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

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.