User:Jhartman

John Hartman IV, M.D. Assistant Professor Department of Genetics University of Alabama School of Medicine Tel: (205) 996-4195 Fax: (205) 975-5689 jhartman (AT) UAB (DOT) EDU

Biographical Sketch

John Hartman completed undergraduate studies at Duke University , and graduated from University of Alabama School of Medicine. During medical school, he worked in Eric Sorscher's laboratory at UAB, and at the NIH as an HHMI Medical Student Research Scholar. Internal Medicine residency and hematology fellowships were completed at the University of Washington , and post-doctoral research was performed in Lee Hartwell's laboratory at the Fred Hutchinson Cancer Research Center in Seattle . John joined the UAB faculty in the Department of Genetics, Division of Genetic and Translational Medicine in 2004.

Research Focus

• Genetic Buffering of DNA Replication

Research Summary

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.

Selected Publications

Hartman JL , Tippery NP: Systematic quantification of gene interactions by phenotypic array analysis. Genome Biol 2004, 5(7):R49. Abstract.

Hartman JL , Garvik B, Hartwell L: Principles for the buffering of genetic variation. Science 2001, 291(5506):1001-1004. Abstract.

Hartman JL , Northup JK: Functional reconstitution in situ of 5-hydroxytryptamine2c (5HT2c) receptors with alphaq and inverse agonism of 5HT2c receptor antagonists. J Biol Chem 1996, 271(37):22591-22597.

Hartman J , Huang Z, Rado TA, Peng S, Jilling T, Muccio DD, Sorscher EJ: Recombinant synthesis, purification, and nucleotide binding characteristics of the first nucleotide binding domain of the cystic fibrosis gene product. J Biol Chem 1992, 267(10):6455-6458.