Interdisciplinary Training

Michael Schlador

"The Role of Natural Genetic Variation in Odorant Recognition"

The olfactory receptor (OR) family contains ip to 1000 genes arrayed in clusters throughout the genome. Because ORs appear to bind multiple odorants, it is thought that odor information is specified by a combinatorial code of ORs. The OR family has an unusually dynamic history and has evolved through a series of gene deuplication, recombination, and conversion events. It is not known how much diversity exists among orthologous genes or the extent to which orthologs differ in ligand recognition. Furthermore, some studies have found that the family is highly polymorphic in humans. The presence of nonsynonymous changes in mnay of the alleles suggests that OR diveristy has been maintained by selective pressure. Unfortunately, almost nothing is known about the effects of intra- or interspecies variation on ligand recognition by ORs. In addition, very few ligands have been identified for ORs making it difficult to systematically test the effects of this variation.

The long-term goal of this project is to understand the combinatorial code used by different species for odor recognition and the ways that inter- and intra-species variation has altered these codes. In order to accomplish this, we will measure allelic diversity of selected OR genes in humans and different species of mice, determine whether the sequence variation found leads to changes in OR ligand selectivity, and develop a ligand-based method for the identification of the combinatorial codes that specify odor information for individual odorants. These studies will help us to understand how the gross changes in OR repertoires and the presence of allelic diversity have affected the combinatorial codes used by different species to detect odors.

Fred Hutchinson Cancer Research Center is a world leader in research to prevent, detect and treat cancer and other life-threatening diseases.