Single-cell chromatin accessibility profiling reveals regulatory mechanisms and evolution in pig brains

Abstract Background Pig brains serve as a valuable biomedical model for studying brain-related diseases due to their significant structural similarities to the human brain. Furthermore, the long-term domestication and artificial selection of domestic pigs have profoundly shaped their brains, making them an interesting subject for research. However, a comprehensive understanding of the regulatory mechanisms governing pig brain function and their impact on various phenotypes remains elusive due to the high degree of cellular heterogeneity present in the brain. Results In this study, we profiled 71,798 cells from domestic pig and wild boar cerebral cortex and cerebellum, identifying nine cell types, and integrated single-cell RNA sequencing data to explore cell type-specific regulatory landscapes and oligodendrocyte developmental trajectory. Furthermore, comparative analysis of each cell type between domestic pigs and wild boars indicated that oligodendrocyte progenitor cells may potentially exhibit a faster evolutionary rate. Finally, cross-species analysis suggested that, compared to humans, the proportion of sequence-conserved and functionally conserved regulatory elements in each cell type appears to be higher in pigs than in mice. Studies on the enrichment of genetic variants associated with 15 human diseases and complex traits in conserved regulatory elements across cell types indicated that immune-related diseases were more enriched in pigs, whereas neurological diseases were somewhat more enriched in mice. However, the enrichment of Alzheimer’s disease-associated variants in pigs but not in mice suggests that pigs could be a more suitable model for this condition. Conclusions Our research offers preliminary insights into the heterogeneity of pig brains and suggests the potential underlying regulatory mechanisms. Additionally, we explore the possible impact of nervous system differences on phenotypic changes, which could lay the groundwork for further biomedical studies.