Leveraging the genotype-phenotype relationship to understand the traditional and novel facets of cell biology

Genotypes and phenotypes form two fundamentally different levels of biological abstraction. The challenge has been to understand how they articulate with each other. In how genotypes map onto phenotypes by perturbing cellular networks. Furthermore, how phenotypes interact with the organism’s environment to map back onto the genotype via forces of natural selection. In our effort to explore the genotype-phenotype relationship we will first present work where we developed an experimental and analytical tool that makes observing subtle changes in phenotype in high-throughput more accurate. Then we will present work that employed the power of forward genetics to examine an unexpected phenotype that defied decades of established research. This phenotype was eventually found to be context-dependent and led to the discovery of an alternate enzyme encoded by a previously uncharacterized gene. We will then transition from the established to the evolutionarily novel and review why yeast, Saccharomyces cerevisiae in particular, serves as a crucial model organism for probing the birth of new genes from scratch. Finally, in this dissertation, we will utilize the techniques of reverse genetics to investigate the phenotypic impact of evolutionarily novel sequences (proto-genes). We will also present a detailed analysis of how a prototypical proto-gene might be interacting with existing cellular processes. The focus of this dissertation extends across established and novel cellular systems. It represents a comprehensive exploration of the genotype-phenotype relationship by employing a systems biology approach. This wholistic exploration has resulted in vital insights to the broader realms of genetics and evolutionary biology.