The onset of prezygotic and postzygotic barriers to gene flow between 
populations is a hallmark of speciation. One of the earliest postzygotic 
isolating barriers to arise between incipient species is the sterility of the 
heterogametic sex in interspecies' hybrids. Four genes that underlie hybrid 
sterility have been identified in animals: Odysseus, JYalpha, and Overdrive in 
Drosophila and Prdm9 (Meisetz) in mice. Mouse Prdm9 encodes a protein with a 
KRAB motif, a histone methyltransferase domain and several zinc fingers. The 
difference of a single zinc finger distinguishes Prdm9 alleles that cause hybrid 
sterility from those that do not. We find that concerted evolution and positive 
selection have rapidly altered the number and sequence of Prdm9 zinc fingers 
across 13 rodent genomes. The patterns of positive selection in Prdm9 zinc 
fingers imply that rapid evolution has acted on the interface between the Prdm9 
protein and the DNA sequences to which it binds. Similar patterns are apparent 
for Prdm9 zinc fingers for diverse metazoans, including primates. Indeed, 
allelic variation at the DNA-binding positions of human PRDM9 zinc fingers show 
significant association with decreased risk of infertility. Prdm9 thus plays a 
role in determining male sterility both between species (mouse) and within 
species (human). The recurrent episodes of positive selection acting on Prdm9 
suggest that the DNA sequences to which it binds must also be evolving rapidly. 
Our findings do not identify the nature of the underlying DNA sequences, but 
argue against the proposed role of Prdm9 as an essential transcription factor in 
mouse meiosis. We propose a hypothetical model in which incompatibilities 
between Prdm9-binding specificity and satellite DNAs provide the molecular basis 
for Prdm9-mediated hybrid sterility. We suggest that Prdm9 should be 
investigated as a candidate gene in other instances of hybrid sterility in 
metazoans.