Common risk alleles for inflammatory diseases are targets of recent positive selection.
Common risk alleles for inflammatory diseases are targets of recent positive selection.
复制标题
DOI：
10.1016/j.ajhg.2013.03.001
复制
发表时间：
2013-04
影响因子：
9.8
通讯作者：
T. Raj;Manik Kuchroo;J. Replogle;S. Raychaudhuri;B. Stranger;P. D. De Jager
中科院分区：
文献类型：
--
作者：
T. Raj;Manik Kuchroo;J. Replogle;S. Raychaudhuri;B. Stranger;P. D. De Jager
全基因组关联研究（GWAS）已经确定了数百个基因座，这些基因座包含影响人类炎症性疾病易感性的遗传变异。据推测，当今炎症性疾病的出现可能部分是由于人类历史上宿主对病原体的抵抗力的多效性效应，其中显着的选择压力会增加宿主对病原体的抵抗力。炎症性疾病易感性的遗传因素在多大程度上受到选择性过程的影响，现在可以比以前更全面地量化。为了理解形成炎症性疾病易感性的进化力量，并阐明受选择影响的功能途径，我们进行了基于系统的分析，以整合（1）已发表的炎症性疾病的GWAS，（2）欧洲血统人群中正选择特征的全基因组扫描，（3）由蛋白质-蛋白质相互作用网络组成的功能基因组学数据，（4）外周血单个核细胞（PBMC）全基因组表达数量性状基因座（eQTL）定位研究。我们证明，炎症性疾病的易感性基因座是丰富的基因组签名最近积极的自然选择，与选定的基因座形成一个高度互连的蛋白质-蛋白质相互作用网络。此外，我们确定了21个位点的炎症性疾病的易感性，显示最近的积极选择的签名，其中13个也显示相关位点内的基因的顺式调节作用的证据。因此，我们的综合分析突出了一组易感基因座，这些基因座可能有助于共享分子功能，并在人类历史过程中经历了选择压力;今天，这些基因座在影响多种不同炎症性疾病的易感性方面发挥着关键作用，部分原因是通过改变免疫细胞中的基因表达。
Genome-wide association studies (GWASs) have identified hundreds of loci harboring genetic variation influencing inflammatory-disease susceptibility in humans. It has been hypothesized that present day inflammatory diseases may have arisen, in part, due to pleiotropic effects of host resistance to pathogens over the course of human history, with significant selective pressures acting to increase host resistance to pathogens. The extent to which genetic factors underlying inflammatory-disease susceptibility has been influenced by selective processes can now be quantified more comprehensively than previously possible. To understand the evolutionary forces that have shaped inflammatory-disease susceptibility and to elucidate functional pathways affected by selection, we performed a systems-based analysis to integrate (1) published GWASs for inflammatory diseases, (2) a genome-wide scan for signatures of positive selection in a population of European ancestry, (3) functional genomics data comprised of protein-protein interaction networks, and (4) a genome-wide expression quantitative trait locus (eQTL) mapping study in peripheral blood mononuclear cells (PBMCs). We demonstrate that loci for inflammatory-disease susceptibility are enriched for genomic signatures of recent positive natural selection, with selected loci forming a highly interconnected protein-protein interaction network. Further, we identify 21 loci for inflammatory-disease susceptibility that display signatures of recent positive selection, of which 13 also show evidence ofcis-regulatory effects on genes within the associated locus. Thus, our integrated analyses highlight a set of susceptibility loci that might subserve a shared molecular function and has experienced selective pressure over the course of human history; today, these loci play a key role in influencing susceptibility to multiple different inflammatory diseases, in part through alterations of gene expression in immune cells.