Complexity_of_genetic_incompatibility

On the molecular level, speciation takes place via accumulation of mutations that lead to genetic incompatibilities. The alleles can be incompatible during meiosis (e.g. chromosome segregation errors due to different karyotypes), or in the gametes (e.g. a complement of loss-of-function alleles that fails to carry out an essential task). There is a veritable debate in the genetic complexity of such incompatibilities. A model due to Orr[1] posits that speciation mainly proceeds via combinations of variants in three or more genes, but this has not been explicitly tested yet. Here, we propose to low coverage sequence a large number of meiotic progeny of all pairwise crosses of four yeast strains in order to explicitly test the Orr model. We are generating 1,500 segregants from each of six crosses between African, Japanese, European, and North American wild yeast strains, and are looking to test for presence of two- and three-allele combinations that are underrepresented in the viable ones. This design also has sufficient power to estimate the variance in spore viability due to interactions of different orders. As four gametes are isolated from the same meiotic event, inviable genotypes can be inferred, and one of the most detailed view of the meiotic recombination landscape is generated as a byproduct. The complete genome sequence of the parental strains will allow to investigate how recombination is affected by both sequence and structural variation. We are looking to sequence genomic DNA of 1,500 meiotic progeny from each of 6 pairwise crosses (9,000 yeast strains total) to up to 10x coverage. The library preparation can take place in high throughput, taking advantage of the single cell facility automation, and low volume protocols. 1. Orr, H. A. (1995). The Population Genetics of Speciation: The Evolution of Hybrid Incompatibilities. Genetics 139(4), 1805-1815.