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My laboratory is beginning a new research program aimed at studying how molecular circuits support evolution. Evolution acts through selection of preexisting genetic variation in populations. Three important questions are: 1) How does variation occur? 2)How is variation maintained? 3) How is genetic variation expressed as phenotypic variation? The first question is well studied. We are currently focused on the second. A variety of biochemical mechanisms (including gene redundancy, co-assembly of proteinsinto macromolecular complexes, positive feedback, robust circuit design, repair processes) minimize the phenotypic consequences of genetic variation and thereby allow cells to tolerate it. These relationships can be revealed by synthetic-phenotypes. That is, if one gene plays a role that buffers the phenotypic expression of variation in another, then loss of the first reveals the phenotypic consequences of variation in the second. Synthetic-lethal relationships have been widely studied in yeast althoughrarely systematically or comprehensively. Anecdotal results strongly suggest that buffering mechanisms are modular.
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