 28 immune cell types, and reveal dynamic regulatory effects using cell-state inference. Matched single-cell assay for transposase-accessible chromatin with high-throughput sequencing profiles from more than 3.4million nuclei in 922 individuals3 uncover chromatin accessibility quantitative trait loci for nearly one-third of expression-associated TRs, supporting coordinated effects on cis-regulatory architecture. Fine-mapping implicates 1,490 TRs as candidate causal drivers of gene expression in 6.1% of tested genes, and colocalization analyses highlight more than 200 genes in which TRs likely mediate genetic associations with immune and haematological traits. Together, these results provide a genome-wide, multiomic view of TR-mediated regulation in the human immune system, establishing TRs as key contributors to cell type-specific regulatory variation and complex trait architecture.

DOI: 10.1038/s41586-026-10438-2

Source:https://www.nature.com/articles/s41586-026-10438-2