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

## TL;DR

This study creates a detailed map of reproductive and brain cells in sheep and humans, revealing shared genetic programs that control fertility.

## Contribution

The study introduces a cross-species single-cell atlas linking sheep and human reproductive and CNS tissues with GWAS data to uncover conserved fertility mechanisms.

## Key findings

- 76 major cell types were identified across 15 tissues in sheep and humans, with 54 shared cell types showing strong conservation.
- UNC5–SLIT–BMP signaling was found to coordinate neuroendocrine regulation of fertility along the HPO axis.
- Conserved cell types in sheep recapitulate key human GWAS associations for complex 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.

A cross‐species single‐cell transcriptomic atlas of reproductive and central nervous system tissues from sheep and humans reveals conserved cellular programs and regulatory networks that regulated fertility. Integration with GWAS for sheep lifetime average litter size identifies UNC5–SLIT–BMP signaling as a core pathway coordinating neuroendocrine–ovarian communication, providing a valuable resource for dissecting the genetic regulation of reproduction.