IntGenMap · Genetic mapping of complex trait intermediates

Many important traits are heritable, and have a strong genetic component. Numerous genome-wide association studies of common human diseases have corroborated that no single gene explains all or even a large part of their heritable variability. Each effect of a single locus genotype on such a global trait has to be mediated by cellular, tissue, and organ phenotypes. Thus, genetics of intermediate cellular traits is central to developing an understanding of the genetic basis of complex traits. Studies in model organisms, where causality can be addressed by reverse genetic tools, are required for mechanistic understanding of these phenotypes.We aim to develop most powerful ways to understand the mechanism of moderate effect genetic variants in yeast Saccharomyces cerevisiae. The effect of genetic variation is via protein sequence, level, and localisation, as well as metabolite concentrations. Thus, we seek to assay all these traits on large scale to trace the effect of alleles contributing to a global complex fitness phenotype. The measurements will be made from very large pools of genetically diverse individuals using cutting edge assays, measuring either population average in low throughput, or many individuals in medium throughput. We will then compare genetically adapted and reference populations to understand which traits underlie the complex fitness, how the alleles that have moderate effects on the global trait contribute, and where potential targets for modulation lie.This project combines state of the art cellular assays with leading methods for genetic mapping to understand mechanisms behind complex traits. The intermediate traits have not been mapped with high power thus far in any organism. The project will result in a researcher trained at the intersection of quantitative analysis and experimental genomics, and deliver methods for understanding mechanism of alleles with small effect sizes, for both of which there is an acute need.