Elsevier

Gene

Volume 340, Issue 2, 13 October 2004, Pages 303-312
Gene

Rapid turnover and species-specificity of vomeronasal pheromone receptor genes in mice and rats

https://doi.org/10.1016/j.gene.2004.07.037Get rights and content

Abstract

Pheromones are used by individuals of the same species to elicit behavioral or physiological changes, and they are perceived primarily by the vomeronasal organ (VNO) in terrestrial vertebrates. VNO pheromone receptors are encoded by the V1r and V2r gene superfamilies in mammals. A comparison of the V1r and V2r repertoires between closely related species can provide significant insights into the evolutionary genetic mechanisms responsible for species-specific pheromone communications. A total of 137 putatively functional V1r genes of 12 families were previously identified from the mouse genome. We report the identification of 95 putatively functional V1r genes from the draft rat genome sequence. These genes map primarily to four blocks in two chromosomes. The rat V1r genes can be phylogenetically grouped into 10 families, which are shared with mouse, and 2 new families, which are rat-specific. Even in many shared families, gene numbers differ between the two species, apparently due to frequent gene duplication and pseudogenization after the separation of the two species. Molecular dating suggests that most of the rat V1r families emerged before or during the radiation of mammalian orders, but many duplications within families occurred as recently as in the past 10 million years (MY). Our results show that the evolution of the V1r repertoire is characterized by exceptionally fast gene turnover via gains and losses of individual genes, suggesting rapid and substantial changes in pheromone communication between species.

Introduction

Pheromones are used by individuals of the same species to elicit behavioral or physiological changes, such as male–male aggression, puberty, estrus, and induction of mating, and are perceived primarily by the vomeronasal organ (VNO; reviewed in Keverne, 1999, Dulac and Torello, 2003). Two superfamilies of vomeronasal pheromone receptors, V1r and V2r, are known in mammals and they differ in expression location and gene structure (Dulac and Axel, 1995, Herrada and Dulac, 1997, Matsunami and Buck, 1997, Ryba and Tirindelli, 1997; reviewed in Dulac and Torello, 2003). While both types of receptors are seven-transmembrane (TM) G-protein coupled receptors, V1rs are characterized by an intronless coding region, while V2rs are characterized by a long highly variable N-terminal domain. V1rs are expressed in Gαi2 neurons and V2rs are expressed in Gα0 neurons (reviewed in Dulac and Torello, 2003). Targeted deletion of some V1r genes in mice show altered aggression and sexual behaviors (Del Punta et al., 2002). Additionally, a third vomeronasal receptor superfamily, V3r, has been described (Pantages and Dulac, 2000); however, V3rs were later found to be a family of V1rs (Rodriguez et al., 2002). Because they lack introns, V1r genes are more accessible than V2r genes to bioinformatic as well as experimental studies. For example, the entire mouse V1r repertoire, including 137 putatively functional members of 12 families has been described (Rodriguez et al., 2002), while the mouse V2r repertoire has yet to be described.

The identification of V1r and V2r genes has opened the door to studies on the molecular mechanisms and origins of species-specific pheromone communications. V1rs were originally discovered and described in rat (Dulac and Axel, 1995). The absence of highly conserved regions in V1r prohibits the design of degenerate primers that can amplify a large number of genes across wide taxonomic scale (Giorgi and Rouquier, 2002). Therefore, the V1r superfamily was not extensively described in any species until the availability of the human and mouse genome sequences (Lane et al., 2002, Rodriguez et al., 2002, Rodriguez and Mombaerts, 2002). The comparison of V1rs between human and mouse is not informative because the two species are distantly related and because humans lack VNO sensitivity due to loss of important components of the VNO pheromone transduction pathway (Zhang and Webb, 2003, Liman and Innan, 2003). Zhang et al. (2004) compared the V1r repertoires of two genome assemblies generated from different strains of inbred mice. While this comparison is useful for identifying polymorphisms within species, it does not address interspecific differences which are the hallmark of pheromone communication. The availability of the draft rat genome sequence (Rat Genome Sequencing Consortium, 2004) provides the opportunity to compare for the first time pheromone receptor repertoires of relatively closely related species, as mouse and rat diverged only 18±6 million years (MY) ago (Rat Genome Sequencing Consortium, 2004).

Divergence in the V1r repertoires between species can occur in three ways: functional divergence of orthologs, loss or gain of family members, and loss or gain of entire families. Two recent studies compared a small number of V1r genes between mouse and rat (Lane et al., 2004, Emes et al., 2004) but did not provide a general picture on the evolution of the V1r repertoire. We compare the entire V1r repertoires in an attempt to examine which of the three processes dominate the divergence of V1r genes between species.

Section snippets

Database searches

TBLASTN searches for rat V1r genes were done on the rat genome sequence available in the National Center for Biotechnology Information (NCBI) with the rat genome build 2 version 1 (http://www.ncbi.nlm.nih.gov/genome/guide/rat/index.html). The previously described 137 mouse V1r genes were used as query sequences. V1r pseudogenes were identified by premature stop codons or incomplete sequence across the 13 protein domains (7 transmembrane, 3 extracellular (EC), and 3 intracellular (IC)) of the 15

Composition of the rat V1r gene superfamily

From the database searches with mouse V1r queries, we identified from the rat genome sequence 116 V1r genes. Additional searches with human V1r-like genes (Rodriguez and Mombaerts, 2002) did not yield any additional sequences. Because the rat genome is over 90% complete (Rat Genome Sequencing Consortium, 2004), the V1r repertoire we describe here is probably over 90% complete as well. We examined the conceptually translated protein sequences encoded by the retrieved DNA sequences and found that

Discussion

In this study, we identified 95 putatively functional V1r genes from the rat genome sequence, supporting the prediction of ∼100 distinct genes in the original description of the rat V1r gene superfamily (Dulac and Axel, 1995). This number is about two-thirds of that in the mouse. Wild mice and rats have different social/reproductive structures (Abbott, 2004). Mice live in groups with one highly aggressive alpha male monopolizing the females, whereas rats are promiscuous and less aggressive. It

Acknowledgments

We thank Soochin Cho and David Webb for valuable comments. This work was supported by a startup fund from the University of Michigan and National Institutes of Health grant GM67030 to J.Z.

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