Genome-wide functional screen of 3'UTR variants uncovers causal variants for human disease and evolution.
Genome-wide functional screen of 3'UTR variants uncovers causal variants for human disease and evolution.
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DOI：
10.1016/j.cell.2021.08.025
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发表时间：
2021-09-30
期刊：
影响因子：
64.5
通讯作者：
Sabeti PC
中科院分区：
文献类型：
--
作者：
Griesemer D;Xue JR;Reilly SK;Ulirsch JC;Kukreja K;Davis JR;Kanai M;Yang DK;Butts JC;Guney MH;Luban J;Montgomery SB;Finucane HK;Novina CD;Tewhey R;Sabeti PC
3'非翻译区（3'UTR）变异与人类性状和疾病密切相关，但很少有因果关系。我们开发了针对3'UTR的大规模平行报告基因测定（MPRAu），以灵敏地测定12，173个3'UTR变体。我们将MPRAu应用于六种人类细胞系，重点关注与全基因组关联研究（GWAS）和人类进化适应相关的遗传变异。MPRAu扩展了我们对3'UTR功能的理解，表明简单序列主要解释3'UTR调控活性。我们调整MPRAu以揭示碱基对分辨率的不同分子机制，包括与东亚人潜在代谢进化适应相关的LEPR中富含AU的元素。我们提名了数百个3'UTR因果变异与遗传精细映射表型协会。使用内源性等位基因替换，我们表征了一种破坏调节病毒防御基因TRIM14的miRNA位点的变体，以及一种改变PILRB丰度的变体，提名了年龄相关性黄斑变性中转录变化的因果变体。针对3′ UTR的大规模平行报告基因检测可测量与人类疾病和许多细胞类型中的进化选择相关的12，000多种3′UTR变体的个体调控效应，从而命名功能性遗传变异。
3’ untranslated region (3’UTR) variants are strongly associated with human traits and diseases, yet few have been causally identified. We developed the Massively Parallel Reporter Assay for 3’UTRs (MPRAu) to sensitively assay 12,173 3’UTR variants. We applied MPRAu to six human cell lines, focusing on genetic variants associated with genome-wide association studies (GWAS) and human evolutionary adaptation. MPRAu expands our understanding of 3’UTR function, suggesting that simple sequences predominately explain 3’UTR regulatory activity. We adapt MPRAu to uncover diverse molecular mechanisms at base-pair resolution, including an AU-rich element of LEPR linked to potential metabolic evolutionary adaptations in East Asians. We nominate hundreds of 3’UTR causal variants with genetically fine-mapped phenotype associations. Using endogenous allelic replacements, we characterize one variant that disrupts a miRNA site regulating the viral defense gene TRIM14, and one that alters PILRB abundance, nominating a causal variant underlying transcriptional changes in age-related macular degeneration. Massively Parallel Reporter Assay for 3′UTRs measures individual regulatory effects of over 12,000 3′UTR variants associated with human disease and evolutionary selection in many cell types, nominating functional genetic variation.
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DOI：
10.1126/science.1260793
发表时间：
2015-02-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Battle A;Khan Z;Wang SH;Mitrano A;Ford MJ;Pritchard JK;Gilad Y
通讯作者：
Gilad Y
影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
64.5
作者：
Hafner M;Landthaler M;Burger L;Khorshid M;Hausser J;Berninger P;Rothballer A;Ascano M Jr;Jungkamp AC;Munschauer M;Ulrich A;Wardle GS;Dewell S;Zavolan M;Tuschl T
通讯作者：
Tuschl T
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen
影响因子：
64.8
作者：
Berkovits BD;Mayr C
通讯作者：
Mayr C