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The Dobzhansky-Muller model of incompatibilities explains reproductive isolation between species by incorrect epistatic interactions. Although the mechanisms of speciation are of great interest, no incompatibility has been characterized at the gene level in mammals. The  Hybrid sterility 1  gene ( Hst1 ) participates in the arrest of meiosis in F 1  males of certain strains from two  Mus musculus  subspecies, e.g., PWD from  M. m. musculus  and C57BL/6J (henceforth B6) from  M. m. domesticus .  Hst1  has been identified as a meiotic PR-domain gene ( Prdm9 ) encoding histone 3 methyltransferase in the male offspring of PWD females and B6 males, (PWD×B6)F 1 . To characterize the incompatibilities underlying hybrid sterility, we phenotyped reproductive and meiotic markers in males with altered copy numbers of  Prdm9 . A partial rescue of fertility was observed upon removal of the B6 allele of  Prdm9  from the azoospermic (PWD×B6)F 1  hybrids, whereas removing one of the two  Prdm9  copies in PWD or B6 background had no effect on male reproduction. Incompatibility(ies) not involving  Prdm9 B6   also acts in the (PWD×B6)F 1  hybrids, since the correction of hybrid sterility by  Prdm9 B6   deletion was not complete. Additions and subtractions of  Prdm9  copies, as well as allelic replacements, improved meiotic progression and fecundity also in the progeny-producing reciprocal (B6×PWD)F 1  males. Moreover, an increased dosage of  Prdm9  and reciprocal cross enhanced fertility of other sperm-carrying male hybrids, (PWD×B6-C3H. Prdm9 )F 1 , harboring another  Prdm9  allele of  M. m. domesticus  origin. The levels of  Prdm9  mRNA isoforms were similar in the prepubertal testes of all types of F 1  hybrids of PWD with B6 and B6-C3H. Prdm9  despite their different prospective fertility, but decreased to 53% after removal of  Prdm9 B6  . Therefore, the  Prdm9 B6   allele probably takes part in posttranscriptional dominant-negative hybrid interaction(s) absent in the parental strains.

Interallelic and Intergenic Incompatibilities of the Prdm9 (Hst1) Gene in Mouse Hybrid Sterility