Genomic variation in the vomeronasal receptor gene repertoires of inbred mice

Abstract

BackgroundVomeronasal receptors (VRs), expressed in sensory neurons of the vomeronasal organ, are thought to bind pheromones and mediate innate behaviours. The mouse reference genome has over 360 functional VRs arranged in highly homologous clusters, but the vast majority are of unknown function. Differences in these receptors within and between closely related species of mice are likely to underpin a range of behavioural responses. To investigate these differences, we interrogated the VR gene repertoire from 17 inbred strains of mice using massively parallel sequencing.ResultsApproximately half of the 6222 VR genes that we investigated could be successfully resolved, and those that were unambiguously mapped resulted in an extremely accurate dataset. Collectively VRs have over twice the coding sequence variation of the genome average; but we identify striking non-random distribution of these variants within and between genes, clusters, clades and functional classes of VRs. We show that functional VR gene repertoires differ considerably between different Mus subspecies and species, suggesting these receptors may play a role in mediating behavioural adaptations. Finally, we provide evidence that widely-used, highly inbred laboratory-derived strains have a greatly reduced, but not entirely redundant capacity for differential pheromone-mediated behaviours.ConclusionsTogether our results suggest that the unusually variable VR repertoires of mice have a significant role in encoding differences in olfactory-mediated responses and behaviours. Our dataset has expanded over nine fold the known number of mouse VR alleles, and will enable mechanistic analyses into the genetics of innate behavioural differences in mice.

The complexity of pheromone-mediated behaviour in mammals

“…Mice have 543 VR genes arranged in clusters distributed across the genome, though only two thirds encode potentially functional proteins [19]. The number of functional VRs varies dramatically between and even within mammalian species [4,15,42]; most humans are likely to have very few, if any [43]. VR expression is largely restricted to sensory neurons in the olfactory system, where they are thought to be specialised to detect chemical signals that provoke behaviour, including pheromones.…”

“…From the perspective of an investigating male, receptor redundancy would insure against the reproductively catastrophic consequences of losing the ability to assess when a female is receptive. Indeed, the VR gene repertoire has unusually high levels of genetic variation: when compared across laboratory strains numerous loss-of-function mutations are present which would render single VRs non-responsive to their ligands [15,16]. On the other hand, two classes of VSN activated by the same pheromone could indicate a synergistic or additive model of neural coding.…”

Cross-Species Analysis of Mouse and Human Cancer Genomes

“…Some gene families have also been expanded or contracted through evolution (Demuth et al 2006;Krushna Padhi et al 2006). A particularly notable example is the expansion of olfactory receptors in mouse (Wynn et al 2012) when compared to human (Rouquier et al 2000). Other genes such as the Ubiquitin-specific protease 6 (USP6) are apparently absent from the mouse genome and found in primates (Flicek et al 2013).…”

Seeking signatures of reinforcement at the genetic level: a hitchhiking mapping and candidate gene approach in the house mouse

“…) and the repertoire of which varies between mouse subspecies (Wynn et al . ). Both MUPs and VRs belong to large multigene families whose genomic organization has been characterized in the mouse genome (Fig.…”

“…Hurst et al 2001;Cheetham et al 2007) and are produced in different quantity in the urine of the two European subspecies of mice (Stopkov a et al 2007) and (ii) the Vomeronasal Receptors (VRs), a family of G proteincoupled receptors that mediate pheromone reception and signal transduction in mammals (e.g. Lane et al 2004;Ibarra-Soria et al 2013), have the potential to specifically detect sex-specific, conspecific and heterospecific signals in mice (Isogai et al 2011) and the repertoire of which varies between mouse subspecies (Wynn et al 2012). Both MUPs and VRs belong to large multigene families whose genomic organization has been characterized in the mouse genome ( Fig.…”