Speciation genes restrict gene flow between the incipient species and related taxa. Three decades ago, we mapped a mammalian speciation gene, hybrid sterility 1 (Hst1), in the intersubspecific hybrids of house mouse. Here, we identify this gene as Prdm9, encoding a histone H3 lysine 4 trimethyltransferase. We rescued infertility in male hybrids with bacterial artificial chromosomes carrying Prdm9 from a strain with the "fertility" Hst1(f) allele. Sterile hybrids display down-regulated microrchidia 2B (Morc2b) and fail to compartmentalize gammaH2AX into the pachynema sex (XY) body. These defects, seen also in Prdm9-null mutants, are rescued by the Prdm9 transgene. Identification of a vertebrate hybrid sterility gene reveals a role for epigenetics in speciation and opens a window to a hybrid sterility gene network.

No abstract

According to the Dobzhansky-Muller model, hybrid sterility is a consequence of the independent evolution of related taxa resulting in incompatible genomic interactions of their hybrids. The model implies that the incompatibilities evolve randomly, unless a particular gene or nongenic sequence diverges much faster than the rest of the genome. Here we propose that asynapsis of heterospecific chromosomes in meiotic prophase provides a recurrently evolving trigger for the meiotic arrest of interspecific F1 hybrids. We observed extensive asynapsis of chromosomes and disturbance of the sex body in >95% of pachynemas of Mus m. musculus × Mus m. domesticus sterile F1 males. Asynapsis was not preceded by a failure of double-strand break induction, and the rate of meiotic crossing over was not affected in synapsed chromosomes. DNA double-strand break repair was delayed or failed in unsynapsed autosomes, and misexpression of chromosome X and chromosome Y genes was detected in single pachynemas and by genome-wide expression profiling. Oocytes of F1 hybrid females showed the same kind of synaptic problems but with the incidence reduced to half. Most of the oocytes with pachytene asynapsis were eliminated before birth. We propose the heterospecific pairing of homologous chromosomes as a preexisting condition of asynapsis in interspecific hybrids. The asynapsis may represent a universal mechanistic basis of F1 hybrid sterility manifested by pachytene arrest. It is tempting to speculate that a fast-evolving subset of the noncoding genomic sequence important for chromosome pairing and synapsis may be the culprit. meiosis | meiotic sex chromosome inactivation | Prdm9 | chromosome substitution strains | Haldane's rule H ybrid sterility (HS) is a postzygotic reproductive isolation mechanism contributing to the genesis of new species. It occurs when two parental forms, each which is fertile, produce a sterile hybrid. The widespread occurrence of HS in animal and plant species puzzled evolutionary biologists until Theodosius Dobzhansky and later Herman Muller devised a two-gene model now termed "Dobzhansky-Muller (D-M) incompatibility" (1, 2). The model postulates functional incompatibility of a minimum of two interacting genes that, after independent evolution in two related taxa, lose their ability to cooperate when combined in a hybrid (3, 4). HS almost invariably obeys the Haldane's rule of preferential impairment of the heterogametic (XY or ZW) sex (5); hence male sterility occurs predominantly in mammalian or Drosophila hybrids, whereas in birds and Lepidoptera female hybrids are most often affected (5, 6). HS is under the control of multiple genes, a disproportionally large number of which are located on the X chromosome (7,8). The development of methods of molecular genetics renewed interest in HS (4), and, as a result, OdsH, Ovd, and JYalpha HS genes defined by their DNA sequence were identified in Drosophila (9-11). We identified Prdm9 as a vertebrate HS gene in mouse intersubspecific hybrids (12, 13). Although generalizati...