Genetic and Regulatory Basis of Temporal Variation in Complex Traits

Proliferation and metabolism are complex microbial traits controlled by large numbers of genetic loci. Exploiting the power of genome editing technology to control phenotype requires detailed models of how growth traits emerge from the genome. To this end, we have developed technologies to map the genotype-to-phenotype relationship with single-nucleotide resolution in the budding yeast Saccharomyces cerevisiae, using a large, inbred population of over 18,000 genotyped diploid strains. By combining this platform with high-throughput automated phenotyping, we can now measure growth rate across the mapping panel with 3-minute time resolution and capture the genetic basis of the temporal synergies and tradeoffs occurring throughout microbial culture.

In combination with allele-specific expression analyses, detailed time-resolved genetic mapping revealed the widespread contributions of protein-coding, synonymous, and both cis- and trans-acting regulatory variation to phenotype. These effects had pronounced temporal patterns, with some natural variants exhibiting antagonism across different metabolic phases of culture. Cis-acting regulatory variation was pervasive in metabolism and many of these variants made important contributions to phenotype. Enzymes and regulatory proteins each played key roles and opposing cis-regulatory effects at isozymes suggested kinetic tuning through differential expression. Understanding the molecular regulatory basis of complex traits emerging from natural genetic variation will be essential to achieve the potential of genome reading and writing in industry and medicine.