Avpr1a Locus Research Articles

Complex selection on a regulator of social cognition: Evidence of balancing selection, regulatory interactions and population differentiation in the prairie vole Avpr1a locus.

Adaptive variation in social behaviour depends upon standing genetic variation, but we know little about how evolutionary forces shape genetic diversity relevant to brain and behaviour. In prairie voles (Microtus ochrogaster), variants at the Avpr1a locus predict expression of the vasopressin 1a receptor in the retrosplenial cortex (RSC), a brain region that mediates spatial and contextual memory; cortical V1aR abundance in turn predicts diversity in space use and sexual fidelity in the field. To examine the potential contributions of adaptive and neutral forces to variation at the Avpr1a locus, we explore sequence diversity at the Avpr1a locus and throughout the genome in two populations of wild prairie voles. First, we refine results demonstrating balancing selection at the locus by comparing the frequency spectrum of variants at the locus to a random sample of the genome. Next, we find that the four single nucleotide polymorphisms that predict high V1aR expression in the RSC are in stronger linkage disequilibrium than expected by chance despite high recombination among intervening variants, suggesting that epistatic selection maintains their association. Analysis of population structure and a haplotype network for two populations revealed that this excessive LD was unlikely to be due to admixture alone. Furthermore, the two populations differed considerably in the region shown to be a regulator of V1aR expression despite the extremely low levels of genomewide genetic differentiation. Together, our data suggest that complex selection on Avpr1a locus favours specific combinations of regulatory polymorphisms, maintains the resulting alleles at population-specific frequencies, and may contribute to unique patterns of spatial cognition and sexual fidelity among populations.

Individual Differences in Social Behavior and Cortical Vasopressin Receptor: Genetics, Epigenetics, and Evolution.

Social behavior is among the most complex and variable of traits. Despite its diversity, we know little about how genetic and developmental factors interact to shape natural variation in social behavior. This review surveys recent work on individual differences in the expression of the vasopressin 1a receptor (V1aR), a major regulator of social behavior, in the neocortex of the socially monogamous prairie vole. V1aR exhibits profound variation in the retrosplenial cortex (RSC), a region critical to spatial and contextual memory. RSC-V1aR abundance is associated with patterns of male space-use and sexual fidelity in the field: males with high RSC-V1aR show high spatial and sexual fidelity to partners, while low RSC-V1aR males are significantly more likely to mate outside the pair-bond. Individual differences in RSC-V1aR are predicted by a set of linked single nucleotide polymorphisms within the avpr1a locus. These alternative alleles have been actively maintained by selection, suggesting that the brain differences represent a balanced polymorphism. Lastly, the alleles occur within regulatory sequences, and result in differential sensitivity to environmental perturbation. Together the data provide insight into how genetic, epigenetic and evolutionary forces interact to shape the social brain.

Effects of avpr1a length polymorphism on male social behavior and reproduction in semi‐natural populations of prairie voles (Microtus ochrogaster)

AbstractIntraspecific variation in sociosexual behavior has typically been investigated in the context of its relationship with environmental factors, but neurogenetic factors can also influence sociosexual behavior. In laboratory studies of prairie voles (Microtus ochrogaster), length polymorphism of microsatellite DNA within the gene (avpr1a) encoding the vasopressin 1a receptor is correlated with variation in male sociosexual behavior. However, field studies of prairie voles have found the relationship between male avpr1a microsatellite allele length and sociosexual behavior to be more ambiguous, possibly because most males had alleles of intermediate length. We tested the hypothesis that avpr1a microsatellite allele length mediates male sociosexual behavior in field settings by releasing voles into field enclosures where every male possessed two avpr1a microsatellite alleles at least one standard error longer or shorter than the mean length in their population of origin. Voles from an Illinois and Kansas population were examined separately as social monogamy appears more prevalent in the Illinois population. Illinois males with long avpr1a microsatellite alleles had smaller home ranges and overlapped a greater proportion of the home range of the female that they overlapped the most. Kansas males showed the opposite pattern. Illinois, but not Kansas, males with long avpr1a microsatellite alleles sired offspring with more females and sired more litters. Our results support the hypothesis that genetic variation associated with the avpr1a gene plays a role in mediating male prairie vole sociosexual behavior in nature. However, the relationship between specific male behaviors and male avpr1a microsatellite allele length sometimes differed significantly between Kansas and Illinois voles, suggesting relationships between specific male sociosexual behaviors and polymorphism associated with the avpr1a locus are complex, possibly involving specific nucleotide sequences or other population‐specific genetic differences.

Sexual fidelity trade-offs promote regulatory variation in the prairie vole brain.

Individual variation in social behavior seems ubiquitous, but we know little about how it relates to brain diversity. Among monogamous prairie voles, levels of vasopressin receptor (encoded by the gene avpr1a) in brain regions related to spatial memory predict male space use and sexual fidelity in the field. We find that trade-offs between the benefits of male fidelity and infidelity are reflected in patterns of territorial intrusion, offspring paternity, avpr1a expression, and the evolutionary fitness of alternative avpr1a alleles. DNA variation at the avpr1a locus includes polymorphisms that reliably predict the epigenetic status and neural expression of avpr1a, and patterns of DNA diversity demonstrate that avpr1a regulatory variation has been favored by selection. In prairie voles, trade-offs in the fitness consequences of social behaviors seem to promote neuronal and molecular diversity.

Length polymorphism at the avpr1a locus is correlated with male reproductive behavior in a natural population of prairie voles (Microtus ochrogaster)

Laboratory studies have shown that vasopressin can influence sociosexual behavior through its action on the vasopressin 1a receptor (V1aR). There is substantial evidence that the length of a microsatellite in the gene (avpr1a) encoding for the V1aR can affect social attachment to females and paternal behavior in male prairie voles under laboratory conditions. However, previous field studies of prairie voles have failed to detect a strong effect of the length of a male’s avpr1a allele on their sociosexual behavior, but these studies are typically much shorter than the average prairie vole breeding lifespan. We examined the relationship between male avpr1a microsatellite allele length and sociosexual behavior in a natural population of prairie voles for 15 weeks, closer to the lifespan of prairie voles in nature. Contrary to predictions, we found that males with the longest avpr1a microsatellite alleles were significantly more likely to sire offspring with more than one female and to sire offspring that survived until trappable age than males with the shortest avpr1a microsatellite allele lengths. This relationship was the strongest for males with the longest tenure on the study site. As in previous field studies, we did not find evidence of a relationship between a male’s avpr1a genotype and any index of social behavior including male residency status or the number of females with which males associate. This is the first study to support the hypothesis that a male’s avpr1a genotype is a factor underlying variation in the genetic mating system of prairie voles under natural conditions.

BAC-Based Sequencing of Behaviorally-Relevant Genes in the Prairie Vole

The prairie vole (Microtus ochrogaster) is an important model organism for the study of social behavior, yet our ability to correlate genes and behavior in this species has been limited due to a lack of genetic and genomic resources. Here we report the BAC-based targeted sequencing of behaviorally-relevant genes and flanking regions in the prairie vole. A total of 6.4 Mb of non-redundant or haplotype-specific sequence assemblies were generated that span the partial or complete sequence of 21 behaviorally-relevant genes as well as an additional 55 flanking genes. Estimates of nucleotide diversity from 13 loci based on alignments of 1.7 Mb of haplotype-specific assemblies revealed an average pair-wise heterozygosity (8.4×10−3). Comparative analyses of the prairie vole proteins encoded by the behaviorally-relevant genes identified >100 substitutions specific to the prairie vole lineage. Finally, our sequencing data indicate that a duplication of the prairie vole AVPR1A locus likely originated from a recent segmental duplication spanning a minimum of 105 kb. In summary, the results of our study provide the genomic resources necessary for the molecular and genetic characterization of a high-priority set of candidate genes for regulating social behavior in the prairie vole.

Comparison of Morphological Versus Molecular Characters for Discriminating Between Sympatric Meadow and Prairie Voles

Abstract Prairie (Microtus ochrogaster) and meadow (M. pennsylvanicus) voles are morphologically very similar species of rodents that are often found sympatrically. To assess the reliability of morphological characters typically used to differentiate between these two species, we compared the concordance of species identification based on morphological characteristics with identifications based on a species-specific difference within the avpr1a gene. We found that intraspecific variation in morphological characteristics resulted in erroneous or ambiguous species identification in the field (generally ≤5%) as well as for preserved specimens (up to ∼45%). Our data suggests that genotyping putative M. ochrogaster and M. pennsylvanicus at their avpr1a locus may be warranted for some individuals to ensure accurate species identification.

Beating the boojum: Comparative approaches to the neurobiology of social behavior

Neuropeptides coordinate complex social behaviors important to both basic and applied science. Understanding such phenomena requires supplementing the powerful tools of behavioral neuroscience with less conventional model species and more rigorous evolutionary analyses. We review studies that use comparative methods to examine the roles of vasopressin and oxytocin in mammalian social behavior. We find that oxytocin and vasopressin receptor distributions are remarkably variable within species. Studies of socially monogamous prairie voles reveal that pronounced individual differences in spatial memory structures (retrosplenial cortex and hippocampus) are better predictors of social and sexual fidelity than are areas known to regulate pairbonding directly, a pattern that seems to be mediated by the contributions of the neuropeptides to space use in natural settings. We next examine studies of individual and species differences in cis-regulatory regions of the avpr1a locus. While individual differences in social behaviors are linked to length of a microsatellite at the avpr1a locus, phylogenetic analyses reveal that the presence or absence of a microsatellite does not explain major differences between species. There seems to be no simple relationship between microsatellite length and behavior, but rather microsatellite length may be a marker for more subtle sequence differences between individuals. Lastly, we introduce the singing mouse, Scotinomys teguina, whose neuropeptide receptor distributions and unique natural history make it an exciting new model for mammalian vocalization and social cognition. The findings demonstrate how taxonomic and conceptual diversity provide a broader basis for understanding social behavior and its dysfunction.

Field tests of cis-regulatory variation at the prairie vole avpr1a locus: Association with V1aR abundance but not sexual or social fidelity

The neuropeptide vasopressin and its receptor V1aR are broadly implicated in social behavior and play a central role in several key aspects of male mating tactics in voles. In the prairie vole, a microsatellite in the cis-regulatory region of the gene encoding V1aR ( avpr1a) provides a potential genetic basis for individual variation in neural phenotype and behavior; recent studies found that allele length predicts V1aR expression and male social attachment in the laboratory. Here, we explore the relationship between avpr1a microsatellite length, V1aR neural phenotype, and field measures of monogamy and fitness in male prairie voles. We found significant effects of allele length on V1aR expression in structures integral to pairbond formation. These effects did not, however, translate to differences in mating tactics or reproductive success. Together, these data suggest that, while length polymorphism in the avpr1a microsatellite influences neuronal phenotype, this variation does not contribute significantly to male reproductive success and field behavior. We propose that previously reported behavioral effects may be mediated primarily by sequence variation at this locus, for which allele length is an imperfect proxy. By combining genetic, neuronal and ecological approaches, these data provide novel insights into the contribution of genotype to natural diversity in brain and behavior.

On switches and knobs, microsatellites and monogamy

Comparative studies in voles have suggested that a polymorphic microsatellite upstream of the Avpr1a locus contributes to the evolution of monogamy. A recent study challenged this hypothesis by reporting that there is no relationship between microsatellite structure and monogamy in 21 vole species. Although the study demonstrates that the microsatellite is not a universal genetic switch that determines mating strategy, the findings do not preclude a substantial role for Avpr1a in regulating social behaviors associated with monogamy.

Study of V1-vascular Vasopressin Receptor Gene Microsatellite Polymorphisms in Human Essential Hypertension

M. Thibonnier, M. K. Graves, M. S. Wagner, N. Chatelain, F. Soubrier, P. Corvol, H. F. Willard and X. Jeunemaitre. Study of V1-vascular Vasopressin Receptor Gene Microsatellite Polymorphisms in Human Essential Hypertension. Journal of Molecular and Cellular Cardiology (2000) 32, 557–564. Vasopressin (AVP) actions on vascular tone and blood pressure are mainly mediated by the V1-vascular receptor (V1R). We recently reported the structure and functional expression of the human V1R cDNA and described the genomic characteristics, tissue expression, chromosomal localization, and regional mapping of the human V1R gene, AVPR1A. To test whether the V1R is a marker for human essential hypertension, we sequenced the human AVPR1A gene and its 5 upstream region and found several DNA microsatellite motifs. One (GT)14-(GA)13-(A)8microsatellite is located 2983 bp downstream of the transcription start site, within a 2.2 kbp intron interrupting the coding sequence of the receptor. Three other microsatellites are present in the 5 flanking DNA of the AVPR1A gene: a (GT)25dinucleotide repeat, a complex (CT)4-TT-(CT)8-(GT)24motif and a (GATA)14tetranucleotide repeat located respectively 3956 bp, 3625 bp and 553 bp upstream of the transcription start site. Analysis of these polymorphisms in 79 hypertensive and 86 normotensive subjects for the (GT)14-(GA)13-(A)8and the (GT)25motifs revealed a high percentage of heterozygosity but no difference in alleles frequencies between the two groups. A linkage study using the affected sib pair method and the (GT)25repeat in 446 hypertensive sib pairs from 282 French Caucasian pedigrees showed no excess of alleles sharing at the AVPR1A locus. No linkage was found in the subgroups of patients with early onset hypertension (diagnosis before age 40) or severe hypertension (diastolic blood pressure ≥100 mmHg or requirement for ≥two medications). These findings suggest that molecular variants of the V1R gene are not involved in unselected forms of essential hypertension.