美国纽西奈山伊坎医学院Towfique Raj小组的研究认为人类小胶质细胞亚型的长读RNA测序图谱阐明了剪接的疾病相关遗传调控。该项研究成果发表在2025年3月3日出版的《自然—遗传学》上。

研究人员提出了以同种异构体为中心的小胶质细胞基因组图谱（isoMiGA），它利用长读RNA测序来鉴定35879种新的小胶质细胞同种异构体。研究组发现这些同工型参与刺激反应和大脑区域特异性。然后，研究组对来自391名供体的555个人类小胶质细胞短读RNA测序样本进行多祖先荟萃分析，量化了已知和新亚型的表达，并发现了与阿尔茨海默病和帕金森病遗传风险位点的关联。该团队提出了几个可能通过异构体和剪接位点的复杂变化而起作用的位点。

研究人员表示，小胶质细胞是中枢神经系统的先天免疫细胞，在遗传上与多种神经退行性疾病有关。绘制人类小胶质细胞基因表达的遗传学图谱，已经确定了与小胶质细胞特异性调控元件中疾病相关遗传变异相关的几个位点。然而，由于短测序读数的主题，确定剪接的遗传影响是具有挑战性的。

附：英文原文

Title: Long-read RNA sequencing atlas of human microglia isoforms elucidates disease-associated genetic regulation of splicing

Author: Humphrey, Jack, Brophy, Erica, Kosoy, Roman, Zeng, Biao, Coccia, Elena, Mattei, Daniele, Ravi, Ashvin, Naito, Tatsuhiko, Efthymiou, Anastasia G., Navarro, Elisa, De Sanctis, Claudia, Flores-Almazan, Victoria, Muller, Benjamin Z., Snijders, Gijsje J. L. J., Allan, Amanda, Mnch, Alexandra, Kitata, Reta Birhanu, Kleopoulos, Steven P., Argyriou, Stathis, Malakates, Periklis, Psychogyiou, Konstantina, Shao, Zhiping, Francoeur, Nancy, Tsai, Chia-Feng, Gritsenko, Marina A., Monroe, Matthew E., Paurus, Vanessa L., Weitz, Karl K., Shi, Tujin, Sebra, Robert, Liu, Tao, de Witte, Lot D., Goate, Alison M.

Issue&Volume: 2025-03-03

Abstract: Microglia, the innate immune cells of the central nervous system, have been genetically implicated in multiple neurodegenerative diseases. Mapping the genetics of gene expression in human microglia has identified several loci associated with disease-associated genetic variants in microglia-specific regulatory elements. However, identifying genetic effects on splicing is challenging because of the use of short sequencing reads. Here, we present the isoform-centric microglia genomic atlas (isoMiGA), which leverages long-read RNA sequencing to identify 35,879 novel microglia isoforms. We show that these isoforms are involved in stimulation response and brain region specificity. We then quantified the expression of both known and novel isoforms in a multi-ancestry meta-analysis of 555 human microglia short-read RNA sequencing samples from 391 donors, and found associations with genetic risk loci in Alzheimer’s and Parkinson’s disease. We nominate several loci that may act through complex changes in isoform and splice-site usage.

DOI: 10.1038/s41588-025-02099-0

Source: https://www.nature.com/articles/s41588-025-02099-0