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PubMed2002

Detecting recent positive selection in the human genome from haplotype structure.

The ability to detect recent natural selection in the human population would have profound implications for the study of human history and for medicine. Here, we introduce a framework for detecting the genetic imprint of recent positive selection by analysing long-range haplotypes in human populations. We first identify haplotypes at a locus of interest (core haplotypes). We then assess the age of each core haplotype by the decay of its association to alleles at various distances from the locus, as measured by extended haplotype homozygosity (EHH). Core haplotypes that have unusually high EHH and a high population frequency indicate the presence of a mutation that rose to prominence in the human gene pool faster than expected under neutral evolution. We applied this approach to investigate selection at two genes carrying common variants implicated in resistance to malaria: G6PD and CD40 ligand. At both loci, the core haplotypes carrying the proposed protective mutation stand out and show significant evidence of selection. More generally, the method could be used to scan the entire genome for evidence of recent positive selection.

Africa↗

PubMed2006

Long-range polony haplotyping of individual human chromosome molecules.

We report a method for multilocus long-range haplotyping on human chromosome molecules in vitro based on the DNA polymerase colony (polony) technology. By immobilizing thousands of intact chromosome molecules within a polyacrylamide gel on a microscope slide and performing multiple amplifications from single molecules, we determined long-range haplotypes spanning a 153-Mb region of human chromosome 7 and found evidence of rare mitotic recombination events in human lymphocytes. Furthermore, the parallel nature of DNA polony technology allows efficient haplotyping on pooled DNAs from a population on one slide, with a throughput three orders of magnitudes higher than current molecular haplotyping methods. Linkage disequilibrium statistics established by our pooled DNA haplotyping method are more accurate than statistically inferred haplotypes. This haplotyping method is well suited for candidate gene-based association studies as well as for investigating the pattern of recombination in mammalian cells.

Chromosome Mapping↗

PubMed2006

A worldwide survey of haplotype variation and linkage disequilibrium in the human genome.

Recent genomic surveys have produced high-resolution haplotype information, but only in a small number of human populations. We report haplotype structure across 12 Mb of DNA sequence in 927 individuals representing 52 populations. The geographic distribution of haplotypes reflects human history, with a loss of haplotype diversity as distance increases from Africa. Although the extent of linkage disequilibrium (LD) varies markedly across populations, considerable sharing of haplotype structure exists, and inferred recombination hotspot locations generally match across groups. The four samples in the International HapMap Project contain the majority of common haplotypes found in most populations: averaging across populations, 83% of common 20-kb haplotypes in a population are also common in the most similar HapMap sample. Consequently, although the portability of tag SNPs based on the HapMap is reduced in low-LD Africans, the HapMap will be helpful for the design of genome-wide association mapping studies in nearly all human populations.

Chromosome Mapping↗

PubMed2006

ATM haplotypes and breast cancer risk in Jewish high-risk women.

While genetic factors clearly play a role in conferring breast cancer risk, the contribution of ATM gene mutations to breast cancer is still unsettled. To shed light on this issue, ATM haplotypes were constructed using eight SNPs spanning the ATM gene region (142 kb) in ethnically diverse non-Ashkenazi Jewish controls (n=118) and high-risk (n=142) women. Of the 28 haplotypes noted, four were encountered in frequencies of 5% or more and accounted for 85% of all haplotypes. Subsequently, ATM haplotyping of high-risk, non-Ashkenazi Jews was performed on 66 women with breast cancer and 76 asymptomatic. One SNP (rs228589) was significantly more prevalent among breast cancer cases compared with controls (P=4 x 10(-9)), and one discriminative ATM haplotype was significantly more prevalent among breast cancer cases (33.3%) compared with controls (3.8%), (P< or =10(-10)). There was no significant difference in the SNP and haplotype distribution between asymptomatic high-risk and symptomatic women as a function of disease status. We conclude that a specific ATM SNP and a specific haplotype are associated with increased breast cancer risk in high-risk non-Ashkenazi Jews.

Adult↗

PubMed2006

Clustering of haplotypes based on phylogeny: how good a strategy for association testing?

Haplotypes are now widely used in association studies between markers and disease susceptibility locus. However, when a large number of markers are considered, the number of possible haplotypes increases leading to two problems: an increased number of degrees of freedom that may result in a lack of power and the existence of rare haplotypes that may be difficult to take into account in the statistical analysis. In a recent paper, Durrant et al proposed a method, CLADHC, to group haplotypes based on distance matrices and showed that this could considerably increase the power of the association test as compared to either single-locus analysis or haplotype analysis without prior grouping. Although the authors considered different one-disease-locus susceptibility models in their simulations, they did not study the impact of the linkage disequilibrium (LD) pattern and of the susceptibility allele frequency on their conclusions. Here, we show, using haplotype data from five regions of the genome of different lengths and with different LD patterns, that, when a single disease susceptibility locus is simulated, the prior grouping of haplotypes based on the algorithm of Durrant et al does not increase the power of association testing except in very particular situations of LD patterns and allele frequencies.

Computer Simulation↗

PubMed2006

Identification of probable genotyping errors by consideration of haplotypes.

Undetected genotyping errors pose a problem in genetic epidemiological studies, as they may invalidate statistical analysis or reduce its power. Haplotype analysis requires an improved standard of the data, because a haplotype can be inferred correctly only if the genotypes of all its markers are correct. Here, we present a method that identifies probable genotyping errors in trio samples with the help of the estimated haplotype frequency distribution of the sample. If the likelihood of the most likely haplotype explanation depends strongly on just one genotype, in the sense that setting the genotype to be missing leads to a much more likely haplotype explanation, this genotype is considered as a potential genotyping error. We describe a method that systematically searches the whole data set for such potential errors. Based on the haplotype distribution of a real data set, we carry out a simulation study to estimate the sensitivity and specificity of the method. In addition, we apply our approach to the real data set itself. Potentially erroneous genotypes are re-determined via sequencing. The results of both the simulation study and of the application to the real data set show that a considerable proportion of true genotyping errors is detected and that the number of false-positive signals is acceptable. We conclude that it is indeed possible to identify probable genotyping errors by considering haplotypes. The method described here will be part of the next release of our FAMHAP software.

Computer Simulation↗

PubMed2006

Haplotypes in the CTLA4 region are associated with coeliac disease in the Irish population.

Chromosomal region 2q33 encodes the immune regulatory genes, CTLA4, ICOS and CD28, which are involved in regulation of T-cell activity and has been studied as a candidate gene locus in autoimmune diseases, including coeliac disease (CD). We have investigated whether an association exists between this region and CD in the Irish population using a comprehensive analysis for genetic variation. Using a haplotype-tagging approach, this gene cluster was investigated for disease association in a case-control study comprising 394 CD patients and 421 ethnically matched healthy controls. Several SNPs, including CTLA4_CT60, showed association with disease; however, after correction for multiple-testing, CTLA4-658C/T was the only polymorphism found to show significant association with disease when allele, genotype, or carrier status frequency were analysed (carrier status (Allele C), P = 0.0016). Haplotype analysis revealed a haplotype incorporating the CD28/CTLA4 and two 5' ICOS polymorphisms to be significantly associated with disease (patients 24.1%; controls 31.5%; P = 0.035), as was a shorter haplotype composed of the CTLA4 markers only (30.9 vs 34.9%; P = 0.042). The extended haplotype incorporating CD28/CTLA4 and 5' ICOS is more strongly associated with disease than haplotypes of individual genes. This suggests a causal variant associated with this haplotype may be associated with disease in this population.

Antigens, CD↗

PubMed2004

Fitness and life-history traits of the two major mitochondrial DNA haplotypes of Drosophila subobscura.

Mitochondrial DNA restriction site analyses on natural populations of Drosophila subobscura have proved the existence of two common, coexisting haplotypes (I and II), as well as a set of less frequent ones derived from them. To explain this distribution, experiments to date point practically to all possible genetic mechanisms being involved in the changes of gene frequencies (cytonuclear coadaptation, direct natural selection on mtDNA and genetic drift). In an attempt to find differences that help to understand the dynamics of these haplotypes and to detect the effect of selection, we measured certain fitness components and life-history traits (egg-larva and larva-adult viabilities and developmental times, longevity, resistance to desiccation and optimal density) of the two main haplotypes I and II when maintained in laboratory population cages. As a general trend, haplotype II showed a higher net fitness than haplotype I, which explains the superiority of haplotype II over haplotype I in experimental populations but not their coexistence in nature, where additional factors must be considered.

Animals↗

PubMed2005

Haplotype association analysis of the polymorphisms Arg16Gly and Gln27Glu of the adrenergic beta2 receptor in a Swedish hypertensive population.

The Arg16Gly and the Gln27Glu polymorphisms in the gene for the beta2-adrenergic receptor (beta2AR) have been linked to an increased risk for cardiovascular disease. The aim of the present study was to evaluate the significance of these haplotypes for development of myocardial infarction (MI) as well as other cardiovascular phenotypes. In a prospective study cohort (CAPPP), 522 hypertensive patients (174 MI and 348 matched controls) were analysed for the Arg16Gly and the Gln27Glu polymorphisms by dynamic allele-specific hybridisation. The haplotype could successfully be determined in 516 patients. Haplotype was not significantly associated with MI. Systolic blood pressure (SBP) was higher in patients with Arg16Gly+Gln27Gln and lower in patients with Arg16Gly+Gln27Glu as compared with the other haplotypes. Haplotype was not associated with body mass index, diastolic blood pressure, cholesterol, LDL, HDL triglycerides or a diagnosis of diabetes mellitus. The present study found no evidence that haplotype for the two most common polymorphisms in the beta2AR are associated with development of MI in a Swedish hypertensive population, but haplotype may be associated with SBP.

Arginine↗

PubMed2004

Will haplotype maps be useful for finding genes?

From its introduction into the literature, the idea of haplotype map-based linkage disequilibrium (LD) studies has been the subject of disputes. These queries involve the extent to which the haplotype blocks exist, the validity of fundamental concepts such as the recombination hotspot, and the application of this idea in the form of the HapMap project. In this article, we review the relevant literature to evaluate the potential importance of haplotype maps for psychiatric genetics. We first take a closer look at the nature of haplotype blocks and then address the impact of block definitions and methodological factors, such as single-nucleotide polymorphism density and sample size, on findings from haplotype block studies. After distinguishing between two types of haplotype map-based LD studies, we discuss the importance of the recombination hotspot and the nature of the disease mutations affecting complex traits. In the final section, we summarize our main conclusions and comment on the usefulness of haplotype maps for finding genes.

Chromosome Mapping↗

PubMed2006

Significant association of catechol-O-methyltransferase (COMT) haplotypes with nicotine dependence in male and female smokers of two ethnic populations.

The catechol-O-methyltransferase (COMT) gene plays a prominent role in dopaminergic circuits central to drug reward. Allelic variants within the COMT gene are therefore potential candidates for examining interindividual differences in vulnerability to nicotine dependence (ND). We analyzed five single nucleotide polymorphisms (SNPs), including the Val/Met variant (rs4680), which results in a three- to four-fold difference in enzyme activity within COMT, for association with the three ND measures, SQ, HSI, and FTND, in 602 nuclear families of African-American (AA) or European-American (EA) origin. The Val/Met variant showed a significant association with the three ND measures in the pooled and EA samples and with FTND in the AA sample. Haplotype analysis revealed a major protective A-G-T haplotype (frequency 23.6%) for rs740603-rs4680-rs174699 in the AA sample (minimum Z=-3.35; P=0.0005 for FTND), a major protective T-G-T haplotype (frequency 15.2%; minimum Z=-2.92; P=0.003 for FTND) in the EA sample, and a high-risk C-A-T haplotype (frequency 16.9%; minimum Z=3.16; P=0.002 for SQ) in the AA sample for rs933271-rs4680-rs174699. Furthermore, we found that the significant haplotypes within COMT were gender-specific and the significantly associated A-G-T is protective in AA females only, whereas T-G-T is protective in EA males only. Moreover, we found a major high-risk T-A-T haplotype (frequency 56.7%) that showed significant association with the three ND measures in EA males. Further examination of two protective haplotypes, A-G-T in AAs and T-G-T in EAs, indicated that the low COMT enzyme activity Met allele is protective to become nicotine dependent. In summary, our results provide evidence for a role of COMT in the susceptibility to ND and further confirm that its effect is ethnic and gender specific.

Adult↗

PubMed1999

DNA sequence of SSCP haplotypes at the bovine growth hormone (bGH) gene.

Previous studies using SSCP and PCR-RFLP methodologies uncovered nine polymorphic sites within the bGH gene, defining eight intragenic haplotypes falling into two main groups. In the present study we report the DNA sequence of these eight haplotypes. A total of 1494 bp were sequenced uncovering a total of 12 sequence variants. Haplotypes within groups differed among themselves at one or two sites, compared across groups, haplotypes of the two groups differed consistently at six sites, each of which was monomorphic within the respective groups. This comes to 4 differentiating sites per kb, suggesting that the two haplotype groups began to diverge about 400,000 years ago. This corresponds approximately to the estimated time of divergence of the Bos taurus and Bos indicus lineages, raising the possibility, supported by other evidence, that the two haplotype classes represent taurine and indicine haplotypes, respectively. Nucleotide sequence divergence of taurine and indicine genomes of this magnitude has far reaching implications with respect to QTL mapping and marker assisted selection in breeds derived from taurine x indicine crosses.

Animals↗

PubMed2000

Molecular characterization of major and minor MHC class I and II genes in B21-like haplotypes in chickens.

The major histocompatibility complex (MHC) sequences of three B21-like haplotypes deriving from very different origins including the Red Jungle Fowl Gallus Gallus gallus were compared with the MHC sequences of the standard B21 haplotype from Scandinavian White Leghorn Gallus domesticus. The present analysis reveals two cDNA sequences for B-F and two cDNA sequences for B-LB for every B21-like haplotype, including B21 itself. Contrary to expectation, no sequence polymorphism in the antigen-binding domains of the MHC genes, between the investigated haplotypes, was found. The relative level of MHC class I molecules on the surface of leukocytes measured by flow cytometry was also analysed and found to be low in Marek's Disease (MD)-resistant B haplotypes (B21 and B21-like) and high in MD-susceptible B haplotypes (B15 and B19). However, in heterozygous (resistant/susceptible) animals, the relative level was almost as high as in susceptible haplotypes.

Amino Acid Sequence↗

PubMed1999

Polymorphism of DR52-associated haplotypes in a Croatian population.

We investigated DR52 haplotype polymorphism in a population of 78 Croatian families with at least one parent and one offspring positive for a DR52-associated allele, using the PCR-SSOP method. The haplotypes DRB1*0301-DQA1*0501-DQB1*0201, DRB1*11-DQA1*0501-DQB1*0301 and DRB1*1201-DQA1*0501-DQB1*0301 seem to be conserved haplotypes in this Croatian population, while DRB1*13 haplotypes showed high diversity. Among 10 different DRB1*13 haplotypes, four consist of common alleles, while six have an unusual combination of DRB1-DQA1-DQB1 alleles. Three haplotypes (DRB1*1301-DQA1*0103-DQB1*0503, DRB1*1302-DQA1*0102-DQB1*0502 and DRB1*1303-DQA1*0102-*DQB1*0502) have not been reported. These results on DR52-associated haplotype polymorphisms in a Croatian population must be taken into consideration in organ transplantation, especially when searching for unrelated bone marrow donors.

Croatia↗

PubMed2003

Alleles of the proximal promoter of BAT1, a putative anti-inflammatory gene adjacent to the TNF cluster, reduce transcription on a disease-associated MHC haplotype.

BACKGROUND: BAT1 belongs to the DEAD-box family of proteins, and is encoded in the central region of the MHC, a region containing genes affecting immunopathological disorders including Type 1 diabetes. We showed that BAT1 can reduce inflammatory cytokine production, supporting its candidacy as a disease gene. Here we examined the proximal promoter region of BAT1. RESULTS: Ten single nucleotide polymorphisms were identified in approximately 1.4 kb of sequence, defining at least seven alleles. Sections of the BAT1 promoter region were amplified from cells homozygous for the MHC haplotypes associated with susceptibility (HLA-A1, B8, DR3; 8.1 haplotype) and resistance (HLA-A3, B7, DR15; 7.1 haplotype) to diabetes and cloned into a promoter-less luciferase-encoding plasmid. Jurkat cells transiently transfected with fragments from the 8.1 haplotype exhibited a lower luciferase activity than those transfected with fragments from the 7.1 haplotype, indicating reduced transcription. The effect was clearest with the 520 bp immediately upstream of the transcriptional start site. Electrophoretic mobility shift assays using oligonucleotides spanning polymorphic sites within the 520 bp (proximal) promoter fragment showed haplotype-specific binding of nuclear proteins. CONCLUSIONS: In view of the anti-inflammatory role of BAT1, reduced production on a disease-associated haplotype constitutes a novel and self-consistent model for the effect of central MHC genes on disease.

Alleles↗

PubMed2004

A new algorithm for haplotype-based association analysis: the Stochastic-EM algorithm.

It is now widely accepted that haplotypic information can be of great interest for investigating the role of a candidate gene in the etiology of complex diseases. In the absence of family data, haplotypes cannot be deduced from genotypes, except for individuals who are homozygous at all loci or heterozygous at only one site. Statistical methodologies are therefore required for inferring haplotypes from genotypic data and testing their association with a phenotype of interest. Two maximum likelihood algorithms are often used in the context of haplotype-based association studies, the Newton-Raphson (NR) and the Expectation-Maximisation (EM) algorithms. In order to circumvent the limitations of both algorithms, including convergence to local minima and saddle points, we here described how a stochastic version of the EM algorithm, referred to as SEM, could be used for testing haplotype-phenotype association. Statistical properties of the SEM algorithm were investigated through a simulation study for a large range of practical situations, including small/large samples and rare/frequent haplotypes, and results were compared to those obtained by use of the standard NR algorithm. Our simulation study indicated that the SEM algorithm provides results similar to those of the NR algorithm, making the SEM algorithm of great interest for haplotype-based association analysis, especially when the number of polymorphisms is quite large.

Algorithms↗

PubMed2006

Association between functional FABP2 promoter haplotype and type 2 diabetes.

Fatty acid-binding protein 2 (FABP2) is a cytosolic protein expressed exclusively in epithelial cells of the small intestine. Some, albeit not conclusive, evidence indicates that the Thr-allele of FABP2 Ala54Thr polymorphism is associated with type 2 diabetes. More recently, common FABP2 promoter polymorphisms have shown association with postprandial increase of triglycerides, body composition and plasma lipid levels. Therefore, we reasoned that variants in the FABP2 promoter may also predispose to type 2 diabetes mellitus. In our Caucasian study population, we found three SNPs and three insertion-deletion polymorphisms that are in complete linkage disequilibrium defining promoter haplotype A and B within 1kb 5' of the FABP2 initiation codon. Haplotype calculations indicated that the FABP2 promoter and Ala54Thr variants were strongly linked. Functional analysis of promoter fragments demonstrated that haplotype difference is caused by polymorphisms within 260 bp downstream of the FABP2 initiation codon. Using a prospective case-control study nested within the EPIC-Potsdam cohort of 192 incident type 2 diabetes cases and 384 sex-/age-matched controls, male subjects carrying the FABP2 haplotype B allele showed significantly decreased risk of type 2 diabetes when adjusted for BMI (OR = 0.50, 95 % CI = 0.28 - 0.87, p < 0.05) and additional covariates (OR = 0.42, 95 % CI 0.22 - 0.81, p < 0.01). Further adjustment for the Ala54Thr polymorphism revealed an OR of 0.18 (95 % CI 0.06 - 0.49, p < 0.001). Similarly, Ala/Ala homozygote males carrying the promoter haplotype B had decreased risk (0.33, 0.11 - 0.94, p < 0.05) of type 2 diabetes after stratification for the Ala54Thr polymorphism. FABP2 promoter haplotypes or genotype combinations defined by the promoter and Ala54Thr polymorphism were not associated with BMI, body fat, leptin, HbA (1c), total cholesterol or HDL. In conclusion, our findings suggest that the functional FABP2 promoter haplotype may contribute to type 2 diabetes in a sex-specific manner.

Adult↗

PubMed2002

Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene.

OBJECTIVE: We investigated the effect of polymorphisms in the P-glycoprotein (P-gp) MDR1 gene on steady-state pharmacokinetics of digoxin in Caucasians. According to earlier data, homozygous TT of the exon 26 complementary deoxyribonucleic acid (cDNA) 3435C>T polymorphism was associated with low P-gp expression in the human intestine. METHODS: Eight healthy male homozygous carriers of the wild-type exon-26 3435C>T (CC), 8 heterozygous subjects (CT), and 8 homozygous mutant (TT) subjects were selected. Seven further MDR1 polymorphisms were determined. Digoxin was administered orally twice daily on the first two study days; on days 3 to 5, 0.25 mg was given in the morning. On day 5, kinetic parameters were analyzed for genotype-phenotype and haplotype-phenotype relationships. RESULTS: The area under the plasma concentration-time curve from time zero to 4 hours [AUC(0-4)] (P =.042) and C(max) (P =.043) values of digoxin were higher in subjects with the 3435TT genotype than in those with the 3435CC. No influence of other single nucleotide polymorphisms (SNPs) on digoxin parameters was detected. Comparison of genotypes deduced from SNPs 2677G>T (exon 21) and 3435C>T revealed significant differences for AUC(0-4) (P =.034) and C(max) (P =.039), which were substantiated by haplotype analysis. Haplotype 12 (2677G/3435T), which had a frequency of 13.3% in a randomly drawn Caucasian sample (n = 687), was associated (Mann-Whitney test) with higher AUC(0-4) values (P =.009) than were found in noncarriers (mean +/- SD, 5.7 +/- 0.9 microg. h/L [n = 7] versus 4.8 +/- 0.9 microg. h/L [n = 17]). Haplotype 11 (2677G/3435C) had lower AUC(0-4) values (P =.013) compared with those of noncarriers (mean +/- SD, 4.7 +/- 0.9 microg. h/L [n = 16] versus 5.6 +/- 0.9 microg. h/L [n = 8]). Results of haplotype analysis match data of other MDR1 studies. CONCLUSION: Haplotype 12 codes for high values of AUC(0-4) and C(max) of orally administered digoxin. Analysis of MDR1 haplotypes is superior to unphased SNP analysis to predict MDR1 phenotype.

Animals↗