Epigenomics and genotype-phenotype association analyses reveal conserved genetic architecture of complex traits in cattle and human

Authors: LIU, SHULI - China Agricultural University; YU, YING - China Agricultural University; ZHANG, SHENGLI - China Agricultural University; Cole, John; TENESA, ALBERT - Roslin Institute; WANG, TING - Washington University; McDaneld, Tara; MA, LI - University Of Maryland; Liu, Ge - George; FANG, LINGZHAO - Roslin Institute

Submitted to: BMC Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/12/2020
Publication Date: 7/3/2020
Citation: Liu, S., Yu, Y., Zhang, S., Cole, J.B., Tenesa, A., Wang, T., Mcdaneld, T.G., Ma, L., Liu, G., Fang, L. 2020. Epigenomics and genotype-phenotype association analyses reveal conserved genetic architecture of complex traits in cattle and human. BMC Biology. 18(1). Article 80. https://doi.org/10.1186/s12915-020-00792-6.
DOI: https://doi.org/10.1186/s12915-020-00792-6

Interpretive Summary: By cross-mapping of human epigenomic data onto the cattle genome, we detected tissue-specific promoters, enhancers, trait-relevant tissues and cell types. Through genotype-phenotype association analyses, we revealed conserved genetic architecture underlying complex traits between cattle and human. These results fill our knowledge gaps and provide the foundation for utilizing epignomic data from human and other model species for investigation of target species with less resources. Farmers, scientist, and policy planners who need improve animal health and production, as well as human health based on genomic data will benefit from this study.

Technical Abstract: Lack of comprehensive functional annotations across a large range of tissues and cell types severely hinders biological interpretations for phenotypic variation, adaptive evolution and domestication in livestock. We here cross-mapped 8 histone marks (e.g., H3K4me3 and H3K9ac) of 1,300 samples from human to cattle, covering 178 unique tissues/cell types. By uniformly analyzing 723 and 40 RNA-seq and whole genome bisulfite sequencing (WGBS) datasets in cattle, we validated that cross-mapped histone marks captured tissue-specific expression and methylation, reflecting tissue-relevant biology. Through integrating cross-mapped tissue-specific histone marks with large-scale genome-wide association study (GWAS) and selection signature, we for the first time detected relevant tissues and cell types for 45 economically important traits and artificial selection in cattle. For instance, immune tissues significantly associated with health and reproduction traits, multiple tissues for milk production and body conformation traits (reflecting their highly polygenic architecture), and thyroid for the different selection between beef and dairy cattle. Similarly, we detected relevant tissues for 58 complex traits and diseases in humans, and observed that immune and fertility traits in humans significantly correlated with those in cattle in terms of relevant tissues, which facilitated the identification of causal genes for such traits. For instance, PIK3CG, a gene highly specifically expressed in mononuclear cells, was significantly associated with both age-at-menopause in human and daughter-still-birth in cattle. ICAM, a T-cell specific gene, was significantly associated with both allergic diseases in human and metritis in cattle. Collectively, our results highlighted that comparative epigenomics in conjunction with GWAS and selection signature could provide biological insights into the phenotypic variation and adaptive evolution in the target species. Cattle may serve as a model for human complex traits, by providing additional information beyond laboratory model organisms (e.g., mouse), particularly when more novel phenotypes become available in the near future.