Admixture-driven structural variation diversity and its functional implications

Abstract

Population admixture is a potent evolutionary force shaping genomic diversity, yet its influence on the dynamics and functional consequences of structural variation (SV) remains poorly understood. Here, we present a comprehensive whole-genome sequencing analysis of SVs in the Uyghurs, a model admixed Eurasian population with distinct Western and Eastern ancestral contributions. We identified 9965 high-confidence SVs, revealing that Uyghurs exhibit 32% novel SVs and 1.19-fold greater SV-transcription diversity compared to their ancestral source populations. Crucially, SV diversity follows a non-linear parabolic relationship with ancestry proportions (r = 0.94), peaking when Western/Eastern ancestry contributions are balanced. Admixture-induced recombination at ancestry junctions creates SV hotspots via non-allelic homologous recombination (NAHR), with 60% of post-admixture SVs flanked by homologous repeats. Ancestry-divergent SVs disproportionately regulate gene expression, while admixed variant combinations (e.g. HLA-B and FOXO6 loci) disrupt immune/metabolic pathways via additive regulatory effects. Strikingly, while Uyghurs harbor elevated SV diversity, the burden of pathogenic variants remains comparable to ancestral populations, suggesting buffering mechanisms against genetic load. Evolutionarily, younger SVs tend to be larger in size, exert stronger regulatory impacts and exhibit higher predicted pathogenicity. These findings establish admixture as a dual force of genomic diversification and functional equilibrium, bridging evolutionary dynamics with biomedical insights. Our work underscores the necessity of SV-aware approaches in genetic medicine and highlights how admixed populations broaden genomic diversity beyond ancestral boundaries through novel variant combinations.