Pervasive context-dependent effects in the genetic architecture of complex and quantitative traits revealed by a...

The genetic dissection of complex traits remains a major challenge in basic and biomedical research, but is essential for understanding the molecular pathways that shape phenotypic variation and for developing predictive models of trait and disease susceptibility. Here, we leverage a novel multiparent mapping population of budding yeast, CYClones, comprising 9,344 haploid strains derived from eight genetically diverse founders, to identify quantitative trait loci (QTL) and systematically investigate the genetic architecture of growth rates across ten environmental conditions. In total, we identified 349 QTL (ranging from 19 to 49 QTL per growth condition) that explained between 61% and 100% of narrow sense heritability across traits. The high power and resolution of CYClones revealed that growth traits exhibited distinct, condition-specific genetic architectures with extensive allelic heterogeneity, where a QTL was the result of multiple tightly linked causal variants. We also observed pleiotropy among QTL with complex, trait-dependent allele effects that are also consistent with allelic heterogeneity. Genetic complexity varied widely, with some traits showing nearly Mendelian architectures, while others were highly polygenic. Introgressed loci played a prominent role in the landscape of growth rate QTL, including one that is localized to a 2.4 kb interval in the PCA1 cadmium transporter and explains 72% of variation in cadmium resistance and another large-effect QTL that alters growth on galactose via complex non-additive interactions with the transcriptional regulator GAL3. In both cadmium and galactose conditions, we show that allelic variation at a small number of loci stratifies the population into regulatory or physiological subgroups, each with distinct genetic architectures, a phenomenon we term allele-dependent stratification. Collectively, our results provide novel insights into the genetics of growth rates in budding yeast, the architectural features of genetic complexity, and demonstrate that CYClones is a powerful platform for revealing the molecular basis of complex trait variation.