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.
Highlights
Copy–number variants (CNVs) have become an appreciated type of variation in the genomes of humans and mice
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
Our subject are allopatric populations of the house mouse Mus musculus domesticus, from the Massif Central in France and around Cologne/Bonn area in Germany that diverged less than 3000 years ago (Cucchi et al, 2005); details of the populations and trappings are published in Ihle et al (2006)
Summary
Copy–number variants (CNVs) have become an appreciated type of variation in the genomes of humans and mice. Since technological advances in microarray technologies and sequencing allowed genome–wide investigation of this type of structural variation in humans (Redon et al, 2006) and mice (Cutler et al, 2007; Graubert et al, 2007), it has become apparent that CNVs are (a) numerous and ubiquitous (b) variable in size, including very large ones and (c) highly mutable. Across 41 strains of inbred mouse lines there were on average 51 CNVs (range 15–106 CNV per genome) with an average size of 183 kb (amplification) and 204 kb (deletion) (Cutler et al, 2007) per genome. In human populations with a history of eating starch, a gene encoding starch–digesting enzyme amylase has more copies and produces more salivary amylase than in populations with no starch–eating history, with population genetic evidence for spread of the multiplied DNA segment in starcheating populations (Perry et al, 2007). Humans with more copies of a ligand that binds the same receptor as HIV-1 are less susceptible to infection www.frontiersin.org
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