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Post by Admin on Jun 20, 2017 20:08:27 GMT
Figure 1 (a) A regression tree with two nodes based on HERC2 haplotypes and country (or region) of origin of each individual (ARM, Armenia; AZR, Azerbaijan; CRM, Crimea (peninsula of Ukraine); GEO, Georgia; KAZ, Kazakhstan; TJK, Tajikistan; UZB, Uzbekistan), most striking is the major node where we have the higher percentage of blue eyes (50.6%) in individuals carrying H1/H1. In the first node, the origin of population of the individuals carrying H1/H1 is not reported because the P-value is not significant. (b) Tree obtained from model-based recursive partitioning; East refers to populations from ESR, and West refers to those from WSR. Given the brown versus not-brown eye trait, we performed the algorithm for model-based recursive partitioning (Figure 1b). Interestingly, a person belonging to WSR and carrying H1/H1 genotype has a higher probability of having blue or green/grey eye (94%) as compared with a person from ESR (72%). In the attempt to combine the roles of OCA2 and HERC2 genes, we used MDR method5 (Figure 2), by using the two analysed haplotypes and rs7495174 SNP position. Our MDR analysis shows a synergistic interaction between them; the prediction accuracy of the tested model is 86.62%, with a sensitivity of 98.02%. The presence of HERC2 H1/H1 plus the A/A OCA2 genotype remarkably predicts blue eyes (ratio brown/not brown: 0.1324), whereas the presence of H2 compared with every alleles of OCA2 SNP is enough to predict brown eye (Figure 2). Figure 2 MDR analysis. Representation of haplotype–SNP combinations among attributes considered in interaction model for brown versus not brown; the dark grey cells represent the genotype combinations associated with ‘high risk’ of having a specific eye colour, light grey cells are associated with ‘low risk’, and white cells mean lack of data. Each cell is a representation of the number of individuals with brown eyes (left bar) and not brown eyes (right bar).
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Post by Admin on Jun 22, 2017 19:20:11 GMT
The Silk Road, a well-known trading route of the ancient Chinese civilisation, has been an important way for cultural and commercial exchange between subjects living in East, South, and Western Asia with those settled in the Mediterranean and European regions for almost 3000 years. The collapse of the Mongol empire and the late fifteenth-century discovery of the sea route from Europe to Asia led to a progressive decline of the Silk Road’s trade in Central Asia. The geography of the Silk Road is a complex interaction between the different physical and climate areas featuring mountains, moorlands or grasslands, and river valleys and oases, often neighbouring uninhabitable deserts. Thus, populations could be dispersed (in the grasslands) or concentrated in the oases and river valleys. The majority of the population is of mixed Turkish descent. The Uighurs are the largest ethnic group, whereas Kyrgyz, Kazaks, Uzbeks, and Tartars are further strongly represented populations. From a linguistic point of view, different varieties of old Turkish are spoken. The colour of the eye’s iris can vary dramatically between individuals, due to genetic differences. Present results confirm, also in these populations, the role of genes such as HERC2 and OCA2, already known to be involved in defining iris colour. Moreover, our findings demonstrate that not only HERC2 and OCA2 genes but also CTNNA2 gene could be under selection pressure. As reported by Sturm and Duffy,7 eye colour is a feature that may fall under multiple selection pressures, including sexual, cultural, and environmental factors (ie, the level of sunlight). In this light, the presence of brown eyes, especially in populations living in the ESR, might be probably due to the combined action of both environmental and cultural factors. One of the interesting outcomes of the present data is the demonstration on how genetic information can be used to predict eye colours. For example, homozygous individuals for a specific HERC2 haplotype (H2) lead to a higher probability of carrying brown eyes in all populations, whereas carriers of the other haplotype (H1) have a significant probability to show a blue or green/grey iris colour. Furthermore, homozygous individuals for the same haplotype have a different probability to develop green/grey iris colour depending on the region in which they live (ie, a person belonging to the Caucasus region has an higher probability as compared with individuals living in Central Asia). An explanation for these findings is the possible presence of population-specific polymorphisms that might interact with HERC2 and OCA2 genes and thus contribute to the phenotypes. These polymorphisms could have a higher frequency in the Caucasus region because of a different history of gene flow between the various populations. Apart from a significant relevance at population level, present findings might also be extremely useful in forensic medicine. European Journal of Human Genetics (2013) 21, 1320–1323.
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Post by Admin on Jun 24, 2017 19:31:38 GMT
Differences in human skin color have been shaped principally and dramatically by selection [1], [2], and therefore the underlying genetic architecture may inform disease-related traits such as obesity or hypertension, for which common susceptibility alleles may have been advantageous to early humans that came to inhabit different environments [3]. But our knowledge of skin and eye color genetics is incomplete, based mostly on the limited range of phenotypic diversity represented by individuals of European ancestry [4]–[10], or on candidate gene studies in African Americans [11]–[15]. Besides serving as a model system for gene action and genetic architecture, more knowledge about human pigmentary variation has the potential to provide important insights into human diversity, disentangling biology from both scientific and social stereotypes. Cape Verde is an archipelago of ten islands located 300 miles off the coast of Western Africa. The previously uninhabited islands were discovered and colonized by the Portuguese in the 15th Century, and subsequently prospered during the transatlantic slave trade. In this population, extensive genetic admixture between the African and European ancestral populations during the last several centuries [16], [17] has facilitated assortment of pigmentary alleles. Blond or red hair color is very rare in Cape Verde, but there is a wide spectrum of variation in both eye and skin color, and individuals with dark skin and blue eyes are not infrequent. Pigmentary variation in Cape Verde also provides an opportunity to investigate and disentangle the effects of locus-specific vs. genome-wide ancestry effects, a problem that is especially relevant to admixed populations, which are poorly represented in existing GWAS efforts, and for whom health disparities often correlate with genome-wide admixture proportions. For example, in previous studies of African-American cohorts, darker skin color (used as a proxy for genome-wide ancestry) correlates with higher blood pressure and with lower socioeconomic status, but the extent to which genetic factors contribute to these correlations is unclear [18]. Previous studies of African-European skin color variation have focused mostly on candidate genes that exhibit large allele frequency differences between ancestral populations, and have led to the view that a small number of loci account for most of the phenotypic variation [13], [15], in which case skin color should correlate poorly with genome-wide ancestry. Availability of dense genotyping information and new analytical tools allow a more rigorous approach in which the effects of individual loci and genome-wide ancestry can be disentangled and comprehensively investigated. In an admixed population, the effects of individual loci on a quantitative trait can be detected either by a correlation between genotype and phenotype, or by a correlation between local ancestry and phenotype. Genotype-based approaches are expected to be more powerful for traits where the causative allele exists at similar frequencies in ancestral populations, while ancestry-based approaches should be more powerful for traits where the causative allele exhibits large frequency differences in ancestral populations. Here we apply and compare genotype-based and ancestry-based association approaches for skin and eye color in 699 Cape Verdean individuals; both approaches identify two major loci for eye color, and four major loci for skin color. Surprisingly, the genetic component with the greatest effect on skin color is not a single locus but average genomic ancestry, which, together with these four major loci, accounts for most of the estimated heritable variation. Our results indicate that Cape Verdean pigmentary variation is the result of variation in a different set of genes from those determining variation within Europe, suggest that long-range regulatory effects help to explain the relationship between skin and eye color, and highlight the potential and the pitfalls of using allele distribution patterns and signatures of selection as indicators of phenotypic differences.
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Post by Admin on Jun 26, 2017 19:11:36 GMT
Genetic admixture in Cape Verdeans We first investigated the pattern and distribution of continental ancestry in 699 Cape Verdeans for whom detailed pigmentary phenotype and high density genotype information was available, the latter obtained with the Illumina 1 M platform as described below. Data from CEU and YRI HapMap individuals [19] was used to partition each Cape Verdean individual's ancestry into “European” and “African” components. We note that there is population substructure and pigmentary heterogeneity within Europe and, of course, within Africa. We also note that the true ancestral populations for Cape Verde are likely to include contributions from several areas of Southern Europe, and several areas of West Africa. In what follows, we use the terms “European” and “African” to refer to different continental origins, and emphasize that our use of these terms should not be taken to infer homogeneity of genotype or phenotype for the true ancestral populations of Cape Verde. The program frappe [20] implements a maximum likelihood clustering approach to infer individual genomic ancestry proportions. Overall, African genomic ancestry in Cape Verdeans ranges from 23.5% to 87.9%, with a median of 58%. Across different islands, the distributions of African genomic ancestry exhibit substantial overlap in range but vary in their median values, from 50.5% in Fogo to 74.4% in the capital island of Santiago (Figure 1a), which suggests a population history of extensive intercontinental admixture accompanied by reduced gene flow between islands. Figure 1. Relationship of geography and ancestry to skin and eye color. Individual ancestry proportions for Cape Verdeans displayed on all four panels were obtained from a supervised analysis in frappe with K = 2 and HapMap's CEU and YRI fixed as European and African parental populations. (a) Bar plots of individual ancestry proportions for Cape Verdeans across the islands. The width of the plots is proportional to sample size (Santiago, n = 172; Fogo, n = 129; NW cluster, n = 192; Boa Vista, n = 27). The proportion of African vs. European ancestry of the individuals is indicated by the proportion of blue vs. red color in each plot. (b) Individual African ancestry distribution in the total cohort of 685 Cape Verdeans (histogram) and in 802 African Americans (kernel density curve) from the Family Blood Pressure Program (FBPP) [21]. (c) Scatter-plot of skin color vs. Individual African ancestry proportions. Skin color is measured by the MM index described in Material and Methods. (d) Scatter-plot of eye color vs. Individual African ancestry proportions. Eye color is measured by the T-index, described in Figure 2 and Material and Methods. Points in scatter-plots are color coded according to the island of origin of the individuals. The pattern of African genomic ancestry in Cape Verde is less skewed than in many other African-European populations. For example, in a randomly sampled African-American cohort from the Family Blood Pressure Study (FBPP) [21], African genomic ancestry ranges from 40.6% to 99.3%, with a median of 89.5% (Figure 1b). The broad range of genomic ancestry makes the Cape Verde population particularly well suited for understanding the genetic basis of Afro-European phenotypic diversity; at the same time, careful adjustment for population stratification is critical in an association analysis. The genome-wide association results described below are based on a linear regression adjusting for the first three principal components (PC) but the same model adjusting for up to 10 PCs does not qualitatively alter our results. Additionally, we have taken two complementary approaches: (1) a linear regression adjusting for African genomic ancestry and self-reported island of birth, and (2) a mixed effect model that considers relatedness and stratification, implemented in the program, EMMAX [22]. All three approaches—genotype-based association, ancestry-based association, and a mixed model—point to the same set of genetic loci.
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Post by Admin on Jun 28, 2017 19:21:10 GMT
Quantitative assessment of pigmentary phenotypes For skin color, we used reflectance spectroscopy on the upper inner arm to calculate a modified melanin (MM) index, which appears normally distributed with a mean of 7.39 and standard deviation of 0.85 for the Cape Verde cohort. By comparison, MM in individuals of European ancestry is smaller and much more narrowly distributed, with a mean of 5.38 and standard deviation of 0.27 [23]. For eye color, we developed a new measure based on automated analysis of digital photographs that captures the full range of African-European variation. We observed that RGB reflectance values project onto an empirical curve that begins and ends, respectively, with very light blue, and very dark brown eyes (Figure 2). We describe the distance along this curve as the “T index”, a quantitative measure in which the categorical descriptions of “hazel”, “light brown”, and “medium brown” progressively increase in value (Figure 2). Figure 2. Quantitative assessment of eye color. Plotted are the normalized median values of green (x-axis) and blue (y-axis) levels of each individual's irises. We fitted a principal curve that explains most of the variation in the data (red dashed curve). The T-index is defined by the arc-length from the projection of each point on the curve to the end of the curve that corresponds to the lightest eye color. In the figure are examples of eye photos at their respective position in the T-index curve. The correlation between skin color and African genomic ancestry (R∧2 = 0.44) is apparent both across and within (Table S1) islands clusters, and is higher than anticipated for a trait determined by the action of a small number of genes. (For example, in a model with 3 major skin color genes that act additively and equally, we predict an R∧2<0.3 between African genomic ancestry and skin color [see Material and Methods]). The strong effect of genomic ancestry on skin color is also striking in the context of eye color; there is only a weak correlation between skin and eye color in Cape Verdeans (R∧2 = 0.14), and African genomic ancestry is also weakly correlated (R∧2 = 0.08) with eye color (Figure 1c, 1d). Overall, these observations point to different genetic architectures for skin and eye color.
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