Large Linkage Disequilibrium Block Research Articles

High-density genomic data reveal fine-scale population structure and pronounced islands of adaptive divergence in lake whitefish (Coregonus clupeaformis) from Lake Michigan.

Understanding patterns of genetic structure and adaptive variation in natural populations is crucial for informing conservation and management. Past genetic research using 11 microsatellite loci identified six genetic stocks of lake whitefish (Coregonus clupeaformis) within Lake Michigan, USA. However, ambiguity in genetic stock assignments suggested those neutral microsatellite markers did not provide adequate power for delineating lake whitefish stocks in this system, prompting calls for a genomics approach to investigate stock structure. Here, we generated a dense genomic dataset to characterize population structure and investigate patterns of neutral and adaptive genetic diversity among lake whitefish populations in Lake Michigan. Using Rapture sequencing, we genotyped 829 individuals collected from 17 baseline populations at 197,588 SNP markers after quality filtering. Although the overall pattern of genetic structure was similar to the previous microsatellite study, our genomic data provided several novel insights. Our results indicated a large genetic break between the northwestern and eastern sides of Lake Michigan, and we found a much greater level of population structure on the eastern side compared to the northwestern side. Collectively, we observed five genomic islands of adaptive divergence on five different chromosomes. Each island displayed a different pattern of population structure, suggesting that combinations of genotypes at these adaptive regions are facilitating local adaptation to spatially heterogenous selection pressures. Additionally, we identified a large linkage disequilibrium block of ~8.5Mb on chromosome 20 that is suggestive of a putative inversion but with a low frequency of the minor haplotype. Our study provides a comprehensive assessment of population structure and adaptive variation that can help inform the management of Lake Michigan's lake whitefish fishery and highlights the utility of incorporating adaptive loci into fisheries management.

Genome-wide association study of cassava starch paste properties.

An understanding of cassava starch paste properties (CSPP) can contribute to the selection of clones with differentiated starches. This study aimed to identify genomic regions associated with CSPP using different genome-wide association study (GWAS) methods (MLM, MLMM, and Farm-CPU). The GWAS was performed using 23,078 single-nucleotide polymorphisms (SNPs). The rapid viscoanalyzer (RVA) parameters were pasting temperature (PastTemp), peak viscosity (PeakVisc), hot-paste viscosity (Hot-PVisc), cool-paste viscosity (Cold-PVisc), final viscosity (FinalVis), breakdown (BreDow), and setback (Setback). Broad phenotypic and molecular diversity was identified based on the genomic kinship matrix. The broad-sense heritability estimates (h2) ranged from moderate to high magnitudes (0.66 to 0.76). The linkage disequilibrium (LD) declined to between 0.3 and 2.0 Mb (r2 <0.1) for most chromosomes, except chromosome 17, which exhibited an extensive LD. Thirteen SNPs were found to be significantly associated with CSPP, on chromosomes 3, 8, 17, and 18. Only the BreDow trait had no associated SNPs. The regional marker-trait associations on chromosome 18 indicate a LD block between 2907312 and 3567816 bp and that SNP S18_3081635 was associated with SetBack, FinalVis, and Cold-PVisc (all three GWAS methods) and with Hot-PVisc (MLM), indicating that this SNP can track these four traits simultaneously. The variance explained by the SNPs ranged from 0.13 to 0.18 for SetBack, FinalVis, and Cold-PVisc and from 0.06 to 0.09 for PeakVisc and Hot-PVisc. The results indicated additive effects of the genetic control of Cold-PVisc, FinalVis, Hot-PVisc, and SetBack, especially on the large LD block on chromosome 18. One transcript encoding the glycosyl hydrolase family 35 enzymes on chromosome 17 and one encoding the mannose-p-dolichol utilization defect 1 protein on chromosome 18 were the most likely candidate genes for the regulation of CSPP. These results underline the potential for the assisted selection of high-value starches to improve cassava root quality through breeding programs.

GWAS for Meat and Carcass Traits Using Imputed Sequence Level Genotypes in Pooled F2-Designs in Pigs.

In order to gain insight into the genetic architecture of economically important traits in pigs and to derive suitable genetic markers to improve these traits in breeding programs, many studies have been conducted to map quantitative trait loci. Shortcomings of these studies were low mapping resolution, large confidence intervals for quantitative trait loci-positions and large linkage disequilibrium blocks. Here, we overcome these shortcomings by pooling four large F2 designs to produce smaller linkage disequilibrium blocks and by resequencing the founder generation at high coverage and the F1 generation at low coverage for subsequent imputation of the F2 generation to whole genome sequencing marker density. This lead to the discovery of more than 32 million variants, 8 million of which have not been previously reported. The pooling of the four F2 designs enabled us to perform a joint genome-wide association study, which lead to the identification of numerous significantly associated variant clusters on chromosomes 1, 2, 4, 7, 17 and 18 for the growth and carcass traits average daily gain, back fat thickness, meat fat ratio, and carcass length. We could not only confirm previously reported, but also discovered new quantitative trait loci. As a result, several new candidate genes are discussed, among them BMP2 (bone morphogenetic protein 2), which we recently discovered in a related study. Variant effect prediction revealed that 15 high impact variants for the traits back fat thickness, meat fat ratio and carcass length were among the statistically significantly associated variants.

Genetic Properties of a Nested Association Mapping Population Constructed With Semi-Winter and Spring Oilseed Rapes.

Nested association mapping (NAM) populations have been widely applied to dissect the genetic basis of complex quantitative traits in a variety of crops. In this study, we developed a Brassica napus NAM (BN-NAM) population consisting of 15 recombination inbred line (RIL) families with 2,425 immortal genotypes. Fifteen high-density genetic linkage maps were constructed by genotyping by sequencing (GBS) based on all RIL families, with further integration into a joint linkage map (JLM) having 30,209 unique markers in common with multiple linkage maps. Furthermore, an ultra-density whole-genome variation map was constructed by projecting 4,444,309 high-quality variants onto the JLM. The NAM population captured a total of 88,542 recombination events (REs). The uneven distribution of recombination rate along chromosomes is positively correlated with the densities of genes and markers, but negatively correlated with the density of transposable elements and linkage disequilibrium (LD). Analyses of population structure and principal components revealed that the BN-NAM population could be divided into three groups with weak stratification. The LD decay distance across genome varied between 170 and 2,400 Kb, with LD decay more rapid in the A than in the C sub-genome. The pericentromeric regions contained large LD blocks, especially in the C sub-genome. This NAM population provides a valuable resource for dissecting the genetic basis of important traits in rapeseed, especially in semi-winter oilseed rape.

Parkinson's disease-associated genetic variation is linked to quantitative expression of inflammatory genes.

Genome-wide association studies (GWAS) have linked dozens of single nucleotide polymorphisms (SNPs) with Parkinson’s disease (PD) risk. Ascertaining the functional and eventual causal mechanisms underlying these relationships has proven difficult. The majority of risk SNPs, and nearby SNPs in linkage disequilibrium (LD), are found in intergenic or intronic regions and confer risk through allele-dependent expression of multiple unknown target genes. Combining GWAS results with publicly available GTEx data, generated through eQTL (expression quantitative trait loci) identification studies, enables a direct association of SNPs to gene expression levels and aids in narrowing the large population of potential genetic targets for hypothesis-driven experimental cell biology. Separately, overlapping of SNPs with putative enhancer segmentations can strengthen target filtering. We report here the results of analyzing 7,607 PD risk SNPs along with an additional 23,759 high linkage disequilibrium-associated variants paired with eQTL gene expression. We found that enrichment analysis on the set of genes following target filtering pointed to a single large LD block at 6p21 that contained multiple HLA-MHC-II genes. These MHC-II genes remain associated with PD when the genes were filtered for correlation between GWAS significance and eQTL levels, strongly indicating a direct effect on PD etiology.

Quantitative Trait Locus and Brain Expression of HLA-DPA1 Offers Evidence of Shared Immune Alterations in Psychiatric Disorders.

Genome-wide association studies of schizophrenia encompassing the major histocompatibility locus (MHC) were highly significant following genome-wide correction. This broad region implicates many genes including the MHC complex class II. Within this interval we examined the expression of two MHC II genes (HLA-DPA1 and HLA-DRB1) in brain from individual subjects with schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and controls by differential gene expression methods. A third MHC II mRNA, CD74, was studied outside of the MHC II locus, as it interacts within the same immune complex. Exon microarrays were performed in anterior cingulate cortex (ACC) in BD compared to controls, and both HLA-DPA1 and CD74 were decreased in expression in BD. The expression of HLA-DPA1 and CD74 were both reduced in hippocampus, amygdala, and dorsolateral prefrontal cortex regions in SZ and BD compared to controls by specific qPCR assay. We found several novel HLA-DPA1 mRNA variants spanning HLA-DPA1 exons 2-3-4 as suggested by exon microarrays. The intronic rs9277341 SNP was a significant cis expression quantitative trait locus (eQTL) that was associated with the total expression of HLA-DPA1 in five brain regions. A biomarker study of MHC II mRNAs was conducted in SZ, BD, MDD, and control lymphoblastic cell lines (LCL) by qPCR assay of 87 subjects. There was significantly decreased expression of HLA-DPA1 and CD74 in BD, and trends for reductions in SZ in LCLs. The discovery of multiple splicing variants in brain for HLA-DPA1 is important as the HLA-DPA1 gene is highly conserved, there are no reported splicing variants, and the functions in brain are unknown. Future work on the function and localization of MHC Class II proteins in brain will help to understand the role of alterations in neuropsychiatric disorders. The HLA-DPA1 eQTL is located within a large linkage disequilibrium block that has an irrefutable association with schizophrenia. Future tests in a larger cohort are needed to determine the significance of this eQTL association with schizophrenia. Our findings support the long-held hypothesis that alterations in immune function are associated with the pathophysiology of psychiatric disorders.

Constructing a Genome-Wide LD Map of Wild A. gambiae Using Next-Generation Sequencing.

Anopheles gambiae is the major malaria vector in Africa. Examining the molecular basis of A. gambiae traits requires knowledge of both genetic variation and genome-wide linkage disequilibrium (LD) map of wild A. gambiae populations from malaria-endemic areas. We sequenced the genomes of nine wild A. gambiae mosquitoes individually using next-generation sequencing technologies and detected 2,219,815 common single nucleotide polymorphisms (SNPs), 88% of which are novel. SNPs are not evenly distributed across A. gambiae chromosomes. The low SNP-frequency regions overlay heterochromatin and chromosome inversion domains, consistent with the lower recombinant rates at these regions. Nearly one million SNPs that were genotyped correctly in all individual mosquitoes with 99.6% confidence were extracted from these high-throughput sequencing data. Based on these SNP genotypes, we constructed a genome-wide LD map for wild A. gambiae from malaria-endemic areas in Kenya and made it available through a public Website. The average size of LD blocks is less than 40 bp, and several large LD blocks were also discovered clustered around the para gene, which is consistent with the effect of insecticide selective sweeps. The SNPs and the LD map will be valuable resources for scientific communities to dissect the A. gambiae genome.

Genetic association study of adiposity and melanocortin-4 receptor (MC4R) common variants: replication and functional characterization of non-coding regions.

Common genetic variants 3′ of MC4R within two large linkage disequilibrium (LD) blocks spanning 288 kb have been associated with common and rare forms of obesity. This large association region has not been refined and the relevant DNA segments within the association region have not been identified. In this study, we investigated whether common variants in the MC4R gene region were associated with adiposity-related traits in a biracial population-based study. Single nucleotide polymorphisms (SNPs) in the MC4R region were genotyped with a custom array and a genome-wide array and associations between SNPs and five adiposity-related traits were determined using race-stratified linear regression. Previously reported associations between lower BMI and the minor alleles of rs2229616/Val103Ile and rs52820871/Ile251Leu were replicated in white female participants. Among white participants, rs11152221 in a proximal 3′ LD block (closer to MC4R) was significantly associated with multiple adiposity traits, but SNPs in a distal 3′ LD block (farther from MC4R) were not. In a case-control study of severe obesity, rs11152221 was significantly associated. The association results directed our follow-up studies to the proximal LD block downstream of MC4R. By considering nucleotide conservation, the significance of association, and proximity to the MC4R gene, we identified a candidate MC4R regulatory region. This candidate region was sequenced in 20 individuals from a study of severe obesity in an attempt to identify additional variants, and the candidate region was tested for enhancer activity using in vivo enhancer assays in zebrafish and mice. Novel variants were not identified by sequencing and the candidate region did not drive reporter gene expression in zebrafish or mice. The identification of a putative insulator in this region could help to explain the challenges faced in this study and others to link SNPs associated with adiposity to altered MC4R expression.

The curse of the missing heritability

The curse of the missing heritability

Abstract 2925: Genome-wide association study identifies 10q24.32 variants associated with arsenic metabolism and premalignant skin lesion risk in Bangladesh

Abstract Arsenic is a class-I human carcinogen, and arsenic contamination of drinking water is a serious public health issue in many countries, increasing risk for a wide array of diseases, including cancers of the bladder, kidney, lung, and skin. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity, however the basis of this variation in not well understood. Here, we have performed the first genome-wide association study (GWAS) of arsenic-related phenotypes to identify genetic determinants of arsenic metabolism and gene-arsenic interactions influencing risk for arsenic-induced premalignant skin lesions (a classical sign of arsenic toxicity). Using data on urinary arsenic metabolite concentrations and genome-wide single nucleotide polymorphisms (SNPs) for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P&amp;lt;5x10^-8) for urinary concentrations of both monomethylarsonic (MMA) and dimethylarsinic (DMA) in a large linkage disequilibrium block containing the AS3MT gene (arsenite methyltransferase; 10q24.32), with five genetic variants showing strong evidence independent association. In a follow-up analysis of 1,085 individuals with premalignant skin lesions and 1,794 controls population-based, we show that one of these five variants (rs9527, which is associated with DMA%) is associated with arsenical skin lesion risk (P=0.0005). Using a subset of individuals with prospectively measured arsenic metabolites (n=769), we show that rs9527 interacts with arsenic exposure to influence skin lesion risk (P=0.01). The direction of the observed association is consistent with the prevailing hypothesis that DMA is the less toxic than MMA. To evaluate the functional role of the five identified SNPs, we conducted expression quantitative trait locus (eQTL) analyses of genome-wide expression data from 950 individual's lymphocyte RNA. Our results suggest that several of our lead SNPs represent cis-eQTLs for AS3MT (P=10^-12) or neighboring gene C10orf32 (P=10^-44). This is an intriguing finding in part because C10orf32 and AS3MT are known to be involved in read-through transcription, producing a transcript that is presumed to be non-functional. To our knowledge, this is the largest genetic association study of arsenic metabolites to date, the only GWAS of arsenic-related traits, and the first to implicate 10q24.32 variants in both arsenic metabolism and arsenical skin lesion risk. Our results suggest that MMA% and DMA% have distinct genetic determinants and support hypothesis that DMA is the less toxic of these two methylated arsenic species. These results have potential translational implications for the prevention and treatment of arsenic-associated toxicities, including several types of cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2925. doi:1538-7445.AM2012-2925

A genome-wide association study of attempted suicide

The heritable component to attempted and completed suicide is partly related to psychiatric disorders and also partly independent of them. While attempted suicide linkage regions have been identified on 2p11–12 and 6q25–26, there are likely many more such loci, the discovery of which will require a much higher resolution approach, such as the genome-wide association study (GWAS). With this in mind, we conducted an attempted suicide GWAS that compared the single nucleotide polymorphism (SNP) genotypes of 1,201 bipolar (BP) subjects with a history of suicide attempts to the genotypes of 1,497 BP subjects without a history of suicide attempts. 2,507 SNPs with evidence for association at p<0.001 were identified. These associated SNPs were subsequently tested for association in a large and independent BP sample set. None of these SNPs were significantly associated in the replication sample after correcting for multiple testing, but the combined analysis of the two sample sets produced an association signal on 2p25 (rs300774) at the threshold of genome-wide significance (p= 5.07 × 10−8). The associated SNPs on 2p25 fall in a large linkage disequilibrium block containing the ACP1 gene, a gene whose expression is significantly elevated in BP subjects who have completed suicide. Furthermore, the ACP1 protein is a tyrosine phosphatase that influences Wnt signaling, a pathway regulated by lithium, making ACP1 a functional candidate for involvement in the phenotype. Larger GWAS sample sets will be required to confirm the signal on 2p25 and to identify additional genetic risk factors increasing susceptibility for attempted suicide.

Analysis of lipid pathway genes indicates association of sequence variation near SREBF1/TOM1L2/ATPAF2 with dementia risk

We conducted dense linkage disequilibrium (LD) mapping of a series of 25 genes putatively involved in lipid metabolism in 1567 dementia cases [including 1270 with Alzheimer disease (AD)] and 2203 Swedish controls. Across a total of 448 tested genetic markers, the strongest evidence of association was as anticipated for APOE (rs429358 at P approximately 10(-72)) followed by a previously reported association of ABCA1 (rs2230805 at P approximately 10(-8)). In the present study, we report two additional markers near the SREBF1 locus on chromosome 17p that were also significant after multiple testing correction (best P = 3.1 x 10(-6) for marker rs3183702). There was no convincing evidence of association for remaining genes, including candidates highlighted from recent genome-wide association studies of plasma lipids (CELSR2/PSRC1/SORT1, MLXIPL, PCSK9, GALNT2 and GCKR). The associated markers near SREBF1 reside in a large LD block, extending more than 400 kb across seven candidate genes. Secondary analyses of gene expression levels of candidates spanning the LD region together with an investigation of gene network context highlighted two possible susceptibility genes including ATPAF2 and TOM1L2. Several markers in strong LD (r(2) > 0.7) with rs3183702 were found to be significantly associated with AD risk in recent genome-wide association studies with similar effect sizes, providing independent support of the current findings.

A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1)

We conducted a three-stage genome-wide association study (GWAS) of breast cancer in 9,770 cases and 10,799 controls in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. In stage 1, we genotyped 528,173 SNPs in 1,145 cases of invasive breast cancer and 1,142 controls. In stage 2, we analyzed 24,909 top SNPs in 4,547 cases and 4,434 controls. In stage 3, we investigated 21 loci in 4,078 cases and 5,223 controls. Two new loci achieved genome-wide significance. A pericentromeric SNP on chromosome 1p11.2 (rs11249433; P = 6.74 x 10(-10) adjusted genotype test, 2 degrees of freedom) resides in a large linkage disequilibrium block neighboring NOTCH2 and FCGR1B; this signal was stronger for estrogen-receptor-positive tumors. A second SNP on chromosome 14q24.1 (rs999737; P = 1.74 x 10(-7)) localizes to RAD51L1, a gene in the homologous recombination DNA repair pathway. We also confirmed associations with loci on chromosomes 2q35, 5p12, 5q11.2, 8q24, 10q26 and 16q12.1.

Effects of common germline genetic variation in cell cycle control genes on breast cancer survival: results from a population-based cohort

IntroductionSomatic alterations have been shown to correlate with breast cancer prognosis and survival, but less is known about the effects of common inherited genetic variation. Of particular interest are genes involved in cell cycle pathways, which regulate cell division.MethodsWe examined associations between common germline genetic variation in 13 genes involved in cell cycle control (CCND1, CCND2, CCND3, CCNE1, CDK2 [p33], CDK4, CDK6, CDKN1A [p21, Cip1], CDKN1B [p27, Kip1], CDKN2A [p16], CDKN2B [p15], CDKN2C [p18], and CDKN2D [p19]) and survival among women diagnosed with invasive breast cancer participating in the SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity) breast cancer study. DNA from up to 4,470 women was genotyped for 85 polymorphisms that tag the known common polymorphisms (minor allele frequency > 0.05) in the genes. The genotypes of each polymorphism were tested for association with survival using Cox regression analysis.ResultsThe rare allele of the tagging single nucleotide polymorphism (SNP) rs2479717 is associated with an increased risk of death (hazard ratio = 1.26 per rare allele carried, 95% confidence interval: 1.12 to 1.42; P = 0.0001), which was not attenuated after adjusting for tumour stage, grade, and treatment. This SNP is part of a large linkage disequilibrium block, which contains CCND3, BYSL, TRFP, USP49, C6ofr49, FRS3, and PGC. We evaluated the association of survival and somatic expression of these genes in breast tumours using expression microarray data from seven published datasets. Elevated expression of the C6orf49 transcript was associated with breast cancer survival, adding biological interest to the finding.ConclusionIt is possible that CCND3 rs2479717, or another variant it tags, is associated with prognosis after a diagnosis of breast cancer. Further study is required to validate this finding.

From association to cause: fine mapping of the TNRC9gene region, a novel susceptibility locus identified in the first genome-wide association study for breast cancer

We identified five novel breast cancer susceptibility loci in a recent Genome Wide Association Study [1] using 227,876 single nucleotide polymorphisms (SNPs) and up to 50,000 female breast cancer cases and controls from 22 studies. One of these loci, tagged by SNP rs3803662, lies in a large linkage disequilibrium (LD) block on chromosome 16q12. This region encompasses the largely uncharacterised TNRC9 gene (also known as TOX3/CAGF9) as well as a hypothetical gene LOC643714. This association is robust and has recently been independently verified [2]. The aim of the present study is to map the associated locus and ultimately identify the causal variant(s) responsible for the increased risk of breast cancer. There are 101 common variants in the 165 kb LD block covering the entire footprints of both genes catalogued by the International HapMap Project. These are efficiently tagged by 19 tagging SNPs (tagSNPs) that were genotyped in 2,270 breast cancer cases and 2,280 controls from the East Anglian region of the UK. Using these, we were able to exclude the coding region of TNRC9 and reduce the associated region to a 133 kb LD block including both the 5' end of the TNRC9 gene and the 3' end of LOC643714. This block was re-sequenced in 45 European subjects. Three hundred and forty-four SNPS were found, of which 170 were not previously recorded and 175 were common (minor allele frequency >0.05). Twenty-two of these SNPs are strongly correlated (r2 > 0.9) with the best tagSNP and have been genotyped, where possible, in an East Anglian case–control study set of increased size. Thus there are 23 potential causative variants, which are distributed across both genes. In an attempt to reduce this set of candidate causative SNPs and to further narrow the region of interest, they are being genotyped in breast cancer case–control sets from Asian and African-American populations. These populations exhibit greater haplotype diversity than the more closely related East Anglians, thus providing greater power to separate the causative variant(s) from the other candidates. To complement this work, a further study to determine the functional properties of the gene region in human breast cells has been initiated.

Replication and Identification of Novel Variants at TCF7L2 Associated with Type 2 Diabetes in Hong Kong Chinese

Variations at a large linkage disequilibrium (LD) block of transcription factor 7-like 2 gene (TCF7L2) were reported to be associated with type 2 diabetes (T2D) in Icelandic, Danish and European-American populations and further replicated in other populations of European, African, and Asian ancestries. However, data for Chinese and comprehensive survey of the whole gene are lacking. We attempted to examine 22 tagging single-nucleotide polymorphisms (SNPs) spanning across the TCF7L2 gene for association with T2D in Hong Kong Chinese. We first studied a case-control sample involving 433 hospital cases with familial early-onset T2D and 419 normal controls and further studied the associated SNPs in 450 members of 142 diabetic families. Two of the previously reported risk alleles at rs11196205 (C) and rs7903146 (T) were rare in Chinese (0.013 and 0.024, respectively, in controls). Rs11196205 was associated with T2D [odds ratio (OR) [95% confidence interval (CI)] = 2.11 (1.04-4.26)], whereas the association for rs7903146 [OR (95% CI) = 1.27 (0.71-2.29)] was not significant in the case-control sample. Interestingly, another SNP (rs11196218 G allele) located in adjacent LD block conferred independent risk for T2D [OR (95%CI) =1.43 (1.14-1.79)] and contributed high-population attributable risk of 42%. The association finding of rs11196218 and its haplotype for T2D was also replicated in the family sample (P < 0.05). Our results are consistent with others' findings that variations at TCF7L2 contribute to T2D, including Chinese. The presence of association signals spanning several LD blocks warrants further examination of extended regions to reveal the causal variant(s) for this important T2D gene.

Genetic signature consistent with selection against the CYP3A4*1B allele in non-African populations

Cytochrome P450 3A enzymes (CYP3A) play a major role in the metabolism of steroid hormones, drugs and other chemicals, including many carcinogens. The individually variable CYP3A expression, which remains mostly unexplained, has been suggested to affect clinical phenotypes. We investigated the CYP3A locus in five ethnic groups. The degree of linkage disequilibrium (LD) differed among ethnic groups, but the most common alleles of the conserved LD regions were remarkably similar. Non-African haplotypes are few; for example, only four haplotypes account for 80% of common European Caucasian alleles. Large LD blocks of high frequencies were suggestive of selection. Accordingly, European Caucasian and Asian cohorts each contained a block of single nucleotide polymorphism (SNPs) with very high P excess values. The overlap between these blocks in these two groups contained only two of the investigated 26 SNPs and one of them was the CYP3A4*1B allele. The region centromeric of CYP3A4*1B exhibited high haplotype homozygosity in European Caucasians as opposed to African-Americans. CYP3A4*1B showed a moderate effect on CYP3A4 mRNA and protein expression, as well as on CYP3A activity assessed as Vmax of testosterone 6beta-hydroxylation in a liver bank. Our data are consistent with a functional relevance of CYP3A4*1B and with selection against this allele in non-African populations. The elimination of CYP3A4*1B involved different parts of the CYP3A locus in European Caucasians and Asians. Because CYP3A4 is involved in the vitamin D metabolism, rickets may have been the underlying selecting factor.

Positive Selection of a Pre-Expansion CAG Repeat of the Human SCA2 Gene

A region of approximately one megabase of human Chromosome 12 shows extensive linkage disequilibrium in Utah residents with ancestry from northern and western Europe. This strikingly large linkage disequilibrium block was analyzed with statistical and experimental methods to determine whether natural selection could be implicated in shaping the current genome structure. Extended Haplotype Homozygosity and Relative Extended Haplotype Homozygosity analyses on this region mapped a core region of the strongest conserved haplotype to the exon 1 of the Spinocerebellar ataxia type 2 gene (SCA2). Direct DNA sequencing of this region of the SCA2 gene revealed a significant association between a pre-expanded allele [(CAG)8CAA(CAG)4CAA(CAG)8] of CAG repeats within exon 1 and the selected haplotype of the SCA2 gene. A significantly negative Tajima's D value (−2.20, p < 0.01) on this site consistently suggested selection on the CAG repeat. This region was also investigated in the three other populations, none of which showed signs of selection. These results suggest that a recent positive selection of the pre-expansion SCA2 CAG repeat has occurred in Utah residents with European ancestry.

Positive Selection of a Pre-expansion CAG Repeat of the Human SCA2 Gene

A region of approximately one megabase of human Chromosome 12 shows extensive linkage disequilibrium in Utah residents with ancestry from northern and western Europe. This strikingly large linkage disequilibrium block was analyzed with statistical and experimental methods to determine whether natural selection could be implicated in shaping the current genome structure. Extended Haplotype Homozygosity and Relative Extended Haplotype Homozygosity analyses on this region mapped a core region of the strongest conserved haplotype to the exon 1 of the Spinocerebellar ataxia type 2 gene (SCA2). Direct DNA sequencing of this region of the SCA2 gene revealed a significant association between a pre-expanded allele [(CAG)8CAA(CAG)4CAA(CAG)8] of CAG repeats within exon 1 and the selected haplotype of the SCA2 gene. A significantly negative Tajima's D value (−2.20, p < 0.01) on this site consistently suggested selection on the CAG repeat. This region was also investigated in the three other populations, none of which showed signs of selection. These results suggest that a recent positive selection of the pre-expansion SCA2 CAG repeat has occurred in Utah residents with European ancestry.