title: Complex signatures of selection for the melanogenic loci TYR, TYRP1 and DCT in humans.
abstract: BACKGROUND
  The observed correlation between ultraviolet light incidence and skin color, together with the geographical apportionment of skin reflectance among human populations, suggests an adaptive value for the pigmentation of the human skin. We have used Affymetrix U133a v2.0 gene expression microarrays to investigate the expression profiles of a total of 9 melanocyte cell lines (5 from lightly pigmented donors and 4 from darkly pigmented donors) plus their respective unirradiated controls. In order to reveal signatures of selection in loci with a bearing on skin pigmentation in humans, we have resequenced between 4 to 5 kb of the proximal regulatory regions of three of the most differently expressed genes, in the expectation that variation at regulatory regions might account for intraespecific morphological diversity, as suggested elsewhere.
  
  
  RESULTS
  Contrary to our expectations, expression profiles did not cluster the cells into unirradiated versus irradiated melanocytes, or into lightly pigmented versus darkly pigmented melanocytes. Instead, expression profiles correlated with the presence of Bovine Pituitary Extract (known to contain alpha-MSH) in the media. This allowed us to differentiate between melanocytes that are synthesizing melanin and those that are not. TYR, TYRP1 and DCT were among the five most differently expressed genes between these two groups. Population genetic analyses of sequence haplotypes of the proximal regulatory flanking-regions included Tajima's D, HEW and DHEW neutrality tests analysis. These were complemented with EHH tests (among others) in which the significance was obtained by a novel approach using extensive simulations under the coalescent model with recombination. We observe strong evidence for positive selection for TYRP1 alleles in Africans and for DCT and TYRP1 in Asians. However, the overall picture reflects a complex pattern of selection, which might include overdominance for DCT in Europeans.
  
  
  CONCLUSIONS
  Diversity patterns clearly evidence adaptive selection in pigmentation genes in Africans and Asians. In Europeans, the evidence is more complex, and both directional and balancing selection may be involved in light skin. As a result, different non-African populations may have acquired light skin by alternative ways, and so light skin, and perhaps dark skin too, may be the result of convergent evolution.
authors.affiliation: Dept, Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, Barrio Sarriena s/n, 48940 Leioa, Bizkaia, Spain. santos.alonso@ehu.es
authors.forename: Santos
authors.initials: S
authors.lastname: Alonso
authors.forename: Neskuts
authors.initials: N
authors.lastname: Izagirre
authors.forename: Isabel
authors.initials: I
authors.lastname: Smith-Zubiaga
authors.forename: Jesús
authors.initials: J
authors.lastname: Gardeazabal
authors.forename: José Luís
authors.initials: JL
authors.lastname: Díaz-Ramón
authors.forename: José Luís
authors.initials: JL
authors.lastname: Díaz-Pérez
authors.forename: Diana
authors.initials: D
authors.lastname: Zelenika
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Boyano
authors.forename: Nico
authors.initials: N
authors.lastname: Smit
authors.forename: Concepción
authors.initials: C
authors.lastname: de la Rúa
mesh_terms: D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics; D002478:Cells, Cultured; D002675:Child, Preschool; D020869:Gene Expression Profiling; D006239:Haplotypes; D006801:Humans; D007223:Infant; D019746:Intramolecular Oxidoreductases / Q000235:genetics*; D008297:Male; D008544:Melanocytes / Q000528:radiation effects*; D008562:Membrane Glycoproteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010088:Oxidoreductases / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D012880:Skin Pigmentation / Q000235:genetics* / Q000528:radiation effects; D014443:Tyrosine / Q000235:genetics*; D014466:Ultraviolet Rays; D044465:White People / Q000235:genetics
chemical_list: D008562:Membrane Glycoproteins; D014443:Tyrosine; D010088:Oxidoreductases; C489799:TYRP1 protein, human; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase