Complex trait analysis with a multi-species approach to disentangle genetic modulators of cellular growth phenotypes under disease-relevant treatments

Complex traits are phenotypes that are described quantitatively and typically have intricate polygenic inheritance. Herein, the cellular growth under genotoxic and mitochondrial-induced oxidative stress, which underlie tumorigenesis and Parkinson’s Disease, were studied as complex traits. It was hypothesized that advanced yeast complex trait mapping could be developed and employed to study these traits.

The yeast population was based on four wild budding yeast isolates, which parented the F12 advanced intercrossed line (AIL). 111 AIL haploids were used in the QTL (Quantitative Trait Locus) -mapping study for growth phenotypes under DNA-damaging, rapamycin and paraquat treatments. Linkage analysis revealed fine-mapped QTLs for each treatment. The growth responses and emerging QTL outputs were mostly unique to each agent. Analysis of AIL growth per allele validated QTL-genes and evidenced mechanisms of phenotype modulation through synonymous SNPs, cis- and trans-regulatory element variation and QTL-QTL interactions. Gene deletion phenotyping in the founders validated 12 genes mapped in 12 QTLs. In-depth exploration was performed on MNN14, PMT2 and GUD1 gene-hits.

(a) MNN14/FKTN - PMT2/POMT2 and (b) MNN14/flyFukutin and GUD1/DhpD were investigated through single-gene knock-down in neuronal models of (a) SH-SY5Y cells and (b) Drosophila, respectively. For example, FKTN and POMT2 was shown to promote neuronal differentiation and protect against DNA damage, respectively. In flies, the knock-down of either gene decreased longevity in a wild-type background. flyFKTN knock-down improved α-synuclein longevity defects and significantly suppress the post-paraquat exposure climbing phenotype.

Overall, our cross-species study evidenced that QTL yeast analysis could identify conserved genes with modifying effects in human cell and Drosophila disease models. However, for the same gene homologue, the yeast-study did not directly predict the other eukaryote’s phenotypes. To provide clinically applicable findings, yeast-based QTL discovery studies may be followed by validation in models closer to human diseases.