title: Latitudinal Clines of the Human Vitamin D Receptor and Skin Color Genes.
abstract: The well-documented latitudinal clines of genes affecting human skin color presumably arise from the need for protection from intense ultraviolet radiation (UVR) vs. the need to use UVR for vitamin D synthesis. Sampling 751 subjects from a broad range of latitudes and skin colors, we investigated possible multilocus correlated adaptation of skin color genes with the vitamin D receptor gene (VDR), using a vector correlation metric and network method called BlocBuster. We discovered two multilocus networks involving VDR promoter and skin color genes that display strong latitudinal clines as multilocus networks, even though many of their single gene components do not. Considered one by one, the VDR components of these networks show diverse patterns: no cline, a weak declining latitudinal cline outside of Africa, and a strong in- vs. out-of-Africa frequency pattern. We confirmed these results with independent data from HapMap. Standard linkage disequilibrium analyses did not detect these networks. We applied BlocBuster across the entire genome, showing that our networks are significant outliers for interchromosomal disequilibrium that overlap with environmental variation relevant to the genes' functions. These results suggest that these multilocus correlations most likely arose from a combination of parallel selective responses to a common environmental variable and coadaptation, given the known Mendelian epistasis among VDR and the skin color genes.
authors.affiliation: Division of Pediatric Endocrinology, Mayer Children's Hospital, Rambam Medical Center Haifa 30196, Israel, Haifa, Israel Rappaport Family Faculty of Medicine, The Technion - Israel Institute of Technology, Haifa 30196, Israel, Haifa, Israel.
authors.forename: Dov
authors.initials: D
authors.lastname: Tiosano
authors.affiliation: Pediatric Endocrinology, Vall d'Hebron Research Institute (VHIR), CIBERER, Autonomous University, 08035 Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Audi
authors.affiliation: Department of Computer Science and Engineering, Washington University, St. Louis, Missouri.
authors.forename: Sharlee
authors.identifier: 0000-0003-2731-7377
authors.initials: S
authors.lastname: Climer
authors.affiliation: Department of Computer Science and Engineering, Washington University, St. Louis, Missouri.
authors.forename: Weixiong
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Biology, Washington University, St. Louis, Missouri 63130-4899 Department of Evolutionary and Environmental Biology, University of Haifa Haifa 39105, Israel.
authors.forename: Alan R
authors.identifier: 0000-0002-0167-845X
authors.initials: AR
authors.lastname: Templeton
authors.affiliation: Pediatric Endocrinology, Vall d'Hebron Research Institute (VHIR), CIBERER, Autonomous University, 08035 Barcelona, Spain.
authors.forename: Monica
authors.initials: M
authors.lastname: Fernández-Cancio
authors.affiliation: Rappaport Family Faculty of Medicine, The Technion - Israel Institute of Technology, Haifa 30196, Israel, Haifa, Israel Department of Evolutionary and Environmental Biology, University of Haifa Haifa 39105, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Gershoni-Baruch
authors.affiliation: Pediatric Service, Area Basica de Salut (ABS), Salt, 17001 Girona, Spain.
authors.forename: José Miguel
authors.initials: JM
authors.lastname: Sánchez-Muro
authors.affiliation: Department of Pediatrics, Ain Shams University, 11566 Cairo, Egypt.
authors.forename: Mohamed
authors.initials: M
authors.lastname: El Kholy
authors.affiliation: Rappaport Family Faculty of Medicine, The Technion - Israel Institute of Technology, Haifa 30196, Israel, Haifa, Israel.
authors.forename: Zèev
authors.initials: Z
authors.lastname: Hochberg
mesh_terms: D000220:Adaptation, Biological / Q000235:genetics; D000483:Alleles; D000531:Altitude; D019295:Computational Biology / Q000379:methods; D004843:Epistasis, Genetic; D005787:Gene Frequency; D053263:Gene Regulatory Networks; D059647:Gene-Environment Interaction; D008040:Genetic Linkage; D015894:Genome, Human; D023281:Genomics / Q000379:methods; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D018167:Receptors, Calcitriol / Q000235:genetics*; D012880:Skin Pigmentation / Q000235:genetics*
chemical_list: D018167:Receptors, Calcitriol; C579457:VDR protein, human
keywords: adaptation; epistasis; linkage disequilibrium; network analysis; skin color; vitamin D