Animesh Ray (Professor, Systems Biology, Director, Center for Networks Studies, Director of PhD Programs, Keck Graduate Institute of Applied Life Sciences)
Abstract: The evolutionary plasticity of an organism depends on its ability to circumvent, through the exploration of novel genetic function, the effects of lethal mutational onslaught. We have addressed the extent of mutational robustness by genome wide dosage suppressor analysis of 55 conditional lethal gene mutations, revealing 845 interactions of which 827 are novel. The results reveal evidence for extensive rewiring of genetic pathways, in which genes with disparate functions are engaged for restoring essential cellular processes. For example, meiotic recombination genes were recruited to bypass a mitotic chromosome condensation defect. Focus on RNA Polymerase II, a well characterized protein machine that is essential for survival,
demonstrates a high degree of plasticity due to structural and functional modularity. Novel functional linkages among genes encoding RNA polymerase II mediator complex proteins, cell cycle control genes, and telomere homeostasis genes, were revealed. The dense dosage suppressor network discovered in this work implies the presence of numerous functionally diverse mechanisms in eukaryotes for circumventing the effects of lethal genetic perturbations, with possible implications for drug treatment and the emergence of drug resistance cells.