Article

Interactions between HERC2, OCA2 and MC1R may influence human pigmentation phenotype

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Abstract

Human pigmentation is a polygenic trait which may be shaped by different kinds of gene-gene interactions. Recent studies have revealed that interactive effects between HERC2 and OCA2 may be responsible for blue eye colour determination in humans. Here we performed a population association study, examining important polymorphisms within the HERC2 and OCA2 genes. Furthermore, pooling these results with genotyping data for MC1R, ASIP and SLC45A2 obtained for the same population sample we also analysed potential genetic interactions affecting variation in eye, hair and skin colour. Our results confirmed the association of HERC2 rs12913832 with eye colour and showed that this SNP is also significantly associated with skin and hair colouration. It is also concluded that OCA2 rs1800407 is independently associated with eye colour. Finally, using various approaches we were able to show that there is an interaction between MC1R and HERC2 in determination of skin and hair colour in the studied population sample.

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... It was reported that the extent of expression of the OCA2 gene (pigmentation gene) is regulated by polymorphism rs12913832 on HERC2 locus (Visser et al. 2012;Eiberg et al. 2008). The rest of all the genes (SLC45A2, TYR, SLC24A4, and IRF4) seem to contribute less in the prediction of eye color and differ with populations (Ruiz et al. 2013;Walsh et al. 2012;Allwood and Harbison 2013;Branicki et al. 2009). Several models have been proposed in the recent past for the prediction of eye color (Liu et al. 2009;Ruiz et al. 2013;Spichenok et al. 2011;Allwood and Harbison 2013;Hart et al. 2013). ...
... The six genetic SNPs, HERC2-rs12913832, OCA2-rs1800407, SLC24A4-rs12896399, SLC45A2-rs16891982, TYR-rs1393350, and IRF4-rs12203592, reported to be associated significantly with the prediction of human eye color in diverse populations are included in IrisPlex web tool (Liu et al. 2009;Walsh et al. 2011a;Walsh et al. 2011b;Walsh et al. 2012). Out of all the above genetic SNPs, HERC2-rs12913832 reported as the most profound genetic predictor of human eye color (Liu et al. 2009;Mengel-From et al. 2010;Walsh et al. 2012;Branicki et al. 2009). This genetic SNP reported having strongly associated with blue eye color (Kastelic et al. 2013). ...
... The model developed by this study had a better goodness-of-fit curve and all study participants with brown eye color were predicted correctly by the IrisPlex system. HERC2-rs12913832 is also reported to play an important role in the prediction of hair and skin color (Branicki et al. 2011;Branicki et al. 2009). ...
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Abstract Background: Forensic DNA phenotyping has gained momentum in the recent past due to the prediction of externally visible characters (EVCs) from the biological sample. The most common phenotypes like eye, hair, and skin color are predicted from the biological samples using a web-based system called IrisPlex. Based on six genetic SNPs, the IrisPlex system is developed and validated for its prediction accuracy in diverse ethnic groups worldwide. In previous studies, this system proved to have significant prediction accuracy. The EVCs vary substantially based on different geographical locations. Hence, the objective of this study was to validate the accuracy of the IrisPlex system in predicting the eye colors in the Iraqi population. Methods: Six genetic single-nucleotide polymorphisms SNPs (HERC2-rs12913832, OCA2- rs1800407, SLC24A4- rs12896399, SLC45A2- rs16891982, TYR-rs1393350, and IRF4- rs12203592) in 58 Iraqi subjects were performed using Sequenom MassARRAY Genotyping. According to Liu et al., a predicted probability of 0.7 was considered as the threshold. Results: Participants in this study of brown color were observed in 44.83%, intermediate in 43.1%, and blue in 12.07%. Completely predictive accuracy is obtained in 1; we observed the AUC at threshold 0.7 was 0.91 for brown, 0.79 for blue, and 0.60 for intermediate eye color. The sensitivity was 42.85% for blue, 0% for intermediate eye color, and 100% for brown-colored eye. Specificity was 100% for blue, 100% for intermediate, and 78.13% for brown eye color. Conclusion: Hence, it was concluded that the prediction accuracy of the IrisPlex system for blue and brown color eye in the Iraqi population is significant in the studied population size. However, a pivotal study with larger sample size is required to represent the prediction accuracy of the IrisPlex system in the whole Iraqi population.
... The rs12913832 polymorphism within the HERC2 gene is also significant for the pigmentation phenotype of man. A number of studies have proven that it is strongly associated with eye color (Eiberg et al. 2008;Sturm et al. 2008;Branicki et al. 2009;Liu et al. 2009;Liu et al. 2010;Pośpiech et al. 2012), hair color (Han et al. 2008;Branicki et al. 2009;Branicki et al. 2011) and skin color Valenzuela et al. 2010;Spichenok et al. 2011). Many recent reports indicate that its participation in the process of melanogenesis consists in control of the OCA2 gene expression (Eiberg et al. 2008;Sturm et al. 2008;Visser et al. 2012) and, moreover, this polymorphism may affect hair and skin color via interactions with MC1R gene variants ), while eye color may be determined in separate interactions with OCA2, SLC24A4 and TYRP1 (Pośpiech et al. 2012). ...
... The rs12913832 polymorphism within the HERC2 gene is also significant for the pigmentation phenotype of man. A number of studies have proven that it is strongly associated with eye color (Eiberg et al. 2008;Sturm et al. 2008;Branicki et al. 2009;Liu et al. 2009;Liu et al. 2010;Pośpiech et al. 2012), hair color (Han et al. 2008;Branicki et al. 2009;Branicki et al. 2011) and skin color Valenzuela et al. 2010;Spichenok et al. 2011). Many recent reports indicate that its participation in the process of melanogenesis consists in control of the OCA2 gene expression (Eiberg et al. 2008;Sturm et al. 2008;Visser et al. 2012) and, moreover, this polymorphism may affect hair and skin color via interactions with MC1R gene variants ), while eye color may be determined in separate interactions with OCA2, SLC24A4 and TYRP1 (Pośpiech et al. 2012). ...
... rs12913832 (HERC2-15q13) and rs1805007 (MC1R-16q24.3). The selection of the abovementioned SNPs was done on the basis of literature reports, which confirm their significance for skin and/or hair pigmentation in adult white subjects (e.g., Graf et al. 2005;Branicki et al. 2009;Branicki et al. 2011;Siewierska 2012;Walsh et al. 2013). ...
Article
Background: Human pigmentation, similarly as many other biological features, changes in the course of postnatal ontogenesis, while in case of hair, pigmentation changes are more distinctive than in the skin or the iris. It is therefore extremely important to identify the genes involved in the constitution of human pigmentation features at various stages of ontogenesis. Results of this type of analyses are of high practical significance in forensic study because they enable to create mathematical tools, allowing for prediction of the pigmentation phenotype, based on DNA studies. Aim: The objective of the investigation was finding out whether the genes, associated with pigmentation of adult subjects, differentiated in any way the newly forming pigmentation phenotype in Polish prepubertal children. Material and methods: The study encompassed Polish children, aged 7 to 10 years, without any abnormalities in skin or hair pigmentation. A total of 245 children were examined. Constitutive skin pigmentation according to skin melanin index (SMI) was evaluated, using a dermaspectrometer, and classified into three groups based on the reference values of 25 and 75 percentile for Polish children. Hair colors were evaluated by means of the descriptive Fischer-Saller scale and classified by a division of color variants (as accepted in that scale) (light blonde, blonde, dark blonde, brown and dark brown). In saliva samples, collected from the children, five (5) single nucleotide polymorphisms were identified: SNPs: rs1800401 (OCA2-15q11.2-q12), rs35264875 (TPCN2-11q13.3), rs16891982 (SLC45A2-5p13.2), rs12913832 (HERC2-15q13) and rs1805007 (MC1R-16q24.3). An association between each allele of verified genotype and skin and hair color phenotypes was assessed, using the z-statistic and associated p-value. The quality of classifiers was evaluated by 10-fold stratified cross-validation and was characterized by the area under the receiver operating characteristic curve (AUC). Results: Light skin pigmentation phenotype (SMI<25 percentile) was associated with rs1805007 (MC1R) (allelic OR=3.95; 95% Cl:1.20–12.99; p=0.0235), while the dark shade of the skin (SMI>75 percentile) with rs16891982 (SLC45A2) (allelic OR =14.37; 95% Cl: 1.78–115.88; p=0.0123). The probability of dark hair (brown and dark brown) in childhood was increased by T rs12913832 allele (HERC2) (OR=3.63); 95% Cl: 2.25–5.85; p < 0.0001) and dependent on it – rs1800401 (OCA2) (OR=6.31; 95% Cl: 1.74–22.91; p=0.0051). Other SNPs were not significantly associated with skin and hair color but improved prediction of these features. Conclusions: From the five gene polymorphisms analysed in Polish children the strongest correlation with hair color has the rs12913832 (HERC2) and with skin color – rs16891982 (SLC45A2). Therefore, the above-mentioned polymorphisms may be used as components of potential models, used to predict pigmentation features in European origin children in prepubertal age. To improve predictive value of the potential scoring model for hair color, the following should be additionally included: rs1800401 (OCA2), rs35264875 (TPCN2) and rs1805007 (MC1R), while for skin color: rs12913832 (HERC2) and rs1805007 (MC1R).
... The most important locus for eye colour determination is the HERC2-OCA2 locus on chromosome 15, and the single nucleotide polymorphism (SNP) universally recognised as most relevant is rs12913832 (HERC2), which mainly distinguishes brown from blue. [115][116][117] Other SNPs in other genes such as OCA2, TYR, SLC45A2 and IRF4, when used in addition to rs12913832, have been shown to further improve eye colour prediction. 115,117,118 As mentioned earlier, SNPs rs12913832 in HERC2 and rs12203592 in IRF4 have been associated with the risk of developing UM. ...
... [115][116][117] Other SNPs in other genes such as OCA2, TYR, SLC45A2 and IRF4, when used in addition to rs12913832, have been shown to further improve eye colour prediction. 115,117,118 As mentioned earlier, SNPs rs12913832 in HERC2 and rs12203592 in IRF4 have been associated with the risk of developing UM. 17,18 Moreover, a recent study of worldwide incidence and risk factors for ocular melanoma showed a very strong correlation and an evident geographic overlap between the incidence of ocular melanoma, the frequency of blue eye colour and the distribution of rs12913832 alleles. ...
... Feather and eye color are polygenic traits influenced by a number of multi-gene interactions (Branicki et al, 2009). Mutations in the HECT and RLD domain-containing E3 ubiquitin protein ligase 2 (HERC2) and oculocutaneous albinism II (OCA2) genes have been reported to be closely associated with diluted iris and skin color in people of European (Branicki et al, 2009), African (Beleza et al, 2013), and Asian heritage (Edwards et al, 2010). ...
... Feather and eye color are polygenic traits influenced by a number of multi-gene interactions (Branicki et al, 2009). Mutations in the HECT and RLD domain-containing E3 ubiquitin protein ligase 2 (HERC2) and oculocutaneous albinism II (OCA2) genes have been reported to be closely associated with diluted iris and skin color in people of European (Branicki et al, 2009), African (Beleza et al, 2013), and Asian heritage (Edwards et al, 2010). Therefore, the main aim of this study was to test the hypothesis that mutations in HERC2 and OCA2 can cause white plumage color and red-eye variations in Beijing white quail. ...
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Mutations in the HERC2 and OCA2 genes have the potential to affect pigment deposition and alter feather color in birds. Therefore, in this study, we evaluated HERC2-OCA2 gene locus polymorphisms in Korean and Beijing white quails using RNA-Seq and KASP technology. The expression levels of HERC2 and OCA2 mRNA in skin tissues were analyzed using RT-qPCR. Ten single nucleotide polymorphisms were identified by RNA-Seq, of which three (n.117627564T>A, n.117674275T>G, n.117686226A>C) exhibited significant association with feather color in quail. The expression of OCA2 mRNA was significantly lower in the skin of Beijing white quails than that in the skin of Korean quails. These results suggested that variants in HERC2-OCA2 intergenic region could influence the expression of OCA2, which may underlie diluted feather color in the Beijing white quail.
... The PAG (pregnancy-associated glycoprotein) gene family in BBU5 is related to placentation in ruminants . In addition to the production traits, genes associated with skin pigmenta-tion were also found: HERC2, OCA2, CDK10, GAS8, MC1R, TCF25, DBNDD1, and VPS9D1 (Branicki et al., 2009;Dalziel et al., 2010;Li et al., 2014;Makina et al., 2015;Nigenda-Morales et al., 2018). ...
... The most prominent ROH island revealed in this population was a putative signature of selection at BBU18, encompassing QTL and genes related to milk traits (APRT, ACSF3, FANCA, ANKRD11, and ZNF276; Cánovas et al., 2013;Zhao et al., 2015;Choudhary et al., 2018), immune system (CDH15 and CDK10; Makina et al., 2015;Ibeagha-Awemu et al., 2016), reproduction (SPATA33 and SPIRE2; Pfender et al., 2011;Chen et al., 2013), and coat pigmentation (TCF25, GAS8, VPS9D1, DBNDD1, and MC1R; Sulem et al., 2007;Branicki et al., 2009;Visser et al., 2012;Li et al., 2014;Kim et al., 2018;Nigenda-Morales et al., 2018;Grilz-Seger et al., 2019).The FANCA, AN-KRD11, and ZNF276 genes were previously identified in signatures of selection study in Holstein-Friesian cattle selected for milk production (Zhao et al., 2015), which lends support to the results obtained in this work. Some of the genes within the signature of selection signal on BBU18, including CDH15 and CDK10, have been previously associated with SCC, which is an important indicator of mammary gland health (Sharif and Muhammad, 2008;Chen et al., 2015). ...
Article
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Characterization of autozygosity is relevant to monitor genetic diversity and manage inbreeding levels in breeding programs. Identification of autozygosity hotspots can unravel genomic regions targeted by selection for economically important traits and can help identify candidate genes for selection. In this study, we estimated the inbreeding levels of a Brazilian population of Murrah buffalo undergoing selection for milk production traits, particularly milk yield. We also studied the distribution of runs of homozygosity (ROH) islands and identified putative genes and quantitative trait loci (QTL) under selection. We genotyped 422 Murrah buffalo for 51,611 SNP; 350 of these had ROH longer than 10 Mb, indicating the occurrence of inbreeding in the last 5 generations. The mean length of the ROH per animal was 4.28 ± 1.85 Mb. Inbreeding coefficients were calculated from the genomic relationship matrix, the pedigree, and the ROH, with estimates varying between 0.242 and 0.035. Inbreeding estimates from the pedigree had a low correlation with the genomic estimates, and estimates from the genomic relationship matrix were much higher than those from the pedigree or the ROH. Signatures of selection were identified in 6 genomic regions, located on chromosomes 1, 2, 3, 5, 16, and 18, encompassing a total of 190 genes and 174 QTL. Many of the genes (e.g., APRT and ACSF3) and QTL identified are related to milk production traits, such as milk yield, milk fat yield and percentage, and milk protein yield and percentage. Other genes are associated with reproduction and immune response traits as well as morphological aspects of the buffalo species. Inbreeding levels in this population are still low but are increasing due to selection and should be managed to avoid future losses due to inbreeding depression. The proximity of genes linked to milk production traits with genes associated with reproduction and immune system traits suggests the need to include these latter genes in the breeding program to avoid negatively affecting them due to selection for production traits.
... The PAG (pregnancy-associated glycoprotein) gene family in BBU5 is related to placentation in ruminants . In addition to the production traits, genes associated with skin pigmenta-tion were also found: HERC2, OCA2, CDK10, GAS8, MC1R, TCF25, DBNDD1, and VPS9D1 (Branicki et al., 2009;Dalziel et al., 2010;Li et al., 2014;Makina et al., 2015;Nigenda-Morales et al., 2018). ...
... The most prominent ROH island revealed in this population was a putative signature of selection at BBU18, encompassing QTL and genes related to milk traits (APRT, ACSF3, FANCA, ANKRD11, and ZNF276; Cánovas et al., 2013;Zhao et al., 2015;Choudhary et al., 2018), immune system (CDH15 and CDK10; Makina et al., 2015;Ibeagha-Awemu et al., 2016), reproduction (SPATA33 and SPIRE2; Pfender et al., 2011;Chen et al., 2013), and coat pigmentation (TCF25, GAS8, VPS9D1, DBNDD1, and MC1R; Sulem et al., 2007;Branicki et al., 2009;Visser et al., 2012;Li et al., 2014;Kim et al., 2018;Nigenda-Morales et al., 2018;Grilz-Seger et al., 2019).The FANCA, AN-KRD11, and ZNF276 genes were previously identified in signatures of selection study in Holstein-Friesian cattle selected for milk production (Zhao et al., 2015), which lends support to the results obtained in this work. Some of the genes within the signature of selection signal on BBU18, including CDH15 and CDK10, have been previously associated with SCC, which is an important indicator of mammary gland health (Sharif and Muhammad, 2008;Chen et al., 2015). ...
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Characterization of autozygosity is relevant to monitor genetic diversity and manage inbreeding levels in breeding programs. Identification of autozygosity hotspots can unravel genomic regions targeted by selection for economically important traits and can help identify candidate genes for selection. In this study, we estimated the inbreeding levels of a Brazilian population of Murrah buffalo undergoing selection for milk production traits, particularly milk yield. We also studied the distribution of runs of homozygosity (ROH) islands and identified putative genes and quantitative trait loci (QTL) under selection. We genotyped 422 Murrah buffalo for 51,611 SNP; 350 of these had ROH longer than 10 Mb, indicating the occurrence of inbreeding in the last 5 generations. The mean length of the ROH per animal was 4.28 ± 1.85 Mb. Inbreeding coefficients were calculated from the genomic relationship matrix, the pedigree, and the ROH, with estimates varying between 0.242 and 0.035. Inbreeding estimates from the pedigree had a low correlation with the genomic estimates, and estimates from the genomic relationship matrix were much higher than those from the pedigree or the ROH. Signatures of selection were identified in 6 genomic regions, located on chromosomes 1, 2, 3, 5, 16, and 18, encompassing a total of 190 genes and 174 QTL. Many of the genes (e.g., APRT and ACSF3) and QTL identified are related to milk production traits, such as milk yield, milk fat yield and percentage, and milk protein yield and percentage. Other genes are associated with reproduction and immune response traits as well as morphological aspects of the buffalo species. Inbreeding levels in this population are still low but are increasing due to selection and should be managed to avoid future losses due to inbreeding depression. The proximity of genes linked to milk production traits with genes associated with reproduction and immune system traits suggests the need to include these latter genes in the breeding program to avoid negatively affecting them due to selection for production traits.
... Blue-eyed females (8.5%) were less than blue-eyed males (14.71%) whereas brown colour was more prevalent in females (78.45%) than males (71.43%) in the Spanish population [22]. Some similar results were found in other countries where blue colour was more prevalent in males than females in populations such as Iceland, Holland [23], Australia [24], Poland [25] ...
... Although previous studies showed significant association of IrisPlex SNPs with eye colour in Northern European populations [16,20,27,28], In this study, rs12913832 (in the HERC2 ), rs1393350 (TYR gene), rs1800407 (OCA2 gene) showed strong association with eye colour (Table 3). Previously, rs12913832 is shown to account for most eye colour variations in Caucasians [12,[14][15][16][17]19,20,[22][23][24][25]27,29], while the remaining 5 SNPs apparently have a relatively minor role [16,20,28,30]. ...
Article
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DNA-based Eye Color Prediction of Pakhtun Population Living in District Swat KP Pakistan Murad Ali Rahat1, Hakim Khan1, Ishtiaq Hassan1, Muhammad Haris1, Muhammad Israr2* ackground: Forensic DNA Phenotyping (FDP) or the prediction of Externally Visible Characteristics (EVCs) from a DNA sample has gained importance in the last decade or so in the forensic community. If and when the traditional forensic DNA typing via Short Tandem Repeats (STR) fails due to the absence of a reference sample, an individual can be traced by a DNA sample using FDP. Amongst the many available EVCs, eye color is one such character that can be predicted by employing previously developed IrisPlex system using Single Nucleotide Polymorphism (SNP) assay. In this study, we applied the IrisPlex system to samples collected from population of District Swat for prediction of eye colours from DNA. Method: Eye colour digital photographs and buccal swab samples were collected from 267 Pakhtun individuals of District Swat. Any person with eye disease was excluded from the study. Genomic DNA was extracted through Phenol-Chloroform extraction method. The amplified SNPs were typed using Multiplexed Single Base Extension (SBE). The genotypes were checked for eye color phenotypes through IrisPlex online tool and correlation were checked between SNPs, Gender, pie score and eye color. Result: Brown eye color was found prevalent as compared to intermediate and blue. Females have highly brown eye color compared to males while males have intermediate and blue. Three SNPs rs12913832 (in the HERC2), rs1393350 (TYR gene), rs1800407 (OCA2 gene) were strongly significant to eye color. Pie score was also significant to eye color and rs12913832 SNP. IrisPlex analysis in 20 individuals of District Swat was performed. The prediction accuracy of IrisPlex for blue or brown was 100% in the studied individuals. However, the IrisPlex tool predicted the intermediate phenotype incorrectly as brown or blue. Conclusion: It is concluded from the data that intermediate eye colour was not predicted accurately, therefore, inclusion of more SNPs in the IrisPlex system is needed to predict intermediate eye colour accurately.
... Our melanocyte eQTL data fully supports the functional effects described for rs12913832; the derived G allele, which is associated with light pigmentation in our meta-analysis, shows a strong association with reduced OCA2 expression (p = 3.14 × 10 − 23 ). Of note, in addition to the extensively reported association with blue eye color, rs12913832 has been associated with skin pigmentation and hair color in previous studies [15,22,[34][35][36][37]. ...
... 3) There is evidence of pleiotropic effects for many significantly associated variants. For example, the HERC2 rs12913832 SNP, which was originally associated with eye color, also plays a role in skin and hair color pigmentation [15,22,[34][35][36][37]. Additionally, many of the variants associated with skin pigmentation are also associated with tanning response (e.g. ...
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Background: Association studies in recently admixed populations are extremely useful to identify the genetic architecture of pigmentation, due to their high genotypic and phenotypic variation. However, to date only four Genome-Wide Association Studies (GWAS) have been carried out in these populations. Results: We present a GWAS of skin pigmentation in an admixed sample from Cuba (N = 762). Additionally, we conducted a meta-analysis including the Cuban sample, and admixed samples from Cape Verde, Puerto Rico and African-Americans from San Francisco. This meta-analysis is one of the largest efforts so far to characterize the genetic basis of skin pigmentation in admixed populations (N = 2,104). We identified five genome-wide significant regions in the meta-analysis, and explored if the markers observed in these regions are associated with the expression of relevant pigmentary genes in human melanocyte cultures. In three of the regions identified in the meta-analysis (SLC24A5, SLC45A2, and GRM5/TYR), the association seems to be driven by non-synonymous variants (rs1426654, rs16891982, and rs1042602, respectively). The rs16891982 polymorphism is strongly associated with the expression of the SLC45A2 gene. In the GRM5/TYR region, in addition to the rs1042602 non-synonymous SNP located on the TYR gene, variants located in the nearby GRM5 gene have an independent effect on pigmentation, possibly through regulation of gene expression of the TYR gene. We also replicated an association recently described near the MFSD12 gene on chromosome 19 (lead variant rs112332856). Additionally, our analyses support the presence of multiple signals in the OCA2/HERC2/APBA2 region on chromosome 15. A clear causal candidate is the HERC2 intronic variant rs12913832, which has a profound influence on OCA2 expression. This variant has pleiotropic effects on eye, hair, and skin pigmentation. However, conditional and haplotype-based analyses indicate the presence of other variants with independent effects on melanin levels in OCA2 and APBA2. Finally, a follow-up of genome-wide signals identified in a recent GWAS for tanning response indicates that there is a substantial overlap in the genetic factors influencing skin pigmentation and tanning response. Conclusions: Our meta-analysis of skin pigmentation GWAS in recently admixed populations provides new insights about the genetic architecture of this complex trait.
... clear clustering according to PCA and elevated heterozygosity in the intermediate samples (Harringmeyer and Hoekstra 2022). Interestingly, we identified one differentiation island corresponding to a location on domestic goat chromosome 2 that contains the genes OCA2 and HERC2, which has been linked with hair and skin color polymorphism in many animals, including humans (Frudakis et al. 2007;Branicki et al. 2009;Pavan and Sturm 2019), medaka (Fukamachi et al. 2004), the Mexican cave tetra (Protas et al. 2006), and zebrafish (Beirl et al. 2014). It would be interesting to investigate whether the conspicuous rump hair color pattern that distinguishes common and defassa waterbucks could be related to the strong differentiation in this genomic region. ...
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African antelope diversity is a globally unique vestige of a much richer world-wide Pleistocene megafauna. Despite this, the evolutionary processes leading to the prolific radiation of African antelopes are not well understood. Here, we sequenced 145 whole genomes from both subspecies of the waterbuck (Kobus ellipsiprymnus), an African antelope believed to be in the process of speciation. We investigated genetic structure and population divergence and found evidence of a mid-Pleistocene separation on either side of the eastern Great Rift Valley, consistent with vicariance caused by a rain shadow along the so-called ‘Kingdon’s Line’. However, we also found pervasive evidence of both recent and widespread historical gene flow across the Rift Valley barrier. By inferring the genome-wide landscape of variation among subspecies, we found 14 genomic regions of elevated differentiation, including a locus that may be related to each subspecies’ distinctive coat pigmentation pattern. We investigated these regions as candidate speciation islands. However, we observed no significant reduction in gene flow in these regions, nor any indications of selection against hybrids. Altogether, these results suggest a pattern whereby climatically driven vicariance is the most important process driving the African antelope radiation, and suggest that reproductive isolation may not set in until very late in the divergence process. This has a significant impact on taxonomic inference, as many taxa will be in a gray area of ambiguous systematic status, possibly explaining why it has been hard to achieve consensus regarding the species status of many African antelopes. Our analyses demonstrate how population genetics based on low-depth whole genome sequencing can provide new insights that can help resolve how far lineages have gone along the path to speciation
... Gene-gene interactions have for a long time been postulated to make an important contribution to the determination of human complex traits 42 . Skin pigmentation plays a crucial role in the response to UV exposure and the efficient synthesis of VD [43][44][45] . ...
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Skin pigmentation is negatively associated with circulating vitamin D (VD) concentration. Therefore, genetic factors involved in skin pigmentation could influence the risk of vitamin D deficiency (VDD). We evaluated the impact genetic variants related to skin pigmentation on VD in Mexican population. This cross-sectional analysis included 848 individuals from the Health Worker Cohort Study (ratio males to females ~ 1:3). Eight genetic variants: rs16891982 (SLC45A2), rs12203592 (IRF4), rs1042602 and rs1126809 (TYR), rs1800404 (OCA2), rs12913832 (HERC2), rs1426654 (SLC24A5), and rs2240751 (MFSD12); involved in skin pigmentation were genotyped. Skin pigmentation was assessed by self-report. Linear and logistic regression were used to assess the association between the variants of interest and VD and VDD, as appropriate. In our study, eight genetic variants were associated with skin pigmentation. A genetic risk score built with the variants rs1426654 and rs224075 was associated with lower VD levels (β = − 1.38, 95% CI − 2.59, − 0.17, p = 0.025). Nevertheless, when examining gene–gene interactions, we observed that rs2240751 × rs12203592 were associated with VD levels (P interaction = 0.021). Whereas rs2240751 × rs12913832 (P interaction = 0.0001) were associated with VDD. Our results suggest that skin pigmentation-related gene variants are associated with lower VD levels in Mexican population. These results underscore the importance of considering genetic interactions when assessing the impact of genetic polymorphisms on VD levels.
... A case-wise study was performed in Himachal Pradesh, Kangra, where the intermediate eye ratio is higher in a few generations at the temperate climate from Uttar Pradesh, Gorakhpur, Bihar and Darbhanga which are humid subtropical regions. Thus, climate might have a role in eye pigmentation due to the differential expression of the genes responsible for eye colour [60]. Hence, the exact molecular mechanisms needed to be unearthed. ...
... A case-wise study was performed in Himachal Pradesh, Kangra, where the intermediate eye ratio is higher in a few generations at the temperate climate from Uttar Pradesh, Gorakhpur, Bihar and Darbhanga which are humid subtropical regions. Thus, climate might have a role in eye pigmentation due to the differential expression of the genes responsible for eye colour [60]. Hence, the exact molecular mechanisms needed to be unearthed. ...
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Unlabelled: The core objective of forensic DNA typing is developing DNA profiles from biological evidence for personal identification. The present study was designed to check the validation of the IrisPlex system and the Prevalence of eye colour in the Pakhtoon population residing within the Malakand Division. Methods: Eye colour digital photographs and buccal swab samples of 893 individuals of different age groups were collected. Multiplexed SNaPshot single base extension chemistry was used, and the genotypic results were analysed. Snapshot data were used for eye colour prediction through the IrisPlex and FROG-kb tool. Results: The results of the present study found brown eye colour to be the most prevalent eye colour in comparison to intermediate and blue coloured. Overall, individuals with brown-coloured eyes possess CT (46.84%) and TT (53.16%) genotypes. Blue eye-coloured individuals are solely of the CC genotype, while individuals of intermediate eye colour carry CT (45.15%) and CC (53.85%) genotypes in rs12913832 SNP in the HERC2 gene. It was also revealed that brown-coloured eyes individuals were dominant among all age groups followed by intermediate and blue. Statistical analysis between particular variables and eye colour showed a significant p-value (<0.05) for rs16891982 SNP in SLC45A2 gene, rs12913832 SNP in HERC2 gene, rs1393350 SNP in SLC45A2, districts and gender. The rest of the SNPs were non-significant with eye colour, respectively. The rs12896399 SNP and SNP rs1800407 were found significant with rs16891982 SNP. The result also demonstrated that the study group differs from the world population based on eye colour. The two eye colour prediction results were compared, and it was discovered that IrisPlex and FROG-Kb had similar higher prediction ratios for Brown and Blue eye colour. Conclusions: The results of the current study revealed brown eye colour to be the most prevalent amongst members of the local population of Pakhtoon ethnicity in the Malakand Division of northern Pakistan. A set of contemporary human DNA samples with known phenotypes are used in this research to evaluate the custom panel's prediction accuracy. With the aid of this forensic test, DNA typing can be supplemented with details about the appearance of the person from whom the sample was taken in cases involving missing persons, ancient human remains, and trace samples. This study may be helpful for future population genetics and forensics studies.
... Under these conditions, melanosomes become neutral and cysteine deficient, leading to the production of trace amounts of pheomelanin and high levels of eumelanin [15]. Several studies have confirmed an association between dark hair and polymorphisms in genes, such as SLC24A5, SLC45A2, HECT and RLD domain containing E3 ubiquitin protein ligase 2 (HERC2), and interferon regulatory factor 4 (IRF4) [14,443,463,466,467]. ...
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The natural colour of hair shafts is formed at the bulb of hair follicles, and it is coupled to the hair growth cycle. Three critical processes must happen for efficient pigmentation: (1) melanosome biogenesis in neural crest-derived melanocytes, (2) the biochemical synthesis of melanins (melanogenesis) inside melanosomes, and (3) the transfer of melanin granules to surrounding pre-cortical keratinocytes for their incorporation into nascent hair fibres. All these steps are under complex genetic control. The array of natural hair colour shades are ascribed to polymorphisms in several pigmentary genes. A myriad of factors acting via autocrine, paracrine, and endocrine mechanisms also contributes for hair colour diversity. Given the enormous social and cosmetic importance attributed to hair colour, hair dyeing is today a common practice. Nonetheless, the adverse effects of the long-term usage of such cosmetic procedures demand the development of new methods for colour change. In this context, case reports of hair lightening, darkening and repigmentation as a side-effect of the therapeutic usage of many drugs substantiate the possibility to tune hair colour by interfering with the biology of follicular pigmentary units. By scrutinizing mammalian pigmentation, this review pinpoints key targetable processes for the development of innovative cosmetics that can safely change the hair colour from the inside out.
... The IrisPlex eye color prediction tool demonstrated a prediction accuracy of over 90% with respect to blue/brown phenotypes using only 31pg of DNA when applied to Dutch Europeans, making this kit sensitive and suitable for applications in low-copy-number DNA samples [57][58][59][60]. However, the tool shows low prediction accuracies for green-hazel or intermediate dark phenotypes and admixed populations, thus indicating the need to further investigate the tool using admixed populations and larger sample sizes [61][62][63]. Another GWAS study incorporating many European participants (~193,000) from 10 population groups identified 124 genetic loci for eye prediction, of which 50 had not been reported previously. ...
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The rapid improvements in identifying the genetic factors contributing to facial morphology have enabled the early identification of craniofacial syndromes. Similarly, this technology can be vital in forensic cases involving human identification from biological traces or human remains, especially when reference samples are not available in the deoxyribose nucleic acid (DNA) database. This review summarizes the currently used methods for predicting human phenotypes such as age, ancestry, pigmentation, and facial features based on genetic variations. To identify the facial features affected by DNA, various two-dimensional (2D)- and three-dimensional (3D)-scanning techniques and analysis tools are reviewed. A comparison between the scanning technologies is also presented in this review. Face-landmarking techniques and face-phenotyping algorithms are discussed in chronological order. Then, the latest approaches in genetic to 3D face shape analysis are emphasized. A systematic review of the current markers that passed the threshold of a genome-wide association (GWAS) of single nucleotide polymorphism (SNP)-face traits from the GWAS Catalog is also provided using the preferred reporting items for systematic reviews and meta-analyses (PRISMA), approach. Finally, the current challenges in forensic DNA phenotyping are analyzed and discussed.
... Our approach also revealed variants and genes like rs1042602 and rs1126809 of TYR (Mondal et al., 2016), rs16891982 of SLC45A2 (Ainger et al. 2017), rs1800401 of OCA2 (Sitek et al. 2016) and rs1805007 of MC1R (Frändberg et al. 1998) that are already well characterized for their functional roles in human pigmentation genetics, thus indicating reliability and reproducibility of our prioritization process. The locus OCA2 that was prioritized by all schemes of analyses we adopted, is well documented to be associated with human pigmentation variation (Frudakis et al. 2003;Shriver et al. 2003;Stokowski et al. 2007;Branicki et al. 2009;Sturm 2009). Interestingly, two prioritized synonymous SNVs (rs12592307, rs1800404) from OCA2 previously came up as significant hits in a 2007 twin study (Duffy et al. 2007), as well as, in a GWAS published in the same year (Stokowski et al. 2007). ...
Article
Modulations in melanin synthesis and distribution caused by underlying genetic variants are considered to be majorly responsible for the inter-personal human pigmentation variation. In the publicly available Color Genes dataset, 171 cloned murine loci are documented to be involved with alterations in mice coat color. We hypothesize that the human orthologues of these 171 loci may also be implicated towards human pigmentation variation through their polymorphic variants. We used several freely available bioinformatic tools and designed a predictive pipeline to prioritize the Single Nucleotide Variants (SNVs) within and in the vicinity of the 171 human orthologues, according to their functional potential. The genes associated with the prioritized SNVs were annotated a potential function in the pigmentation pathway, based on extensive literature review and assessment of protein- protein interaction networks. Our analyses could prioritize 77 candidate SNVs including 10 non-synonymous SNVs, 45 synonymous SNVs and 22 regulatory SNVs associated with 46 genes that can potentially contribute towards human pigmentation variation. Our study, thus outlines a comprehensive bioinformatic pipeline using freely available web-tools that can be utilized in similar kind of studies dealing with other complex human traits and diseases where individual nucleotide variant imparts subtle functional roles in regulating the phenotype.
... 46 OCA2 is not only one of the major pigmentation genes affecting the quantity and quality of melanin in melanocytes, but it is also an independent factor that affects eye color. 47 In addition, HERC2 can also regulate the expression of OCA2, 48,49 which further affects eye pigmentation. The results of this study also found that first-episode untreated schizophrenic patients who had a higher frequency of iris pigment spots exhibited more prominent negative symptoms. ...
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Background: Recently, researchers have conducted many studies on the potential contribution of the retina and other eye structures on schizophrenia. This study aimed to evaluate differences in iris characteristics between patients with schizophrenia and healthy individuals so as to find more easily accessible and easily measurable biomarkers with a view to improving clinical assessments and furthering our understanding of the disease. Methods: Overall, 80 patients with schizophrenia and 52 healthy individuals were included in the case group and the control group, respectively. Iris images were collected from all subjects to compare differences in the structure and color of the iris. The Positive and Negative Symptom Scale (PANSS) and the Modified Overt Aggression Scale (MOAS) were used to evaluate the clinical symptoms and characteristics of 45 first-episode untreated schizophrenics, and analyzed correlations between iris characteristics and schizophrenia symptoms. Results: There were significant differences in iris crypts (P<0.05) and pigment spots (P<0.01) between the case and control group, but no significant difference was found in iris wrinkles (P<0.05). The logistic regression analysis demonstrated that the total iris crypts [odds ratio (OR) 1.166, 95% confidence interval (CI) 1.022-1.330] and total iris pigment spots (OR 1.815, 95% CI 1.186-2.775) increased the risk of suffering from schizophrenia. Furthermore, it was demonstrated that the number of iris crypts was positively associated with the MOAS score (r=0.474, P<0.01). Moreover, the number of the iris pigment spots (r=0.395, P<0.01) and wrinkles (r=0.309, P<0.05) were positively correlated with the subjects' negative symptom scores, respectively. Conclusion: Iris crypts and pigment spots were identified as potential biomarkers for detecting schizophrenia. In patients with first-episode untreated schizophrenia, iris characteristics may help psychiatrists to identify the illness and its severity, and to detect characteristic clinical symptoms.
... After data preparation (Materials and Methods), we obtained 2346 individuals and grouped them into six population groups based on their geographic locations (Table S2). We also selected 52 SNPs in 19 genes for analysis due to their association with human pigmentation in published genome-wide association studies (GWAS) or phenotype prediction models (Table S3; Rebbeck et al., 2002;Bonilla et al., 2005;Graf et al., 2005;Lamason et al., 2005;Stokowki et al., 2007;Miller et al., 2007;Anno et al., 2008;Han et al., 2008;Kayser et al., 2008;Sturm et al., 2008;Sulem et al., 2008;Eiberg et al., 2008;Branicki et al., 2009;Edwards et al., 2010;Branicki et al., 2011;Donnelly et al., 2012;Visser et al., 2012;Hart et al., 2013;Jacobs et al., 2013;Praetorius et al., 2013;Walsh et al., 2013;Guenther et al., 2014;Murray et al., 2015;Yang et al., 2016;Ainger et al., 2017;Crawfold et al., 2017). We then used Eqn 2 with 30 SNPs not in strong linkage disequilibrium (r 2 <0.8) to estimate the total selection differences on human pigmentation (Materials and Methods). ...
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Human pigmentation is a highly diverse and complex trait among populations and has drawn particular attention from both academic and non-academic investigators for thousands of years. Previous studies detected selection signals in several human pigmentation genes, but few studies have integrated contribution from multiple genes to the evolution of human pigmentation. Moreover, none has quantified selective pressures on human pigmentation over epochs and between populations. Here, we dissect dynamics and differences of selective pressures during different periods and between distinct populations with new approaches. We use genotype data of 19 genes associated with human pigmentation from 17 publicly available datasets and obtain data for 2346 individuals of six representative population groups from across the world. Our results quantify the strength of natural selection on light pigmentation not only in modern Europeans (0.0259/generation) but also in proto-Eurasians (0.00650/generation). Our results also suggest that several derived alleles associated with human dark pigmentation may be under positive directional selection in some African populations. Our study provides the first attempt to quantitatively investigate the dynamics of selective pressures during different time periods in the evolution of human pigmentation. This article has an associated First Person interview with the first author of the article.
... Predictions on all other genes have lower scores, indicating less tendencies for eQTL. The last example rs12916300 is intronic to HERC2 and associated with pigmentation pathway (Branicki et al., 2009). It is reported as a significant eQTL variant for HERC2 in GTEx, though IRT predictions picked HERC2P9 as the top gene (0.785) and HERC2 with slight positive signal (0.560). ...
Article
Interpreting genetic variants of unknown significance (VUS) is essential in clinical applications of genome sequencing for diagnosis and personalized care. Noncoding variants remain particularly difficult to interpret, despite making up a large majority of trait associations identified in GWAS analyses. Predicting the regulatory effects of noncoding variants on candidate genes is a key step in evaluating their clinical significance. Here we develop a machine learning algorithm, ICE (Inference of Connected eQTLs), to predict the regulatory targets of noncoding variants identified in studies of expression quantitative trait loci (eQTLs). We assemble datasets using eQTL results from the Genotype-Tissue Expression (GTEx) project and learn to separate positive and negative pairs based on annotations characterizing the variant, gene and the intermediate sequence. ICE achieves an area under the receiver operating characteristic curve (ROC-AUC) of 0.799 using random cross-validation, and 0.700 for a more stringent position-based cross-validation. Further evaluation on rare variants and experimentally-validated regulatory variants shows a significant enrichment in ICE identifying the true target genes versus negative controls. In gene ranking experiments, ICE achieves a top-1 accuracy of 50% and top-3 accuracy of 90%. Salient features, including GC content, histone modifications and Hi-C interactions are further analyzed and visualized to illustrate their influences on predictions. ICE can be applied to any VUS of interest and each candidate nearby gene to output a score reflecting the likelihood of regulatory effect on the expression level. These scores can be used to prioritize variants and genes to assist in patient diagnosis and GWAS follow-up studies. Availability: Codes and data used in this work are available at https://github.com/miaecle/eQTL_Trees. Supplementary information: Supplementary data.
... The human HERC2 gene locus is upstream of that of the OCA2 gene (mutated in oculocutaneous albinism) and certain HERC2 SNPs can interfere OCA2's expression thus affecting eye, skin, and hair pigmentation (Eiberg et al., 2008;Kayser et al., 2008;Sturm et al., 2008;Branicki et al., 2009;Nan et al., 2009). Certain phenotypes are favoured by evolution with a traceable population gradient from Europe to Asia (Ulivi et al., 2013;Wilde et al., 2014). ...
Article
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Homologous to the E6AP carboxyl terminus (HECT) and regulator of chromosome condensation 1 (RCC1)-like domain-containing proteins (HERCs) belong to the superfamily of ubiquitin ligases. HERC proteins are divided into two subfamilies, Large and Small HERCs. Despite their similarities in terms of both structure and domains, these subfamilies are evolutionarily very distant and result from a convergence phenomenon rather than from a common origin. Large HERC genes, HERC1 and HERC2, are present in most metazoan taxa. They encode very large proteins (approximately 5,000 amino acid residues in a single polypeptide chain) that contain more than one RCC1-like domain as a structural characteristic. Accumulating evidences show that these unusually large proteins play key roles in a wide range of cellular functions which include neurodevelopment, DNA damage repair, and cell proliferation. To better understand the origin, evolution, and function of the Large HERC family, this minireview provides with an integrated overview of their structure and function and details their physiological implications. This study also highlights and discusses how dysregulation of these proteins is associated with severe human diseases such as neurological disorders and cancer.
... On the other hand, rs731236 has been shown to be associated with other variants, such as the R variants of MC1R in predicting light vs. dark skin and red vs. non-red hair in UK individuals (Walsh et al. 2017), but also influenced sensitivity to sun and freckling in people of Icelandic, North American and Siberian origin (Bouakaze et al. 2009;Valenzuela et al. 2010;Caliebe et al. 2016;Sulem et al. 2007;Myles et al. 2007). MC1R is considered as one of the strongest factors in melanin synthesis pathway in Europeans and has been particularly associated with red hair and pale skin, mostly through its interactions with other pigmentation markers including HERC2, OCA2 and ASIP (Duffy et al. 2007;Pośpiech et al. 2014;Valenzuela et al. 2010;Caliebe et al. 2016;Lalueza-Fox et al. 2007;Branicki et al. 2009). Interestingly, no strong LD was observed between rs1805007 and other markers in this study and there was only one lighter pigmentation-associated TT variant carrier, who indeed had pale and severe freckled skin, high susceptibility to sunburns, red hair and hazel eyes. ...
Article
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Predicting phenotypes from DNA has recently become extensively studied field in forensic research and is referred to as Forensic DNA Phenotyping. Systems based on single nucleotide polymorphisms for accurate prediction of iris, hair and skin color in global population, independent of bio-geographical ancestry, have recently been introduced. Here, we analyzed 14 SNPs for distinct skin pigmentation traits in a homogeneous cohort of 222 Polish subjects. We compared three different algorithms: General Linear Model based on logistic regression, Random Forest and Neural Network in 18 developed prediction models. We demonstrate Random Forest to be the most accurate algorithm for 3- and 4-category estimations (total of 58.3% correct calls for skin color prediction, 47.2% for tanning prediction, 50% for freckling prediction). Binomial Logistic Regression was the best approach in 2-category estimations (total of 69.4% correct calls, AUC = 0.673 for tanning prediction; total of 52.8% correct calls, AUC = 0.537 for freckling prediction). Our study confirms the association of rs12913832 (HERC2) with all three skin pigmentation traits, but also variants associated solely with certain pigmentation traits, namely rs6058017 and rs4911414 (ASIP) with skin sensitivity to sun and tanning abilities, rs12203592 (IRF4) with freckling and rs4778241 and rs4778138 (OCA2) with skin color and tanning. Finally, we assessed significant differences in allele frequencies in comparison with CEU data and our study provides a starting point for the development of prediction models for homogeneous populations with less internal differentiation than in the global predictive testing.
... Despite this apparent wealth of studies, at least on Europe, we had to exclude a number of them [57][58][59][60][61][62][63][64] for the potentially biased collection of their data, for comprising too small of a sample size, for lack of information on the data sources or for being not population-representative. In total, twelve studies met our quality criteria for population representativeness and were used for the subsequent analysis. ...
Article
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DNA-based prediction of externally visible characteristics has become an established approach in forensic genetics, with the aim of tracing individuals who are potentially unknown to the investigating authorities but without using this prediction as evidence in court. While a number of prediction models have been proposed, use of prior probabilities in those models has largely been absent. Here, we aim at compiling information on the spatial distribution of eye and hair coloration in order to use this as prior knowledge to improve prediction accuracy. To this end, we conducted a detailed literature review and created maps showing the eye and hair pigmentation prevalence both by countries with available information and by interpolation in order to obtain prior estimates for populations without available data. Furthermore, we assessed the association between these two traits in a very large data set. A strong limitation was the quite low amount of available data, especially outside Europe. We hope that our results will facilitate the improvement of already existing and of novel prediction methods for pigmentation traits and induce further studies on the spatial distribution of these traits.
... Outside the forensic field, DNA prediction is applied in anthropology and paleogenetics to reconstruct the appearance of deceased persons from (ancient) DNA analysis of (old) human remains [3][4]. However, EVCs for which both, statistical models providing reasonably high accuracies as well as validated genotyping methods reliably generating data from challenging DNA samples have been established, are currently restricted to the three pigmentation traits, eye, hair and skin colour [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. ...
Article
Human head hair shape, commonly classified as straight, wavy, curly or frizzy, is an attractive target for Forensic DNA Phenotyping and other applications of human appearance prediction from DNA such as in paleogenetics. The genetic knowledge underlying head hair shape variation was recently improved by the outcome of a series of genome-wide association and replication studies in a total of 26,964 subjects, highlighting 12 loci of which 8 were novel and introducing a prediction model for Europeans based on 14 SNPs. In the present study, we evaluated the capacity of DNA-based head hair shape prediction by investigating an extended set of candidate SNP predictors and by using an independent set of samples for model validation. Prediction model building was carried out in 9674 subjects (6068 from Europe, 2899 from Asia and 707 of admixed European and Asian ancestries), used previously, by considering a novel list of 90 candidate SNPs. For model validation, genotype and phenotype data were newly collected in 2415 independent subjects (2138 Europeans and 277 non-Europeans) by applying two targeted massively parallel sequencing platforms, Ion Torrent PGM and MiSeq, or the MassARRAY platform. A binomial model was developed to predict straight vs. non-straight hair based on 32 SNPs from 26 genetic loci we identified as significantly contributing to the model. This model achieved prediction accuracies, expressed as AUC, of 0.664 in Europeans and 0.789 in non-Europeans; the statistically significant difference was explained mostly by the effect of one EDAR SNP in non-Europeans. Considering sex and age, in addition to the SNPs, slightly and insignificantly increased the prediction accuracies (AUC of 0.680 and 0.800, respectively). Based on the sample size and candidate DNA markers investigated, this study provides the most robust, validated, and accurate statistical prediction models and SNP predictor marker sets currently available for predicting head hair shape from DNA, providing the next step towards broadening Forensic DNA Phenotyping beyond pigmentation traits.
... In most of the reports, in addition to this study, no statistically significant differences in hair colour frequencies have been observed between males and females [45,46]. However, a very weak effect of sex influencing frequencies of hair colour was found in our previous investigation (p = 0.023) [47]. Notably, Matheny and Dolan [48] observed hair colour changes in both sexes, although it appeared earlier in females than males. ...
... The in-house SNaPshot SBE multiplex system consists of SNPs of the HECT and RLD domain containing E3 ubiquitin protein ligase 2 (HERC2), oculocutaneous albinism II (OCA2), melanocortin 1 receptor (MCR1), solute carrier family 45 member 2 (SLC45A2), and dopachrome tautomerase (DCT) genes, which play significant roles in SNP genotyping. All of those genes are involved in the mammalian skin, hair, and eye pigmentation systems and are already forensically used for phenotyping (23)(24)(25)(26). All SNPs included into the assay are biallelic [wild type (W) and mutant type (Mt)]. ...
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This study introduces a newly developed in-house SNaPshot single-base extension (SBE) multiplex assay for forensic single nucleotide polymorphism (SNP) genotyping of fresh and degraded samples. The assay was validated with fresh blood samples from four different populations. In addition, altogether 24 samples from skeletal remains were analyzed with the multiplex. Full SNP profiles could be obtained from 14 specimens, while ten remains showed partial SNP profiles. Minor allele frequencies (MAF) of bone samples and different populations were compared and used for association of skeletal remains with a certain population. The results reveal that the SNPs of the bone samples are genetically close to the Pathan population. The findings show that the new multiplex system can be utilized for SNP genotyping of degraded and forensic relevant skeletal material, enabling to provide additional investigative leads in criminal cases.
... Mutations in oca2 in zebrafish (Beirl et al., 2014) and in humans (reviewed in (Gronskov et al., 2007)) can reduce melanin pigmentation without leading to the complete loss of melanin. Additionally, noncoding variants in the herc2 locus are associated with eye, hair, and skin pigmentation variation in humans, and can affect oca2 expression levels (Mengel-From et al., 2010;Sturm et al., 2008;Sulem et al., 2007;Kayser et al., 2008;Han et al., 2008;Visser et al., 2012;Eiberg et al., 2008;Branicki et al., 2009). The herc2 gene is located upstream of oca2 in humans and a search of the cavefish genome (McGaugh et al., 2014) revealed that herc2 is adjacent to oca2 in cavefish as well, raising the possibility that a combination of coding and noncoding mutations is required in cavefish for albinism. ...
Article
Understanding the genetic basis of trait evolution is critical to identifying the mechanisms that generated the immense amount of diversity observable in the living world. However, genetically manipulating organisms from natural populations with evolutionary adaptations remains a significant challenge. Astyanax mexicanus, the blind Mexican cavefish, exists in two interfertile forms, a surface-dwelling form and multiple independently evolved cave-dwelling forms. Cavefish have evolved a number of morphological and behavioral traits and multiple quantitative trait loci (QTL) analyses have been performed to identify loci underlying these traits. These studies provide a unique opportunity to identify and test candidate genes for these cave-specific traits. We have leveraged the CRISPR/Cas9 genome editing techniques to characterize the effects of mutations in oculocutaneous albinism II (oca2), a candidate gene hypothesized to be responsible for the evolution of albinism in A. mexicanus cave populations. We generated oca2 mutant surface A. mexicanus. Surface fish with oca2 mutations are albino due to a disruption in first step in the melanin synthesis pathway, the same step that is disrupted in albino cavefish. Hybrid offspring from crosses between oca2 mutant surface and cavefish are albino, definitively demonstrating the role of this gene in the evolution of albinism in this species. This research elucidates the role oca2 plays in pigmentation in fish, and establishes that this gene is solely responsible for the evolution of albinism in multiple cavefish populations. Finally, it demonstrates the utility of using genome editing to investigate the genetic basis of trait evolution.
... While melanoma is primarily a disease of non-Hispanic Whites, exposure to high UVR produces melanoma in Latinos, especially those working in outdoor occupations (Rouhani, Hu, & Kirsner, 2008). With increasing amounts of genetic admixture occurring especially in urban areas, there is increasing likelihood that individuals with MC1R polymorphisms at risk for developing melanoma will have "dark skin" because of the effects of genetic epistasis on the production of skin color phenotypes (Branicki, Brudnik, & Wojas-Pelc, 2009;Kanetsky et al., 2006Kanetsky et al., , 2010Kennedy et al., 2001;Pasquali et al., 2015). Changing the erroneous belief of physicians, including dermatologists, and Latinos that they have low or no melanoma risk may improve risk awareness, sun protection, and the early detection of melanoma (Pipitone et al., 2002;Rouhani et al., 2008). ...
Article
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Latinos in the United States may have the mistaken assumption that their natural pigmentation protects them from developing skin cancer that, effectively, serves as a barrier to Latinos receiving education in primary and secondary prevention of skin cancer. Latino adults of Mexican or Puerto Rican heritage attending community health fairs in the greater Chicago area responded to a culturally informed and sensitive measure for sunburn and tan, which was previously adapted to capture skin irritation with tenderness from the sun occurring in darker skin types (n=350). By self-reported responses and spectrophotometry assessment of constitutive pigmentation, adapted Fitzpatrick skin types (FST) ranged from skin type I to IV in the Mexican-American participants and from II to V in the Puerto Rican participants. The objectively measured proportion of adapted FST II skin type was greater than commonly perceived and demonstrated that many Latinos do indeed have sun sensitive skin. This article is protected by copyright. All rights reserved.
... The colour of unexposed skin (constitutive skin pigmentation) is a complex trait 11 . Indeed, evidence supports that many genes and other interacting factors are involved in determining normal skin pigmentation 12,13 . However, candidate-gene and genome-wide association studies (GWAS) have revealed only a few of the total estimated number of genes implicated in the variability of human skin colour 2,14,15 . ...
Article
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Skin pigmentation is a complex trait that varies largely among populations. Most genome-wide association studies of this trait have been performed in Europeans and Asians. We aimed to uncover genes influencing skin colour in African-admixed individuals. We performed a genome-wide association study of melanin levels in 285 Hispanic/Latino individuals from Puerto Rico, analyzing 14 million genetic variants. A total of 82 variants with p-value ≤1 × 10−5 were followed up in 373 African Americans. Fourteen single nucleotide polymorphisms were replicated, of which nine were associated with skin colour at genome-wide significance in a meta-analysis across the two studies. These results validated the association of two previously known skin pigmentation genes, SLC24A5 (minimum p = 2.62 × 10−14, rs1426654) and SLC45A2 (minimum p = 9.71 × 10−10, rs16891982), and revealed the intergenic region of BEND7 and PRPF18 as a novel locus associated with this trait (minimum p = 4.58 × 10−9, rs6602666). The most significant variant within this region is common among African-descent populations but not among Europeans or Native Americans. Our findings support the advantages of analyzing African-admixed populations to discover new genes influencing skin pigmentation.
... We found two novel interactions between SLC24A4 rs12896399 and SLC45A2 rs16891982 strongest in pheomelanin (P = 8.7e-04) as well as LYST rs3768056 and DSCR9 rs2835630 solely evident in eumelanin (P = 2.6e-2). Moreover, we confirmed several interaction pairs reported in previous studies using quantitative or categorical eye colour phenotypes, namely: HERC2 rs12913832 and SLC24A4 rs12896399 previously observed for S 24 as well as blue vs. non-blue 43 , observed here in PIEscore (P = 2.3e-16), b* (P = 3.3e-4), S (P = 4.2e-3), non-pigmentation (P = 5.4e-13), and pheomelanin (P = 8e-9); HERC2 rs12913832 and SCL45A2 rs16891982 previously described in blue vs. non-blue 44 , observed here in S (P = 1.3e-12), pheomelanin (P = 1.2e-16), non-pigmentation (P = 1.8e-20), S (P = 1.3e-12), Colour score (P = 3.5e-7), PIEscore (P = 3.6e-21), and b* (P = 3.8e-18); HERC2 rs12913832 and TYPR1 rs1325127 previously described in hazel vs. non-hazel 43 found only in pheomelanin (P = 7.8e-4); HERC2 rs12913832 and IRF4 rs12203592 previously observed in H and S 24 , found here in H (P = 1.9e-3), a* (P = 2.6e-4), and pheomelanin (P = 3.8e-3). ...
Article
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Success of genetic association and the prediction of phenotypic traits from DNA are known to depend on the accuracy of phenotype characterization, amongst other parameters. To overcome limitations in the characterization of human iris pigmentation, we introduce a fully automated approach that specifies the areal proportions proposed to represent differing pigmentation types, such as pheomelanin, eumelanin, and non-pigmented areas within the iris. We demonstrate the utility of this approach using high-resolution digital eye imagery and genotype data from 12 selected SNPs from over 3000 European samples of seven populations that are part of the EUREYE study. In comparison to previous quantification approaches, (1) we achieved an overall improvement in eye colour phenotyping, which provides a better separation of manually defined eye colour categories. (2) Single nucleotide polymorphisms (SNPs) known to be involved in human eye colour variation showed stronger associations with our approach. (3) We found new and confirmed previously noted SNP-SNP interactions. (4) We increased SNP-based prediction accuracy of quantitative eye colour. Our findings exemplify that precise quantification using the perceived biological basis of pigmentation leads to enhanced genetic association and prediction of eye colour. We expect our approach to deliver new pigmentation genes when applied to genome-wide association testing.
... These substitutions are mostly found in the C-terminal half of the protein in amino acid residues that are conserved in murine OCA2 (Lee et al., 1995). Nonpathological polymorphisms in human OCA2 and in the adjacent gene HERC2 are thought to modify OCA2 gene expression, and are strongly linked to ethnic differences in skin color and to the emergence of blue eye color in humans (Lao et al., 2007;Norton et al., 2007;Sulem et al., 2007;Eiberg et al., 2008;Sturm et al., 2008;Branicki et al., 2009;Mengel-From et al., 2010). ...
Article
Version:1.0 StartHTML:0000000224 EndHTML:0000004814 StartFragment:0000002412 EndFragment:0000004778 SourceURL:file://localhost/Users/hastha82/Desktop/temporary%20desktop%20folder/MARKS%20LAB/THESIS/final%20changes.doc Certain cell types harbor specialized lysosome-related organelles (LROs) that derive from the endocytic system like conventional lysosomes but have unique functions. The coexistence of LROs and lysosomes in some cell types implies the existence of sorting mechanisms that divert resident cargo proteins to LROs. Based on the pigment-synthesizing melanosome in melanocytes as a model LRO and two melanosomal resident proteins as model cargoes, current models suggest that cargoes are sorted from early endosomes to melanosomes via one of two independent pathways mediated by the multisubunit complexes AP-3 or BLOC-1, each of which is defective in subtypes of the LRO biogenesis disease Hermansky-Pudlak Syndrome (HPS). An AP-3-related protein complex, AP-1, is thought to function in concert with BLOC-1. In this thesis, I assess the pigment-cell-specific putative transporter protein OCA2, as a third potential cargo protein with which to further dissect the relationships between AP-3, AP-1 and BLOC-1 in melanosomal transport. I first investigate the localization and site of action of OCA2. I use biochemical approaches in combination with site-directed mutagenesis and indirect immunofluorescence microscopic analysis of exogenously-expressed OCA2 in melanocytes to show that OCA2 is indeed a melanosome resident protein and does not function within the endoplasmic reticulum as has been suggested by other models. I show that melanosome localization is essential for OCA2 function and requires an acidic dileucine motif in the N-terminal cytoplasmic domain that can bind to both AP-3 and AP-1. Using site-directed mutagenesis in combination with yeast three hybrid assays and immunofluorescence microscopy analyses in melanocytes derived from mouse models of HPS and controls, I define the features of the OCA2 sorting signal that direct binding to AP-1 or AP-3 and show that OCA2 requires both AP-3 interaction and BLOC-1 for melanosomal localization. My results resolve a controversy regarding OCA2 localization, shed light on the interplay between AP-1 and AP-3 in melanosomal trafficking, and provide the first direct evidence for cooperation between BLOC-1 and AP-3 in trafficking to a LRO.
... Consequently, Polish females were found more likely to have green eye colour (14.2 %) comparing to males (10.0 %), but there were no significant differences between genders for hazel and brown eye colours. In our previous study, higher proportion of Polish blue-eyed males (60.9 %) has been reported comparing to blue-eyed females (52.3 %), but the result has been insignificant which may be explained by significantly lower number of samples analysed (N = 388) [47]. In this large dataset, gender was found to be significantly associated with eye colour, but small size effect was reported with males having~1.5 ...
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The genetics of eye colour has been extensively studied over the past few years, and the identified polymorphisms have been applied with marked success in the field of Forensic DNA Phenotyping. A picture that arises from evaluation of the currently available eye colour prediction markers shows that only the analysis of HERC2-OCA2 complex has similar effectiveness in different populations, while the predictive potential of other loci may vary significantly. Moreover, the role of gender in the explanation of human eye colour variation should not be neglected in some populations. In the present study, we re-investigated the data for 1020 Polish individuals and using neural networks and logistic regression methods explored predictive capacity of IrisPlex SNPs and gender in this population sample. In general, neural networks provided higher prediction accuracy comparing to logistic regression (AUC increase by 0.02-0.06). Four out of six IrisPlex SNPs were associated with eye colour in the studied population. HERC2 rs12913832, OCA2 rs1800407 and SLC24A4 rs12896399 were found to be the most important eye colour predictors (p < 0.007) while the effect of rs16891982 in SLC45A2 was less significant. Gender was found to be significantly associated with eye colour with males having ~1.5 higher odds for blue eye colour comparing to females (p = 0.002) and was ranked as the third most important factor in blue/non-blue eye colour determination. However, the implementation of gender into the developed prediction models had marginal and ambiguous impact on the overall accuracy of prediction confirming that the effect of gender on eye colour in this population is small. Our study indicated the advantage of neural networks in prediction modeling in forensics and provided additional evidence for population specific differences in the predictive importance of the IrisPlex SNPs and gender.
... In addition to OCA2, a neighboring gene, HERC2 encodes a regulatory protein that interacts with the OCA2 promoter; a SNP mutation in HERC2 results in reduced OCA2 expression and explains 78% of brown-blue eye variation. Not surprisingly, OCA2 and HERC2 are also associated with variation in skin and hair color (Branicki, Brudnik, & Wojas-Pelc, 2009). More studies suggested that six SNPs from five regions within OCA2-HERC2, SLC24A4, SLC45A2, TYR, and IRF4 can give successful predictions of 93% for brown, 91.4% for blue, and 72% for intermediate colored eye (Liu et al., 2009). ...
Article
As humans migrated across the world, they encountered new environments requiring them to adapt to new challenges that presented themselves. The distribution of human phenotypes observed today is the result of this continuous adaptation, via biological/physiological and cultural means, and also by the modification of cultural practices, which leads to biological change. In this chapter, we examine a number of adaptive traits and the roles played by their genetic and environmental determinants. We have selected a few traits used for human identification purposes (externally visible characteristics), associated with human metabolism and linked to a shift in subsistence method and food consumption. We discuss the evolutionary processes that have affected the temporal and spatial distribution of these traits, including natural, sexual, and cultural selection.
... Both of them harbour variation known to affect pigmentation 39 and have classical signatures of positive selection 40,41 , recently supported by a targeted SNP analysis in several ancient European samples 17,19 . The derived allele upstream of OCA2 (rs12913832 in HERC2) is associated with blue iris colour in Europeans 42 and light skin pigmentation 43 ; both this variant and its linked variation show that Loschbour carried the predominant European haplotype (Fig. 6a). The derived allele in SLC45A2 non-synonymous rs16891982 is associated with lighter skin pigmentation and increased melanoma risk in Europeans 44,45 . ...
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The influence of positive selection sweeps in human evolution is increasingly debated, although our ability to detect them is hampered by inherent uncertainties in the timing of past events. Ancient genomes provide snapshots of allele frequencies in the past and can help address this question. We combine modern and ancient genomic data in a simple statistic (DAnc) to time allele frequency changes, and investigate the role of drift and adaptation in population differentiation. Only 30% of the most strongly differentiated alleles between Africans and Eurasians changed in frequency during the colonization of Eurasia, but in Europe these alleles are enriched in genic and putatively functional alleles to an extent only compatible with local adaptation. Adaptive alleles-especially those associated with pigmentation-are mostly of hunter-gatherer origin, although lactose persistence arose in a haplotype present in farmers. These results provide evidence for a role of local adaptation in human population differentiation.
... A associação entre marcadores genéticos e características morfológicas tem sido intensamente estudada na tentativa de se obter informações sobre feições físicas a partir de material genético extraído de amostras biológicas como manchas de sangue, pelos e outros fragmentos. Alguns estudos já revelaram polimorfi smos associados à cor da pele, olhos e cabelo [3][4][5][6] ; espessura do fi o de cabelo, formato da face e estatura [7][8][9][10] . ...
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Dentre os genes conhecidos por infl uenciarem a variação normal de pigmentação de olhos, pele e cabelos em humanos, o gene MC1R (receptor de melanocortina 1) é o mais bem caracterizado até o momento. A atuação do MC1R ocorre pela produção de uma proteína transmembrana nos melanócitos, responsável pela regulação da produção de melanina nos mesmos. Sabe-se que a atuação do MC1R determina a proporção entre eumelanina (coloração castanha/preta) e feomelanina (amarela/vermelha) presente nos melanócitos. O presente trabalho tem como objetivo analisar os SNPs conhecidos do gene MC1R com o propósito de se avaliar a infl uência da diversidade deste gene em características como a presença de sardas e variação da pigmentação dos olhos, pele e cabelos em humanos. Foram analisados 29 SNPs conhecidos da região codifi cadora do gene MC1R em 296 indivíduos da região de Ribeirão Preto, SP. A extração do DNA foi feita pela técnica de salting-out. A região codifi cadora do gene MC1R (951pb) foi amplifi cada em uma única reação de PCR, a qual foi sequenciada em um analisador genético ABI-PRISM 310 por eletroforese capilar, utilizando-se os mesmos primers empregados para a amplifi cação. Dos 29 SNPs avaliados, 22 deles mostraram variação nas amostras estudadas, sendo que metade deles demonstrou estar associados a características de pigmentação. Observou-se um conjunto de SNPs associados claramente à fenótipos relacionados à feomelanina (+1645 A, +1831 T,+1858 T e +2260 C), enquanto outros se relacionam à ocorrência de eumelanina (+1558 G, +2322 G, +2346 A). O presente trabalho apresenta associações signifi cativas entre SNPs individuais e pigmentação de olhos, cabelos e pele, sendo que nosso dados confi rmam que tal gene também desempenha papel relevante na variação de pigmentação na população Brasileira.
... The efforts of several groups have led to the identification of a series of SNPs and their corresponding genes, which may influence human pigmentation phenotypes; these include rs885479 at MC1R, rs16891982 at SLC45A2, rs1545397 at OCA2, rs12913832 at HERC2, rs6119471 at ASIP, and rs1426654 at SLC24A5. [19][20][21][22][23][24]. Although many pivotal SNPs have been discovered, they are far less important to explaining the differences among populations, such as the differences in physical appearance, disease susceptibility [25], and drug responses [26]. ...
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Many differences between different ethnic groups have been observed, such as skin color, eye color, height, susceptibility to some diseases, and response to certain drugs. However, the genetic bases of such differences have been under-investigated. Since the HapMap project, large-scale genotype data from Caucasian, African and Asian population samples have been available. The project found that these populations were located in different areas of the PCA (Principal Component Analysis) plot. However, as an unsupervised method, PCA does not measure the differences in each single nucleotide polymorphism (SNP) among populations. We applied an advanced mutual information-based feature selection method to detect associations between SNP status and ethnic groups using the latest HapMap Phase 3 release version 3, which included more sub-populations. A total of 299 SNPs were identified, and they can accurately predicted the ethnicity of all HapMap populations. The 10-fold cross validation accuracy of the SMO (sequential minimal optimization) model on training dataset was 0.901, and the accuracy on independent test dataset was 0.895. In-depth functional analysis of these SNPs and their nearby genes revealed the genetic bases of skin and eye color differences among populations.
... Recent studies have revealed that the interaction between OCA2 and HERC2 may be responsible for determining the blue eye color in humans. In an association study with OCA2 and HERC2, Branicki et al. (2009) verified possible interaction effects with other genes (MC1R, ASIP, and SLC45A2) also associated with variation in eye, hair and skin color in some populations. They concluded that the rs1800407 (Arg419Gln) polymorphism in the OCA2 gene is associated with eye color and that there are significant interactions between MC1R and HERC2 in determining skin and hair color in their Polish sample. ...
Article
Despite the growing number of registered DNA forensic profiles, the rate of profile hits is far below the expected. When a given profile is not found with the standard kits, any available information is important. Ancestry Informative Markers (AIM) have been employed for the identification of the person's ethnicity. However, this is not an adequate approach in certain cases, as, for instance, individuals living in ethnically admixed populations, in which the physical appearance is not necessarily associated with ethnicity. Hence, the use of AIMs in such populations has few or no advantage. The interest in the search for alleles directly linked to physical characteristics is therefore rapidly increasing, resulting in the commercialization of kits for the identification of skin, hair and eye pigmentation phenotypes based on genetic variation of candidate genes such as ASIP, HERC2, MC1R, OCA2, and TYR. This genetic variation may affect different stages of the pigmentation process, including melanogenesis, the stabilization and transport of enzymes during melanin synthesis, melanosome production and maintenance, and the balance between the synthesis of different types of melanin. In this chapter we examine the most important genes associated to human hair, skin and eye pigmentation, discussing the evolutionary background for the observed variation and their functional relevance for the physiological mechanisms involved with pigmentation, highlighting the forensic application of this knowledge. We will also discuss better ways of collecting pigmentation phenotypic data in human populations for forensic and general studies. It is expected that in the near future we may be able to predict with high reliability the externally visible human characteristics based on DNA analyses.
... Other selective events that 3P-CLR infers to have occurred in Eurasians include the region containing HERC2 and OCA2, which are major determinants of eye color (Eiberg et al. 2008;Han et al. 2008;Branicki et al. 2009). There is also evidence that these genes underwent selection more recently in the history of Europeans (Mathieson et al. 2015), which could suggest an extended period of selection-perhaps influenced by migrations between Asia and Europe-or repeated selective events at the same locus. ...
Article
A powerful way to detect selection in a population is by modeling local allele frequency changes in a particular region of the genome under scenarios of selection and neutrality, and finding which model is most compatible with the data. Chen et al. [2010] developed a composite likelihood method called XP-CLR that uses an outgroup population to detect departures from neutrality which could be compatible with hard or soft sweeps, at linked sites near a beneficial allele. However, this method is most sensitive to recent selection and may miss selective events that happened a long time ago. To overcome this, we developed an extension of XP-CLR that jointly models the behavior of a selected allele in a three population tree. Our method - called 3P-CLR - outperforms XP-CLR when testing for selection that occurred before two populations split from each other, and can distinguish between those events and events that occurred specifically in each of the populations after the split. We applied our new test to population genomic data from the 1000 Genomes Project, to search for selective sweeps that occurred before the split of Yoruba and Eurasians, but after their split from Neanderthals, and that could have led to the spread of modern-human-specific phenotypes. We also searched for sweep events that occurred in East Asians, Europeans and the ancestors of both populations, after their split from Yoruba. In both cases, we are able to confirm a number of regions identified by previous methods, and find several new candidates for selection in recent and ancient times. For some of these, we also find suggestive functional mutations that may have driven the selective events.
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African antelope diversity is a globally unique vestige of a much richer world-wide Pleistocene megafauna. Despite this, the evolutionary processes leading to the prolific radiation of African antelopes are not well understood. Here, we sequenced 145 whole genomes from both subspecies of the waterbuck, an African antelope believed to be in the process of speciation. We investigated genetic structure and population divergence and found evidence of a mid-Pleistocene separation on either side of the eastern Great Rift Valley, consistent with vicariance caused by a rain shadow along the so-called ‘Kingdon’s Line’. However, we also found pervasive evidence of not only isolated and recent, but also widespread historical gene flow across the Rift Valley barrier. By inferring the genome-wide landscape of variation among subspecies, we found 14 genomic regions of elevated differentiation, including a locus that may be related to each subspecies’ distinctive coat pigmentation pattern. We investigated these regions as candidate speciation islands. However, we observed no significant reduction in gene flow in these regions, nor any indications of selection against hybrids. Altogether, these results suggest a pattern whereby climatically driven vicariance is the most important process driving the African antelope radiation, and suggest that reproductive isolation may not set in until very late in the divergence process.
Article
Deciphering the molecular architecture of coat coloration for a better understanding of the biological mechanisms underlying pigmentation still remains a challenge. We took advantage of a rabbit French experimental population in which both a pattern and a gradient of coloration from white to brown segregated within the himalayan phenotype. The whole experimental design was genotyped using the high density Affymetrix® AxiomOrcun™ SNP Array and phenotyped into 6 different groups ordered from the lighter to the darker. Genome-wide association analyses pinpointed an oligogenic determinism, under recessive and additive inheritance, involving genes already known in melanogenesis (ASIP, KIT, MC1R, TYR), and likely processed pseudogenes linked to ribosomal function, RPS20 and RPS14. We also identified (i) gene-gene interactions through ASIP:MC1R affecting light cream/beige phenotypes while KIT:RPS responsible of dark chocolate/brown colors and (ii) a genome-wide epistatic network involving several others coloration genes such as POT1 or HPS5. Finally, we determined the recessive inheritance of the English spotting phenotype likely involving a copy number variation affecting at least the end of the coding sequence of the KIT gene. Our analyses of coloration as a continuous trait allowed us to go beyond much of the established knowledge through the detection of additional genes and gene-gene interactions that may contribute to the molecular architecture of the coloration phenotype.
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Skin color is a highly heritable human trait, and global variation in skin pigmentation has been shaped by natural selection, migration, and admixture. Ethnically diverse African populations harbor extremely high levels of genetic and phenotypic diversity, and skin pigmentation varies widely across Africa. Recent genome-wide genetic studies of skin pigmentation in African populations have advanced our understanding of pigmentation biology and human evolutionary history. For example, novel roles in skin pigmentation for loci near MFSD12 and DDB1 have recently been identified in African populations. However, due to an underrepresentation of Africans in human genetic studies, there is still much to learn about the evolutionary genetics of skin pigmentation. Here, we summarize recent progress in skin pigmentation genetics in Africans and discuss the importance of including more ethnically diverse African populations in future genetic studies. In addition, we discuss methods for functional validation of adaptive variants related to skin pigmentation.
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In order to ascertain the effects of past breeding decisions on the genome we studied three Haflinger subpopulations representing the old-type (South-Tyrol), an intermediate type (Slovenia) and the modern type (Austria) by means of a high density 670k SNP geno typing array. High-resolution network analysis, FST- and Admixture analysis, underlined the high genetic distance of the South-Tyrolean Haflinger in relation to the other two samples. This differentiation was also highlighted by ROH analysis, where 15 out of 19 ROH islands were privately detected within the respective subpopulations. Common ROH islands among the three subpopulations were found on ECA3 and ECA7 containing inter alia genes related with behaviour ( JPH3 ) and coat color ( MC1R ). The South-Tyrolean and the Slovenian (below threshold) sample exhibited a ROH island on ECA1 containing OCA2 , which may be involved in the breed-specific sorrel phenotype of the Haflinger. Body size associated SNP genotypes at the LCORL/NCAPG locus revealed a fixation for the small body size associated alleles for all collected samples, whereas for SNPs associated with height at withers at the ZFAT locus a genomic shift towards taller horses was detected in Austrian Haflinger, which were exposed to a high selection pressure for this trait throughout the past four decades.
Article
Background/Purpose Recent GWAS studies, mostly performed in populations of North European origin, have identified the genetic loci associated with pigmentation, sun sensitivity, freckling, and skin cancer susceptibility. Here we aimed at addressing the genetic determinants of sunlight sensitivity in Spain, a southern European population. Methods Nine SNPs located in 8 pigmentation‐related genes (IRF4, TYR, ASP, HERC2, OCA2, BNC2, SLC24A4 and SLC45A2) were genotyped in 456 Spaniards. Additionally, the complete sequence of the MC1R gene was obtained, testing each non‐synonymous mutation supported by the classification as R or r alleles. A standardised questionnaire was used to collect demographic characteristics, pigmentation and sun sensitivity traits, as well as sun exposure habits. Results MC1R R alleles and IRF4 rs12203592 were significantly associated with sunlight sensitivity at the Bonferroni‐corrected level (P‐value < 4.54x10‐3). Genetic variants in SLC45A2 (rs16891982) and HERC2 (rs12913832) were also found to be significantly associated with skin photosensitivity in our Spanish sample. Interaction analysis using the MDR method revealed epistatic effects when these four variants were considered together. Conclusion MC1R, IRF4, HERC2 and SLC45A2 play a significant role in skin sensitivity to sunlight in the Spanish population. Moreover, interaction among these four loci seems to modulate the ability of the skin to respond to UV radiation. This article is protected by copyright. All rights reserved.
Article
Introduction: Recent studies have investigated the relationship between pain perception and specific phenotypes such as red hair color and various eye colors. Further investigations into biomarkers as they relate to pain could be useful in understanding underlying genetic components involved in these pathways. Additionally, it would be clinically useful to determine if a patient would be more likely to experience pain during dental treatment based on eye color. The purpose of this study was to investigate a link between eye color and perceived injection pain in healthy, asymptomatic white women. Methods: Three hundred healthy, adult, white female patients were included, 133 with dark eyes and 167 with light eyes. Dental anxiety was assessed with the Corah Dental Anxiety Scale. Subjects with their eye color masked by dark glasses received a right maxillary lateral incisor infiltration of 1 cartridge of 2% lidocaine with 1:100,000 epinephrine. Patients rated their injection pain on a 170-mm Heft-Parker visual analog scale. Photographs of the subjects' eyes were taken after the infiltrations and categorized into dark- and light-eyed groups by 3 independent observers. Comparisons for injection pain were analyzed using analysis of variance and the Tukey-Kramer test. Results: No significant differences were found for pain of injection between dark- or light-eyed subjects. Conclusions: Eye color was not shown to be a predictor for injection pain in white women. Therefore, eye color would not be clinically useful in determining if a patient would be more likely to experience pain during dental treatment.
Article
Objectives: Human skin color is one of the most conspicuously variable physical traits that has attracted the attention of physical anthropologists, social scientists and human geneticists. Although several studies have established the underlying genes and their variants affecting human skin color, they were mostly confined to Europeans and Africans and similar studies in Indian populations have been scanty. Studying the association between candidate genetic variants and skin color will help to validate previous findings and to better understand the molecular mechanism of skin color variation. Methods: In this study, 22 candidate SNPs from 12 genes were tested for association with skin color in 299 unrelated samples sourced from nine geographical locations in India. Results: Our study establishes the association of 9 SNPs with the phenotype in Indian populations and could explain ∼31% of the variance in skin color. Haplotype analysis of chromosome 15 revealed a significant association of alleles G, A and C of SNPs rs1426654, rs11070627, and rs12913316, respectively, to the phenotype, and accounted for 17% of the variance. Latitude of the sampling location was also a significant factor, contributing to ∼19% of the variation observed in the samples. Conclusions: These observations support the findings that rs1426654 and rs4775730 located in SLC24A5, and rs11070627 and rs12913316 located in MYEF2 and CTXN2 genes respectively, are major contributors toward skin pigmentation and would aid in further unraveling the genotype-phenotype association in Indian populations. These findings can be utilized in forensic DNA applications for criminal investigations.
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Human skin colour is highly heritable and externally visible with relevance in medical, forensic, and anthropological genetics. Although eye and hair colour can already be predicted with high accuracies from small sets of carefully selected DNA markers, knowledge about the genetic predictability of skin colour is limited. Here, we investigate the skin colour predictive value of 77 single-nucleotide polymorphisms (SNPs) from 37 genetic loci previously associated with human pigmentation using 2025 individuals from 31 global populations. We identified a minimal set of 36 highly informative skin colour predictive SNPs and developed a statistical prediction model capable of skin colour prediction on a global scale. Average cross-validated prediction accuracies expressed as area under the receiver-operating characteristic curve (AUC) ± standard deviation were 0.97 ± 0.02 for Light, 0.83 ± 0.11 for Dark, and 0.96 ± 0.03 for Dark-Black. When using a 5-category, this resulted in 0.74 ± 0.05 for Very Pale, 0.72 ± 0.03 for Pale, 0.73 ± 0.03 for Intermediate, 0.87±0.1 for Dark, and 0.97 ± 0.03 for Dark-Black. A comparative analysis in 194 independent samples from 17 populations demonstrated that our model outperformed a previously proposed 10-SNP-classifier approach with AUCs rising from 0.79 to 0.82 for White, comparable at the intermediate level of 0.63 and 0.62, respectively, and a large increase from 0.64 to 0.92 for Black. Overall, this study demonstrates that the chosen DNA markers and prediction model, particularly the 5-category level; allow skin colour predictions within and between continental regions for the first time, which will serve as a valuable resource for future applications in forensic and anthropologic genetics. Electronic supplementary material The online version of this article (doi:10.1007/s00439-017-1808-5) contains supplementary material, which is available to authorized users.
Chapter
Driven by recent evolutionary history, pigmentation traits significantly contribute to the most obvious parts of the overall human phenotypic diversity with skin colour varying between worldwide individuals, while eye and hair colour differences only exist in individuals of European (and neighbouring region) descent. Genetic association studies have discovered various DNA variants that together explain large proportion of phenotypic variance in eye, hair and skin colouration. Besides providing leads in the molecular understanding of human pigmentation, multiple associated DNA variants have also been used for prediction modelling of pigmentation traits. The success of DNA‐based pigmentation prediction laid the foundation for a new subfield of forensic genetics known as Forensic DNA Phenotyping, which aims to help finding unknown perpetrators. Pigmentation DNA prediction is further relevant in anthropological research from old and ancient human remains for reconstructing colour phenotypes of deceased persons including those of historical importance. Key Concepts Driven by recent evolutionary history, differences in pigmentation significantly contribute to the phenotypic diversity in humans. Eye, hair and skin colour reflect complex traits with multiple genes and environmental factors determining phenotypic variation distributed differently around the world. Gene mapping studies identified a number of pigmentation genes that typically but not necessarily determine all three pigmentation traits in humans. Multiple pigmentation‐associated DNA variants have proven useful to predict all three human pigmentation traits with varying accuracies. Several DNA test systems are available for accurate prediction of blue and brown eyes, while for other eye colours further research is needed. Available DNA test systems for hair colour provide accurate prediction of red and (albeit less so) of black hair, while the DNA prediction of blond and brown hair is troubled by age‐dependent hair colour changes in some (but not all) individuals not yet understood on the molecular level. Of the three human pigmentation traits, DNA prediction of skin colour is least advanced, requiring considerable further research. Current DNA prediction on the level of categorical eye, hair and skin colour shall be improved towards more detailed colour phenotypes, if the necessary DNA predictors become available via dedicated future research. Forensic science is a major recipient of pigmentation predictive DNA tests, where they are used to trace unknown perpetrators unidentifiable via conventional DNA profiling. Pigmentation DNA prediction is also relevant in anthropological and human evolutionary research particularly from old and ancient human remains.
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In this study we analysed the genetic variability of the Austrian Haflinger horse population by use of pedigree analysis. For the analysis of inbreeding and genetic variability we defined three different reference populations which included active breeding animals animals between 1978 and 1985 (reference population 3, R3) comprised 6,34%, the effective number of founders was 43 and the effective number of ancestors was 18. In the following two reference populations (R2 1993 and 2000; R1 2008 and 2015) the genetic variability further decreased. The mean inbreeding increased from 8,83% in R2 to 11,92% in R1 and effective number of founders comprised 35 in R2 and 14 in R1, and the effective number of ancestors was 31 in R2 and 12 in R1. The gene pool of the actual Austrian Haflinger population consists of 6,9% Arabian genes, 1,7% Gidran genes, 1,8% Noriker genes, 58,6% genes from Original Haflinger founder mares (Ohast.), 24,1% genes from Haflinger horses, 0,01% genes from crossbred mares and 6,9% of genes go back to a Galician founder mare of the 19th century. Finally the decrease of genetic variability and the mean inbreeding increase of about 1% per generation in the Austrian Haflinger population shows, that in spite its worldwide distribution and the large international population size, it will be necessary to apply strategies from conservation genetics. In this context the major challenge will be the incorporation of founder contributions in small frequencies actually not being used in reproduction in order to increase theamount of alleles in the actual Haflinger gene pool.
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We report a genome-wide association study (GWAS) of cutaneous squamous cell carcinoma (SCC) conducted among non-Hispanic white (NHW) members of the Kaiser Permanente Northern California (KPNC) health care system. The study includes a genome-wide screen of 61,457 members (6,891 cases and 54,566 controls) genotyped on the Affymetrix Axiom European array and a replication phase involving an independent set of 6,410 additional members (810 cases and 5600 controls). Combined analysis of screening and replication phases identified ten loci containing single-nucleotide polymorphisms (SNPs) with P-values < 5x10-8. Six loci contain genes in the pigmentation pathway; SNPs at these loci appear to modulate SCC risk independently of the pigmentation phenotypes. Another locus contains HLA class II genes studied in relation to elevated SCC risk following immunosuppression. SNPs at the remaining three loci include an intronic SNP in FOXP1 at locus 3p13, an intergenic SNP at 3q28 near TP63, and an intergenic SNP at 9p22 near BNC2. These findings provide insights into the genetic factors accounting for inherited SCC susceptibility.
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Arlequin ver 3.0 is a software package integrating several basic and advanced methods for population genetics data analysis, like the computation of standard genetic diversity indices, the estimation of allele and haplotype frequencies, tests of departure from linkage equilibrium, departure from selective neutrality and demographic equilibrium, estimation or parameters from past population expansions, and thorough analyses of population subdivision under the AMOVA framework. Arlequin 3 introduces a completely new graphical interface written in C++, a more robust semantic analysis of input files, and two new methods: a Bayesian estimation of gametic phase from multi-locus genotypes, and an estimation of the parameters of an instantaneous spatial expansion from DNA sequence polymorphism. Arlequin can handle several data types like DNA sequences, microsatellite data, or standard multi-locus genotypes. A Windows version of the software is freely available on http://cmpg.unibe.ch/software/arlequin3.
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Pigmentation is a complex physical trait with multiple genes involved. Several genes have already been associated with natural differences in human pigmentation. The SLC45A2 gene encoding a transporter protein involved in melanin synthesis is considered to be one of the most important genes affecting human pigmentation. Here we present results of an association study conducted on a population of European origin, where the relationship between two non-synonymous polymorphisms in the SLC45A2 gene - rs26722 (E272K) and rs16891982 (L374F) - and different pigmentation traits was examined. The study revealed a significant association between both variable sites and normal variation in hair colour. Only L374F remained significantly associated with hair colour when both SNPs were included in a logistic regression model. No association with other pigmentation traits was detected in this population sample. Our results indicate that the rare allele L374 significantly increases the possibility of having black hair colour (OR = 7.05) and thus may be considered as a future marker for black hair colour prediction.
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The melanocortin-1 receptor (MC1R) and P gene product are two important components of the human pigmentary system that have been shown to be associated with red hair/fair skin and cause type II oculocutaneous albinism, respectively. However, their contribution to inter-individual variation at the population level is not well defined. To this end, we genotyped 3 single nucleotide polymorphisms (SNPs) in the MC1R gene (Arg67Gln, Gln163Arg, Val92Met) and 2 SNPs in the P gene (IVS 13-15 and Gly780Gly) in 184 randomly ascertained Tibetan subjects, whose skin color was measured as a quantitative trait by reflective spectroscopy. Single locus analyses failed to demonstrate an association between any of the 5 SNPs and skin pigmentation. However, when an epistatic model was applied to the data, a significant gene-gene interaction was identified between Val92Met in MCIR and IVS13-15 in the P gene (F=2.43; P=0.0105). We also discuss the possible mechanisms of how gene interactions arise in signal transduction pathways.
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We conducted a multi-stage genome-wide association study of natural hair color in more than 10,000 men and women of European ancestry from the United States and Australia. An initial analysis of 528,173 single nucleotide polymorphisms (SNPs) genotyped on 2,287 women identified IRF4 and SLC24A4 as loci highly associated with hair color, along with three other regions encompassing known pigmentation genes. We confirmed these associations in 7,028 individuals from three additional studies. Across these four studies, SLC24A4 rs12896399 and IRF4 rs12203592 showed strong associations with hair color, with p = 6.0x10(-62) and p = 7.46x10(-127), respectively. The IRF4 SNP was also associated with skin color (p = 6.2x10(-14)), eye color (p = 6.1x10(-13)), and skin tanning response to sunlight (p = 3.9x10(-89)). A multivariable analysis pooling data from the initial GWAS and an additional 1,440 individuals suggested that the association between rs12203592 and hair color was independent of rs1540771, a SNP between the IRF4 and EXOC2 genes previously found to be associated with hair color. After adjustment for rs12203592, the association between rs1540771 and hair color was not significant (p = 0.52). One variant in the MATP gene was associated with hair color. A variant in the HERC2 gene upstream of the OCA2 gene showed the strongest and independent association with hair color compared with other SNPs in this region, including three previously reported SNPs. The signals detected in a region around the MC1R gene were explained by MC1R red hair color alleles. Our results suggest that the IRF4 and SLC24A4 loci are associated with human hair color and skin pigmentation.
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We present results from a genome-wide association study for variants associated with human pigmentation characteristics among 5,130 Icelanders, with follow-up analyses in 2,116 Icelanders and 1,214 Dutch individuals. Two coding variants in TPCN2 are associated with hair color, and a variant at the ASIP locus shows strong association with skin sensitivity to sun, freckling and red hair, phenotypic characteristics similar to those affected by well-known mutations in MC1R.
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We have previously developed the multifactor dimensionality reduction (MDR) method to identify gene-gene and gene-environment interactions (Ritchie et al. AJHG 69, 2001). In brief, MDR is a method that reduces the dimensionality of multilocus information to identify polymorphisms associated with an increased risk of disease. This approach takes multilocus genotypes and develops a model for defining disease risk by pooling high-risk genotype combinations into one group and low-risk combinations into another group. Ten-fold cross validation and permutation testing are used to identify optimal models. The goal of this study was to evaluate the power of MDR for identifying gene-gene and gene-environment interactions in the presence of common sources of noise. Using four different epistasis models, we simulated discordant sib-pairs with 5% genotyping error, 5% phenocopy. 20% phenocopy, or 50% genetic heterogeneity. MDR was able to identify the functional loci with 80-98% power in the presence of genotyping error or phenocopy, and 47-78% power in the presence of genetic heterogeneity. These results demonstrate that MDR is a powerful method for identifying and characterizing gene-gene and gene-environment interactions, even in the presence of some common sources of noise.
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Humans skin is the most visible aspect of the human phenotype. It is distinguished mainly by its naked appearance, greatly enhanced abilities to dissipate body heat through sweating, and the great range of genetically determined skin colors present within a single species. Many aspects of the evolution of human skin and skin color can be reconstructed using comparative anatomy, physiology, and genomics. Enhancement of thermal sweating was a key innovation in human evolution that allowed maintenance of homeostasis (including constant brain temperature) during sustained physical activity in hot environments. Dark skin evolved pari passu with the loss of body hair and was the original state for the genus Homo. Melanin pigmentation is adaptive and has been maintained by natural selection. Because of its evolutionary lability, skin color phenotype is useless as a unique marker of genetic identity. In recent prehistory, humans became adept at protecting themselves from the environment through clothing and shelter, thus reducing the scope for the action of natural selection on human skin.
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We have determined the structure, nucleotide sequence, and polymorphisms of the human P gene. Mutations of the P gene result in type II oculocutaneous albinism (OCA2) in humans and pink-eyed dilution (p) in mice. We find that the human P gene is quite large, consisting of 25 exons spanning 250 to 600 kb in chromosome segment 15q11–q13. The P polypeptide appears to define a novel family of small molecule transporters and may be involved in transport of tyrosine, the precursor to melanin synthesis, within the melanocyte. These results provide the basis for analyses of patients with OCA2 and may point toward eventual pharmacologic treatment of this and related disorders of pigmentation.
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In this study, we assessed the role of melanocortin-1 receptor (MC1R) and agouti signalling protein (ASIP) polymorphisms in cutaneous melanoma and basal cell carcinoma (BCC) development in a Polish population. We enrolled 108 patients with skin malignant melanoma (MM) and 102 patients with BCC. The control group consisted of 93 non-red haired patients, without history of skin cancers and 30 healthy individuals with red hair colour (RHC) phenotype. The complete MC1R exon was sequenced and the A8818G polymorphism of the ASIP gene was analysed using the SnaPshot protocol. Selected MC1R mutations were additionally examined using a convenient minisequencing assay. The study confirmed the important role of MC1R R variants in determining physiological variation in hair and skin colour. Our data show that individuals with R mutations had a 3.7-fold increase in melanoma risk and a 3.3-fold increase in BCC risk. Especially, variant R151C significantly increased the risk of both MM and BCC. The studied ASIP polymorphism was found not to be associated with MM or BCC. Stratified analysis showed that the association between MC1R mutations and the risk of MM and BCC was not significantly influenced by subjects' pigmentation characteristics or the 8818G ASIP variant. Further research is necessary, especially involving analysis of interactions between variation in MC1R and other genes, to find out if analysis of MC1R polymorphisms could be of any importance for skin cancer prevention.
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To identify interacting loci in genetic epidemiological studies the application of multi-locus methods of analysis is warranted. Several more advanced classification methods have been developed in the past years, including multiple logistic regression, sum statistics, logic regression, and the multifactor dimensionality reduction method. The objective of our study was to apply these four multi-locus methods to simulated case-control datasets that included a variety of underlying statistical two-locus interaction models, in order to compare the methods and evaluate their strengths and weaknesses. The results showed that the ability to identify the interacting loci was generally good for the sum statistic method, the logic regression and MDR. The performance of the logistic regression was more dependent on the underlying model and multiple comparison adjustment procedure. However, identification of the interacting loci in a model with two two-locus interactions of common disease alleles with relatively small effects was impaired in all methods. Several practical and methodological issues that can be considered in the application of these methods, and that may warrant further research, are identified and discussed.
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The natural range of hair and skin colour is a continuous spectrum, controlled by multiple genes in a complex fashion. Many of these genes are as yet unknown, but several key pigmentation genes have been characterised, in particular the melanocortin 1 receptor gene (MC1R). Here, the function and known mutations of MC1R and other human pigmentation genes including ASIP, MATP, SLC24A5, TYR, TYRP1 and OCA2 are outlined, and a forensic test based on MC1R SNPs presented. The forensic utility of this and potential future genetic tests for phenotypic traits are discussed, in the light of the extensive debate on the ethics of predicting phenotypic traits from crime scene samples.
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The juvenile development and fertility-2 (jdf2) locus, also called runty-jerky-sterile (rjs), was originally identified through complementation studies of radiation-induced p-locus mutations. Studies with a series of ethylnitrosourea (ENU)-induced jdf2 alleles later indicated that the pleiotropic effects of these mutations were probably caused by disruption of a single gene. Recent work has demonstrated that the jdf2 phenotype is associated with deletions and point mutations in Herc2, a gene encoding an exceptionally large guanine nucleotide exchange factor protein thought to play a role in vesicular trafficking. Here we describe the molecular characterization of a collection of radiation- and chemically induced jdf2/Herc2 alleles. Ten of the 13 radiation-induced jdf2 alleles we studied are deletions that remove specific portions of the Herc2 coding sequence; DNA rearrangements were also detected in two additional mutations. Our studies also revealed that Herc2 transcripts are rearranged, not expressed, or are present in significantly altered quantities in animals carrying most of the jdf2 mutations we analyzed, including six independent ENU-induced alleles. These data provide new molecular clues regarding the wide range of jdf2 and p phenotypes that are expressed by this collection of recently generated and classical p-region mutations.
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Recombination between chromosome-specific low-copy repeats (duplicons) is an underlying mechanism for several genetic disorders. Recently, a chromosome 15 duplicon was discovered in the common breakpoint regions of Prader-Willi and Angelman syndrome deletions. We identified previously the large HERC2 transcript as an ancestral gene in this duplicon, with approximately 11 HERC2-containing duplicons, and demonstrated that recessive mutations in mouse Herc2 lead to a developmental syndrome, juvenile development and fertility 2 (jdf2). We have now constructed and sequenced a genomic contig of HERC2, revealing a total of 93 exons spanning approximately 250 kb and a CpG island promoter. A processed ribosomal protein L41 pseudogene occurs in intron 2 of HERC2, and putative VNTRs occur in intron 70 (28 copies, approximately 76-bp repeat) and 3' exon 40 through intron 40 (6 copies, approximately 62-bp repeat). Sequence comparisons show that HERC2-containing duplicons have undergone several deletion, inversion, and dispersion events to form complex duplicons in 15q11, 15q13, and 16p11. To further understand the developmental role of HERC2, a highly conserved Drosophila ortholog was characterized, with 70% amino acid sequence identity to human HERC2 over the carboxy-terminal 743 residues. Combined, these studies provide significant insights into the structure of complex duplicons and into the evolutionary pathways of formation, dispersal, and genomic instability of duplicons. Our results establish that some genes not only have a protein coding function but can also play a structural role in the genome.
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Current routine genotyping methods typically do not provide haplotype information, which is essential for many analyses of fine-scale molecular-genetics data. Haplotypes can be obtained, at considerable cost, experimentally or (partially) through genotyping of additional family members. Alternatively, a statistical method can be used to infer phase and to reconstruct haplotypes. We present a new statistical method, applicable to genotype data at linked loci from a population sample, that improves substantially on current algorithms; often, error rates are reduced by > 50%, relative to its nearest competitor. Furthermore, our algorithm performs well in absolute terms, suggesting that reconstructing haplotypes experimentally or by genotyping additional family members may be an inefficient use of resources.
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One of the greatest challenges facing human geneticists is the identification and characterization of susceptibility genes for common complex multifactorial human diseases. This challenge is partly due to the limitations of parametric-statistical methods for detection of gene effects that are dependent solely or partially on interactions with other genes and with environmental exposures. We introduce multifactor-dimensionality reduction (MDR) as a method for reducing the dimensionality of multilocus information, to improve the identification of polymorphism combinations associated with disease risk. The MDR method is nonparametric (i.e., no hypothesis about the value of a statistical parameter is made), is model-free (i.e., it assumes no particular inheritance model), and is directly applicable to case-control and discordant-sib-pair studies. Using simulated case-control data, we demonstrate that MDR has reasonable power to identify interactions among two or more loci in relatively small samples. When it was applied to a sporadic breast cancer case-control data set, in the absence of any statistically significant independent main effects, MDR identified a statistically significant high-order interaction among four polymorphisms from three different estrogen-metabolism genes. To our knowledge, this is the first report of a four-locus interaction associated with a common complex multifactorial disease.
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The chromosomal region, 15q11-q13, involved in Prader-Willi and Angelman syndromes (PWS and AS) represents a paradigm for understanding the relationships between genome structure, epigenetics, evolution, and function. The PWS/AS region is conserved in organization and function with the homologous mouse chromosome 7C region. However, the primate 4 Mb PWS/AS region is bounded by duplicons derived from an ancestral HERC2 gene and other sequences that may predispose to chromosome rearrangements. Within a 2 Mb imprinted domain, gene function depends on parental origin. Genetic evidence suggests that PWS arises from functional loss of several paternally expressed genes, including those that function as RNAs, and that AS results from loss of maternal UBE3A brain-specific expression. Imprinted expression is coordinately controlled in cis by an imprinting center (IC), a genetic element functional in germline and/or early postzygotic development that regulates the establishment of parental specific allelic differences in replication timing, DNA methylation, and chromatin structure.
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Human pigmentation, including eye color, has been associated with skin cancer risk. The P gene is the human homologue to the mouse pink-eye dilution locus and is responsible for oculocutaneous albinism type 2 and other phenotypes that confer eye hypopigmentation. The P gene is located on chromosome 15q11.2-q12, which is also the location of a putative eye pigmentation gene (EYCL3) inferred to exist by linkage analysis. Therefore, the P gene is a strong candidate for determination of human eye color. Using a sample of 629 normally pigmented individuals, we found that individuals were less likely to have blue or gray eyes if they had P gene variants Arg305Trp (P = 0.002), Arg419Gln (P = 0.001), or the combination of both variants (P = 0.003). These results suggest that P gene, in part, determines normal phenotypic variation in human eye color and may therefore represent an inherited biomarker of cutaneous cancer risk.
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Epistasis, the interaction between genes, is a topic of current interest in molecular and quantitative genetics. A large amount of research has been devoted to the detection and investigation of epistatic interactions. However, there has been much confusion in the literature over definitions and interpretations of epistasis. In this review, we provide a historical background to the study of epistatic interaction effects and point out the differences between a number of commonly used definitions of epistasis. A brief survey of some methods for detecting epistasis in humans is given. We note that the degree to which statistical tests of epistasis can elucidate underlying biological interactions may be more limited than previously assumed.