Estimating the distribution of fitness effects of loss of heterozygosity (LOH) events using an engineered library of Saccharomyces cerevisiae.

Loss of heterozygosity (LOH) is a large contributor of genetic variation in natural populations or lab-evolved asexual diploids. However, its contribution to adaptation is uncertain, because the full spectrum of its fitness effects remains largely uncharacterized. To systematically investigate the distribution of fitness effects (DFE) of LOH, we engineered a diverse, barcoded library of heterozygous diploid Saccharomyces cerevisiae strains, each containing randomly induced LOH events. By employing competitive fitness assays and barcode sequencing (Bar-seq) across seven distinct environments, including various stressors from chemicals, temperature, and an in vivo host model, we quantified the fitness consequences of LOH events. Our results reveal that the DFE of LOH is predominantly neutral to deleterious, with a general trend of decreasing fitness correlated with larger cumulative lengths of LOH tracts. However, the fitness effects were variable and the fitness landscape was highly environment-dependent. While beneficial LOH events were rare and of small effect in standard rich media, they were common and conferred substantial fitness gains in novel or stressful conditions. A key finding was the prevalence of antagonistic pleiotropy where over 75% of strains exhibited fitness trade-offs, gaining an advantage in one environment at the cost of fitness in others. The magnitude of these trade-offs was also found to correlate with longer LOH tracts. Overall, this work demonstrates that LOH plays a dual role in evolution. While it often imposes a genetic burden, it also provides a powerful mechanism for rapid, environment-specific adaptation, driving specialization by trading general robustness for niche-specific advantages.