Improved genotype inference reveals cis- and trans-driven variation in the loss-of-heterozygosity rates in yeast

Loss-of-heterozygosity (LOH) events are an important source of genetic variation in diploids and are implicated in cancer. LOH-event rates vary across the genome and across genetic backgrounds, but our understanding of this variation is incomplete. State-of-the-art measurements of LOH rates are obtained from mutation accumulation (MA) experiments in heterozygous hybrids, mainly in yeast Saccharomyces cerevisiae. These measurements hinge on the accuracy of inference of diploid genotypes from short sequencing reads. We analyzed a new large yeast MA dataset and found that the currently standard "single-reference" genotyping approach can lead to errors in LOH-rate estimates and produce spurious homolog biases. To address this problem, we developed a novel genotyping approach for MA experiments that is symmetric with respect to both homologs, removes dubious heterozygous markers, and corrects for undetected LOH events. We report revised estimates of LOH rates across 12 yeast hybrids, which differ by factors between 0.19 and 5.3 from previously published ones. Our revised estimates do not support the previously reported positive correlation between the rate of terminal LOH events and the hybrid heterozygosity. Finally, our analysis reveals that the 60-fold variation in the rates of interstitial LOH events across yeast hybrids is driven overwhelmingly by genetic factors with genome-wide (trans) effects. In contrast, the 6-fold variation in terminal LOH events is driven by both trans and local (cis) factors. Our results provide a foundation for reliable detection of LOH events and further investigations into the genetic underpinnings of LOH-rate variation.