Complex Signatures of Natural Selection at the Duffy Blood Group Locus

The Duffy blood group locus (FY) has long been considered a likely target of natural selection, because of the extreme pattern of geographic differentiation of its three major alleles (FY*B, FY*A, and FY*O). In the present study, we resequenced the FY region in samples of Hausa from Cameroon (fixed for FY*O), Han Chinese (fixed for FY*A), Italians, and Pakistanis. Our goals were to characterize the signature of directional selection on FY*O in sub-Saharan Africa and to understand the extent to which natural selection has also played a role in the extreme geographic differentiation of the other derived allele at this locus, FY*A. The data from the FY region are compared with the patterns of variation observed at 10 unlinked, putatively neutral loci from the same populations, as well as with theoretical expectations from the neutral-equilibrium model. The FY region in the Hausa shows evidence of directional selection in two independent properties of the data (i.e., level of sequence variation and frequency spectrum), observations that are consistent with the FY*O mutation being the target. The Italian and Chinese FY data show patterns of variation that are very unusual, particularly with regard to frequency spectrum and linkage disequilibrium, but do not fit the predictions of any simple model of selection. These patterns may represent a more complex and previously unrecognized signature of positive selection

Functional constraints on the constitutive androstane receptor inferred from human sequence variation and cross-species comparisons

<p>Abstract</p> <p>Members of the NR1I subfamily of nuclear receptors play a role in the transcriptional activation of genes involved in drug metabolism and transport. NR1I3, the constitutive androstane receptor (CAR), mediates the induction of several genes involved in drug response, including members of the <it>CYP3A</it>, <it>CYP2B </it>and <it>UGT1A </it>subfamilies. Large inter-individual variation in drug clearance has been reported for many drug metabolising enzyme genes. Sequence variation at the <it>CAR </it>locus could potentially contribute to variation in downstream targets, as well as to the substantial variation in expression level reported. We used a comparative genomics-based approach to select resequencing segments in 70 subjects from three populations. We identified 21 polymorphic sites, one of which results in an amino acid substitution. Our study reveals a common haplotype shared by all three populations which is remarkably similar to the ancestral sequence, confirming that CAR is under strong functional constraints. The level and pattern of sequence variation is approximately similar across populations, suggesting that interethnic differences in drug metabolism are not likely to be due to genetic variation at the <it>CAR </it>locus. We also identify several common non-coding variants that occur at highly conserved sites across four major branches of the mammalian phylogeny, suggesting that they may affect <it>CAR </it>expression and, ultimately, the activity of its downstream targets.</p

Allele-Specific Down-Regulation of RPTOR Expression Induced by Retinoids Contributes to Climate Adaptations

The mechanistic target of rapamycin (MTOR) pathway regulates cell growth, energy homeostasis, apoptosis, and immune response. The regulatory associated protein of MTOR encoded by the RPTOR gene is a key component of this pathway. A previous survey of candidate genes found that RPTOR contains multiple SNPs with strong correlations between allele frequencies and climate variables, consistent with the action of selective pressures that vary across environments. Using data from a recent genome scan for selection signals, we honed in on a SNP (rs11868112) 26 kb upstream to the transcription start site of RPTOR that exhibits the strongest association with temperature variables. Transcription factor motif scanning and mining of recently mapped transcription factor binding sites identified a binding site for POU class 2 homeobox 1 (POU2F1) spanning the SNP and an adjacent retinoid acid receptor (RAR) binding site. Using expression quantification, chromatin immunoprecipitation (ChIP), and reporter gene assays, we demonstrate that POU2F1 and RARA do bind upstream of the RPTOR gene to regulate its expression in response to retinoids; this regulation is affected by the allele status at rs11868112 with the derived allele resulting in lower expression levels. We propose a model in which the derived allele influences thermogenesis or immune response by altering MTOR pathway activity and thereby increasing fitness in colder climates. Our results show that signatures of genetic adaptations can identify variants with functional effects, consistent with the idea that selection signals may be used for SNP annotation

Allele-Specific Down-Regulation of <i>RPTOR</i> Expression Induced by Retinoids Contributes to Climate Adaptations

The mechanistic target of rapamycin (MTOR) pathway regulates cell growth, energy homeostasis, apoptosis, and immune response. The regulatory associated protein of MTOR encoded by the RPTOR gene is a key component of this pathway. A previous survey of candidate genes found that RPTOR contains multiple SNPs with strong correlations between allele frequencies and climate variables, consistent with the action of selective pressures that vary across environments. Using data from a recent genome scan for selection signals, we honed in on a SNP (rs11868112) 26 kb upstream to the transcription start site of RPTOR that exhibits the strongest association with temperature variables. Transcription factor motif scanning and mining of recently mapped transcription factor binding sites identified a binding site for POU class 2 homeobox 1 (POU2F1) spanning the SNP and an adjacent retinoid acid receptor (RAR) binding site. Using expression quantification, chromatin immunoprecipitation (ChIP), and reporter gene assays, we demonstrate that POU2F1 and RARA do bind upstream of the RPTOR gene to regulate its expression in response to retinoids; this regulation is affected by the allele status at rs11868112 with the derived allele resulting in lower expression levels. We propose a model in which the derived allele influences thermogenesis or immune response by altering MTOR pathway activity and thereby increasing fitness in colder climates. Our results show that signatures of genetic adaptations can identify variants with functional effects, consistent with the idea that selection signals may be used for SNP annotation.</p

Adaptive Variation Regulates the Expression of the Human <i>SGK1</i> Gene in Response to Stress

The Serum and Glucocorticoid-regulated Kinase1 (SGK1) gene is a target of the glucocorticoid receptor (GR) and is central to the stress response in many human tissues. Because environmental stress varies across habitats, we hypothesized that natural selection shaped the geographic distribution of genetic variants regulating the level of SGK1 expression following GR activation. By combining population genetics and molecular biology methods, we identified a variant (rs9493857) with marked allele frequency differences between populations of African and European ancestry and with a strong correlation between allele frequency and latitude in worldwide population samples. This SNP is located in a GR-binding region upstream of SGK1 that was identified using a GR ChIP-chip. SNP rs9493857 also lies within a predicted binding site for Oct1, a transcription factor known to cooperate with the GR in the transactivation of target genes. Using ChIP assays, we show that both GR and Oct1 bind to this region and that the ancestral allele at rs9493857 binds the GR-Oct1 complex more efficiently than the derived allele. Finally, using a reporter gene assay, we demonstrate that the ancestral allele is associated with increased glucocorticoid-dependent gene expression when compared to the derived allele. Our results suggest a novel paradigm in which hormonal responsiveness is modulated by sequence variation in the regulatory regions of nuclear receptor target genes. Identifying such functional variants may shed light on the mechanisms underlying inter-individual variation in response to environmental stressors and to hormonal therapy, as well as in the susceptibility to hormone-dependent diseases.</p

Adaptive Variation Regulates the Expression of the Human SGK1 Gene in Response to Stress

The Serum and Glucocorticoid-regulated Kinase1 (SGK1) gene is a target of the glucocorticoid receptor (GR) and is central to the stress response in many human tissues. Because environmental stress varies across habitats, we hypothesized that natural selection shaped the geographic distribution of genetic variants regulating the level of SGK1 expression following GR activation. By combining population genetics and molecular biology methods, we identified a variant (rs9493857) with marked allele frequency differences between populations of African and European ancestry and with a strong correlation between allele frequency and latitude in worldwide population samples. This SNP is located in a GR-binding region upstream of SGK1 that was identified using a GR ChIP-chip. SNP rs9493857 also lies within a predicted binding site for Oct1, a transcription factor known to cooperate with the GR in the transactivation of target genes. Using ChIP assays, we show that both GR and Oct1 bind to this region and that the ancestral allele at rs9493857 binds the GR-Oct1 complex more efficiently than the derived allele. Finally, using a reporter gene assay, we demonstrate that the ancestral allele is associated with increased glucocorticoid-dependent gene expression when compared to the derived allele. Our results suggest a novel paradigm in which hormonal responsiveness is modulated by sequence variation in the regulatory regions of nuclear receptor target genes. Identifying such functional variants may shed light on the mechanisms underlying inter-individual variation in response to environmental stressors and to hormonal therapy, as well as in the susceptibility to hormone-dependent diseases

Prevalence of common disease-associated variants in Asian Indians

<p>Abstract</p> <p>Background</p> <p>Asian Indians display a high prevalence of diseases linked to changes in diet and environment that have arisen as their lifestyle has become more westernized. Using 1200 genome-wide polymorphisms in 432 individuals from 15 Indian language groups, we have recently shown that: (i) Indians constitute a distinct population-genetic cluster, and (ii) despite the geographic and linguistic diversity of the groups they exhibit a relatively low level of genetic heterogeneity.</p> <p>Results</p> <p>We investigated the prevalence of common polymorphisms that have been associated with diseases, such as atherosclerosis (<it>ALOX5</it>), hypertension (<it>CYP3A5</it>, <it>AGT</it>, <it>GNB3</it>), diabetes (<it>CAPN10</it>, <it>TCF7L2</it>, <it>PTPN22</it>), prostate cancer (DG8S737, rs1447295), Hirschsprung disease (<it>RET</it>), and age-related macular degeneration (<it>CFH</it>, <it>LOC387715</it>). In addition, we examined polymorphisms associated with skin pigmentation (<it>SLC24A5</it>) and with the ability to taste phenylthiocarbamide (<it>TAS2R38</it>). All polymorphisms were studied in a cohort of 576 India-born Asian Indians sampled in the United States. This sample consisted of individuals whose mother tongue is one of 14 of the 22 "official" languages recognized in India as well as individuals whose mother tongue is Parsi, a cultural group that has resided in India for over 1000 years. Analysis of the data revealed that allele frequency differences between the different Indian language groups were small, and interestingly the variant alleles of <it>ALOX5 </it>g.8322G>A and g.50778G>A, and <it>PTPN22 </it>g.36677C>T were present only in a subset of the Indian language groups. Furthermore, a latitudinal cline was identified both for the allele frequencies of the SNPs associated with hypertension (<it>CYP3A5</it>, <it>AGT</it>, <it>GNB3</it>), as well as for those associated with the ability to taste phenylthiocarbamide (<it>TAS2R38</it>).</p> <p>Conclusion</p> <p>Although caution is warranted due to the fact that this US-sampled Indian cohort may not represent a random sample from India, our results will hopefully assist in the design of future studies that investigate the genetic causes of these diseases in India. Our results also support the inclusion of the Indian population in disease-related genetic studies, as it exhibits unique genotype as well as phenotype characteristics that may yield new insights into the underlying causes of common diseases that are not available in other populations.</p

Adaptations to Climate in Candidate Genes for Common Metabolic Disorders

Evolutionary pressures due to variation in climate play an important role in shaping phenotypic variation among and within species and have been shown to influence variation in phenotypes such as body shape and size among humans. Genes involved in energy metabolism are likely to be central to heat and cold tolerance. To test the hypothesis that climate shaped variation in metabolism genes in humans, we used a bioinformatics approach based on network theory to select 82 candidate genes for common metabolic disorders. We genotyped 873 tag SNPs in these genes in 54 worldwide populations (including the 52 in the Human Genome Diversity Project panel) and found correlations with climate variables using rank correlation analysis and a newly developed method termed Bayesian geographic analysis. In addition, we genotyped 210 carefully matched control SNPs to provide an empirical null distribution for spatial patterns of allele frequency due to population history alone. For nearly all climate variables, we found an excess of genic SNPs in the tail of the distributions of the test statistics compared to the control SNPs, implying that metabolic genes as a group show signals of spatially varying selection. Among our strongest signals were several SNPs (e.g., LEPR R109K, FABP2 A54T) that had previously been associated with phenotypes directly related to cold tolerance. Since variation in climate may be correlated with other aspects of environmental variation, it is possible that some of the signals that we detected reflect selective pressures other than climate. Nevertheless, our results are consistent with the idea that climate has been an important selective pressure acting on candidate genes for common metabolic disorders.</p

A longitudinal cline characterizes the genetic structure of human populations in the Tibetan plateau

Indigenous populations of the Tibetan plateau have attracted much attention for their good performance at extreme high altitude. Most genetic studies of Tibetan adaptations have used genetic variation data at the genome scale, while genetic inferences about their demography and population structure are largely based on uniparental markers. To provide genome-wide information on population structure, we analyzed new and published data of 338 individuals from indigenous populations across the plateau in conjunction with worldwide genetic variation data. We found a clear signal of genetic stratification across the east-west axis within Tibetan samples. Samples from more eastern locations tend to have higher genetic affinity with lowland East Asians, which can be explained by more gene flow from lowland East Asia onto the plateau. Our findings corroborate a previous report of admixture signals in Tibetans, which were based on a subset of the samples analyzed here, but add evidence for isolation by distance in a broader geospatial context

Discovery and functional assessment of gene variants in the vascular endothelial growth factor pathway

Angiogenesis is a host-mediated mechanism in disease pathophysiology. The vascular endothelial growth factor (VEGF) pathway is a major determinant of angiogenesis, and a comprehensive annotation of the functional variation in this pathway is essential to understand the genetic basis of angiogenesis-related diseases. We assessed the allelic heterogeneity of gene expression, population specificity of cis expression quantitative trait loci (eQTLs), and eQTL function in luciferase assays in CEU and Yoruba people of Ibadan, Nigeria (YRI) HapMap lymphoblastoid cell lines in 23 resequenced genes. Among 356 cis-eQTLs, 155 and 174 were unique to CEU and YRI, respectively, and 27 were shared between CEU and YRI. Two cis-eQTLs provided mechanistic evidence for two genome-wide association study findings. Five eQTLs were tested for function in luciferase assays and the effect of two KRAS variants was concordant with the eQTL effect. Two eQTLs found in each of PRKCE, PIK3C2A, and MAP2K6 could predict 44%, 37%, and 45% of the variance in gene expression, respectively. This is the first analysis focusing on the pattern of functional genetic variation of the VEGF pathway genes in CEU and YRI populations and providing mechanistic evidence for genetic association studies of diseases for which angiogenesis plays a pathophysiologic role. (C) 2013 Wiley Periodicals, Inc