Hybrid sterility with meiotic metaphase arrest in intersubspecific mouse crosses.

Risako Nishino
Sabrina Petri
Mary Ann Handel, The Jackson Laboratory
Tetsuo Kunieda
Yasuhiro Fujiwara

We are indebted to the members of the Kunieda, Handel and Okada laboratories, particularly Dr. Tanmoy Bhattacharyya, for the discussion of this work in progress. We thank Drs. Tanmoy Bhattacharyya, Yuki Okada, Laura Reinholdt, Beverly Richards-Smith and Hiroki Shibuya for their review on this manuscript.


Although organisms belonging to different species and subspecies sometimes produce fertile offspring, a hallmark of the speciation process is reproductive isolation, characterized by hybrid sterility (HS) due to failure in gametogenesis. In mammals, HS is usually exhibited by males, the heterogametic sex. The phenotypic manifestations of HS are complex. The most frequently observed are abnormalities in both autosomal and sex chromosome interactions that are linked to meiotic prophase arrest or post-meiotic spermiogenesis aberrations and lead to defective or absent gametes. The aim of this study was to determine the HS phenotypes in intersubspecific F1 mice produced by matings between Mus musculus molossinus-derived strains and diverse Mus musculus domesticus-inbred laboratory mouse strains. Most of these crosses produced fertile F1 offspring. However, when female BALB/cJ (domesticus) mice were mated to male JF1/MsJ (molossinus) mice, the (BALBdomxJF1mol)F1 males were sterile, whereas the (JF1molxBALBdom)F1 males produced by the reciprocal crossings were fertile; thus the sterility phenotype was asymmetric. The sterile (BALBdomxJF1mol) F1 males exhibited a high rate of meiotic metaphase arrest with misaligned chromosomes, probably related to a high frequency of XY dissociation. Intriguingly, in the sterile (BALBdomxJF1mol)F1 males we observed aberrant allele-specific expression of several meiotic genes, that play critical roles in important meiotic events including chromosome pairing. Together, these observations of an asymmetrical HS phenotype in intersubspecific F1 males, probably owing to meiotic defects in the meiotic behavior of the XY chromosomes pair and possibly also transcriptional misregulation of meiotic genes, provide new models and directions for understanding speciation mechanisms in mammals.