Barry Williams, Ph.D.

barryw@msu.edu

Research

Despite the wealth of DNA sequence data and sophisticated computational methods of describing patterns of sequence variation, there remains a fundamental mystery as to the functional significance of the conservation and divergence of DNA sequences. While sequence comparisons are routine in modern biology, there is little empirical data demonstrating the forces that shape variation, conservation, and divergence. What are the fitness effects of substitutions segregating within species and fixed between species? Do substitutions with fitness effects correspond to functional evolution? How pervasive is compensatory mutation and epistasis among substitutions? What is the structural and molecular/biochemical nature of mutations that alter function versus compensatory substitutions? What types of substitutions are tolerated at a given gene?

Research in the Williams’ lab seeks to determine, at the molecular level, the ecological and evolutionary forces that lead to either phenotypic diversification or stasis, in natural populations. Most of the work in our lab takes advantage of the model organism /Saccharomyces cerevisiae/ (a.k.a. baker’s yeast, brewer’s yeast, or budding yeast). The advantages of working with this species include: a eukaryotic cellular system; an excellent experimental toolkit in genetics, molecular biology, and biochemistry; genome sequences from many strains and related ‘biological’ yeast species, which range in divergence from hundreds to billions of generations; phenotypic traits with implications for human health (yeast is an opportunist pathogen) and agriculture (viniculture). Many fascinating traits with interesting evolutionary patterns have been identified in yeast, because of this rich comparative framework combined with the detailed phenotypic information from this well studied organism. Our goal is to characterize how these traits arose, were maintained or altered over time, and identify the molecular genetic changes that occurred during the evolutionary process.

Typically, work in our lab first involves the identification of genes with interesting patterns of molecular evolution, or interesting phenotypes that are segregating variation among isolates of the same species. Next, we manipulate the genome by either standard genetic crosses or by directly transforming strains to carry mutations observed in other strains, species, or inferred ancestral (ancient) sequences. Finally, we seek to determine the phenotypic effect of these mutations at the molecular level in ecologically relevant environmental conditions. In all, this work involves comparative and population genomics, computational modeling, molecular genetics, biochemistry, classical genetics, and occasionally, field work.

Some of the projects we are currently working on are listed below:

The fitness effects of mutations fixed between lineages.
The identification and fitness landscape of compensatory substitutions.
Functional evolution of the HPS70 gene family.
Empirical demonstration of the cost of transcription, translation, and codon bias.
Functional, structural, and fitness effects of all classes of amino acid substitutions at all sites in a single protein.
Determine the deleterious and beneficial mutation rate of multiple strains in a range of environments.
Fine-scale, advanced intercross QTL mapping from multiple wild strains combined with high-throughput phenotyping data.
Digital evolution as a means to characterize the role of natural selection and historical demography in speciation, population genomics, and systematics.