X-linked small GTPase and OXPHOS genes are candidates for the genetic basis of hybrid inviability in Drosophila.

Genetic studies on postmating reproductive isolation in Drosophila have suggested that the genetic basis of hybrid inviability is much less complex than the basis of hybrid sterility, and may be associated with defects affecting the cell cycle. Here I report the identification of a cluster of genes in the middle of the X chromosome of D. melanogaster, which may be responsible for the inviability of hybrids between Drosophila species. Genes from this cluster code for small Ras GTPases proteins, which are hypothesized here to interact with proteins involved in oxidative phosphorylation (OXPHOS), encoded by genes present within the same cluster. At least six genes influencing small Ras GTPases/OXPHOS activity are transcribed from the same strand across 35 kb genomic DNA. This interval is predicted to harbor genes which, when mutated, rescue otherwise inviable hybrids between D. melanogaster and its three most closely related species. Moreover, a total of 16 small GTPase/OXPHOS genes are found within 530 kb genomic DNA encompassing the above cluster. In D. melanogaster mutants which fully rescue lethal hybrids, major lesions have now been identified very near or within untranslated regions of two OXPHOS genes from the above cluster. These observations led to a hypothesis focusing on antagonistic co-evolution between biparentally inherited genes influencing putative GTPase/OXPHOS activity and mitochondrial genes encoding OXPHOS proteins. Alterations in some of these genes are postulated to override hybrid inviability, thus revealing a pathway which implicates mitotic genes as critical players in this barrier to reproduction.