Epigenomics and Genotype-Phenotype Association
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Liu et al. BMC Biology (2020) 18:80 https://doi.org/10.1186/s12915-020-00792-6 RESEARCH ARTICLE Open Access Epigenomics and genotype-phenotype association analyses reveal conserved genetic architecture of complex traits in cattle and human Shuli Liu1,2, Ying Yu2, Shengli Zhang2, John B. Cole1, Albert Tenesa3,4, Ting Wang5, Tara G. McDaneld6,LiMa7*, George E. Liu1* and Lingzhao Fang1,3,7* 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 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. (Continued on next page) * Correspondence: [email protected]; [email protected]; [email protected] 1Animal Genomics and Improvement Laboratory, Agricultural Research Service, USDA, BARC-East, Beltsville, MD 20705, USA 7Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Liu et al. BMC Biology (2020) 18:80 Page 2 of 16 (Continued from previous page) 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. Keywords: Comparative epigenomics, GWAS enrichment, Trait-relevant tissues, Human-cattle comparison Background significantly enriched in active promoters and en- Understanding genetic and biological mechanisms under- hancers in bovine rumen epithelial primary cells [16]. lying complex traits (e.g., causal variants and their corre- The observation that epigenomes are generally conserved sponding tissues at specific physiological stages) is a main across species [17–21] facilitated the emergence of com- theme of research in the field of genetics and biology. In parative epigenomics. This opened a new avenue to explore the past decade, genome-wide association studies (GWAS) the biological basis of complex outcomes and adaptive evo- have revealed thousands of genomic regions associated lution in the target species (e.g., cattle and swine) by bor- with a wide range of complex traits and diseases in human rowing functional annotations from well-studied species and other species [1–3]. However, the vast majority of such as humans and mice. For example, Zhou et al. re- GWAS hits locate outside protein-coding regions, hinder- ported that the primary sequence conservation drove the ing their biological interpretations and medical applica- conservation of tissue-specific DNA methylation among tions [4], while reflecting the important roles of regulatory human, mouse, and rat [22]. Ebert et al. showed that pre- regions in phenotypic diversity and adaptive evolution [5– dicted epigenomes by cross-species mapping could identify 7]. Therefore, researchers have put great efforts into the tissue-specific expression in the target species [23]. We annotation of regulatory elements (e.g., promoters and en- thereby hypothesized that comparative epigenomics in con- hancers) across multiple tissues and cell types in human junction with large-scale GWAS could enable us to explore and model organisms, such as ENCODE projects in hu- the biological basis underlying complex traits of economic man, mouse, and Drosophila [8–10] and human Roadmap importance and positive selection in cattle. In addition, Epigenomics Project [11]. By integrating such functional Holstein cattle has a unique population structure (e.g., annotations with GWAS from large cohorts (e.g., UK bio- strong selection and high inbreeding) and a large amount bank), investigators gained novel biological insights into of phenotypic records measured with high accuracy [24, the genetic architecture underlying complex traits and dis- 25], including growth, health, and fertility traits. These may eases in human [12–14]. For instance, Finucane et al. ob- make Holstein cattle a potentialanimalmodelforstudying served a significant association of central nervous system certain human complex traits and diseases. Recently, by cells with body mass index and smoking behavior, through comparing sperm methylomes between human and Hol- estimating the heritability enrichment of cell type-specific stein cattle, we demonstrated that genomic variants of elements across multiple complex phenotypes [12]. Road- morphology-relevant traits were consistently and signifi- map Epigenomics Consortium demonstrated that GWAS cantly enriched in the evolutionarily conserved hypomethy- signals of late-onset Alzheimer’s disease were unexpect- lated regions in human and cattle [26]. Furthermore, the edly and significantly enriched in enhancers of immune rapidly reduced immune and reproductive capacity of dairy cell types rather than brain tissues [11]. However, in live- cattle has been observed during the strong selection for stock and other non-model organisms, lack of com- milk production over the past decades [27]. Using these prehensive functional annotations across multiple cattle resources, it is possible to extrapolate genomic tissues and cell types severely limits our biological in- changes associated with immune and reproduction in cattle terpretations for their phenotypic diversity and adap- to further advance human biomedical researches. tive evolution, although numerous genomic variants In this study (Fig. 1), we first cross-mapped 1300 epi- have been detected for thousands of complex pheno- genomes (i.e., eight distinct histone marks) from human types and positive selection in those animals [3]. The to cattle, including 178 tissues and cell types. We then val- Functional Annotation of Animal Genomes consor- idated cross-mapped epigenomes by analyzing experimen- tium (FAANG), still in its early phase, aims to gener- tally generated ChIP-seq data of histone marks (n =4), ate a comprehensive catalogue of regulatory elements RNA-seq (n = 723) and whole genome bisulfite sequen- for domestic and non-model organism species [15]. cing (WGBS; n = 40) in cattle. Through integrating cross- By constructing the first map of regulatory elements mapped epigenomes with 45 GWAS datasets (n = 27,214) in the livestock species, we recently showed that and selection signature (Run 6 of the 1000 Bull Genome GWAS signals of multiple complex traits were Project) in cattle [28], we for the first time identified Liu et al. BMC Biology (2020) 18:80 Page 3 of 16 Fig. 1 Schematic overview of current study. We retrieved human epigenome data, including eight histone marks (H3K4me1, H3K4me2, H3K4me3, H3K9me3, H3K9ac, H3K27ac, H3K27me3, and H3K36me3),