A multi-tissue epigenomic atlas links the sheep non-coding genome to domestication and complex traits

Meng, Z.; Zhang, S.; Zhuang, Z.; He, J.; Liu, F.; Wu, L.; Sun, X.; Lu, J.; Li, X.; Yang, H.; Gong, M.; Du, X.; Mei, Q.; Li, H.; Zhang, G.; He, X.; Guo, X.; Nie, S.; Zhang, X.; Shan, M.; Yang, J.; Hu, Y.; He, Y.; Tian, S.; Wu, X.; Zhan, K.; Wang, M.; Lu, X.; Zhou, H.; Zhao, G.; Zhao, P.; Ling, Y.; Ren, C.; Yang, Y.; Jiang, Y.; Wu, W.; Xiang, R.; Crooijmans, R. P. M. A.; Madsen, O.; MacHugh, D. E.; Daly, K. G.; Clark, E. L.; Fang, L.; Zhang, Z.; Chu, M.; Guan, D.; Pan, Z.

doi:10.64898/2026.08.22.746371

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bioRxiv · 10.64898/2026.08.22.746371

A multi-tissue epigenomic atlas links the sheep non-coding genome to domestication and complex traits

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Abstract

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.

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Meng, Z., Zhang, S., Zhuang, Z., He, J., Liu, F., Wu, L., Sun, X., Lu, J., Li, X., Yang, H., Gong, M., Du, X., Mei, Q., Li, H., Zhang, G., He, X., Guo, X., Nie, S., Zhang, X., Shan, M., Yang, J., Hu, Y., He, Y., Tian, S., Wu, X., Zhan, K., Wang, M., Lu, X., Zhou, H., Zhao, G., Zhao, P., Ling, Y., Ren, C., Yang, Y., Jiang, Y., Wu, W., Xiang, R., Crooijmans, R. P. M. A., Madsen, O., MacHugh, D. E., Daly, K. G., Clark, E. L., Fang, L., Zhang, Z., Chu, M., Guan, D., Pan, Z.. 2026-08-26. A multi-tissue epigenomic atlas links the sheep non-coding genome to domestication and complex traits. https://doi.org/10.64898/2026.08.22.746371

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