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科学家实现干扰T细胞调节元件活性的自身免疫性疾病相关遗传变异的优先排序
2022-05-08 23:03

美国博德研究所John P. Ray等研究人员合作实现干扰T细胞调节元件活性的自身免疫性疾病相关遗传变异的优先排序。2022年5月5日,《自然—遗传学》杂志在线发表了这项成果。

研究人员进行了高通量的等位基因特异性报告测定,用于优先考虑五种自身免疫性疾病的疾病相关变体。通过检查那些既能促进等位基因特异性报告表达又位于可及染色质中的变体,研究人员确定了60个推定的因果变体,这些变体对统计学上的精细映射变体的富集程度高达57.8倍。

研究人员将一个优先变体(rs72928038)的风险等位基因引入人类T细胞系,并删除了小鼠中的同源序列,两者都导致了BACH2表达的减少。含有该缺失的小鼠的初始CD8 T细胞抑制活化和维持干性的基因表达减少,在急性病毒感染时,显示出更大的倾向,成为效应T细胞。这些结果代表了一个有效方法的例子,即优先考虑变体并研究其生理相关的影响。

据了解,全基因组关联研究(GWAS)已经发现了数百个自身免疫性疾病相关的位点;然而,每个位点内的因果遗传变异大多是未知的。

附:英文原文

Title: Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells

Author: Mouri, Kousuke, Guo, Michael H., de Boer, Carl G., Lissner, Michelle M., Harten, Ingrid A., Newby, Gregory A., DeBerg, Hannah A., Platt, Winona F., Gentili, Matteo, Liu, David R., Campbell, Daniel J., Hacohen, Nir, Tewhey, Ryan, Ray, John P.

Issue&Volume: 2022-05-05

Abstract: Genome-wide association studies (GWASs) have uncovered hundreds of autoimmune disease-associated loci; however, the causal genetic variants within each locus are mostly unknown. Here, we perform high-throughput allele-specific reporter assays to prioritize disease-associated variants for five autoimmune diseases. By examining variants that both promote allele-specific reporter expression and are located in accessible chromatin, we identify 60 putatively causal variants that enrich for statistically fine-mapped variants by up to 57.8-fold. We introduced the risk allele of a prioritized variant (rs72928038) into a human T cell line and deleted the orthologous sequence in mice, both resulting in reduced BACH2 expression. Naive CD8 T cells from mice containing the deletion had reduced expression of genes that suppress activation and maintain stemness and, upon acute viral infection, displayed greater propensity to become effector T cells. Our results represent an example of an effective approach for prioritizing variants and studying their physiologically relevant effects. Integrating methods that assess allele-specific regulatory activity and chromatin accessibility in T cells identifies putative causal variants for five autoimmune diseases.

DOI: 10.1038/s41588-022-01056-5

Source: https://www.nature.com/articles/s41588-022-01056-5

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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