Genetic Architecture of Highly Complex Chemical Resistance Traits across Four Yeast Strains

Abstract

Many questions about the genetic basis of complex traits remain unanswered. This is in part due to the low statistical power of traditional genetic mapping studies. We used a statistically powerful approach, extreme QTL mapping (X-QTL), to identify the genetic basis of resistance to 13 chemicals in all 6 pairwise crosses of four ecologically and genetically diverse yeast strains, and we detected a total of more than 800 loci. We found that the number of loci detected in each experiment was primarily a function of the trait (explaining 46% of the variance) rather than the cross (11%), suggesting that the level of genetic complexity is a consistent property of a trait across different genetic backgrounds. Further, we observed that most loci had trait-specific effects, although a small number of loci with effects in many conditions were identified. We used the patterns of resistance and susceptibility alleles in the four parent strains to make inferences about the allele frequency spectrum of functional variants. We also observed evidence of more complex allelic series at a number of loci, as well as strain-specific signatures of selection. These results improve our understanding of complex traits in yeast and have implications for study design in other organisms.

Author Summary

Most heritable traits of agricultural, evolutionary, and medical significance are specified by multiple genetic loci. Despite decades of research, we have only a limited understanding of the genetic basis of such complex traits. Studies in model organisms have the potential to provide fundamental insights into this research area, but most genetic mapping studies in these species have had low statistical power to detect multiple loci with small effects. Using a technique in which we employed millions of cross progeny in genetic mapping, we previously showed that resistance to chemicals has a highly complex genetic basis in a cross of a lab strain and a wine strain of the budding yeast Saccharomyces cerevisiae. Because we only examined a single cross, it was unclear how general our findings were. Here, we expand our work to all six possible crosses of four strains—the two isolates we used in our last study, as well as an isolate from an immunocompromised human being and an isolate from the sap of an oak tree. Our results based on these four ecologically and genetically distinct S. cerevisiae strains suggest that resistance to chemicals commonly exhibits a highly complex genetic basis among yeast isolates.