title: The interplay between natural selection and susceptibility to melanoma on allele 374F of SLC45A2 gene in a South European population.
abstract: We aimed to study the selective pressures interacting on SLC45A2 to investigate the interplay between selection and susceptibility to disease. Thus, we enrolled 500 volunteers from a geographically limited population (Basques from the North of Spain) and by resequencing the whole coding region and intron 5 of the 34 most and the 34 least pigmented individuals according to the reflectance distribution, we observed that the polymorphism Leu374Phe (L374F, rs16891982) was statistically associated with skin color variability within this sample. In particular, allele 374F was significantly more frequent among the individuals with lighter skin. Further genotyping an independent set of 558 individuals of a geographically wider population with known ancestry in the Spanish population also revealed that the frequency of L374F was significantly correlated with the incident UV radiation intensity. Selection tests suggest that allele 374F is being positively selected in South Europeans, thus indicating that depigmentation is an adaptive process. Interestingly, by genotyping 119 melanoma samples, we show that this variant is also associated with an increased susceptibility to melanoma in our populations. The ultimate driving force for this adaptation is unknown, but it is compatible with the vitamin D hypothesis. This shows that molecular evolution analysis can be used as a useful technology to predict phenotypic and biomedical consequences in humans.
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, Leioa, Bizkaia, Spain.
authors.forename: Saioa
authors.initials: S
authors.lastname: López
authors.affiliation: Ertzaintza Forensic Unit, Erandio, Bizkaia, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: García
authors.affiliation: Ertzaintza Forensic Unit, Erandio, Bizkaia, Spain.
authors.forename: Iñaki
authors.initials: I
authors.lastname: Yurrebaso
authors.affiliation: CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Research Unit, Hospital Universitario N.S. de Candelaria, Tenerife, Spain; Applied Genomics Group (G2A), Genetics Laboratory, Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna, Tenerife, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Flores
authors.affiliation: CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Research Unit, Hospital Universitario N.S. de Candelaria, Tenerife, Spain; Research Unit, Universitary Hospital Dr. Negrin, Las Palmas de Gran Canaria, Spain.
authors.forename: Marialbert
authors.initials: M
authors.lastname: Acosta-Herrera
authors.affiliation: Center for Computational Genetics and Genomics, Temple University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Hua
authors.initials: H
authors.lastname: Chen
authors.affiliation: Dermatology Service, BioCruces Health Research Institute, Cruces University Hospital, Cruces-Barakaldo, Bizkaia, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Gardeazabal
authors.affiliation: Dermatology Service, BioCruces Health Research Institute, Basurto University Hospital, Bilbao, Bizkaia, Spain.
authors.forename: Jesús María
authors.initials: JM
authors.lastname: Careaga
authors.affiliation: Department of Cell Biology and Histology, University of the Basque Country UPV/EHU, Leioa, Bizkaia, Spain.
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Boyano
authors.affiliation: Dermatology Service, BioCruces Health Research Institute, Basurto University Hospital, Bilbao, Bizkaia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Sánchez
authors.affiliation: Dermatology Service, BioCruces Health Research Institute, Cruces University Hospital, Cruces-Barakaldo, Bizkaia, Spain.
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Ratón-Nieto
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, Leioa, Bizkaia, Spain.
authors.forename: Arrate
authors.initials: A
authors.lastname: Sevilla
authors.affiliation: Department of Zoology and Animal Cell Biology, University of the Basque Country UPV/EHU, Leioa, Bizkaia, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Smith-Zubiaga
authors.affiliation: Department of Cell Biology and Histology, University of the Basque Country UPV/EHU, Leioa, Bizkaia, Spain.
authors.forename: Alicia García
authors.initials: AG
authors.lastname: de Galdeano
authors.affiliation: Department of Medicine, Jaume I University of Castellón, Castellón, Spain.
authors.forename: Conrado
authors.initials: C
authors.lastname: Martinez-Cadenas
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, Leioa, Bizkaia, Spain.
authors.forename: Neskuts
authors.initials: N
authors.lastname: Izagirre
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, Leioa, Bizkaia, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: de la Rúa
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, Leioa, Bizkaia, Spain.
authors.forename: Santos
authors.initials: S
authors.lastname: Alonso
mesh_terms: D000483:Alleles; D000951:Antigens, Neoplasm / Q000235:genetics*; D005060:Europe; D005787:Gene Frequency; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics*; D016366:Open Reading Frames; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D013030:Spain; D044465:White People / Q000235:genetics*
chemical_list: D000951:Antigens, Neoplasm; D026901:Membrane Transport Proteins; C510061:SLC45A2 protein, human
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