美国哈佛大学James R. Xue团队通过3′UTR变体的全基因组功能筛选发现人类疾病和进化的因果变体。这一研究成果于2021年9月16日在线发表在国际学术期刊《细胞》上。
研究人员开发了3′非翻译区（3′UTR）大规模平行报告基因测定法（MPRAu），能够灵敏地测定12173个3′UTR变异。研究人员将MPRAu应用于六个人类细胞系，重点研究与全基因组关联研究（GWAS）和人类进化适应有关的遗传变异。MPRAu扩大了人们对3′UTR功能的理解，表明简单序列主要解释了3′UTR的调节活性。研究人员对MPRAu进行了调整，在碱基对分辨率上发现了不同的分子机制，包括LEPR的一个富含腺苷酸（AU）的元件与东亚人潜在的代谢进化适应有关。
研究人员揭示了数百个3′UTR的因果变体，这些变体在遗传学上有细微的表型关联。利用内源性等位基因替换，研究人员描述了一个破坏调节病毒防御基因TRIM14的miRNA位点的变体和一个改变PILRB丰度的变体，并报道了年龄相关性黄斑变性中转录变化的一个因果变体。
据介绍，3′UTR变体与人类性状和疾病密切相关，但很少有因果关系被确认。
附：英文原文
Title: Genome-wide functional screen of 3′UTR variants uncovers causal variants for human disease and evolution
Author: Dustin Griesemer, James R. Xue, Steven K. Reilly, Jacob C. Ulirsch, Kalki Kukreja, Joe R. Davis, Masahiro Kanai, David K. Yang, John C. Butts, Mehmet H. Guney, Jeremy Luban, Stephen B. Montgomery, Hilary K. Finucane, Carl D. Novina, Ryan Tewhey, Pardis C. Sabeti
Issue&Volume: 2021-09-16
Abstract: 3′ untranslated region (3′UTR) variants are strongly associated with human traitsand diseases, yet few have been causally identified. We developed the massively parallelreporter assay for 3′UTRs (MPRAu) to sensitively assay 12,173 3′UTR variants. We appliedMPRAu to six human cell lines, focusing on genetic variants associated with genome-wideassociation studies (GWAS) and human evolutionary adaptation. MPRAu expands our understandingof 3′UTR function, suggesting that simple sequences predominately explain 3′UTR regulatoryactivity. We adapt MPRAu to uncover diverse molecular mechanisms at base pair resolution,including an adenylate-uridylate (AU)-rich element of LEPR linked to potential metabolic evolutionary adaptations in East Asians. We nominatehundreds of 3′UTR causal variants with genetically fine-mapped phenotype associations.Using endogenous allelic replacements, we characterize one variant that disrupts amiRNA site regulating the viral defense gene TRIM14 and one that alters PILRB abundance, nominating a causal variant underlying transcriptional changes in age-relatedmacular degeneration.
DOI: 10.1016/j.cell.2021.08.025
Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00999-5