Integrative genotype-environment association and single-cell transcriptomic analyses identify candidate mechanisms of...

As one of the earliest domesticated and most globally ubiquitous livestock, pigs (Sus scrofa) have undergone profound environmental adaptation while following human expansion across diverse bioclimatic zones. Despite their evolutionary significance, the genomic mechanisms enabling pigs to thrive in disparate ecological settings remain poorly understood. Here, we present a comprehensive global analysis using a dataset of 1,151 pig genome sequences representing 146 distinct populations. By integrating three complementary genotype-environment association (GEA) frameworks including Redundancy Analysis (RDA), BayPass, and Latent Factor Mixed Models (LFMM), we identified genomic regions and candidate genes associated with environmental variation. Our analysis detected several candidate genes associated with high-altitude adaptation, particularly those involved in ultraviolet radiation response. By integrating lung single-cell RNA sequencing analysis (scRNA) from high-altitude and commercial breeds, we identified ASXL1 as a candidate gene potentially involved in high-altitude adaptation. Meanwhile, scRNA revealed candidate regulatory pathways, including the NOTCH signaling pathway, that were overlooked by traditional GEA methods, suggested the complex regulatory landscape of physiological adaptation. Together, this study integrates large-scale population genomics and scRNA to provide insights into the genetic associations and regulatory landscapes potentially contributing to environmental adaptation in domestic pigs, advancing our understanding of livestock evolutionary responses to diverse ecological conditions.