Xiang Yue, Zhang Saixian, Huang Yi, Zheng Zhuqing, Sun Jiahui, Zhao Qiulin, Zhou Peng, Qi Xiaolong, Li Jingjin, Xiong Fuyang, Xu Jing, Wang Shengquan, Fu Liangliang, Li Xinyun
Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education & Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan, 430070, P.R. China.
Institute of Agricultural Biotechnology, Jingchu University of Technology, Jingmen, 448000, P.R. China.
BMC Biol. 2025 Jun 9;23(1):163. doi: 10.1186/s12915-025-02263-2.
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.
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.
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.
猪脑因其与人类大脑在结构上有显著相似性，是研究脑相关疾病的重要生物医学模型。此外，家猪经过长期驯化和人工选择，其大脑受到了深刻影响，使其成为一个有趣的研究对象。然而，由于大脑中存在高度的细胞异质性，对调控猪脑功能的机制及其对各种表型的影响仍缺乏全面了解。
在本研究中，我们对家猪和野猪大脑皮层及小脑的71798个细胞进行了分析，鉴定出九种细胞类型，并整合单细胞RNA测序数据以探索细胞类型特异性调控图谱和少突胶质细胞发育轨迹。此外，对家猪和野猪各细胞类型的比较分析表明，少突胶质细胞祖细胞可能具有更快的进化速率。最后，跨物种分析表明，与人类相比，猪各细胞类型中序列保守和功能保守的调控元件比例似乎高于小鼠。对跨细胞类型保守调控元件中与15种人类疾病和复杂性状相关的遗传变异富集情况的研究表明，免疫相关疾病在猪中富集程度更高，而神经疾病在小鼠中富集程度略高。然而，猪中存在与阿尔茨海默病相关的变异而小鼠中没有，这表明猪可能是这种疾病更合适的模型。
我们的研究对猪脑的异质性提供了初步见解，并提出了潜在的调控机制。此外，我们探讨了神经系统差异对表型变化的可能影响，这可为进一步的生物医学研究奠定基础。
