Comparative epigenomics reveals the impact of ruminant-specific regulatory elements on complex traits
Siqian Chen,
Shuli Liu,
Shaolei Shi,
Yifan Jiang,
Mingyue Cao,
Yongjie Tang,
Wenlong Li,
Jianfeng Liu,
Lingzhao Fang,
Ying Yu,
Shengli Zhang
Affiliations
Siqian Chen
Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affairs & National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University
Shuli Liu
Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affairs & National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University
Shaolei Shi
Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affairs & National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University
Yifan Jiang
Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affairs & National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University
Mingyue Cao
Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affairs & National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University
Yongjie Tang
Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affairs & National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University
Wenlong Li
Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affairs & National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University
Jianfeng Liu
Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affairs & National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University
Lingzhao Fang
MRC Human Genetics Unit at the Institute of Genetics and Cancer, University of Edinburgh
Ying Yu
Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affairs & National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University
Shengli Zhang
Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affairs & National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University
Abstract Background Insights into the genetic basis of complex traits and disease in both human and livestock species have been achieved over the past decade through detection of genetic variants in genome-wide association studies (GWAS). A majority of such variants were found located in noncoding genomic regions, and though the involvement of numerous regulatory elements (REs) has been predicted across multiple tissues in domesticated animals, their evolutionary conservation and effects on complex traits have not been fully elucidated, particularly in ruminants. Here, we systematically analyzed 137 epigenomic and transcriptomic datasets of six mammals, including cattle, sheep, goats, pigs, mice, and humans, and then integrated them with large-scale GWAS of complex traits. Results Using 40 ChIP-seq datasets of H3K4me3 and H3K27ac, we detected 68,479, 58,562, 63,273, 97,244, 111,881, and 87,049 REs in the liver of cattle, sheep, goats, pigs, humans and mice, respectively. We then systematically characterized the dynamic functional landscapes of these REs by integrating multi-omics datasets, including gene expression, chromatin accessibility, and DNA methylation. We identified a core set (n = 6359) of ruminant-specific REs that are involved in liver development, metabolism, and immune processes. Genes with more complex cis-REs exhibited higher gene expression levels and stronger conservation across species. Furthermore, we integrated expression quantitative trait loci (eQTLs) and GWAS from 44 and 52 complex traits/diseases in cattle and humans, respectively. These results demonstrated that REs with different degrees of evolutionary conservation across species exhibited distinct enrichments for GWAS signals of complex traits. Conclusions We systematically annotated genome-wide functional REs in liver across six mammals and demonstrated the evolution of REs and their associations with transcriptional output and conservation. Detecting lineage-specific REs allows us to decipher the evolutionary and genetic basis of complex phenotypes in livestock and humans, which may benefit the discovery of potential biomedical models for functional variants and genes of specific human diseases.
