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

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

doi:10.1186/s12915-020-00792-6

Abstract

BackgroundLack 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.ResultsWe cross-mapped 8 histone marks of 1300 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.ConclusionCollectively, 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.

Highlights

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
In livestock and other non-model organisms, lack of comprehensive functional annotations across multiple tissues and cell types severely limits our biological interpretations for their phenotypic diversity and adaptive evolution, numerous genomic variants have been detected for thousands of complex phenotypes and positive selection in those animals [3]
We observed that distributions of all predicted histone marks around transcription start sites (TSS) and transcription terminal sites (TTS) in cattle were similar to those originally observed in humans, providing evidences for the conservation of epigenomes between human and cattle (Additional file 1: Fig. S1A)

Summary

Introduction

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. Researchers have put great efforts into the annotation of regulatory elements (e.g., promoters and enhancers) across multiple tissues and cell types in human and model organisms, such as ENCODE projects in human, mouse, and Drosophila [8,9,10] and human Roadmap Epigenomics Project [11] By integrating such functional annotations with GWAS from large cohorts (e.g., UK biobank), investigators gained novel biological insights into the genetic architecture underlying complex traits and diseases in human [12,13,14]. In livestock and other non-model organisms, lack of comprehensive functional annotations across multiple tissues and cell types severely limits our biological interpretations for their phenotypic diversity and adaptive evolution, numerous genomic variants have been detected for thousands of complex phenotypes and positive selection in those animals [3]. By constructing the first map of regulatory elements in the livestock species, we recently showed that GWAS signals of multiple complex traits were significantly enriched in active promoters and enhancers in bovine rumen epithelial primary cells [16]

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Results

Conclusion