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The relative contribution of proximal 5' flanking sequence and microsatellite variation on brain vasopressin 1a receptor (Avpr1a) gene expression and behavior.

Donaldson ZR, Young LJ - PLoS Genet. (2013)

Bottom Line: Previous work has suggested that both the proximal 5' flanking region and a polymorphic microsatellite element within that region of the vole Avpr1a gene are associated with variation in V1a receptor (V1aR) distribution and behavior, but neither has been causally linked.This is the first direct evidence that polymorphic microsatellite elements near behaviorally relevant genes can contribute to diversity in brain gene expression profiles, providing a mechanism for generating behavioral diversity both at the individual and species level.However, our results suggest that many features of species-specific expression patterns are mediated by elements outside of the immediate 5' flanking region of the gene.

View Article: PubMed Central - PubMed

Affiliation: Division of Integrative Neuroscience, Department of Psychiatry, Columbia University, New York, New York, United States of America. zoe.donaldson@gmail.com

ABSTRACT
Certain genes exhibit notable diversity in their expression patterns both within and between species. One such gene is the vasopressin receptor 1a gene (Avpr1a), which exhibits striking differences in neural expression patterns that are responsible for mediating differences in vasopressin-mediated social behaviors. The genomic mechanisms that contribute to these remarkable differences in expression are not well understood. Previous work has suggested that both the proximal 5' flanking region and a polymorphic microsatellite element within that region of the vole Avpr1a gene are associated with variation in V1a receptor (V1aR) distribution and behavior, but neither has been causally linked. Using homologous recombination in mice, we reveal the modest contribution of proximal 5' flanking sequences to species differences in V1aR distribution, and confirm that variation in V1aR distribution impacts stress-coping in the forced swim test. We also demonstrate that the vole Avpr1a microsatellite structure contributes to Avpr1a expression in the amygdala, thalamus, and hippocampus, mirroring a subset of the inter- and intra-species differences observed in central V1aR patterns in voles. This is the first direct evidence that polymorphic microsatellite elements near behaviorally relevant genes can contribute to diversity in brain gene expression profiles, providing a mechanism for generating behavioral diversity both at the individual and species level. However, our results suggest that many features of species-specific expression patterns are mediated by elements outside of the immediate 5' flanking region of the gene.

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Allelic differences in the Avpr1a microsatellite contribute to intraspecies variation in V1aR binding.Comparison of mouse lines homozygous for either the long (A, C) or short version (B, D) of the Avpr1a microsatellite showed that mice carrying the long version had higher levels of V1a in the dentate gyrus (DG) (E). Data are represented as mean ± SEM; n = 8 animals/group; **p<0.01, #p<0.05 compared to WT.
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pgen-1003729-g005: Allelic differences in the Avpr1a microsatellite contribute to intraspecies variation in V1aR binding.Comparison of mouse lines homozygous for either the long (A, C) or short version (B, D) of the Avpr1a microsatellite showed that mice carrying the long version had higher levels of V1a in the dentate gyrus (DG) (E). Data are represented as mean ± SEM; n = 8 animals/group; **p<0.01, #p<0.05 compared to WT.

Mentions: Allelic variation in Avpr1a has also been tied to intra-species variation in V1aR patterns in prairie voles [17], [36], [37]. However, these studies could not distinguish direct effects of the microsatellite from the possibility that the microsatellite is in linkage disequilibrium with other functional elements. In order to determine the direct contribution of the microsatellite to individual differences in neural V1aR distributions, we compared V1aR binding patterns in mice homozygous for either the long (pvKI-long) or the short version (pvKI-short) of the prairie vole microsatellite in the VP, LS, CeA, PVthal, and DG. The prairie long and short form of the microsatellite are substantially more similar to each other than to the meadow microsatellite. As such, we predicted that the potential differences conferred by this region would be relatively subtle. A 2-way ANOVA revealed a main effect of both brain region (F(4, 80) = 165.0, p<0.001) and genotype (F(4, 80) = 12.1, p = 0.001) on V1aR levels (Figure 5E). In addition, there was a significant interaction between brain region and genotype (F(4, 80) = 7.8, p<0.001), and simple main effects analysis with Sidak-adjusted α showed that pvKI-long mice had higher V1aR levels in the DG (p<0.01) but not in the CeA (p = 0.42), PVThal (p = 0.96), LS (p = 0.93) or VP (p = 0.77; Figure 5). Although significant for the DG, the differences observed between these mice are less profound than reported for prairie voles with different microsatellite lengths, suggesting that while individual differences in microsatellite structure do directly impact expression in the brain, other linked polymorphisms may account for the larger number of regional differences found in prairie voles.


The relative contribution of proximal 5' flanking sequence and microsatellite variation on brain vasopressin 1a receptor (Avpr1a) gene expression and behavior.

Donaldson ZR, Young LJ - PLoS Genet. (2013)

Allelic differences in the Avpr1a microsatellite contribute to intraspecies variation in V1aR binding.Comparison of mouse lines homozygous for either the long (A, C) or short version (B, D) of the Avpr1a microsatellite showed that mice carrying the long version had higher levels of V1a in the dentate gyrus (DG) (E). Data are represented as mean ± SEM; n = 8 animals/group; **p<0.01, #p<0.05 compared to WT.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757045&req=5

pgen-1003729-g005: Allelic differences in the Avpr1a microsatellite contribute to intraspecies variation in V1aR binding.Comparison of mouse lines homozygous for either the long (A, C) or short version (B, D) of the Avpr1a microsatellite showed that mice carrying the long version had higher levels of V1a in the dentate gyrus (DG) (E). Data are represented as mean ± SEM; n = 8 animals/group; **p<0.01, #p<0.05 compared to WT.
Mentions: Allelic variation in Avpr1a has also been tied to intra-species variation in V1aR patterns in prairie voles [17], [36], [37]. However, these studies could not distinguish direct effects of the microsatellite from the possibility that the microsatellite is in linkage disequilibrium with other functional elements. In order to determine the direct contribution of the microsatellite to individual differences in neural V1aR distributions, we compared V1aR binding patterns in mice homozygous for either the long (pvKI-long) or the short version (pvKI-short) of the prairie vole microsatellite in the VP, LS, CeA, PVthal, and DG. The prairie long and short form of the microsatellite are substantially more similar to each other than to the meadow microsatellite. As such, we predicted that the potential differences conferred by this region would be relatively subtle. A 2-way ANOVA revealed a main effect of both brain region (F(4, 80) = 165.0, p<0.001) and genotype (F(4, 80) = 12.1, p = 0.001) on V1aR levels (Figure 5E). In addition, there was a significant interaction between brain region and genotype (F(4, 80) = 7.8, p<0.001), and simple main effects analysis with Sidak-adjusted α showed that pvKI-long mice had higher V1aR levels in the DG (p<0.01) but not in the CeA (p = 0.42), PVThal (p = 0.96), LS (p = 0.93) or VP (p = 0.77; Figure 5). Although significant for the DG, the differences observed between these mice are less profound than reported for prairie voles with different microsatellite lengths, suggesting that while individual differences in microsatellite structure do directly impact expression in the brain, other linked polymorphisms may account for the larger number of regional differences found in prairie voles.

Bottom Line: Previous work has suggested that both the proximal 5' flanking region and a polymorphic microsatellite element within that region of the vole Avpr1a gene are associated with variation in V1a receptor (V1aR) distribution and behavior, but neither has been causally linked.This is the first direct evidence that polymorphic microsatellite elements near behaviorally relevant genes can contribute to diversity in brain gene expression profiles, providing a mechanism for generating behavioral diversity both at the individual and species level.However, our results suggest that many features of species-specific expression patterns are mediated by elements outside of the immediate 5' flanking region of the gene.

View Article: PubMed Central - PubMed

Affiliation: Division of Integrative Neuroscience, Department of Psychiatry, Columbia University, New York, New York, United States of America. zoe.donaldson@gmail.com

ABSTRACT
Certain genes exhibit notable diversity in their expression patterns both within and between species. One such gene is the vasopressin receptor 1a gene (Avpr1a), which exhibits striking differences in neural expression patterns that are responsible for mediating differences in vasopressin-mediated social behaviors. The genomic mechanisms that contribute to these remarkable differences in expression are not well understood. Previous work has suggested that both the proximal 5' flanking region and a polymorphic microsatellite element within that region of the vole Avpr1a gene are associated with variation in V1a receptor (V1aR) distribution and behavior, but neither has been causally linked. Using homologous recombination in mice, we reveal the modest contribution of proximal 5' flanking sequences to species differences in V1aR distribution, and confirm that variation in V1aR distribution impacts stress-coping in the forced swim test. We also demonstrate that the vole Avpr1a microsatellite structure contributes to Avpr1a expression in the amygdala, thalamus, and hippocampus, mirroring a subset of the inter- and intra-species differences observed in central V1aR patterns in voles. This is the first direct evidence that polymorphic microsatellite elements near behaviorally relevant genes can contribute to diversity in brain gene expression profiles, providing a mechanism for generating behavioral diversity both at the individual and species level. However, our results suggest that many features of species-specific expression patterns are mediated by elements outside of the immediate 5' flanking region of the gene.

Show MeSH
Related in: MedlinePlus