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

## TL;DR

This study explores how loss of heterozygosity (LOH) affects yeast fitness in different environments, revealing that LOH can be both harmful and beneficial depending on the context.

## Contribution

The study introduces a novel engineered library of yeast strains with random LOH events to directly measure their fitness effects before natural selection acts.

## Key findings

- LOH events are mostly neutral or harmful but can be beneficial in stressful environments.
- Most strains exhibit antagonistic pleiotropy, gaining fitness in one environment while losing it in another.
- Longer LOH tracts are associated with greater fitness trade-offs and environment-specific adaptation.

## Abstract

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.

Loss of heterozygosity (LOH) is a common genetic process in diploid organisms, where one allele of a gene on one chromosome is replaced by a duplicate copy of the allele from the other chromosome. Although LOH occurs frequently as diploid cells divide, our understanding of its effects is limited, because most studies focus on events that have already been filtered by natural selection. To fully capture both the beneficial and detrimental effects LOH may generate, we engineered a mutant library of the baker’s yeast Saccharomyces cerevisiae containing with randomly induced LOH events. Unlike traditional methods, our approach allowed us to measure the immediate consequences of these changes across the genome before they were lost to natural selection. By testing these strains across various environments, we found that while LOH is often deleterious or neutral, it can be a source of beneficial genetic variation depending on the environmental context. We observed a high prevalence of trade-offs associated with LOH, where strains gained an advantage in one environment at the cost of fitness in others. These findings suggest that LOH is capable of facilitating rapid adaptation as a form of short-sighted evolution and specialization.