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.

Mikronährstoffe als Motor der Evolution

“…Hellhäutige Europäer tragen 374F und haben ein höheres Melanomrisiko (Lopez et al 2014). Zwei Allele sind 374L und 374F.…”

SLC45A2 protein stability and regulation of melanosome pH determine melanocyte pigmentation

“…membrane associated transporter protein, MATP or antigen isolated from immunoselected melanoma-1, AIM1) (Newton, Cohen-Barak et al, 2001). Mutations in the homologous gene underlie pigment dilution in a number of vertebrate species, including gorilla, several breeds of dog, tigers, horses, mice, shrew, chickens, pigeons, quail, frogs, fish and perhaps cattle (Caduff, Bauer et al, 2017, DeLay, Corkins et al, 2018, Domyan, Guernsey et al, 2014, Dooley, Schwarz et al, 2013, Fukamachi, Shimada et al, 2001, Gunnarsson, Hellström et al, 2007, Mariat, Taourit et al, 2003, Minvielle, Cecchi et al, 2009, Newton et al, 2001, Prado-Martinez, Hernando-Herraez et al, 2013, Rothammer, Kunz et al, 2017, Tsetskhladze, Canfield et al, 2012, Tsuboi, Hayashi et al, 2009, Wijesena & Schmutz, 2015, Winkler, Gornik et al, 2014, Xu, Dong et al, 2013, and polymorphisms at the SLC45A2 locus are associated with skin tone differences and skin aging in several human population studies (Adhikari et al, 2019, Branicki et al, 2008, Cerqueira, Hunemeier et al, 2014, Fracasso, de Andrade et al, 2017, Han et al, 2008, Jonnalagadda, Norton et al, 2016, Law, Medland et al, 2017, Liu et al, 2015, Lopez, Garcia et al, 2014, Soejima & Koda, 2007, Stokowski et al, 2007, Yuasa, Umetsu et al, 2006. OCA4 patients have very low levels of pigmentation and phenotypically resemble OCA2 patients who lack the melanosomal chloride channel, OCA2 (Bellono, Escobar et al, 2014), suggesting that SLC45A2 plays an important role in melanogenesis (Montoliu et al, 2014).…”

“…Differences in skin and hair pigmentation among European, Chinese, South American and South Asian human populations have been ascribed to a single genetic variant in SLC45A2 associated with the SNP rs16891982. This encodes a single amino acid change at position 374leucine (L374) in dark skinned individuals and phenylalanine (F374) in light skinned individuals (Adhikari et al, 2019, Branicki et al, 2008, Cerqueira et al, 2014, Han et al, 2008, Jonnalagadda et al, 2016, Liu et al, 2015, Lopez et al, 2014, Soejima & Koda, 2007, Stokowski et al, 2007, Yuasa et al, 2006; this residue lies within the 8th predicted transmembrane domain of SLC45A2 (Newton et al, 2001).…”

Genetic variants associated with skin photosensitivity in a southern European population from Spain

“…Due to higher UV radiation in South Europe, mainly during the summer months, evolution has probably influenced the distribution of allele frequencies of several human pigmentation genes in a different way to North Europe. For example, the F374 allele in SLC45A2 , responsible for darker skin, is significantly more frequent in Spain than in more northerly European populations …”

“…For example, the F374 allele in SLC45A2, responsible for darker skin, is significantly more frequent in Spain than in more northerly European populations. 27,28 In this study, we set out to elucidate the genetic determinants of sun photosensitivity in Spain, a population of Mediterranean origin, by means of testing variation in the genes previously associated with sun sensitivity. We have performed SNP genotyping in 8 pigmentation-related genes (HERC2, SLC45A2, SLC24A4, TYR, ASIP, OCA2, BNC2 and IRF4) as well as complete gene sequencing of the MC1R gene in 456 individuals of Spanish origin.…”