Mobile element variation contributes to population-specific genome diversification, gene regulation and disease risk
Mobile element variation contributes to population-specific genome diversification, gene regulation and disease risk
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DOI：
10.1038/s41588-023-01390-2
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发表时间：
2023-05
期刊：
影响因子：
30.8
通讯作者：
Shohei Kojima;S. Koyama;Mirei Ka;Yuka Saito;E. Parrish;Mikiko Endo;Sadaaki Takata;Misaki Mizukoshi;K. Hikino;Atsushi Takeda;Asami F. Gelinas;Steven M Heaton;Rie Koide;A. Kamada;Michiya Noguchi;Michiaki Hamada;Y. Kamatani;Yasuhiro Murakawa;K. Ishigaki;Y. Nakamura;K. Ito;C. Terao;Y. Momozawa;N. Parrish
中科院分区：
文献类型：
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作者：
Shohei Kojima;S. Koyama;Mirei Ka;Yuka Saito;E. Parrish;Mikiko Endo;Sadaaki Takata;Misaki Mizukoshi;K. Hikino;Atsushi Takeda;Asami F. Gelinas;Steven M Heaton;Rie Koide;A. Kamada;Michiya Noguchi;Michiaki Hamada;Y. Kamatani;Yasuhiro Murakawa;K. Ishigaki;Y. Nakamura;K. Ito;C. Terao;Y. Momozawa;N. Parrish
移动的遗传元件（ME）是递归地产生结构变体（SV）的可遗传诱变剂。ME变异体（MEV）很难在统计遗传学中进行基因分型和整合，模糊了它们对基因组多样性和性状的影响。我们开发了一种工具，使用短读全基因组测序（WGS）准确地对MEV进行基因分型，并将其应用于全球人群。我们发现了意想不到的人群特异性MEV差异，包括区分日本人与其他人群的插入分布。整合MEV与表达数量性状基因座（eQTL）地图显示，MEV类调节组织特异性基因表达的共享机制，包括创建或减弱增强子和招募转录后调节因子，支持类的可解释性。MEV比SNV更常与基因表达变化相关，因此可能影响性状。对MEV进行全基因组关联研究（GWAS）可以精确定位疾病风险的潜在原因，包括与瘢痕疙瘩和筋膜炎相关的LINE-1插入。这项工作暗示MEV是人类分歧和疾病风险的驱动因素。
Mobile genetic elements (MEs) are heritable mutagens that recursively generate structural variants (SVs). ME variants (MEVs) are difficult to genotype and integrate in statistical genetics, obscuring their impact on genome diversification and traits. We developed a tool that accurately genotypes MEVs using short-read whole-genome sequencing (WGS) and applied it to global human populations. We find unexpected population-specific MEV differences, including anAluinsertion distribution distinguishing Japanese from other populations. Integrating MEVs with expression quantitative trait loci (eQTL) maps shows that MEV classes regulate tissue-specific gene expression by shared mechanisms, including creating or attenuating enhancers and recruiting post-transcriptional regulators, supporting class-wide interpretability. MEVs more often associate with gene expression changes than SNVs, thus plausibly impacting traits. Performing genome-wide association study (GWAS) with MEVs pinpoints potential causes of disease risk, including a LINE-1 insertion associated with keloid and fasciitis. This work implicates MEVs as drivers of human divergence and disease risk.