UC San Diego

In this thesis, I develop a high-throughput framework to systematically identify beneficial genetic perturbations relative to a wild-type strain using an ultra-high density colony array. I applied the method to measure the fitness of ~8000 deletion and overexpression mutants across 6 metabolic conditions after growth on either an environment supplemented with all amino acids or an amino acid limited environment. I identified a set of genes corresponding to the respiration pathway, specifically the pyruvate dehydrogenase (PDH) complex, whose loss of function increases fitness. This phenomenon is involved in cancer pathogenesis and contributes to the Warburg effect. We find that the beneficial growth effect of loss of PDH function is only present under amino acid limited environments, which could suggest conditional requirements for beneficial events in cancer.

I also found that the environmental history experienced by the cell affects the process of adaptation to a novel environment and can lead to a beneficial growth effect. Although this is a transient process, it is further evidence for the role of epigenetic inheritance in determining evolutionary outcome.