Molecular Evolvability In Theory And In A Bacterial Drug-Resistence Gene

Harvard University, Cambridge MA

Investigators

Abstract

Genetic mutations are random changes in an organism's genome. They are almost always harmful to the individual, but rare beneficial mutations do occur. Familiar examples of the latter include mutations for antibiotic resistance in bacteria, vaccine resistance in influenza viruses, and insecticide resistance in insects. In spite of their great medical and agricultural importance, beneficial mutations are not well understood because they are so rare. One critical issue is whether two or more beneficial mutations interact to produce greater effects than would be expected from their individual effects. Drs. Weinreich and Hartl will study this issue in the bacterium Escherichia coli, using a gene for resistance to the widely used antibiotic cefotaxime. Five different mutations in that gene have been associated with resistance. To investigate their interactions, the researchers will make all possible combinations of those mutations and study their effects on cefotaxime resistance. Broad benefits are likely to flow from the proposed research. Many infectious diseases are caused by viruses or microorganisms that, in response to clinical use of drug therapy, evolve beneficial mutations so rapidly that even the newest drugs become ineffective before still newer drugs can be developed. Research on drug resistance will lead to a better understanding of the origin of these "super bugs" and of drug resistance in viruses such as HIV. The study also addresses several general questions of evolutionary theory.