Biology subjects

Kern, A. F.

Publications and source records attributed to Kern, A. F..

2 recordsLinked to original sources

bioRxiv2022

Gene-by-environment interactions are pervasive among natural genetic variants

Gene-by-Environment (GxE) interactions are fundamental to understanding fitness landscapes and evolution, but have been difficult to identify at the single-nucleotide level, precluding understanding of their prevalence and molecular mechanisms. Most examples involving natural genetic variants exist at the level of entire genomes, e.g. measurement of microbial strain growth across environments, or loci encompassing many variants identified by quantitative trait loci mapping. Here, we introduce CRISPEY- BAR, a high-throughput precision-editing strategy, and use it to map base-pair resolution GxE interactions impacting yeast growth under stress conditions. First, we used CRISPEY-BAR to uncover 338 variants with fitness effects within QTLs previously mapped in different environments. We then measured 1432 ergosterol pathway variants from diverse lineages across six environments, identifying 205 natural variants affecting fitness measured in all six conditions, of which 93.7% showed GxE interactions. Finally, we examine pleiotropic cis-regulatory variants suggesting molecular mechanisms of GxE interaction. In sum, our results suggest an extremely complex, context-dependent fitness landscape characterized by pervasive GxE interactions, while also demonstrating high- throughput genome editing as an effective means for investigating this complexity.

genomics↗

bioRxiv2022

Widespread epistasis among beneficial genetic variants revealed by high-throughput genome editing

Genetic interactions occur when a variants phenotypic effect is altered by variation at other genomic loci. Also known as epistasis, these interactions shape the genetic architecture of complex traits and modify phenotypes across genetic backgrounds. However, the factors associated with their occurrence remain poorly understood. To investigate this, we employed high-throughput genome editing to measure the fitness effects of 1,826 naturally polymorphic variants in four genetically diverse strains of Saccharomyces cerevisiae. About 31% of variants affect fitness in a common laboratory environment, of which 24% have strain-specific fitness effects indicative of epistasis. We found that beneficial variants are more likely to exhibit genetic interactions, and that genetic interactions are depleted among variants at higher allele frequencies. In addition, we demonstrate that these epistatic interactions for fitness can be mediated by specific traits such as flocculation ability. This work suggests that adaptive evolution from standing variation will often involve trade-offs where a variant is only beneficial in some genetic backgrounds, potentially explaining why many beneficial variants remain polymorphic. In sum, we provide a framework to understand the factors influencing epistasis in natural genetic variants with single-nucleotide resolution, revealing widespread epistasis among beneficial variants.

genomics↗