日本理研综合医学科学中心和理研先锋研究集群Nicholas F. Parrish和Shohei Kojima共同合作，近期取得重要工作进展。他们研究发现移动元件变异有助于群体特异性基因组多样化、基因调控和疾病风险。相关研究成果2023年5月11日在线发表于《自然—遗传学》杂志上。

据介绍，移动遗传元件（ME）是可遗传的诱变剂，可递归地产生结构变异（SV）。ME变异体（MEV）很难在统计遗传学中进行基因分型和整合，掩盖了它们对基因组多样性和性状的影响。

研究人员开发了一种工具，使用短读全基因组测序（WGS）准确地对MEV进行基因分型，并将其应用于人类群体。研究人员发现了意想不到的群体特异性MEV差异，包括将日本人与其他群体区分开来的Alu插入分布。将MEV与表达定量性状基因座（eQTL）图谱整合表明，MEV类通过共享机制调节组织特异性基因表达，包括产生或减弱增强子和招募转录后调节因子，支持类间的可解释性。与SNV相比，MEV更常与基因表达变化联系在一起，因此似乎会影响性状。对MEV进行全基因组关联研究（GWAS）可以确定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。

总之，这项研究表明，MEV是人类差异和疾病风险的驱动因素。

附：英文原文

Title: Mobile element variation contributes to population-specific genome diversification, gene regulation and disease risk

Author: Kojima, Shohei, Koyama, Satoshi, Ka, Mirei, Saito, Yuka, Parrish, Erica H., Endo, Mikiko, Takata, Sadaaki, Mizukoshi, Misaki, Hikino, Keiko, Takeda, Atsushi, Gelinas, Asami F., Heaton, Steven M., Koide, Rie, Kamada, Anselmo J., Noguchi, Michiya, Hamada, Michiaki, Kamatani, Yoichiro, Murakawa, Yasuhiro, Ishigaki, Kazuyoshi, Nakamura, Yukio, Ito, Kaoru, Terao, Chikashi, Momozawa, Yukihide, Parrish, Nicholas F.

Issue&Volume: 2023-05-11

Abstract: 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 an Alu insertion 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.

DOI: 10.1038/s41588-023-01390-2

Source: https://www.nature.com/articles/s41588-023-01390-2