Near Fixation of 374l Allele Frequencies of the Skin Pigmentation Gene SLC45A2 in Africa

The L374F polymorphism of the SLC45A2 gene, encoding the membrane-associated transporter protein that plays an important role in melanin synthesis, has been suggested to be associated with skin color in human populations. In this study, the detailed distribution of the 374f and 374l alleles has been investigated in 2,581 unrelated subjects from 36 North, East, West, and Central African populations. We found once more the highly significant (p < 0.001) correlation coefficient (r = 0.957) cline of 374f frequencies with degrees of latitude in European and North African populations. Almost all the African populations located below 16° of latitude are fixed for the 374l allele. Peul, Toucouleur, and Soninké populations have 374l allele frequencies of 0.06, 0.03, and 0.03, respectively.     

The Southall Diabetes Survey: prevalence of known diabetes in Asians and Europeans.

A house to house inquiry for patients with known diabetes was carried out in a defined area of Southall, west London, which contained over 34 000 Asians and 27 000 Europeans in the 1981 Census: 1143 diabetic patients were ascertained, of whom 761 were Asian and 324 European. The prevalence adjusted for age of known diabetes in Asians was at least 3.8 times higher than that in Europeans. For patients aged between 40 and 64 years it was at least five times higher, was over 12% in Asians aged 60-69, and over 8% in those aged 50-59. These data are important in planning for the care of diabetic patients in health districts with large Asian communities. The causes and later consequences of this exceptionally high prevalence require further study.     

Genetic relationships of Asians and Northern Europeans, revealed by Y-chromosomal DNA analysis.

We have identified a new T-->C transition on the human Y chromosome. C-allele chromosomes have been found only in a subset of the populations from Asia and northern Europe and reach their highest frequencies in Yakut, Buryats, and Finns. Examination of the microsatellite haplotypes of the C-allele chromosomes suggests that the mutation occurred recently in Asia. The Y chromosome thus provides both information about population relationships in Asia and evidence for a substantial paternal genetic contribution of Asians to northern European populations such as the Finns.     

Haplotypes in SLC24A5 Gene as Ancestry Informative Markers in Different Populations

Ancestry informative markers (AIMs) are human polymorphisms that exhibit substantially allele frequency differences among populations. These markers can be useful to provide information about ancestry of samples which may be useful in predicting a perpetrator’s ethnic origin to aid criminal investigations. Variations in human pigmentation are the most obvious phenotypes to distinguish individuals. It has been recently shown that the variation of a G in an A allele of the coding single-nucleotide polymorphism (SNP) rs1426654 within SLC24A5 gene varies in frequency among several population samples according to skin pigmentation. Because of these observations, the SLC24A5 locus has been evaluated as Ancestry Informative Region (AIR) by typing rs1426654 together with two additional intragenic markers (rs2555364 and rs16960620) in 471 unrelated individuals originating from three different continents (Africa, Asia and Europe). This study further supports the role of human SLC24A5 gene in skin pigmentation suggesting that variations in SLC24A5 haplotypes can correlate with human migration and ancestry. Furthermore, our data do reveal the utility of haplotype and combined unphased genotype analysis of SLC24A5 in predicting ancestry and provide a good example of usefulness of genetic characterization of larger regions, in addition to single polymorphisms, as candidates for population-specific sweeps in the ancestral population.     

Detecting Identity by Descent and Homozygosity Mapping in Whole-Exome Sequencing Data

The detection of genetic segments of Identical by Descent (IBD) in Genome-Wide Association Studies has proven successful in pinpointing genetic relatedness between reportedly unrelated individuals and leveraging such regions to shortlist candidate genes. These techniques depend on high-density genotyping arrays and their effectiveness in diverse sequence data is largely unknown. Due to decreasing costs and increasing effectiveness of high throughput techniques for whole-exome sequencing, an influx of exome sequencing data has become available. Studies using exomes and IBD-detection methods within known pedigrees have shown that IBD can be useful in finding hidden genetic candidates where known relatives are available. We set out to examine the viability of using IBD-detection in whole exome sequencing data in population-wide studies. In doing so, we extend GERMLINE, a method to detect IBD from exome sequencing data by finding small slices of matching alleles between pairs of individuals and extending them into full IBD segments. This algorithm allows for efficient population-wide detection in dense data. We apply this algorithm to a cohort of Crohn''s Disease cases where whole-exome and GWAS array data is available. We confirm that GWAS-based detected segments are highly accurate and predictive of underlying shared variation. Where segments inferred from GWAS are expected to be of high accuracy, we compare exome-based detection accuracy of multiple detection strategies. We find detection accuracy to be prohibitively low in all assessments, both in terms of segment sensitivity and specificity. Even after isolating relatively long segments beyond 10cM, exome-based detection continued to offer poor specificity/sensitivity tradeoffs. We hypothesize that the variable coverage and platform biases of exome capture account for this decreased accuracy and look toward whole genome sequencing data as a higher quality source for detecting population-wide IBD.     

The Interplay between Natural Selection and Susceptibility to Melanoma on Allele 374F of SLC45A2 Gene in a South European Population

We aimed to study the selective pressures interacting on SLC45A2 to investigate the interplay between selection and susceptibility to disease. Thus, we enrolled 500 volunteers from a geographically limited population (Basques from the North of Spain) and by resequencing the whole coding region and intron 5 of the 34 most and the 34 least pigmented individuals according to the reflectance distribution, we observed that the polymorphism Leu374Phe (L374F, rs16891982) was statistically associated with skin color variability within this sample. In particular, allele 374F was significantly more frequent among the individuals with lighter skin. Further genotyping an independent set of 558 individuals of a geographically wider population with known ancestry in the Spanish population also revealed that the frequency of L374F was significantly correlated with the incident UV radiation intensity. Selection tests suggest that allele 374F is being positively selected in South Europeans, thus indicating that depigmentation is an adaptive process. Interestingly, by genotyping 119 melanoma samples, we show that this variant is also associated with an increased susceptibility to melanoma in our populations. The ultimate driving force for this adaptation is unknown, but it is compatible with the vitamin D hypothesis. This shows that molecular evolution analysis can be used as a useful technology to predict phenotypic and biomedical consequences in humans.     

Detecting Identity by Descent and Estimating Genotype Error Rates in Sequence Data

Existing methods for identity by descent (IBD) segment detection were designed for SNP array data, not sequence data. Sequence data have a much higher density of genetic variants and a different allele frequency distribution, and can have higher genotype error rates. Consequently, best practices for IBD detection in SNP array data do not necessarily carry over to sequence data. We present a method, IBDseq, for detecting IBD segments in sequence data and a method, SEQERR, for estimating genotype error rates at low-frequency variants by using detected IBD. The IBDseq method estimates probabilities of genotypes observed with error for each pair of individuals under IBD and non-IBD models. The ratio of estimated probabilities under the two models gives a LOD score for IBD. We evaluate several IBD detection methods that are fast enough for application to sequence data (IBDseq, Beagle Refined IBD, PLINK, and GERMLINE) under multiple parameter settings, and we show that IBDseq achieves high power and accuracy for IBD detection in sequence data. The SEQERR method estimates genotype error rates by comparing observed and expected rates of pairs of homozygote and heterozygote genotypes at low-frequency variants in IBD segments. We demonstrate the accuracy of SEQERR in simulated data, and we apply the method to estimate genotype error rates in sequence data from the UK10K and 1000 Genomes projects.     

Genetic evidence for the convergent evolution of light skin in Europeans and East Asians

Human skin pigmentation shows a strong positive correlation with ultraviolet radiation intensity, suggesting that variation in skin color is, at least partially, due to adaptation via natural selection. We investigated the evolution of pigmentation variation by testing for the presence of positive directional selection in 6 pigmentation genes using an empirical F(ST) approach, through an examination of global diversity patterns of these genes in the Centre d'Etude du Polymorphisme Humain (CEPH)-Diversity Panel, and by exploring signatures of selection in data from the International HapMap project. Additionally, we demonstrated a role for MATP in determining normal skin pigmentation variation using admixture mapping methods. Taken together (with the results of previous admixture mapping studies), these results point to the importance of several genes in shaping the pigmentation phenotype and a complex evolutionary history involving strong selection. Polymorphisms in 2 genes, ASIP and OCA2, may play a shared role in shaping light and dark pigmentation across the globe, whereas SLC24A5, MATP, and TYR have a predominant role in the evolution of light skin in Europeans but not in East Asians. These findings support a case for the recent convergent evolution of a lighter pigmentation phenotype in Europeans and East Asians.     

A Decreasing Gradient of 374F Allele Frequencies in the Skin Pigmentation Gene SLC45A2, from the North of West Europe to North Africa

The 374F mutation in the SLC45A2 gene, encoding the membrane-associated transporter protein (MATP) that plays an important role in melanin synthesis, has been suggested to be associated with skin color in Caucasians. In this study, the detailed distribution of the 374F allele has been investigated in 2063 unrelated subjects from 18 European and three North African populations. The highest allele frequency is observed in Denmark (0.980), and the lowest frequencies are observed in Tunisia (0.610) and in Morocco (0.691). A significant latitudinal cline in 374F allele frequencies was observed, ranging from the north of West Europe to North Africa (r = 0.869). The results confirm that the distribution of the 374F allele may reflect the ultraviolet radiation level and can be associated with skin color variation in these regions.     

The mitochondrial solute carrier SLC25A5 at Xq24 is a novel candidate gene for non-syndromic intellectual disability

Loss-of-function mutations in several different neuronal pathways have been related to intellectual disability (ID). Such mutations often are found on the X chromosome in males since they result in functional null alleles. So far, microdeletions at Xq24 reported in males always have been associated with a syndromic form of ID due to the loss of UBE2A. Here, we report on overlapping microdeletions at Xq24 that do not include UBE2A or affect its expression, in patients with non-syndromic ID plus some additional features from three unrelated families. The smallest region of overlap, confirmed by junction sequencing, harbors two members of the mitochondrial solute carrier family 25, SLC25A5 and SLC25A43. However, identification of an intragenic microdeletion including SLC25A43 but not SLC25A5 in a healthy boy excluded a role for SLC25A43 in cognition. Therefore, our findings point to SLC25A5 as a novel gene for non-syndromic ID. This highly conserved gene is expressed ubiquitously with high levels in cortex and hippocampus, and a presumed role in mitochondrial exchange of ADP/ATP. Our data indicate that SLC25A5 is involved in memory formation or establishment, which could add mitochondrial processes to the wide array of pathways that regulate normal cognitive functions.     

Molecular characterization of SLC24A5 variants and evaluation of Nitisinone treatment efficacy in a zebrafish model of OCA6

Skin pigmentation is a highly heterogeneous trait with diverse consequences worldwide. SLC24A5, encoding a potent K⁺‐dependent Na⁺/Ca²⁺ exchanger, is among the known color‐coding genes that participate in melanogenesis by maintaining pH in melanosomes. Deficient SLC24A5 activity results in oculocutaneous albinism (OCA) type 6 in humans. In this study, by utilizing a exome sequencing (ES) approach, we identified two new variants [p. (Gly110Arg) and p. (IIe189Ilefs*1)] of SLC24A5 cosegregating with the OCA phenotype, including nystagmus, strabismus, foveal hypoplasia, albinotic fundus, and vision impairment, in three large consanguineous Pakistani families. Both of these variants failed to rescue the pigmentation in zebrafish slc24a5 morphants, confirming the pathogenic effects of the variants. We also phenotypically characterized a commercially available zebrafish mutant line (slc24a5^ko) that harbors a nonsense (p.Tyr208*) allele of slc24a5. Similar to morphants, homozygous slc24a5^ko mutants had significantly reduced melanin content and pigmentation. Next, we used these slc24a5^ko zebrafish mutants to test the efficacy of nitisinone, a compound known to increase ocular and fur pigmentation in OCA1 (TYR) mutant mice. Treatment of slc24a5^ko mutant zebrafish embryos with varying doses of nitisinone did not improve melanin production and pigmentation, suggesting that treatment with nitisinone is unlikely to be therapeutic in OCA6 patients.     

Influence of the CXCL1 rs4074 A Allele on Alcohol Induced Cirrhosis and HCC in Patients of European Descent

Background and Aims

CXCL1 (CXC chemokine-ligand-1) is a ligand for CXC chemokine receptor 2 expressed on hepatic stellate cells (HSC). Thus, CXCL1 might contribute to HSC activation and fibrogenesis. In the present study, we investigated the influence of the CXCL1 rs4074 polymorphism on the occurrence of alcohol induced liver cirrhosis and hepatocellular carcinoma (HCC).

Methods

The study involved 458 patients with alcoholic cirrhosis (170 with HCC), 115 alcoholics without liver disease and 342 healthy controls. All subjects were genotyped for the CXCL1 rs4074 polymorphism and CXCL1 serum levels of 132 patients were measured. In vitro CXCL1 secretion in TLR-transfected cell lines were studied by ELISA.

Results

Distribution of the CXCL1 genotypes (GG/GA/AA) was 159/219/80 in patients with alcoholic cirrhosis, 52/44/19 in alcoholic controls and 158/140/44 in healthy controls. Patients with alcohol-induced cirrhosis were significantly more often carriers of the CXCL1 rs4074 A allele (65.3%) than alcoholics without liver disease (54.8%, OR=1.55; 95%CI=1.025-2.350; p=0.04) and healthy controls (53.8%, OR=1.62; 95%CI=1.212-2.151; p=0.001). Accordingly, the frequency of the CXCL1 rs4074 A allele was significantly higher in the cirrhotic patients than in the subjects without cirrhosis (41.4% vs. 33.9%, OR=1.38, 95% CI:1.14–1.66, p=0.001). Furthermore cirrhotic carriers of the CXCL1 rs4074 A allele had significantly higher CXCL1 serum levels than carriers of the GG genotype. In contrast to sera from healthy controls, sera from patients with alcoholic cirrhosis induced CXCL1 secretion in TLR2- (p=0.016) and TLR4- (p=0.008) transfected HEK293 cells. This finding indicates that sera from patients with alcoholic cirrhosis contain soluble ligands that can induce CXCL1 production via stimulation of TLRs.

Conclusion

The enhanced CXCL1 serum levels in carriers of the rs4074 A allele together with their increased frequency in patients with alcohol induced cirrhosis suggest the CXCL1 rs4074 A allele as a genetic risk factor for alcoholic cirrhosis.     

Serum concentrations of 25-hydroxy vitamin D in Europeans and Asians after oral vitamin D3.

Serum concentrations of 25-hydroxy vitamin D (25-OHD3) were measured in seven Asians of Indian extraction and eight Europeans before and at intervals after taking 1 mg vitamin D3 by mouth. In all subjects the concentrations rose in the 24 hours after ingestion. There was little change over the next nine days in the concentrations in the Europeans but those in the Asians continued to rise until about day 10. Subsequent rates of fall in 25-OHD3 were similar in the two groups. Our observations suggest that the low serum concentrations of 25-OHD3 found in Asians are not caused by either impaired intestinal absorption of vitamin D or rapid clearance of 25-ODH3 from the plasma.