Z. Meng, S. Zhang, Z. Zhuang, J. He, F. Liu, L. Wu, X. Sun, J. Lu, X. Li, H. Yang, M. Gong, X. Du, Q. Mei, H. Li, G. Zhang, X. He, J. He, X. Guo, S. Nie, X. Zhang, M. Shan, J. Yang, X. Li, H. Yang, Y. Hu, Y. He, S. Tian, X. Wu, X. Wu, K. Zhan, M. Wang, X. Lu, H. Zhou, G. Zhao, P. Zhao, Y. Ling, C. Ren, Y. Yang, X. Zhang, Y. Jiang, W. Wu, R. Xiang, R. P. M. A. Crooijmans, O. Madsen, D. E. MacHugh, K. G. Daly, E. L. Clark, L. Fang, Z. Zhang, M. Chu, D. Guan, Z. Pan
Non-coding regulatory variation drives complex traits, domestication, and evolutionary adaptation, yet the sheep genome lacks high-resolution functional annotation. Here we present SheepEpimap, a multi-tissue regulatory atlas harmonizing 516 CUT&Tag histone modifications, ATAC-seq, and RNA-seq datasets across 43 adult tissues in sheep. We annotated 2.93 million cis-regulatory elements, yielding 557,441 enhancer-gene pairs and 145,407 variants with allele-specific effects. By training a sequence-to-function deep-learning model, we decoded the base-pair syntax of chromatin accessibility, annotated transcription factor motif instances genome-wide, and constructed 12,210 tissue-specific gene regulatory networks (GRNs). Integrating this resource with multi-tissue expression quantitative trait loci, selection sweeps, and genome-wide association studies prioritized non-coding variants driving domestication and complex traits. Finally, cross-species analysis revealed that sequence-conserved, tissue-matched enhancers were significantly enriched in the heritability of complex traits and diseases in humans. In summary, SheepEpimap (https://genome.ucsc.edu/s/mengzhu/SheepEpimap) provides an open-access foundational ecosystem for sheep functional genomics, precision breeding, and comparative biology.