Although organisms belonging to different subspecies sometimes produce fertile offspring, a hallmark of the speciation process is reproductive isolation, with 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, but most frequently manifested as abnormalities during meiotic prophase, or aberrations in post-meiotic spermiogenesis, all leading 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 and diverse Mus musculus domesticus classical 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, while the (JF1molxBALBdom)F1 males produced by the reciprocal cross were fertile; thus the sterility phenotype is asymmetric. The sterile (BALBdomxJF1mol)F1 males exhibited a high rate of meiotic metaphase arrest with misaligned chromosomes, likely related to a high frequency of XY dissociation. Intriguingly, in the sterile (BALBdomxJF1mol)F1 males we observed aberrant expression of the Spo11 gene, encoding a meiosis-specific endonuclease playing a critical role in recombination and thereby affecting chromosome pairing. Together, these observations of an asymmetrical HS phenotype in intersubspecific F1 mice, causing misregulation of Spo11 gene expression and subsequent meiotic segregation defects of the XY chromosomes, provide new directions for understanding mechanisms leading to speciation in mammals.
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