Genetic Architecture of Behavior

Genetics of Human Diseases

Olfactomedins

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The Genetics of Human Diseases

We are using Drosophila melanogaster as a gene discovery model for alcoholism and glaucoma.

Alcohol is one of the most widely abused substances, and alcoholism contributes to economic, social and health problems throughout the industrialized world. Alcohol sensitivity, the development of tolerance to alcohol, and susceptibility to addiction vary in the population. Although there is no functional correlate of addiction in Drosophila, flies display many behaviors resembling human intoxication when exposed to alcohol vapors, including development of tolerance after an initial exposure to ethanol. This suggests that at least some aspects of alcohol sensitivity and tolerance may be similar across species. We are using a whole-genome approach to identify genes that contribute to alcohol sensitivity and/or tolerance in Drosophila with the goal of assessing whether polymorphisms in human orthologues of these genes are associated with susceptibility for developing alcohol dependence in human populations.

This work is supported by a grant from the National Institute for Alcoholism and Alcohol Abuse with our collaborator, Dr. Trudy Mackay, as Principal Investigator.

Glaucoma is the leading treatable cause of blindness, which affects about one in every 100 persons over the age of 40 with an even higher incidence in African-American and Hispanic populations. The disease is often, but not always, associated with ocular hypertension, an increase in pressure in the eye, which is normally regulated by outflow through the trabecular meshwork. A protein, which is overexpressed under conditions of stress, such as increased pressure, in the trabecular meshwork has been associated in some cases of congenital glaucoma in several different populations. This protein, the “trabecular meshwork glucocorticoid inducible response (TIGR) protein”, also known as “myocilin”, is a member of the family of olfactomedin proteins, initially discovered in the Anholt lab about 15 years ago. Overexpression of the human TIGR protein in the Drosophila eye induces an ocular hypertension phenotype. This leads to altered expression of other proteins, many of which have human homologues that may play a role in ocular hypertension and glaucoma in people.

Based on data we obtain from the Drosophila model, the effects of such candidate genes can be assessed in perfused postmortem human eyes, which can be maintained in organ culture for many weeks and genes can be introduced into cells of the trabecular meshwork via an adenovirus delivery system. These studies are done in collaboration by Dr. Teresa Borrás at the University of North Carolina at Chapel Hill. Furthermore, we can assess whether polymorphisms in human homologues of these genes predispose to the development of glaucoma in human populations.

These studies are funded by a grant from the National Eye Institute.

Representative publications:

Borrás, T., Morozova, T. V., Heinsohn, S. L., Lyman, R. F., Mackay, T. F. C. and Anholt, R. R. H. (2003) Transcription profiling in Drosophila eyes that overexpress the human glaucoma-associated trabecular meshwork-inducible glucocorticoid response protein/myocilin (TIGR/MYOC). Genetics 163: 637-645.

Mackay, T. F. C. and Anholt, R. R. H. (2006) Of flies and man: Drosophila as a model for human complex traits. Annu. Rev. Genomics Hum. Genet., in press.