Genome dynamics of a hybrid yeast reveals extensive loss of heterozygosity associated with vegetative divisions

Mutation and recombination are the major sources of genetic diversity in all organisms. In the baker's yeast, all mutation rate estimates are in isogenic backgrounds. We sought to determine the extent of genetic change through mutation and loss of heterozygosity (LOH) in a heterozygous Saccharomyces cerevisiae genome during successive vegetative and meiotic divisions. We measured genome wide LOH and mutational rates associated with vegetative and meiotic divisions in a hybrid (S288c/ YJM789) S. cerevisiae strain. The S288c/YJM789 hybrid showed improved spore viability and nearly complete reduction in heterozygosity within 31 generations of meiosis. LOH in the meiotic lines was driven primarily by the sib-sib mating of spores within the tetrad. The S288c/YJM789 hybrid lines propagated vegetatively for the same duration as the meiotic lines, showed variable LOH (from 2-3% and up to 35%) and maintained spore viability. Two of the vegetative lines with extensive LOH, showed frequent and large internal LOH tracts that suggest a high frequency of mitotic recombination. The average base substitution rates for the vegetative lines (1.82 x 10-10 per base per division) and the meiotic lines (1.22 x 10-10 per base per division), are the first genome wide mutation rate estimates for a hybrid yeast. Vegetative lines with extensive LOH showed more mutations, suggesting a high frequency of mitotic recombination in heterozygous genomes may be mutagenic. These results demonstrate that although mitotic recombination events are infrequent, they can significantly contribute to genetic diversity in heterozygous genomes over a large number of mitotic divisions through extensive LOH. In addition, the hybrid meiotic lines with different heterozygosities were used to create a panel of heterogeneous inbred families (1369 crosses) that are useful for QTL mapping of traits that differ between S288c and YJM789.