The interplay between natural selection and susceptibility to melanoma on allele 374F of SLC45A2 gene in a South European population

PLoS One. 2014 Aug 5;9(8):e104367. doi: 10.1371/journal.pone.0104367. eCollection 2014.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Antigens, Neoplasm / genetics*
  • Europe
  • Gene Frequency
  • Gene-Environment Interaction
  • Genetic Predisposition to Disease*
  • Haplotypes
  • Humans
  • Melanoma / genetics*
  • Membrane Transport Proteins / genetics*
  • Open Reading Frames
  • Polymorphism, Single Nucleotide
  • Quantitative Trait, Heritable
  • Selection, Genetic*
  • Sequence Analysis, DNA
  • Spain
  • White People / genetics*


  • Antigens, Neoplasm
  • Membrane Transport Proteins
  • SLC45A2 protein, human

Grant support

This work was supported by the former Spanish Ministerio de Ciencia e Innovación, project CGL2008-04066/BOS to S.A.; by the Dpt. Educacion, Universidades e Investigación of the Basque Government, project IT542-10 to C.R.; the University of the Basque Country program UFI11/09; a predoctoral fellowship from the Dept. Educación, Universidades e Investigación of the Basque Government to S.L. (BFI09.248); "Programa de Investigacion Cientifica de la Universidad de La Laguna" (boc-a-2010-255-7177) the Health Institute “Carlos III” (FIS PI11/00623) to C.F. and co-financed by the European Regional Development Funds, “A way of making Europe” from the European Union. M.A.H. was supported by a fellowship from the Instituto de Salud Carlos III (FI11/00074). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.