Scope of collateral fitness effects and their mechanisms

Understanding the effects of protein mutations is fundamentally important in the study of molecular evolution. Harmful mutations are generally understood to cause negative effects by disrupting the normal functions of the affected protein. However, the deleterious effects of mutations might also arise from causing the mutated protein to do things it should not do, such as interfere with unrelated biological processes.

This project is a systematic study of the effects of all possible mutations in three proteins. This will contribute to the understanding of how proteins evolve and the mechanisms by which mutations can affect cell physiology. Such knowledge is important for understanding human disease and the evolution of antibiotic resistance.

Each year of this research, three graduate students, two undergraduates, and one high school student will be trained in research. The graduate students will present research at scientific conferences and gain mentorship experience supervising the undergraduate and high school students.

The distribution of fitness effects of mutations plays a central role in setting protein evolution rates, but the molecular underpinnings of this constraint are unclear. One possibility is that mutant proteins misfold or misinteract with other proteins with deleterious consequences. Such effects are examples of collateral fitness effects, as opposed to primary fitness effects that derive from changes in the physiological function of the protein.

Very little is known about the frequency, magnitude, and mechanisms of collateral fitness effects, but such information is critical for understanding protein evolution. This research will comprehensively determine the collateral fitness effects of mutations in three proteins using growth competition and next-generation sequencing techniques in Escherichia coli.

Molecular biology techniques will be used to discover the mechanisms behind select mutational effects. This study will generate a wealth of data from which to understand the contribution of collateral fitness effects to evolution.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.