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

Biobank Japan Project Consortium

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)939-951
Number of pages13
JournalNature genetics
Volume55
Issue number6
DOIs
Publication statusPublished - 2023 Jun
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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