Biological systems are robust, meaning that they can maintain relatively stable phenotypic outputs over a range of perturbing genetic and environmental inputs. Genetic buffering refers to the gene activities within a cell that confer phenotypic stability. Research in the lab is aimed at discovering how the arrangement of gene circuitry provides robustness through global analysis of genetic interactions. Genetic interaction is defined by the phenotypic effect of altering one gene being non-additive with the effect of a second perturbation. By this definition, when a gene interacts the phenotypic response to perturbation is dependent upon the activity of that gene, and therefore the gene has the capacity to modify phenotypic robustness to the perturbation, or to buffer the perturbation.
To measure gene interaction globally, we perturb an array of ~5000 isogenic yeast deletion strains, and use cell proliferation as a phenotypic readout to quantify the interacting effects between the perturbation and deletion at each locus. By varying the type and intensity of perturbation the resulting selectivity and strengths of interaction are determined, revealing the relative buffering specificity of each gene. Using gene annotation and other bioinformatics resources to analyze the quantitative patterns of gene interaction, testable hypotheses are generated to further understand the molecular basis of the observed gene interaction networks.
Understanding genetic principles underlying buffering of biological systems is intended to facilitate the study of complex genotype-phenotype relationships resulting from natural genetic variation in genes that buffer (and thus modify) disease-associated genetic and environmental perturbations, such as disease-susceptibility alleles and environmental hazards. While aiming to establish general methods for studying genetic interaction networks in any cell type, initial studies have focused on perturbations of DNA replication in yeast. Genetic buffering of DNA replication should highlight design properties of genetic systems that confer protection against perturbations that cause genome instability and initiate cancer.
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PI: John Hartman