The growing collection of complete genome sequences presents a major opportunity to understand how genetic variation (and conservation) maps to phenotypic diversity. By studying evolutionary statistics across many genomes we hope to decipher the global pattern of functional constraints between genes, and distinguish interactions critical to core cellular function from those that occur idiosyncratically within particular species.

Evolutionary conservation and co-evolution can be quantified for many properties, and at varying spatial scales or resolutions.  For example, correlations in gene presence or absence (co-occurrence), genomic location (synteny) and protein sequence (amino acid frequency) provide three separate but potentially complementary mappings of genetic interaction.  In all cases, the underlying goal is to understand the organization and function of cellular systems quantitatively and at a depth that allows rational manipulation and de novo design. 

This objective is currently manifested as three main projects within our lab:

I.  Allosteric regulation and communication between proteins.

Regulation and communication between individual protein domains is a basic building block for the assembly of larger cellular systems.  Analysis of amino acid co-evolution indicates a general architecture for natural proteins in which sparse networks of amino acids underlie basic aspects of structure and function.  These networks, termed sectors, are spatially organized such that active sites are physically linked to particular surface sites distributed throughout the protein structure. We have recently shown that perturbations at specific sector-connected surface positions are able to rapidly initiate conformational control over protein function.  These findings suggest that the heterogeneous sector architecture of proteins might facilitate the evolution of intermolecular communication and regulation.  We plan to further test this evolutionary model by (1) examining how natural proteins exploit sector-connected sites for regulation and (2) conducting forward evolution experiments to produce novel allosteric switches.

II.  Mapping functional constraints in central metabolism.

Central metabolism is a universal biological process in which the collective action of many genes provides the energy and raw material for cell growth and division.  While we know the parts list of metabolic enzymes and connectivity of chemical reactions, non-additivity (or epistasis, or cooperativity) between genes makes it non-trivial to predict metabolic behaviors based on knowledge of the activity of the parts taken independently.  For this reason, we would like to re-parameterize metabolic systems into evolutionary modules - cooperative groups of genes that represent core cellular functions. Experimentally, we aim to test these predicted modules by transplanting rationally-chosen groups of genes between bacterial species and assaying for the complementation of function or phenotype.

III.  Evolvability and organization in a large physical complex...

the bacterial flagellum.

The bacterial flagellum is assembled from roughly 40 interacting proteins and the apparent precision of its design draws analogies to human-engineered motors, with terms such as “rotor”, “stator” and “bushing” used to describe the underlying macromolecular components.  Nonetheless, motility in bacteria is a common feature across much of prokaryotic evolutionary history, and these systems display great physical and functional variation. The degeneracy of evolutionary solutions to the problem of bacterial motility suggests that there are simple “core” constraints essential to motor function, with additional components that might be added more or less modularly.  We are interested in (1) understanding what the pattern of constraints between flagellar components looks like and (2) how this construction might facilitate the generation of phenotypic diversity. Addressing these questions might begin to explain how such seemingly “irreducibly complex” systems are possible through a naïve process of stepwise variation and selection.

Last updated: Jan. 3, 2014

The Green Center for Systems Biology

University of Texas Southwestern Medical Center

Dallas, TX

Flagellar motor diversity.

Redrawn From:  Chen et al (2011). EMBO J. v. 30, p. 2972