miércoles, 15 de enero de 2014

Simultaneous Purifying Selection on the Ancestral MC1R Allele and Positive Selection on the Melanoma-Risk Allele V60L in South Europeans

Simultaneous Purifying Selection on the Ancestral MC1R Allele and Positive Selection on the Melanoma-Risk Allele V60L in South Europeans




Simultaneous Purifying Selection on the Ancestral MC1R Allele and Positive Selection on the Melanoma-Risk Allele V60L in South Europeans


















  1. Santos Alonso*,2



+Author Affiliations



  1. 1Department of Medicine, University of Castellón, Castellón, Spain



  2. 2Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, Bizkaia, Spain



  3. 3INCLIVA Biomedical Research Institute, Valencia, Spain



  4. 4Research Unit, University Hospital N.S. de Candelaria, Tenerife, Spain



  5. 5CIBER on Respiratory Diseases, ISCIII, Madrid, Spain



  6. 6Forensic Science Unit, Forensic Genetics Section, Basque Country Police, Erandio, Bizkaia, Spain



  7. 7Department of Zoology and Animal Cell Biology, University of the Basque Country, Bizkaia, Spain



  8. 8Department of Medicine, University of California, San Francisco, CA, USA



  9. 9Dermatology Service, Cruces Hospital, Bizkaia, Spain



  10. 10Department of Cell Biology and Histology, University of the Basque Country, Bizkaia, Spain




  1. *Corresponding author: E-mail: santos.alonso@ehu.es.





Abstract



In humans, the geographical apportionment of the coding diversity of the pigmentary locus melanocortin-1 receptor (MC1R) is, unusually, higher in Eurasians than in Africans. This atypical observation has been interpreted as the result of purifying selection due to functional constraint on MC1R in high UV-B radiation environments. By analyzing 3,142 human MC1Ralleles from different regions of Spain in the context of additional haplotypic information from the 1000 Genomes (1000G) Project data, we show that purifying selection is also strong in southern Europe, but not so in northern Europe. Furthermore, we show that purifying and positive selection act simultaneously on MC1R. Thus, at least in Spain, regions at opposite ends of the incident UV-B radiation distribution show significantly different frequencies for the melanoma-risk allele V60L (a mutation also associated to red hair and fair skin and even blonde hair), with higher frequency of V60L at those regions of lower incident UV-B radiation. Besides, using the 1000G south European data, we show that the V60L haplogroup is also characterized by an extended haplotype homozygosity (EHH) pattern indicative of positive selection. We, thus, provide evidence for an adaptive value of human skin depigmentation in Europe and illustrate how an adaptive process can simultaneously help to maintain a disease-risk allele. In addition, our data support the hypothesis proposed by Jablonski and Chaplin (Human skin pigmentation as an adaptation to UVB radiation. Proc Natl Acad Sci U S A. 2010;107:8962–8968), which posits that habitation of middle latitudes involved the evolution of partially depigmented phenotypes that are still capable of suitable tanning.



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