Comprehensive functional genome annotation is crucial to elucidate the molecular mechanisms of agronomic traits in livestock, yet systematic functional annotation of the sheep genome is lacking. Here, we generated 92 transcriptomic and epigenomic datasets from nine tissues, along with whole-genome data from 2357 individuals across 29 breeds worldwide, and 4006 phenotypic data related to tail fat weight. We constructed the first multi-tissue epigenome atlas in terms of functional elements, chromatin states and their functions, and explored the utility of the functional elements in interpreting phenotypic variation during sheep domestication and improvement. Particularly, we identified a total of 753,723 non-redundant functional elements, with over 60% being novel. We found tissue-specific promoters and enhancers related to sensory abilities and immune response that were highly enriched in genomic regions influenced by domestication, while rumen and tail fat tissue-specific active promoters and enhancers were highly enriched in genomic regions influenced by breeding and improvement. Notably, a variant, Chr13:51760995A>C, located in an enhancer region regulating bone morphogenetic protein 2 expression, was identified as a causal variant for tail fat deposition based on multi-layered datasets. Overall, this research provides foundational resources and a successful case for future investigations of complex traits in sheep through the integration of multi-omics datasets.

Multi-omics, Epigenomics, Regulatory elements, GWAS, Sheep