Nonlinear effect of copy number variation on gene expression

Mathematical Biology Seminar
Wednesday, February 25, 2009 - 11:00am for 1 hour (actually 50 minutes)
Skiles 255
Yuriy Mileyko – School of Biology, Georgia Tech
Leonid Bunimovich
The expression dynamics of interacting genes depends on the topology of the regulatory network, the quantitative nature of feedbacks and interactions between DNA, RNA and proteins, and the biochemical state of the intracellular and surrounding environment. In this talk we show that dynamics of a gene regulatory network can also depend sensitively on the copy number of genes and promoters. Genetic regulatory networks include an overrepresentation of subgraphs commonly known as network motifs. We consider positive feedback, bistable feedback, and toggle switch motifs and show that variation in gene copy number can cause a sequence of saddle-node bifurcations in the corresponding differential equations models, which leads to multiple orders of magnitude change in gene expression. A similar analysis of a 3-gene motif with successive inhibition (the ``repressilator'') reveals that changes in gene copy number can also cause a Hopf bifurcation, thus leading to a qualitative switch in system behavior among oscillatory and equilibrium dynamics. Importantly, we show that these bifurcations exist over a wide range of parameter values, thus reinforcing our claim that copy number is a key control parameter in the expression dynamics of regulatory networks.