title: 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.
authors.affiliation: Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Polimanti
authors.affiliation: Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Piacentini
authors.affiliation: Clinical Pathophysiology Center, AFaR - 'San Giovanni Calibita' Fatebenefratelli Hospital, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Iorio
authors.affiliation: Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.
authors.forename: Flavio
authors.initials: F
authors.lastname: De Angelis
authors.affiliation: Institute and Museum of Anthropology, M. Lomonosov State University, Moscow, Russia.
authors.forename: Andrey
authors.initials: A
authors.lastname: Kozlov
authors.affiliation: Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Novelletto
authors.affiliation: Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Fuciarelli
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D002892:Chromosomes, Human, Pair 22; D056915:DNA Copy Number Variations; D004777:Environment; D005787:Gene Frequency; D056726:Genetic Association Studies; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000737:chemistry / Q000235:genetics; D008263:Macrophage Migration-Inhibitory Factors / Q000737:chemistry / Q000235:genetics; D008957:Models, Genetic; D008969:Molecular Sequence Data; D005810:Multigene Family; D012307:Risk Factors; D012641:Selection, Genetic; D016415:Sequence Alignment; D012880:Skin Pigmentation / Q000235:genetics
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human