Understanding the genetic basis of pigmentation in human populations

   Pigmentation shows a tremendous amount of variation in human populations, most probably due to the action of natural selection. In spite of decades of study, there are many gaps in our knowledge of the genetic basis of normal pigmentation variation and the evolutionary history of the genes responsible for pigmentation. One of the main reasons for this lack of knowledge is the multifactorial nature of this trait. Although the last century has witnessed impressive advances in our understanding of simple Mendelian traits and diseases, elucidating the genetic factors responsible for variation in complex traits remains a challenge. However, conditions are in place to identify the ultimate genetic factors involved in pigmentation variation within and between populations. We have better technologies and a better knowledge of the pigmentary system than anytime in the past, and there is much that can be learned from a systematic study of pigmentation candidate genes in multiple population groups. To date, most of the studies focusing on the genetics of pigmentation have been carried out in populations of European ancestry, so it is critical to expand this research to other population groups.

   In 2010, we described that a non-synonymous polymorphism in the OCA2 gene (rs1800414) is significantly associated with skin pigmentation in East Asians (Edwards et al. 2010. PLoS Genet. 6:e1000867). This was one of the first polymorphisms associated with skin pigmentation in East Asian populations. More recently, we described that another non-synonymous variant in the OCA2 gene (rs74653330) also shows a strong association with skin pigmentation in East Asians (Eaton et al. 2015. Am. J. Hum Biol. 27:520-525). Interestingly, our research shows that the OCA2 gene has been independently involved in the evolution of pigmentation in Europe and East Asia. In Europe, haplotypes in the OCA2/HERC2 gene are associated with blue eye color and light skin, and these haplotypes are not present in East Asian populations. On the other side, the rs1800414 G and the rs74653330 A alleles, which are associated with light skin in East Asia, are very rare or absent in other population groups. This is one of the most fascinating examples of convergent evolution in our species.

   We have also tackled another fascinating research question: When did the reduction in melanin levels take place in Europe and East Asia? In order to do this, we estimated the age of some of the key alleles associated with pigmentation in both continents. In collaboration with Sandra Beleza (Stanford University) and Jorge Rocha (Universidade do Porto) we estimated that the alleles of three genes associated with light skin in Europe (SLC24A5, SLC45A2 and TYRP1) began to increase in frequency between 19,000 and 11,000 years ago, possibly coinciding with population size expansions in Europe (Beleza et al. 2012. Mol. Biol. Evol. 30:24-35). We used a different method to date the two OCA2 alleles associated with pigmentation in East Asia. Our estimates of the Most Recent Common Ancestor (MRCA) were under 10,000 years ago for both alleles (Murray et al. 2015. Hum Genome Var. 2:15058). Therefore, it seems that the major events involved in the lightening of skin pigmentation in Europe and East Asia took place long after the arrival of anatomically modern humans to these regions (around 45,000 years ago). Recent ancient DNA studies in Europe tend to support these findings. Similar studies in East Asia will provide relevant information about the timing of the selective events in this continent.

   We are also interested in the development of quantitative methods to study pigmentary phenotypes, including iris color. This is important, because the categorical classifications widely used to classify iris color (e.g. brown, blue, green) do not capture the continuous nature of this trait. In a paper published in 2012 we described an automated method to quantify iris color using high-resolution pictures. (Edwards et al. 2012. Am. J. Phys. Anthropol. 147:141-149). More recently, we improved the method to provide, not only information about iris color, but also about different surface features present in the iris, such as Fuchs crypts, Wolfflin nodules, pigment spots, contraction furrows and conjunctival melanosis (Edwards et al. 2016. Pigment Cell Melanoma Res. in press, and Edwards et al. 2016. R. Soc. Open Sci. 3:150470).

   Through the years, we have done many candidate gene association studies focused on pigmentation in multiple population groups (see list of references for additional information). Currently, in collaboration with Heather Norton (University of Cincinnati), we are involved in a genome-wide association study of pigmentary traits and iris surface features in five population groups: African Americans, East Asians, Europeans, Hispanics and South Asians. We hope that this study, using quantitative approaches to describe the relevant traits, will provide interesting insights about the genetic architecture of pigmentary traits in these populations.

Graphical representation of a melanocyte showing some of the important genes involved in melanogenesis

Method used to quantify iris color using high resolution photographs (for more details, see Edwards et al. 2015. Pigment Cell Melanoma Res.).

3D representation of the color coordinates (in CIELAB space) of irises of individuals of diverse ancestry (East Asians, Europeans and South Asians). The color of each point in the graph corresponds to the actual average color of each iris. Use your computer mouse to rotate the image!