A framework for exploring functional variability in olfactory receptor genes
Orna Man1,2,5, David C. Willhite3,5, Chiquito J. Crasto3, Gordon M. Sheperd3 and Yoav Gilad4
1 Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
2 Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel
3 Department of Neurobiology, Yale University School of Medicine, New Haven, CT
4 Department of Human Genetics, University of Chicago, Chicago, IL
5 These authors contributed equally to this work
Background: Olfactory receptors (ORs) constitute the largest gene family in mammalian genomes. Mice have roughly three times as many functional OR genes as humans. At face value, this observation suggests that humans have lost the ability to detect a subset of the odorant space accessible to mouse. However, psychophysical data indicate that, at least with respect to some the tested odorants, discrimination capabilities do not differ markedly between the two species. This apparent paradox may be resolved by invoking a non-random loss of OR genes in humans, in which the intact human olfactory repertoire retains the capability to detect most of the odorant space.
Results: To test this hypothesis, we used the entire OR gene repertoires of human and mouse and inferred the odorant space of the two species by using Grantham’s metric as a proxy for functional differences in binding site properties. We show that our analysis of OR functional variability yields results that differ from those inferred by other, sequence-based phylogenetic methods and often do not correspond to the common subfamily classification of OR genes.
Conclusions: While the odorant spaces of humans and mice largely overlaps, there are marked species-specific differences, including five clusters where we predict that humans have superior olfactory capability compared with mouse, and 35 such mouse clusters. We conjecture that these clusters point to major olfactory threshold differences between the human and mouse.
This webpage contains supplementary material to the publication above. For detailed methodology, please see the PUBMED link. For an interactive version of our representation of odorant space, please click here. This is a file in PDB format for three dimensional viewing. While the results depicted do not represent a macromolecule, this format was chosen to facilitate free access to the data. Many free PDB viewers are available. As an example, the "Deep View Swiss-PDB Viewer" is available at http://us.expasy.org/spdbv. The mouse ORs are represented in red, human ORs are blue and the yellow points indicate that 100% identity of the mouse and human OR in the selected binding residues. The intent of this model-format is to facilitate identification of ORs of interest. ORs of interest can be selected using a PDB viewer, and an "atom" number will be identified. The table here can be used to identify the OR sequences for cloning purposes or further manipulation. Please contact david.willhite@yale.edu or gilad@uchicago.edu for further information and comments.