日前，中科院北京基因組研究所重大疾病基因組與個(gè)體化醫(yī)療實(shí)驗(yàn)室，“百人計(jì)劃”方向東研究員項(xiàng)目組助理研究員渠鴻竹博士等開(kāi)展的國(guó)際合作研究“人類(lèi)疾病全基因組關(guān)聯(lián)分析研究”獲得重大進(jìn)展,，相關(guān)研究成果Systematic Localization of Common Disease-Associated Variation in Regulatory DNA于2012年9月在Science雜志發(fā)表。本研究進(jìn)一步采用新一代高通量測(cè)序技術(shù),，在表觀基因組水平上開(kāi)展全基因組關(guān)聯(lián)分析(Genome-wide association study; GWAS)研究,，并且在該研究領(lǐng)域取得了新的進(jìn)展。
渠鴻竹博士和華盛頓大學(xué)美國(guó)國(guó)立衛(wèi)生研究院西北注釋表觀基因組繪圖中心(Northwest Reference Epigenome Mapping Center,，NIH)主任,、華盛頓大學(xué)基因組學(xué)系副教授John A. Stamatoyannopoulis博士所領(lǐng)導(dǎo)實(shí)驗(yàn)室的研究人員，通過(guò)分析人類(lèi)349種細(xì)胞和組織樣本的全基因組DNase I圖譜與已有的GWAS SNPs數(shù)據(jù),，發(fā)現(xiàn)約93％的與疾病和性狀相關(guān)的SNPs位于非編碼序列內(nèi),，并且集中在DNase I高敏感位點(diǎn)區(qū)域(DHSs)。88％含有SNP的DHSs存在于胎兒發(fā)育階段,，并且在這些DHSs內(nèi)的SNPs與妊娠暴露相關(guān)表型(gestational exposure-related phenotypes)有關(guān),。此外,，與含有SNP的DHS密切相關(guān)的遠(yuǎn)距離靶基因(絕大多數(shù)基因距離該DHSs超過(guò)100 kb)行使的功能與同一SNP相關(guān)的疾病表型相類(lèi)似，該聯(lián)系拓展了在基因組水平疾病與性狀之間的關(guān)聯(lián)性,，同時(shí)提供了一個(gè)潛在的致病基因庫(kù)來(lái)解釋這種關(guān)聯(lián)性,。93.2%DHSs內(nèi)部的疾病相關(guān)SNPs同時(shí)位于轉(zhuǎn)錄因子識(shí)別序列內(nèi)，并影響了局部的染色質(zhì)結(jié)構(gòu),。這些轉(zhuǎn)錄因子進(jìn)一步形成復(fù)雜的網(wǎng)絡(luò)系統(tǒng),，調(diào)控與疾病相關(guān)的基因表達(dá)。此項(xiàng)研究突破性地從表觀基因組水平進(jìn)行GWAS分析,，并在系統(tǒng)生物學(xué)理論的指導(dǎo)下,，通過(guò)統(tǒng)合的生物信息學(xué)分析策略，從而建立疾病與生物學(xué)性狀之間關(guān)聯(lián)性的調(diào)控網(wǎng)絡(luò)模型,，為闡明人類(lèi)常見(jiàn)疾病與基因性狀之間的相互關(guān)系提供了嶄新的科學(xué)視角和有利的研究工具,。
全基因組關(guān)聯(lián)分析(GWAS)的主要目的是在人類(lèi)全基因組范圍內(nèi)尋找與疾病相關(guān)的序列變異，即單核苷酸多態(tài)性(SNP),。GWAS研究在某種疾病患者的全基因組范圍內(nèi)檢測(cè)出SNP位點(diǎn)并與對(duì)照組人群進(jìn)行比較,，篩選所有的變異等位基因頻率，避免了象候選基因策略一樣需要預(yù)先假設(shè)致病基因,，從而為復(fù)雜疾病的發(fā)病機(jī)制研究提供了更多的線索,。（生物谷Bioon.com）
doi: 10.1126/science.1222794
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Systematic Localization of Common Disease-Associated Variation in Regulatory DNA
Matthew T. Maurano, Richard Humbert, Eric Rynes, Robert E. Thurman, Eric Haugen, Hao Wang1, Alex P. Reynolds, Richard Sandstrom, Hongzhu Qu, Jennifer Brody, Anthony Shafer, Fidencio Neri1, Kristen Lee, Tanya Kutyavin, Sandra Stehling-Sun, Audra K. Johnson, Theresa K. Canfield, Erika Giste, Morgan Diegel, Daniel Bates, R. Scott Hansen, Shane Neph, Peter J. Sabo, Shelly Heimfeld, Antony Raubitschek, Steven Ziegler, Chris Cotsapas, Nona Sotoodehnia, Ian Glass, Shamil R. Sunyaev, Rajinder Kau, John A. Stamatoyannopoulos
Genome-wide association studies have identified many noncoding variants associated with common diseases and traits. We show that these variants are concentrated in regulatory DNA marked by deoxyribonuclease I (DNase I) hypersensitive sites (DHSs). Eighty-eight percent of such DHSs are active during fetal development and are enriched in variants associated with gestational exposure–related phenotypes. We identified distant gene targets for hundreds of variant-containing DHSs that may explain phenotype associations. Disease-associated variants systematically perturb transcription factor recognition sequences, frequently alter allelic chromatin states, and form regulatory networks. We also demonstrated tissue-selective enrichment of more weakly disease-associated variants within DHSs and the de novo identification of pathogenic cell types for Crohn’s disease, multiple sclerosis, and an electrocardiogram trait, without prior knowledge of physiological mechanisms. Our results suggest pervasive involvement of regulatory DNA variation in common human disease and provide pathogenic insights into diverse disorders.
