Biological systems are robust, meaning that they can maintain relatively stable phenotypic outputs over a range of perturbing genetic and environmental inputs. Our lab investigates genetic interactions that confer phenotypic stability. The broader goal is to understand how gene circuitry is organized to provide robustness, and thus how genetic variation can be expressed. Genetic interaction is defined when a genetic variant alters the phenotype otherwise observed in response to perturbation. Genes interact in a context (perturbation)- specific manner, and thus genetic interaction profiles provide functional insight about a genes activity.
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 buffering specificity and capacity (strength of interaction) for 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 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.
Hartman Lab, Division of Translational Medicine, Department of Genetics, University of Alabama at Birmingham (UAB).
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