Marc Ostermeier, Ph.D.
Chemical & Biomolecular Engineering
Johns Hopkins University
Title: Collateral fitness effects of mutations
Abstract: The mechanisms of mutational effects are important for genetic diseases, infectious diseases, cancer, and evolution. Mutational effects are commonly understood to result from changes in the ability of the gene to perform its physiological function, e.g. through changes in a protein’s specific activity or abundance. Many genetic diseases are caused by deleterious mutations reducing or eliminating a protein’s activity in the cell. But other diseases, most notably protein misfolding diseases, are thought to be caused by the mutant protein having toxic effects and not by changes in cellular level of protein activity per se. This leads to the question: How often do mutations cause deleterious effects to the organism (i.e. fitness effects) through mechanisms unrelated to the protein’s function? We measured the fitness effects of 16,900 unique mutations in the E. coli TEM-1 beta-lactamase antibiotic resistance gene using growth competition experiments in the absence of beta-lactam antibiotics. We term these effects “collateral fitness effects.” At least 42% of missense mutations in TEM-1 were deleterious, indicating that for some proteins, collateral fitness effects occur as frequently as effects on protein activity and abundance. Deleterious mutations caused improper post-translational processing, incorrect disulfide-bond formation, protein aggregation, changes in gene expression, and pleiotropic effects on cell phenotype. Our study suggests that protein sequence evolution is under selective constraint both to maintain function and to avoid collateral negative effects.
Bio: Marc Ostermeier is Professor of Chemical and Biomolecular Engineering at Johns Hopkins University. He received a B.S. in Chemical Engineering from the University of Wisconsin in 1990 and a Ph.D. in Chemical Engineering from the University of Texas at Austin in 1996. He was an NIH Postdoctoral Fellow in the Chemistry Department at the Pennsylvania State University before joining the faculty at Department of Chemical and Biomolecular Engineering at Johns Hopkins University in 2000. Professor Ostermeier was promoted to Associate Professor in 2007 and Professor in 2011. Professor Ostermeier’s research is in the areas of protein engineering, synthetic biology, protein evolution, and allostery. He is a member of the Editorial Review Board for Protein Engineering Design and Selection. He is a recipient of an NSF CAREER award and a fellow of the American Institute for Medical and Biological Engineering.
Department of Chemical Engineering