Population genomic scan of endogenous retrovirus insertions revealed cryptic drivers of selective sweep in wild house mouse genomes

Detecting selective sweeps in population genomic scans is often complicated by the presence of missing drivers of hitchhiking, lacking known functional genes or mutations in the target regions. Non-reference genomic insertions, such as endogenous retroviruses (ERVs), are common in mammalian genomes and are potential drivers of genetic hitchhiking. In this study, we performed a population genomic scan of non-reference ERV insertions in wild house mice (Mus musculus). Using a newly developed bioinformatics pipeline, we identified and characterized >100,000 non-reference ERV insertions from short-read sequencing data across 163 wild house mouse genomes. Our analysis revealed substantial variation in ERV insertion patterns among wild house mice. Focusing on the Fv4, a known ERV-derived defense gene against murine leukemia viruses (MLVs) and mainly restricted in the range of M. m. castaneus, we detected evidence of adaptive introgression from M. m. castaneus to M. m. musculus, particularly in a part of northern East Asia. Selective sweep analysis in Korean M. m. musculus, where Fv4 is prevalent despite a predominantly musculus-like genetic background, indicated that the spread of Fv4 has been driven by recent positive selection presumably owing to the protection against MLVs. Additional genomic scans identified several other ERV insertions associated with high-frequency selective sweeps, suggesting that ERVs serve as cryptic drivers of adaptive evolution. Our findings highlight the role of ERV as genetic elements subject to selection, serving as potential contributors to host-pathogen interactions. This study provides novel insights into the evolutionary dynamics of ERV insertions and their impact on genome evolution.