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Copy number variants and selective sweeps in natural populations of the house mouse (Mus musculus domesticus).

Bryk J, Tautz D - Front Genet (2014)

Bottom Line: Roughly two thirds of all CNVs found were deletions.We found no enrichment of CNVs among the differentially expressed genes between the populations compared to the invariant ones, nor any meaningful correlation between CNVs and gene expression changes.Among the CNV genes, we found cellular component gene ontology categories of the synapse overrepresented among all the 2444 genes tested.

View Article: PubMed Central - PubMed

Affiliation: Max Planck Institute for Evolutionary Biology Plön, Germany.

ABSTRACT
Copy-number variants (CNVs) may play an important role in early adaptations, potentially facilitating rapid divergence of populations. We describe an approach to study this question by investigating CNVs present in natural populations of mice in the early stages of divergence and their involvement in selective sweeps. We have analyzed individuals from two recently diverged natural populations of the house mouse (Mus musculus domesticus) from Germany and France using custom, high-density, comparative genome hybridization arrays (CGH) that covered almost 164 Mb and 2444 genes. One thousand eight hundred and sixty one of those genes we previously identified as differentially expressed between these populations, while the expression of the remaining genes was invariant. In total, we identified 1868 CNVs across all 10 samples, 200 bp to 600 kb in size and affecting 424 genic regions. Roughly two thirds of all CNVs found were deletions. We found no enrichment of CNVs among the differentially expressed genes between the populations compared to the invariant ones, nor any meaningful correlation between CNVs and gene expression changes. Among the CNV genes, we found cellular component gene ontology categories of the synapse overrepresented among all the 2444 genes tested. To investigate potential adaptive significance of the CNV regions, we selected six that showed large differences in frequency of CNVs between the two populations and analyzed variation in at least two microsatellites surrounding the loci in a sample of 46 unrelated animals from the same populations collected in field trappings. We identified two loci with large differences in microsatellite heterozygosity (Sfi1 and Glo1/Dnahc8 regions) and one locus with low variation across the populations (Cmah), thus suggesting that these genomic regions might have recently undergone selective sweeps. Interestingly, the Glo1 CNV has previously been implicated in anxiety-like behavior in mice, suggesting a differential evolution of a behavioral trait.

No MeSH data available.


Related in: MedlinePlus

Graphical overview of the Canonical Pathway analysis. This image was generated by Canonical Pathways analysis and shows genes that belong to the category of neuropathic pain signaling in dorsal horn neurons. Nodes in gray and purple depict genes from the CGH array submitted for the analysis: in gray, genes without CNVs and in purple, genes with CNVs. Solid lines around a node depict a kinase and dashed lines depict an ion transporter. Double lines indicate complex of several subunits.
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Figure 4: Graphical overview of the Canonical Pathway analysis. This image was generated by Canonical Pathways analysis and shows genes that belong to the category of neuropathic pain signaling in dorsal horn neurons. Nodes in gray and purple depict genes from the CGH array submitted for the analysis: in gray, genes without CNVs and in purple, genes with CNVs. Solid lines around a node depict a kinase and dashed lines depict an ion transporter. Double lines indicate complex of several subunits.

Mentions: While we expected to identify many CNVs in our samples, we found it surprising that they affected genes involved in synaptic structures and cellular membranes of Gene Ontology categories. This finding prompted us to check the genes with CNV in a pathway enrichment analysis using Ingenuity's Canonical Pathways software. We found out that the genes with CNVs are overrepresented in synaptic neuropathic pain signaling in dorsal horn neurons, where several genes (KCh, NMDAR, PKG, IP3R, and PI3K) contribute to activation of the transcription factors Elk1, c-Fos, and CREB. This in turn is consistent with our findings from gene expression analysis (Bryk et al., 2013), where differentially expressed genes were overrepresented in the TRANSFAC category of CREB family of transcription factors. However, our choice of loci for analysis is evidently biased toward genes that we had identified in the previous expression study. Still, the CNV analysis provides a line of evidence suggesting that the synaptic signaling in the populations tested harbors changes on DNA and transcriptome levels (overview of the Canonical Pathway analysis is shown in Figure 4). However, it is worth emphasizing here that these are CNVs found in both populations; when we ran the GO or Canonical Pathway analysis only on CNVs that differentiate the two groups, we found no significant enrichment of genes from any GO category or pathway tested. It is currently unclear whether the synaptic and membrane structures-related genes that seem prone to harbor CNVs in our populations have any functional significance.


Copy number variants and selective sweeps in natural populations of the house mouse (Mus musculus domesticus).

Bryk J, Tautz D - Front Genet (2014)

Graphical overview of the Canonical Pathway analysis. This image was generated by Canonical Pathways analysis and shows genes that belong to the category of neuropathic pain signaling in dorsal horn neurons. Nodes in gray and purple depict genes from the CGH array submitted for the analysis: in gray, genes without CNVs and in purple, genes with CNVs. Solid lines around a node depict a kinase and dashed lines depict an ion transporter. Double lines indicate complex of several subunits.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4042557&req=5

Figure 4: Graphical overview of the Canonical Pathway analysis. This image was generated by Canonical Pathways analysis and shows genes that belong to the category of neuropathic pain signaling in dorsal horn neurons. Nodes in gray and purple depict genes from the CGH array submitted for the analysis: in gray, genes without CNVs and in purple, genes with CNVs. Solid lines around a node depict a kinase and dashed lines depict an ion transporter. Double lines indicate complex of several subunits.
Mentions: While we expected to identify many CNVs in our samples, we found it surprising that they affected genes involved in synaptic structures and cellular membranes of Gene Ontology categories. This finding prompted us to check the genes with CNV in a pathway enrichment analysis using Ingenuity's Canonical Pathways software. We found out that the genes with CNVs are overrepresented in synaptic neuropathic pain signaling in dorsal horn neurons, where several genes (KCh, NMDAR, PKG, IP3R, and PI3K) contribute to activation of the transcription factors Elk1, c-Fos, and CREB. This in turn is consistent with our findings from gene expression analysis (Bryk et al., 2013), where differentially expressed genes were overrepresented in the TRANSFAC category of CREB family of transcription factors. However, our choice of loci for analysis is evidently biased toward genes that we had identified in the previous expression study. Still, the CNV analysis provides a line of evidence suggesting that the synaptic signaling in the populations tested harbors changes on DNA and transcriptome levels (overview of the Canonical Pathway analysis is shown in Figure 4). However, it is worth emphasizing here that these are CNVs found in both populations; when we ran the GO or Canonical Pathway analysis only on CNVs that differentiate the two groups, we found no significant enrichment of genes from any GO category or pathway tested. It is currently unclear whether the synaptic and membrane structures-related genes that seem prone to harbor CNVs in our populations have any functional significance.

Bottom Line: Roughly two thirds of all CNVs found were deletions.We found no enrichment of CNVs among the differentially expressed genes between the populations compared to the invariant ones, nor any meaningful correlation between CNVs and gene expression changes.Among the CNV genes, we found cellular component gene ontology categories of the synapse overrepresented among all the 2444 genes tested.

View Article: PubMed Central - PubMed

Affiliation: Max Planck Institute for Evolutionary Biology Plön, Germany.

ABSTRACT
Copy-number variants (CNVs) may play an important role in early adaptations, potentially facilitating rapid divergence of populations. We describe an approach to study this question by investigating CNVs present in natural populations of mice in the early stages of divergence and their involvement in selective sweeps. We have analyzed individuals from two recently diverged natural populations of the house mouse (Mus musculus domesticus) from Germany and France using custom, high-density, comparative genome hybridization arrays (CGH) that covered almost 164 Mb and 2444 genes. One thousand eight hundred and sixty one of those genes we previously identified as differentially expressed between these populations, while the expression of the remaining genes was invariant. In total, we identified 1868 CNVs across all 10 samples, 200 bp to 600 kb in size and affecting 424 genic regions. Roughly two thirds of all CNVs found were deletions. We found no enrichment of CNVs among the differentially expressed genes between the populations compared to the invariant ones, nor any meaningful correlation between CNVs and gene expression changes. Among the CNV genes, we found cellular component gene ontology categories of the synapse overrepresented among all the 2444 genes tested. To investigate potential adaptive significance of the CNV regions, we selected six that showed large differences in frequency of CNVs between the two populations and analyzed variation in at least two microsatellites surrounding the loci in a sample of 46 unrelated animals from the same populations collected in field trappings. We identified two loci with large differences in microsatellite heterozygosity (Sfi1 and Glo1/Dnahc8 regions) and one locus with low variation across the populations (Cmah), thus suggesting that these genomic regions might have recently undergone selective sweeps. Interestingly, the Glo1 CNV has previously been implicated in anxiety-like behavior in mice, suggesting a differential evolution of a behavioral trait.

No MeSH data available.


Related in: MedlinePlus