Comparative Single‐Cell Transcriptomic Atlas Reveals the Genetic Regulation of Reproductive Traits

ABSTRACT Reproduction is a fundamental biological process regulated by complex cellular and molecular networks across the neuroendocrine and reproductive systems. To explore conserved and species‐specific mechanisms of fertility regulation, we constructed a high‐resolution single‐cell transcriptomic atlas of 15 reproductive and central nervous system (CNS) tissues from sheep and integrated it with human single‐cell datasets from 13 matched tissues. This comparative atlas comprises over 1.09 million cells and identifies 76 major cell types across species. Cross‐species integration based on 15 748 orthologous genes revealed that 54 cell types (71.1%) are shared between sheep and humans, showing strong conservation in transcriptional programs, cell lineage trajectories, and regulatory networks. Integrating genome‐wide association studies (GWAS) for sheep lifetime average litter size with the single‐cell atlas identified crucial fertility‐associated genes and signaling pathways. Cell–cell communication analysis revealed UNC5–SLIT–BMP signaling cascades coordinating neuroendocrine regulation of fertility along the hypothalamus–pituitary–ovary (HPO) axis. Trait–cell type enrichment analyses for 41 human complex traits further demonstrated that conserved reproductive and CNS cell types in sheep recapitulate key human GWAS associations. Together, this cross‐species single‐cell atlas ( https://csca.njau.edu.cn/ ) provides a valuable resource for understanding how conserved cellular programs and inter‐organ signaling networks regulate fertility and other complex traits.