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Haplotype differences for copy number variants in the 22q11.23 region among human populations: a pigmentation-based model for selective pressure.

ABSTRACT: Two gene clusters are tightly linked in a narrow region of chromosome 22q11.23: the macrophage migration inhibitory factor (MIF) gene family and the glutathione S-transferase theta class. Within 120?kb in this region, two 30-kb deletions reach high frequencies in human populations. This gives rise to four haplotypic arrangements, which modulate the number of genes in both families. The variable patterns of linkage disequilibrium (LD) between these copy number variants (CNVs) in diverse human populations remain poorly understood. We analyzed 2469 individuals belonging to 27 human populations with different ethnic origins. Then we correlated the genetic variability of 22q11.23 CNVs with environmental variables. We confirmed an increasing strength of LD from Africa to Asia and to Europe. Further, we highlighted strongly significant correlations between the frequency of one of the haplotypes and pigmentation-related variables: skin color (R(2)=0.675, P<0.001), distance from the equator (R(2)=0.454, P<0.001), UVA radiation (R(2)=0.439, P<0.001), and UVB radiation (R(2)=0.313, P=0.002). The fact that all MIF-related genes are retained on this haplotype and the evidences gleaned from experimental systems seem to agree with the role of MIF-related genes in melanogenesis. As such, we propose a model that explains the geographic and ethnic distribution of 22q11.23 CNVs among human populations, assuming that MIF-related gene dosage could be associated with adaptation to low UV radiation.

SUBMITTER: Polimanti R

PROVIDER: S-EPMC4266733 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Haplotype differences for copy number variants in the 22q11.23 region among human populations: a pigmentation-based model for selective pressure.

Polimanti Renato R Piacentini Sara S Iorio Andrea A De Angelis Flavio F Kozlov Andrey A Novelletto Andrea A Fuciarelli Maria M

European journal of human genetics : EJHG 20140326 1

Two gene clusters are tightly linked in a narrow region of chromosome 22q11.23: the macrophage migration inhibitory factor (MIF) gene family and the glutathione S-transferase theta class. Within 120 kb in this region, two 30-kb deletions reach high frequencies in human populations. This gives rise to four haplotypic arrangements, which modulate the number of genes in both families. The variable patterns of linkage disequilibrium (LD) between these copy number variants (CNVs) in diverse human pop ...[more]

PMID: 24667780

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Project description: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.

Dataset Information

Haplotype differences for copy number variants in the 22q11.23 region among human populations: a pigmentation-based model for selective pressure.

Publications

Haplotype differences for copy number variants in the 22q11.23 region among human populations: a pigmentation-based model for selective pressure.

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