# Divergent Amplification of Y-Linked Dosage-Sensitive Genes Triggers Regulatory Mismatch Underlying Cattle–Yak Male Sterility

## TL;DR

Male cattle–yaks are sterile due to Y chromosome gene amplification differences between cattle and yaks.

## Contribution

A near-complete yak Y chromosome assembly and a novel regulatory mismatch model for hybrid male sterility.

## Key findings

- Yaks have a greater expansion of Y-linked ampliconic genes compared to cattle.
- Yak Y genes show 2-to-4-fold higher transcriptional activity in spermatogenesis-related genes.
- A 'cis-trans regulatory mismatch' model is proposed to explain cattle–yak male sterility.

## Abstract

As the hybrid offspring of cattle and yak, cattle–yaks suffer from male sterility, manifesting as cascading spermatogenic failure. Despite the Y chromosome’s pivotal role in spermatogenesis, the absence of a high-quality yak Y assembly has long impeded mechanistic understandings from this perspective. Here, a near-complete 42.4 Mb yak Y chromosome is constructed through a multi-stage assembly strategy that integrates de novo assembly with pangenome graph construction and Hi-C guided refinement. By developing a rigorously standardized gene annotation pipeline for precise cross-species comparison, we find that yaks have undergone a greater expansion of Y-linked ampliconic genes than cattle. Integrating this ampliconic landscape with short-read and full-length transcriptomics further demonstrates that yaks exhibit a drastic 2-to-4-fold increase in transcriptionally active copies of spermatogenesis-related ampliconic genes (including TSPY1, ZNF280BY, HSFY and PRAMEY) relative to cattle. Given negligible homology outside the pseudoautosomal region and conservation of key meiotic proteins, we propose a ‘cis-trans regulatory mismatch’ model driven by divergent Y-linked amplification as a working hypothesis to explain the primary genetic mechanism of cattle–yak male sterility. Together, these findings offer critical insights for addressing cattle–yak male sterility and establish the Y chromosome as an active driver of reproductive isolation beyond its traditional degenerate characterization.