Our Research Themes

How do mutations affect cell physiology?

Fitness, i.e., the number of offspring that an individual produces, is the most important phenotype because it is what natural selection acts on. It is very hard to predict how a new mutation will affect fitness because fitness is determined by many underlying physiological phenotypes. For example, fitness of a particular yeast cell may depend on how rapidly and efficiently it consumes nutrients, how well it can survive when nutrients are depleted, how effective it is at mating, etc. We measure the effects of different classes of mutations and their combinations on various physiologically important phenotypes (gene expression profiles, life-history traits, etc). We attempt to uncover general principles of how different classes of mutations affect fitness across environments.

How do mutations interact?

How a mutation affects fitness of an individual depends on the presence of other mutations in the genome of that individual. This dependence is termed epistasis. Fitness effects of some adaptive mutations change from one genetic background to another in a predictable way called “diminishing returns epistasis”. We seek to uncover other statistical regularities that govern epistasis beyond “diminishing returns”. We carry out experiments in budding yeast S.cerevisiae to characterize how various classes of mutations interact with each other at the level of fitness in different environments.

hierarchical experimental design

How to predict effects of mutations from first principles?

Many mutations affect cellular metabolism and its regulation, which are fairly well understood in model microorganisms, particularly in E.coli. We are working on combining the classical metabolic control analysis and the recent theory of bacterial proteome partitioning to understand how mutations that perturb metabolic networks affect fitness. One question of particular interest is what organization of these networks leads to the diminishing returns epistasis.

metabolic network cartoon

Our tools

Experimental evolution
experimental evolution cartoon
Mathematical modeling
math cartoon
Sequencing
Sequence alignment cartoon
Yeast genetics
Yeast mating cartoon