Epigenomics and Genotype-Phenotype Association Analyses Reveal Conserved Genetic Architecture of Complex Traits in Cattle and Human

Shuli Liu, Ying Yu, Shengli Zhang, John B. Cole, Albert Tenesa, Ting Wang, Tara G. McDaneld, Li Ma, George E Liu, Lingzhao Fang

Research output: Contribution to journalArticlepeer-review

Abstract

Background
Lack of comprehensive functional annotations across a wide range of tissues and cell types severely hinders the biological interpretations of phenotypic variation, adaptive evolution and domestication in livestock. Here we used a combination of comparative epigenomics, genome-wide association study (GWAS) and selection signature analysis, to shed light on potential adaptive evolution in cattle.

Results
We cross-mapped 8 histone marks of 1,300 samples from human to cattle, covering 178 unique tissues/cell types. By uniformly analyzing 723 RNA-seq and 40 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 GWAS and selection signature results, 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 are 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.

Conclusion
Collectively, our results highlighted that comparative epigenomics in conjunction with GWAS and selection signature analyses could provide biological insights into the phenotypic variation and adaptive evolution. Cattle may serve as a model for human complex traits, by providing additional information beyond laboratory model organisms, particularly when more novel phenotypes become available in the near future.
Original languageEnglish
JournalBMC Biology
Early online date3 Jul 2020
DOIs
Publication statusE-pub ahead of print - 3 Jul 2020

Keywords

  • Comparative epigenomics
  • GWAS enrichment
  • Trait-relevant tissue
  • Human-Cattle comparison

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