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. That is, the cellular circuitry is organized into modules that buffer the expression within their module but do not affect other modules.We are developing methods to be both systematic and comprehensive in the investigation of synthetic phenotypes and are focusing on tolerance of genetic variation in the DNA synthetic apparatus. Since the very mechanisms that permit the maintenance of variation also diminish its phenotypic expression, the third question becomes significant. Phenotypic expression of genetic variation in the DNA synthetic apparatus has additional implications for evolution (and cancer) since this variation can be expressed as mutator phenotypes.
Simon JA; Szankasi P; Nguyen DK; Ludlow C; Dunstan HM; Roberts CJ; Jensen EL; Hartwell LH; Friend SH. Differential toxicities of anticancer agents among DNA repair and checkpoint mutants of Saccharomyces cerevisiae.. Cancer Res. 60(2): 328-33, 15 2000
Simon, J.A., Szankaski, P., Nguyen, D.K., Ludlow, C, Dunstan, H.M., Roberts, C.J., Jensen, E.L., Hartwell, L.H., Friend, S.H.. Differential toxicities of anticancer agents among DNA repair and checkpoint mutants of Saccharomyces cerevisiae. Cancer Research. 60(2): 328-333, 2000
Hartwell, L.H., Hopfield, J.J., Leibler, S., Murray, A.W.. From molecular to modular cell Biology. Nature 402 supplement. 6761: C47-C52, 1999
Marton MJ, DeRisi JL, Bennett HA, Iyer VR, Meyer MR, Roberts CJ, Stoughton R, Burchard J, Slade D, Dai H, Bassett DE Jr, Hartwell LH, Brown PO, Friend SH. Drug target validation and identification of secondary drug target effects using DNA microarrays. Nature Medicine. 4(11): 1293-301, Nov 1998
Paulovich AG, Armour CD, Hartwell LH. The Saccharomyces cerevisiae RAD9, RAD17, RAD24 and MEC3 genes are required for tolerating irreparable, ultraviolet-induced DNA damage. Genetics. 150(1): 75-93, Sep 1998