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 low-complexity 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 phenotypes 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.

中文翻译：

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全基因组3'UTR变异的功能筛选揭示了人类疾病和进化的因果变异

3'非翻译区（3'UTR）变异与人类特征和疾病密切相关，但因果关系很少。我们开发了针对3'UTR（MPRAu）的大规模平行报道基因检测技术，可以灵敏地检测12,173个3'UTR变异体。我们将MPRAu应用于六种人类细胞系，重点研究与全基因组关联研究（GWAS）和人类进化适应相关的遗传变异。MPRAu扩展了我们对3'UTR功能的理解，表明低复杂度序列主要解释了3'UTR调节活性。我们使MPRAu适应于以碱基对的分辨率揭示各种分子机制，包括LEPR的富含AU的元素，该元素与东亚人的潜在代谢进化适应有关。我们提名数百个3' 具有遗传精细映射表型关联的UTR因果变体。使用内源性等位基因置换，我们表征了一个变异，该变异破坏了调控病毒防御基因TRIM14的miRNA位点，而一个变异则改变了PILRB的丰度，从而指出了与年龄相关的黄斑变性转录变化的潜在因果变异。