ABSTRACT: Background: The Dobzhansky-Muller (D-M) model of speciation by genic incompatibility is widely accepted as the primary cause of interspecific postzygotic isolation. Since the introduction of this model, there have been theoretical and experimental data supporting the existence of such incompatibilities. However, speciation genes have been largely elusive, with only a handful of candidate genes identified in a few organisms. The Saccharomyces sensu stricto yeasts have small genomes, can be easily cultured, and can mate interspecifically to produce sterile hybrids, are thus an ideal model for studying postzygotic isolation. Among them, only a single D-M pair has been found, between S. bayanus and S. cerevisiae, comprising the mitochondrially targeted product of a nuclear gene, AEP2, and a mitochondrially encoded locus, OLI1, the 5' region of whose transcript is bound by Aep2. Thus far, no D-M pair of nuclear genes has been identified between any sensu stricto yeasts. Methods: We report here the first detailed genome-wide analysis of rare F2 progeny from an otherwise sterile hybrid, and show that no classic D-M pairs of speciation genes exist between the nuclear genomes of the closely related yeasts S. cerevisiae and S. paradoxus. Instead, our analyses suggest that more complex interactions may be responsible for their post-zygotic separation. These interactions most likely involve multiple loci having weak effects, as there were multiple significant pairwise combinations of loci, with no single combination being completely excluded from the viable F2s. Conclusions: The lack of a nuclear encoded classic D-M pair between these two yeasts, yet the existence of multiple loci that may each exert a small effect through complex interactions, suggests that initial speciation events might not always be mediated by D-M pairs. An alternative explanation may be that "death by a thousand cuts" leads to speciation, whereby an accumulation of polymorphisms can lead to an incompatibility between the species "transcriptional and metabolic networks, with no single pair at least initially being responsible for the incompatibility. After such a speciation event, it is possible that one or more D-M pairs might subsequently arise following isolation. Genotypes for hybrids between S. cerevisiae and S. paradoxus. A genotyping experiment design type classifies an individual or group of individuals on the basis of alleles, haplotypes, SNP's.
