Text

theses

Evolution is the defining feature of living matter. It occurs most fundamentally on the scale of biomolecules such as DNA and proteins, which carry out all the processes of cells. How do the physical properties of these molecules shape the course of evolution? We address this question using a synthesis of biophysical models, theoretical tools from stochastic processes, and high-throughput data. We first review some basic features of population and evolutionary dynamics, focusing especially on fitness landscapes and how they determine accessible pathways of evolution. We then derive a universal scaling law describing time reversibility and steady state of monomorphic populations on arbitrary fitness landscapes. We use this result to study the evolution of transcription factor (TF) binding sites using high-throughput data on TF-DNA interactions and genome-wide site locations. We find that binding sites for a given TF appear to be subjected to universal selection pressures, independent of the properties of their corresponding genes, and their binding energy-dependent fitness is consistent with a simple functional form inspired by a thermodynamic model. We next consider the properties of evolutionary pathways. We develop a general approach for calculating statistical properties of the path ensemble in a stochastic process. We first demonstrate this approach on a series of simple examples, including evolution on a neutral network and two reaction rate problems. We then apply these techniques to a model of how proteins evolve new binding interactions while maintaining folding stability. In particular we show how the structural coupling of protein folding and binding results in protein traits emerging as evolutionary "spandrels'': proteins can evolve strong binding interactions that confer no intrinsic fitness advantage but merely serve to stabilize the protein if misfolding is deleterious. These observations may explain the abundance of apparently nonfunctional interactions among proteins observed in high-throughput assays. When there are distinct selection pressures on both folding and binding, evolutionary paths of proteins can be tightly constrained so that folding stability is first gained and then partially lost as the new binding function is developed. This suggests the evolution of many natural proteins is highly predictable at the level of biophysical traits.

ETD_5774

Ph.D.

Includes bibliographical references

by Michael Manhart

doi:10.7282/T3M61HZW

ETD doctoral

The author owns the copyright to this work.