背景:在过去的十年中,通过在全基因组关联研究(GWAS)中检测遗传变异,已经对人类和牲畜物种的复杂性状和疾病的遗传基础进行了深入的研究。大多数这样的变异位于非编码基因组区域,尽管在驯养动物的多个组织中已经预测到许多调控元件(RE)的参与,它们的进化保守性和对复杂性状的影响尚未完全阐明,尤其是反刍动物。这里,我们系统分析了六种哺乳动物的137个表观基因组和转录组数据集,包括牛,绵羊,山羊,猪,老鼠,和人类,然后将它们与复杂性状的大规模GWAS进行整合。
结果:使用H3K4me3和H3K27ac的40个ChIP-seq数据集,我们在牛的肝脏中检测到68,479,58,562,63,273,97,244,111,881和87,049REs,绵羊,山羊,猪,人类和老鼠,分别。然后,我们通过整合多组学数据集来系统地表征这些RE的动态功能景观,包括基因表达,染色质可及性,和DNA甲基化。我们确定了与肝脏发育有关的反刍动物特异性REs的核心集(n=6359),新陈代谢,和免疫过程。具有更复杂的顺式RE的基因在物种中表现出更高的基因表达水平和更强的保守性。此外,我们整合了牛和人类44和52个复杂性状/疾病的表达数量性状基因座(eQTLs)和GWAS,分别。这些结果表明,跨物种具有不同程度的进化保守性的REs对复杂性状的GWAS信号表现出明显的富集。
结论:我们系统地注释了六种哺乳动物肝脏中的全基因组功能性REs,并证明了REs的进化及其与转录输出和保守性的关联。检测谱系特异性REs使我们能够破译牲畜和人类复杂表型的进化和遗传基础,这可能有利于发现特定人类疾病的功能变体和基因的潜在生物医学模型。
Insights into the genetic basis of complex traits and disease in both human and livestock species have been achieved over the past decade through detection of genetic variants in genome-wide association studies (GWAS). A majority of such variants were found located in noncoding genomic regions, and though the involvement of numerous regulatory elements (REs) has been predicted across multiple tissues in domesticated animals, their evolutionary conservation and effects on complex traits have not been fully elucidated, particularly in ruminants. Here, we systematically analyzed 137 epigenomic and transcriptomic datasets of six mammals, including cattle, sheep, goats, pigs, mice, and humans, and then integrated them with large-scale GWAS of complex traits.
Using 40 ChIP-seq datasets of H3K4me3 and H3K27ac, we detected 68,479, 58,562, 63,273, 97,244, 111,881, and 87,049 REs in the liver of cattle, sheep, goats, pigs, humans and mice, respectively. We then systematically characterized the dynamic functional landscapes of these REs by integrating multi-omics datasets, including gene expression, chromatin accessibility, and DNA methylation. We identified a core set (n = 6359) of ruminant-specific REs that are involved in liver development, metabolism, and immune processes. Genes with more complex cis-REs exhibited higher gene expression levels and stronger conservation across species. Furthermore, we integrated expression quantitative trait loci (eQTLs) and GWAS from 44 and 52 complex traits/diseases in cattle and humans, respectively. These results demonstrated that REs with different degrees of evolutionary conservation across species exhibited distinct enrichments for GWAS signals of complex traits.
We systematically annotated genome-wide functional REs in liver across six mammals and demonstrated the evolution of REs and their associations with transcriptional output and conservation. Detecting lineage-specific REs allows us to decipher the evolutionary and genetic basis of complex phenotypes in livestock and humans, which may benefit the discovery of potential biomedical models for functional variants and genes of specific human diseases.