David Threadgill

University Distinguished Professor | Tom and Jean McMullin Chair, Genetics
Professor | Genetics, Biochemistry & Biophysics

quantitative genetics, cancer genetics, gene-environment interactions, EGFR, ERBB, stem cells

Office:REYN / 428

Our research program broadly focuses on the intersection of genetics and the environment (GXE). The lab uses model systems to investigate genetic factors that contribute to inter-individual differences in susceptibility to the adverse effects of environmental exposures focusing on a variety of exposures and target organs and diseases. This include exposures such as diet, toxicants, and infectious agents. To achieve this, the lab pioneered the development of the Collaborative Cross (CC) mouse genetic reference population to support systems genetics analysis of GxE interactions. Our group also has an ongoing interest in cancer genetics and the development of improved mouse models for studying the initiation through metastasis stages of cancer, with a particular focus on colon cancer.

Cancer genetics

We are focusing on colorectal and kidney cancer to identify environmental factors and genetic polymorphisms contributing to differential susceptibility to the development and progression of cancer. We are also developing approaches to exploit these factors to prevent or delay cancer as well as to identify new therapies.

Haplotype association mapping of loci influencing colon carcinogenesis. (A) Distribution of statistical associations (y-axis) between colon tumor phenotypes and genomic region (x-axis). (B) Map of colon tumor modifier locations compared to previously mapped modifiers (green bars). Modifiers for categorical penetrance (red), original penetrance (blue) mean tumor size (purple), mean tumor multiplicity (yellow), and tumor load (green) are marked by squares.
See Genetics 214, 691–702 (2020).

A. C. Bissahoyo, Y. Xie, L. Yang, R. S. Pearsall, D. Lee, R. W. Elliott, P. Demant, L. McMillan, F. Pardo-Manuel de Villena, J. M. Angel, D. W. Threadgill, A new polygenic model for nonfamilial colorectal cancer inheritance based on the genetic architecture of the azoxymethane-induced mouse model. Genetics 214, 691–702 (2020).

Epidermal growth factor receptor (Egfr)

We are using mouse models with genetically engineered or spontaneous mutations to elucidate the biological role of Egfr and other member of the Erbb gene family in vivo. These studies have lead to new insights into the role of these genes in neuronal survival and behavior, obesity, cancer and cardiovascular disease. We are currently performing mechanistic studies to identify how the Erbb genes contribute to normal and abnormal phenotypes.

Model of Egfr activity requirements during intestinal tumorigenesis. Red dots represent nuclear β-catenin-positive cells. Solid green lines indicate evidence for Egfr activity during establishment and adenocarcinoma expansion. Dashed green lines indicate that a requirement for Egfr activity during adenoma expansion, progression, and invasion has yet to be demonstrated conclusively.
See PNAS 99, 1521–1526 (2002).

R. B. Roberts, L. Min, M. K. Washington, S. J. Olsen, S. H. Settle, R. J. Coffey, D. W. Threadgill, Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis. Proc. Natl. Acad. Sci. U. S. A. 99, 1521–1526 (2002).

Genetics of environmental response

Just as individuals differ in their genetic constitution and disease susceptibility, they also differ in their responses to exogenous stimuli. We are using mouse models to investigate responses to environmental factors like the enteric flora of the gastrointestinal tract, diet and toxicants like dioxin and lead (Pb), trichloroethylene, and arsenic. The goal of these studies is to identify how individual responses to environmental factors leads to differential disease susceptibilities and methods to prevent disease in exposed individuals.

Diet ingredient profiles and geographic origins of human-comparable diets representative of the dietary patterns in human populations including.
See Genetics 208, 399–417 (2018).

W. T. Barrington, P. Wulfridge, A. E. Wells, C. Mantilla Rojas, S. Y. F. Howe, A. Perry, K. Hua, M. A. Pellizzon, K. D. Hansen, B. H. Voy, B. J. Bennett, D. Pomp, A. P. Feinberg, D. W. Threadgill, Improving metabolic health through precision dietetics in mice. Genetics 208, 399–417 (2018).

Systems genetics resources

We are participating in a large international effort to develop and exploit a new mouse genetic resources that will support the integration of genetics into systems biological analyses at the whole animal level. These efforts are based upon the Collaborative Cross, which is a unique recombinant inbred population of mice that have randomly assorted the genetic polymorphisms present in the eight founder inbred strains. A major focus of our work is the development and use of cell-based platforms for in vitro genetic studies.

Cladogram of eutherian mammal orders with rodent genus groups and the eight M. musculus lines. Groups that have representatives from which ESC or iPSC have been derived are noted in color. Red, based on culture conditions are non-permissive to simple derivation; green, permissive to simple pluripotent stem cell derivation.
See Sci. Rep. 8, 14706 (2018).

T. A. Garbutt, T. I. Konneker, K. Konganti, A. E. Hillhouse, F. Swift-Haire, A. Jones, D. Phelps, D. L. Aylor, D. W. Threadgill, Permissiveness to form pluripotent stem cells may be an evolutionarily derived characteristic in Mus musculus. Sci. Rep. 8, 14706 (2018).