A Framework for Exploring Functional Variability in Olfactory Receptor Genes

BACKGROUND: Olfactory receptors (ORs) are the largest gene family in mammalian genomes. Since nearly all OR genes are orphan receptors, inference of functional similarity or differences between odorant receptors typically relies on sequence comparisons. Based on the alignment of entire coding region sequence, OR genes are classified into families and subfamilies, a classification that is believed to be a proxy for OR gene functional variability. However, the assumption that overall protein sequence diversity is a good proxy for functional properties is untested. METHODOLOGY: Here, we propose an alternative sequence-based approach to infer the similarities and differences in OR binding capacity. Our approach is based on similarities and differences in the predicted binding pockets of OR genes, rather than on the entire OR coding region. CONCLUSIONS: Interestingly, our approach yields markedly different results compared to the analysis based on the entire OR coding-regions. While neither approach can be tested at this time, the discrepancy between the two calls into question the assumption that the current classification reliably reflects OR gene functional variability

Co-regulation of a large and rapidly evolving repertoire of odorant receptor genes

The olfactory system meets niche- and species-specific demands by an accelerated evolution of its odorant receptor repertoires. In this review, we describe evolutionary processes that have shaped olfactory and vomeronasal receptor gene families in vertebrate genomes. We emphasize three important periods in the evolution of the olfactory system evident by comparative genomics: the adaptation to land in amphibian ancestors, the decline of olfaction in primates, and the delineation of putative pheromone receptors concurrent with rodent speciation. The rapid evolution of odorant receptor genes, the sheer size of the repertoire, as well as their wide distribution in the genome, presents a developmental challenge: how are these ever-changing odorant receptor repertoires coordinated within the olfactory system? A central organizing principle in olfaction is the specialization of sensory neurons resulting from each sensory neuron expressing only ~one odorant receptor allele. In this review, we also discuss this mutually exclusive expression of odorant receptor genes. We have considered several models to account for co-regulation of odorant receptor repertoires, as well as discussed a new hypothesis that invokes important epigenetic properties of the system