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. 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. 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.

中文翻译：

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表观基因组学和基因型-表型关联分析揭示了牛和人类复杂性状的保守遗传结构。

在广泛的组织和细胞类型中缺乏全面的功能注释严重阻碍了对家畜表型变异、适应性进化和驯化的生物学解释。在这里，我们结合了比较表观基因组学、全基因组关联研究 (GWAS) 和选择特征分析，以阐明牛的潜在适应性进化。我们交叉映射了从人到牛的 1300 个样本的 8 个组蛋白标记，涵盖了 178 种独特的组织/细胞类型。通过统一分析牛的 723 个 RNA-seq 和 40 个全基因组亚硫酸氢盐测序 (WGBS) 数据集，我们验证了交叉映射的组蛋白标记捕获了组织特异性表达和甲基化，反映了组织相关的生物学。通过将交叉映射的组织特异性组蛋白标记与大规模 GWAS 和选择特征结果相结合，我们首次检测了牛的 45 种经济重要性状和人工选择的相关组织和细胞类型。例如，免疫组织与健康和繁殖特征、产奶和身体构象特征（反映其高度多基因结构）的多种组织以及牛肉和奶牛之间不同选择的甲状腺显着相关。同样，我们检测了人类 58 种复杂性状和疾病的相关组织，并观察到人类的免疫和生育性状与牛的相关组织显着相关，这有助于识别这些性状的因果基因。例如，PIK3CG，一种在单核细胞中高度特异性表达的基因，与人类的绝经年龄和牛的女儿死产显着相关。ICAM 是一种 T 细胞特异性基因，与人类过敏性疾病和牛子宫炎显着相关。总的来说，我们的结果强调了比较表观基因组学与 GWAS 和选择特征分析相结合可以为表型变异和适应性进化提供生物学见解。牛可以作为人类复杂性状的模型，通过提供实验室模式生物之外的额外信息，特别是当在不久的将来出现更多新的表型时。一种 T 细胞特异性基因，与人类的过敏性疾病和牛的子宫炎显着相关。总的来说，我们的结果强调了比较表观基因组学与 GWAS 和选择特征分析相结合可以为表型变异和适应性进化提供生物学见解。牛可以作为人类复杂性状的模型，通过提供实验室模式生物之外的额外信息，特别是当在不久的将来出现更多新的表型时。一种 T 细胞特异性基因，与人类的过敏性疾病和牛的子宫炎显着相关。总的来说，我们的结果强调了比较表观基因组学与 GWAS 和选择特征分析相结合可以为表型变异和适应性进化提供生物学见解。牛可以作为人类复杂性状的模型，通过提供实验室模式生物之外的额外信息，特别是当在不久的将来出现更多新的表型时。