Speaker
Griffin Chure
Description
Quantitative explorations of evolutionary process often rely on the
generation of fitness landscapes frequently depicted as two-
dimensional surfaces upon which peaks and valleys in fitness are given
as functions of phenotypes. However, we are often unable to
quantitatively describe these phenotypes in experimentally accessible
terms, hindering our ability to test these predictive models. This is
especially true in the context of gene expression where the rich
phenomenology of gene expression dose-response curves (such as
leakiness, dynamic range, and sensitivity of response) are left to
qualitative or semi-quantitative description through the use of Hill
functions. Here, we present a general theory of allosteric transcriptional
regulation using the Monod-Wyman-Changeux model and derive an
expression for the free energy of an allosteric repressor. We rigorously
test this model using the simple repression motif in bacteria by
predicting and measuring the behavior of strains that span a swath of
repressor copy numbers and DNA binding strengths. Our model
captures the induction profiles of these strains and generates analytic
expressions for key properties such as dynamic range and [EC50].
Furthermore, we explore how mutations at the level of amino acid
substitutions are connected to the various biophysical parameters
which govern the response of the system and generate predictions of
how each mutation modulates the free energy of the repressor. With an
array of well characterized point mutants of the repressor, we test the
predictions of how the pairwise double mutants behave, revealing that
in most cases the energetic contributions of each individual mutation
are additive. Finally, we explore how epistatic interactions could be
manifest in our model.
Primary author
Griffin Chure
