Merging Molecular Mechanism and Evolution: Theoretical Concepts and Experimental Explorations of Biophysical Fitness Landscapes

EUGENE SHAKHNOVICH, HARVARD UNIVERSITY

Fitness landscape (FL) is a common metaphoric description of genotype-phenotype relationship. However its precise nature is not known: “Axes” on the pictorial presentations of FL remain unlabeled. In this talk I will present our theoretical and experimental efforts, to outline FL of viruses and bacteria in terms of biophysical properties of their proteins such as thermodynamic stability, catalytic activity and intracellular abundances as well as functional and non-functional interactions with other proteins. We develop computational multiscale models where the link between effects of mutations on molecular properties of proteins and fitness is derived from general physical-chemical principles guiding protein folding and protein-protein interactions. Experimental approaches aim to test and improve assumptions of multiscale evolutionary models. In our “bottom up” experiments genome editing is used to introduce rational genetic variation in ORFs of essential genes dihydrofolate reductase and adenylate kinase on E. coli chromosome. The effects of genetic variation on biophysical properties of proteins are then mapped to changes in fitness of edited strains. We show how genetic variation propagates on all scales including responses by Protein Quality Control that creates a major fitness barrier to horizontal transfer of “foreign’’ genes. Metabolomic, genomic and proteomic comparative analyses of “naïve” genomically edited and evolved strains highlight major elements in the relationship between molecular and organismal traits providing a crucial feedback for “ab initio” computational modeling of evolutionary dynamics.

October 1st, 2015 at 12:15 PM in Clark Center Seminar Room S360

Hosted by:

Judith Frydman, Professor of Biology and Genetics, Stanford University

Pre-Seminar September 29th, 2015 at 12:15 PM in Clark S361