Hybrid female sterility due to cohesin protection errors in mouse oocytes

TL;DR

This study shows that hybrid female sterility in mice is caused by errors in chromosome separation during meiosis due to cohesin misregulation.

Contribution

The paper identifies cohesin protection errors as a novel mechanism for hybrid female sterility in mammals.

Findings

Hybrid female sterility in mice is caused by homologous-chromosome separation failure during oocyte meiosis.

Mislocalization of SGO2 and increased BUB1 activity lead to cohesin overprotection in hybrid oocytes.

Cohesion defects are also observed in Peromyscus hybrids, showing a broader role in speciation.

Abstract

Hybrid incompatibility can lead to lethality and sterility of F1 hybrids, promoting speciation. The cell biological basis underlying hybrid incompatibility remains largely unknown, especially in mammals. Here, we found that female hybrids between Mus musculus domesticus and Mus spicilegus mice are sterile due to the failure of homologous-chromosome separation in oocyte meiosis, producing aneuploid eggs. This nondisjunction phenotype was driven by the mislocalization of the cohesin protector, SGO2, along the chromosome arms instead of its typical centromeric enrichment, resulting in cohesin overprotection. The upstream kinase, BUB1, showed a higher activity in hybrid oocytes, explaining SGO2 mistargeting. Higher BUB1 activity was not observed in mitosis, consistent with viable hybrid mice. Cohesion defects were also evident in hybrid mice from another genus, Peromyscus, wherein cohesin protection is weakened. Defective cohesion in oocytes is a leading cause of reduced fertility. Our work provides evidence that a major cause of human infertility may play a positive role in mammalian speciation.

Misregulation of chromosome cohesion during female meiosis serves as a reproductive isolating barrier in mice.

Figures