CAREER: Fluctuations and fitness - fundamental limits and selection conflicts

Harvard University, Cambridge MA

Investigators

Abstract

Natural selection occurs at all levels of biological organization. At higher levels it favors cooperation between lower-level units and at lower levels it favors cheaters that exploit the common good for their own interests. The corresponding molecular mechanisms are best characterized for the replication control genes of plasmids in Escherichia coli that face selection at two distinct levels: plasmid copies that systematically over-replicate relative to their cellmates have a higher chance of fixing in descendent cells, but these cells typically have a lower chance of fixing in the population. To analyze the conflict, the mathematical frameworks for multi-scale selection and drift in cells will be extended, focusing on conflict suppression mechanisms, meta-control of selfishness, and how cooperation is prevented by clonal interference. In addition, an experimental platform will be developed to test how different conditions select for altruism or selfishness, and monitor the dynamics of the conflict by mapping arising mutations to the known control systems. All social elements--from microorganisms to humans--can benefit from both cooperation and selfishness, and the most successful behavior depends on the parameters of the social scene. The investigators have identified a clean-cut conflict between selfish and altruistic elements in one of the simplest and best studied processes in bacterial cells: Self-replicating pieces of DNA get an immediate advantage by selfishly over-reproducing, but then instead indirectly suffer because they impose a larger burden on the cells upon which they rely. Because other aspects of this system are so well-studied, this provides a unique opportunity to rigorously analyze a complex phenomenon like cooperation in terms of molecular mechanisms and physical chemistry. General rules for such conflicts will be mathematically derived and experimentally tested, determining conditions for altruistic behavior and identifying mechanisms that enhance or suppress selfishness. By focusing on testable theorems and broad intuitive principles, the results are equally important for education and research.