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PubMed1992

Hb City of Hope [beta 69(E13)Gly----Ser] in Italy: association of the gene with haplotype IX.

Hb City of Hope [beta 69(E13)Gly----Ser] was detected by reversed phase high performance liquid chromatography in an asymptomatic carrier from Naples, Southern Italy. The amino acid substitution, identified by fast atom bombardment mass spectrometry, was due to a TGG----TGA substitution as assessed by DNA sequencing. Analysis of the chromosomal background indicates that the globin gene cluster containing the mutant gene has most probably been rearranged by a recombination event, since the mutation was associated with restriction fragment length polymorphism haplotype IX, instead of haplotype I, as previously reported.

Base Sequence↗
PubMed2006

Biases and reconciliation in estimates of linkage disequilibrium in the human genome.

Genetic association studies of common disease often rely on linkage disequilibrium (LD) along the human genome and in the population under study. Although understanding the characteristics of this correlation has been the focus of many large-scale surveys (culminating in genomewide haplotype maps), the results of different studies have yielded wide-ranging estimates. Since understanding these differences (and whether they can be reconciled) has important implications for whole-genome association studies, in this article we dissect biases in these estimations that are due to known aspects of study design and analytic methodology. In particular, we document in the empirical data that the long-known complicating effects of allele frequency, marker density, and sample size largely reconcile all large-scale surveys. Two exceptions are an underappraisal of redundancy among single-nucleotide polymorphisms (SNPs) when evaluation is limited to short regions (as in candidate-gene resequencing studies) and an inflation in the extent of LD in HapMap phase I, which is likely due to oversampling of specific haplotypes in the creation of the public SNP map. Understanding these factors can guide the understanding of empirical LD surveys and has implications for genetic association studies.

Genome, Human↗
PubMed2005

Direct molecular haplotyping of the IVS-8 poly(TG) and polyT repeat tracts in the cystic fibrosis gene by melting curve analysis of hybridization probes.

BACKGROUND: Molecular haplotyping is a developing technology with great potential for use in clinical diagnostics. We describe a haplotyping method that uses PCR combined with hybridization probes. METHODS: We designed a LightCycler assay that uses fluorescence resonance energy transfer hybridization probes to haplotype the poly(TG) and polyT (TG-T) tract in the IVS-8 region of the CFTR gene. The reporter probe was designed as a perfect match to the TG12-5T allele. RESULTS: Analysis of 132 samples revealed 9 unique derivative melting temperatures (Tms); the lowest was 42.4 degrees C and the highest was 63.6 degrees C. The lowest Tms were in the TGn-9T group, the intermediate Tms in the TGn-7T group, and the highest Tms in the TGn-5T group. Haplotype frequencies were highest (39%) for TG11-7T and lowest (0.4%) for TG13-5T. CONCLUSIONS: Different combinations of polymorphisms under the reporter hybridization probe had unique and characteristic Tms. This property enables genotyping as well as determination of the phase of multiple variants under the probe, a principle we demonstrated by haplotyping the TG-T repeat tract in the IVS-8 region of the CFTR gene.

Cystic Fibrosis↗
PubMed1991

Research note: T-cell activity of White Leghorn chickens selected for high and low antibody responses to sheep erythrocytes.

Mitogen responses of peripheral blood lymphocytes (PBL) and the cell cycle analysis of T-cells were examined for lines of chickens selected for high (HA) and low (LA) antibody response to SRBC. At 6 wk of age, within each line, blood samples and thymic tissue were collected from chicks representing the B13B13, B13B21, B21B13, and B21B21 genotypes. Although no influence of Ea-B haplotype on T-cell activity was detected in either line, there were line differences in phytohemagglutin-M (PHA-M) and concanavalin A (Con A) mitogen responses and the percentage G0/G1 and S phase T-cells. The HA PBL had greater in vitro PHA-M and Con A responses, and the cell cycle analysis of T-cells revealed a greater percentage of cells in S phase for Line HA chicks than for LA chicks. There were significantly more resting cells in the G0/G1 phase of LA than HA chicks. Although there was no Ea-B haplotype effect observed on T-cells from either line, generalized selection for high or low antibody response did result in divergent T-cell activity.

Animals↗
PubMed1994

Analysis of 133 meioses places the genes for nevoid basal cell carcinoma (Gorlin) syndrome and Fanconi anemia group C in a 2.6-cM interval and contributes to the fine map of 9q22.3.

Four disease genes (NBCCS, ESS1, XPAC, FACC) map to 9q22.3-q31. A fine map of this region was produced by linkage and haplotype analysis using 12 DNA markers. The gene for nevoid basal cell carcinoma syndrome (NBCCS, Gorlin) has an important role in congenital malformations and carcinogenesis. Phase-known recombinants in a study of 133 meioses place NBCCS between (D9S12/D9S151) and D9S176. Haplotype analysis in a two-generation family suggests that NBCCS lies in a smaller interval of 2.6 cM centromeric to D9S287. These flanking markers will be useful clinically for gene tracking. Recombinants also map FACC (Fanconi anemia, group C) to the same region, between (D9S196/D9S197) and D9S287. The recombination rate between (D9S12/D9S151) and D9S53 in males is 8.3% and 13.2% in females, giving a sex-specific male:female ratio of 1:1.6 and a sex-averaged map distance of 10.4 cM. No double recombinants were detected, in agreement with the apparently complete level of interference predicted from the male chiasmata map.

Basal Cell Nevus Syndrome↗
PubMed2003

On the identification of disease mutations by the analysis of haplotype similarity and goodness of fit.

The observation that haplotypes from a particular region of the genome differ between affected and unaffected individuals or between chromosomes transmitted to affected individuals versus those not transmitted is sound evidence for a disease-liability mutation in the region. Tests for differentiation of haplotype distributions often take the form of either Pearson's chi(2) statistic or tests based on the similarity among haplotypes in the different populations. In this article, we show that many measures of haplotype similarity can be expressed in the same quadratic form, and we give the general form of the variance. As we describe, these methods can be applied to either phase-known or phase-unknown data. We investigate the performance of Pearson's chi(2) statistic and haplotype similarity tests through use of evolutionary simulations. We show that both approaches can be powerful, but under quite different conditions. Moreover, we show that the power of both approaches can be enhanced by clustering rare haplotypes from the distributions before performing a test.

Chromosomes, Human↗
PubMed1999

Bayesian mapping of multiple quantitative trait loci from incomplete outbred offspring data.

A general fine-scale Bayesian quantitative trait locus (QTL) mapping method for outcrossing species is presented. It is suitable for an analysis of complete and incomplete data from experimental designs of F2 families or backcrosses. The amount of genotyping of parents and grandparents is optional, as well as the assumption that the QTL alleles in the crossed lines are fixed. Grandparental origin indicators are used, but without forgetting the original genotype or allelic origin information. The method treats the number of QTL in the analyzed chromosome as a random variable and allows some QTL effects from other chromosomes to be taken into account in a composite interval mapping manner. A block-update of ordered genotypes (haplotypes) of the whole family is sampled once in each marker locus during every round of the Markov Chain Monte Carlo algorithm used in the numerical estimation. As a byproduct, the method gives the posterior distributions for linkage phases in the family and therefore it can also be used as a haplotyping algorithm. The Bayesian method is tested and compared with two frequentist methods using simulated data sets, considering two different parental crosses and three different levels of available parental information. The method is implemented as a software package and is freely available under the name Multimapper/outbred at URL http://www.rni.helsinki.fi/mjs/.

Algorithms↗
PubMed1981

A variant alpha-chain in an Ia molecule from the I-A subregion of the mouse major histocompatibility complex: a possible intragenic recombination.

The recombinant MHC haplotype t1, present in mouse strain A.TL and B10.TL, encodes an I-A molecule with a variant alpha-chain that was recognized when tryptic peptide digests from t1 and the nominal parental haplotype (a1 or k) were compared by double-label reverse phase HPLC. The t1 I-A alpha-chain possesses a tryptic peptide absent from a1 and k I-A alpha-chains, and lacks several peptides present in a1 and k. The peptide that differs in t1 is not a mannose-bearing peptide, and thus its altered mobility is probably not due to carbohydrate modification. The alteration in t1 could result from mutation or intragenic recombination, but the unique t1 peptide migrates in a position identical to a peptide found in haplotype s, a partner in the (s X a1) cross that generated the t1 recombinant. If this apparently shared peptide indicates an intragenic recombination, this places the I-A alpha-gene centromeric to the other I-A subregion gene, and together with the data of Jones, suggests a gene order of I-A alpha, I-A beta, I-E beta (A alpha, A beta, Ae).

Animals↗
PubMed2006

False disease region identification from identity-by-descent haplotype sharing in the presence of phenocopies.

Linkage analysis (either parametric or nonparametric) is commonly applied to identify chromosomal regions using related individuals affected by disease. In complex disease the incomplete relationship between phenotype and genotype can be modeled using a phenocopy parameter, the probability that an individual is affected given they do not carry the disease mutation of interest, and a nonpenetrance parameter, the probability that an individual is not affected given they do carry the disease mutation of interest. If the linkage phase between multiple markers and a putative disease locus is known, then haplotypes carrying the mutation can, in principle, be identified by comparing the chromosome segments that are shared identical-by-descent (IBD) across affected individuals. We consider here the effect of a nonzero phenocopy rate on the linkage peak and hence upon the identification of disease haplotypes that are shared IBD between affected individuals. We show, by theory and computer simulation, that in diseases for which there is a nonzero phenocopy rate, the chromosomal regions identified may not include the true disease locus. We utilize a LOD-1 confidence interval for a widely used nonparametric linkage statistic. We find that in small/moderate samples this confidence interval may be inappropriate. We give specific examples where the phenocopy rates are nonnegligible in some complex diseases. The success of further work to identify the causal mutations underlying the linkage peaks in these diseases will depend on researchers allowing for the presence of phenocopies by examining appropriately wide regions around the initial positive linkage finding.

Alleles↗
PubMed2005

Maximum likelihood estimation of haplotype effects and haplotype-environment interactions in association studies.

The associations between haplotypes and disease phenotypes offer valuable clues about the genetic determinants of complex diseases. It is highly challenging to make statistical inferences about these associations because of the unknown gametic phase in genotype data. We describe a general likelihood-based approach to inferring haplotype-disease associations in studies of unrelated individuals. We consider all possible phenotypes (including disease indicator, quantitative trait, and potentially censored age at onset of disease) and all commonly used study designs (including cross-sectional, case-control, cohort, nested case-control, and case-cohort). The effects of haplotypes on phenotype are characterized by appropriate regression models, which allow various genetic mechanisms and gene-environment interactions. We present the likelihood functions for all study designs and disease phenotypes under Hardy-Weinberg disequilibrium. The corresponding maximum likelihood estimators are approximately unbiased, normally distributed, and statistically efficient. We provide simple and efficient numerical algorithms to calculate the maximum likelihood estimators and their variances, and implement these algorithms in a freely available computer program. Extensive simulation studies demonstrate that the proposed methods perform well in realistic situations. An application to the Carolina Breast Cancer Study reveals significant haplotype effects and haplotype-smoking interactions in the development of breast cancer.

Algorithms↗
PubMed1994

Electrophoresis for genotyping: microtiter array diagonal gel electrophoresis on horizontal polyacrylamide gels, hydrolink, or agarose.

Electrophoresis of DNA has been performed traditionally in either an agarose or acrylamide gel matrix. Considerable effort has been directed to improved quality agaroses capable of high resolution, but for small fragments, such as those from polymerase chain reaction (PCR) and post-PCR digests, acrylamide still offers the highest resolution. Although agarose gels can easily be prepared in an open-faced format to gain the conveniences of horizontal electrophoresis, acrylamide does not polymerize in the presence of air and the usual configurations for gel preparation lead to electrophoresis in the vertical dimension. We describe here a very simple device and method to prepare and manipulate horizontal polyacrylamide gels (H-PAGE). In addition, the open-faced horizontal arrangement enables loading of arrays of wells. Since many procedures are undertaken in standard 96-well microtiter plates, we have also designed a device which preserves the exact configuration of the 8 x 12 array and enables electrophoresis in tracks following a 71.6 degrees diagonal between wells (MADGE, microtiter array diagonal gel electrophoresis), using either acrylamide or agarose. This eliminates almost all of the staff time taken in setup, loading, and recordkeeping and offers high resolution for genotyping pattern recognition. The nature and size of the gels allow direct stacking of gels in one tank, so that a tank used typically to analyze 30-60 samples can readily be used to analyze 1000-2000 samples. The gels would also enable robotic loading. Electrophoresis allows analysis of size and charge, parameters inaccessible to liquid-phase methods: thus, genotyping size patterns, variable length repeats, and haplotypes is possible, as well as adaptability to typing of point variations using protocols which create a difference detectable by electrophoresis.

DNA↗
PubMed2004

Blood ionized calcium is associated with clustered polymorphisms in the carboxyl-terminal tail of the calcium-sensing receptor.

Blood ionized calcium (iCa) is a quantitative trait subject to genetic influence. iCa is maintained in a narrow range through the action of the calcium-sensing receptor (CASR) controlling PTH secretion and calcium excretion. A CASR single nucleotide polymorphism (SNP) prevalent in Caucasian populations (A986S) has shown significant association with iCa in a cohort of young women, but association with the neighboring SNPs, R990G and Q1011E, has not been examined. We studied 377 unrelated adults (184 men and 193 women) recruited as healthy adults from a blood donor clinic. The subjects were not taking any medications, nor did they have disorders of calcium metabolism. Relative frequencies for the CASR 986S, 990G, and 1011E minor alleles were 24%, 4%, and 3% respectively. At the A986S locus, subjects with the AA genotype had significantly lower iCa (P = 0.0001) than subjects with one or two S alleles (mean +/- se, 1.221 +/- 0.003 vs. 1.239 +/- 0.003 mmol/liter). For the R990G site, subjects with the RR genotype had higher iCa than those with one copy of the 990G allele (1.230 +/- 0.002 vs. 1.213 +/- 0.007 mmol/liter; P = 0.032). With respect to the 1011 locus, iCa was lower in QQ genotype subjects than in the QE group (1.227 +/- 0.002 vs. 1.255 +/- 0.008 mmol/liter; P = 0.002). After resolution of phase for the doubly heterozygous subjects, analysis was conducted on haplotypes across all three loci. As expected, subjects with SRQ and ARE haplotypes are relatively hypercalcemic, and those with AGQ are hypocalcemic, relative to subjects with the common ARQ haplotype. Multiple regression analysis with clinical covariates (age, sex and menopausal status, creatinine, and PTH) showed that 16.5% of the total variance in iCa may be explained, and the seven CASR haplotypes contribute significantly (P < 0.0001) and substantially (49.1% of the explained variance) to the model, with the following corrected iCa means: ARQ/AGQ, 1.21 +/- 0.01; ARQ/ARQ, 1.22 +/- 0.01; ARQ/SRQ, 1.24 +/- 0.01; SRQ/AGQ, 1.24 +/- 0.03; SRQ/SRQ, 1.25 +/- 0.01; ARQ/ARE, 1.25 +/- 0.01; and SRQ/ARE, 1.27 +/- 0.01. Our data confirm the association between iCa and the A986S locus and suggest that R990G and Q1011E are also predictive. Given the significant between-population variations in frequency of variant alleles in this CASR SNP cluster, tri-locus haplotyping may prove to be more informative in studies of association between variation in CASR and disease.

Adolescent↗
PubMed1989

[Intermediate homozygous beta-thalassemia with high fetal hemoglobin synthesis. Molecular analysis].

The intermediate character of beta-thalassaemia may be due to a molecular cause capable of reducing the unbalance between alpha and non-alpha chains. We report the case of a child born of consanguineous parents and homozygous for beta-thalassaemia. The patient was irregularly transfused until puberty. His haemoglobin level was around 10 g/dl, and in his erythroid line only foetal haemoglobin was synthesized, except for small amounts of haemoglobin A2. An in vitro study of globin chains biosynthesis confirmed the total absence of beta chains synthesis, and the molecular defect was characterized. This was deletion of a colon 6 nucleotide on both chromosomes, making the messenger RNA unstable and non-traducible. The initial diagnostic approach in this patient included the indirect determination of restriction polymorphism (Orkin's halotype IX), a search for the presence or absence of a nonsense codon 39 often associated with haplotype IX, and the demonstration of a frameshift in the reading phase of codon 6. The very high synthesis of foetal haemoglobin in this patient seems to be linked with a C----T substitution in -158 of the G gamma gene creating an Xmnl site and a gamma phi beta (+-++) subhaplotype which appears to be related in all haemoglobinopathies to an increased synthesis of foetal haemoglobin with predominant G gamma chain.

Adult↗
PubMedDate not supplied

HLA-B27-associated uveitis with a chorioretinitis manifestation.

A 29-year-old man who had been treated for acute anterior uveitis in a local medical office and observed for 1 month presented complaining of distorted vision in his left eye for 1 week. On ophthalmic examination, the anterior segment was relatively quiet with few cells. A posterior segment examination revealed cystoid macular edema and multiple splinter retinal hemorrhages. Results of all laboratory and imaging studies were negative, except for a positive HLA-B27 haplotype. Fluorescein angiography revealed massive leakage in the mid and late phase, consistent with chorioretinitis. Periocular corticosteroid injections and oral prednisolone were administered. The patient responded to the treatment well with subsequent resolution of chorioretinitis 2 months later. Although rare, chorioretinitis can occur in the setting of uveitis associated with HLA-B27 and seems to respond well to corticosteroid treatment.

Adult↗
PubMed1996

MHC class I-mediated antigen presentation and induction of CD8+ cytotoxic T-cell responses in autoimmune diabetes-prone NOD mice.

The common class I alleles (e.g., Kd and Db) within the H2g7 major histocompatibility complex (MHC) clearly contribute to autoimmune IDDM in NOD mice, but the mechanism by which this occurs has been controversial. One laboratory has reported that the peptide transporter encoded by the Tap1 gene within H2g7 is defective, and this contributes to IDDM by impairing MHC class I-mediated antigen presentation. If true, defective MHC class I-mediated antigen presentation should segregate with the H2g7 haplotype. NOD mice, related congenic stocks, and other control strains were used to test this hypothesis. H2g7-positive strains did not differ from those expressing other MHC haplotypes in ability to present MHC class I-restricted H3aa or H3ab minor histocompatibility (H) antigens to cytotoxic T-lymphocytes (CTL). The H2g7 haplotype was found to have a reduced capacity to mediate MHC class I-restricted presentation of the H47a minor H antigen. However, MHC class I-restricted presentation of H47a was found to be Tap independent. NOD mice and control strains also did not differ in ability to activate adenovirus-specific MHC class I restricted CTL. Thus, the H2g7 haplotype is not characterized by a Tap gene defect that only impairs the inductive phase of the immune response. In addition, MHC class I-restricted presentation of either minor H or adenoviral antigens was equivalent in male and female NOD mice. Therefore, while the class I alleles of the H2g7 haplotype exert diabetogenic functions in NOD mice, this is not elicited through a Tap gene defect. The absence of female-specific Tap gene defects also indicates this cannot account for the reduced male incidence of IDDM in some NOD mouse colonies.

Alleles↗
PubMed2005

Analysis of single nucleotide polymorphisms and haplotypes in HOXC gene cluster within susceptible region 12q13 of simple congenital heart disease.

OBJECTIVE: In the candidate region 12q13 of simple congenital heart disease(CHD), four single nucleotide polymorphisms(SNPs) in HOXC4 gene were chosen in order to investigate the distribution of SNP and haplotypes in simple CHD patients and normal people. METHODS: The genotype of 4 SNPs in 108 simple CHD patients and 200 normal people were analyzed by restriction fragment length polymorphism(RFLP) and denaturing high-performance liquid chromatography(DHPLC). The statistical contingency table method was used to analyze SNP genotype frequency and gene frequency in patients and control group; then, the haplotypes were established and their frequencies in the two groups were assessed by PHASE software. RESULTS: C16476T polymorphism was not detected; A17860G located in 3' flanking sequence of HOXC5 gene displayed significant difference between the two groups. The G allele frequency in simple CHD patients was higher than that in healthy controls(P < 0.05); the distribution of frequencies of 4 haplotypes showed significant difference(P < 0.01). CONCLUSION: The A17860G located in 3'flanking sequence of HOXC5 gene is associated with simple CHD; the risk of CHD in the persons with G17860 is higher than that in those with A17860. the haplotype of 3 SNPs may be linked with the susceptible gene of simple CHD.

Adolescent↗
PubMed1992

Familial cardiomyopathy with variable hypertrophic and restrictive features and common HLA haplotype.

We describe a familial cardiomyopathy affecting three generations of family members with similar electrocardiographic abnormalities and human leukocyte antigen (HLA) haplotype. Autopsy findings in two of our patients were diagnostic of hypertrophic cardiomyopathy, although surviving affected members do not show ventricular hypertrophy on echocardiography. One patient's echocardiogram revealed giant atria in the absence of ventricular hypertrophy, suggesting a restrictive form of cardiomyopathy. In this kindred, an HLA haplotype appearing in affected, but not in healthy, family members may predict occurrence of disease during its presymptomatic phase in subsequent generations.

Adolescent↗
PubMedDate not supplied

A measure of phase ambiguity in pairs of SNPs in the presence of linkage disequilibrium.

The extent of haplotype ambiguity in a string of single-nucleotide polymorphisms (SNPs) was quantified by Hodge et al. [Nat Genet 1999;21:360]. In their measure, the level of ambiguity increases with increasing numbers of loci and as loci become more polymorphic. That work assumed linkage equilibrium (LE). However, linkage disequilibrium (LD) provides additional information about the haplotypes at a site, thereby diluting the level of ambiguity. The ambiguity vanishes altogether when LD reaches its maximum value. Here, we introduce the ambiguity measure, Phi, to allow for LD (between pairs of SNPs). We derive the formula Phi = 4x(2)x(3) for ambiguity in individuals, where x(1), x(2), x(3) and x(4) are the probabilities of the A(1)A(2), A(1)B(2), B(1)A(2) and B(1)B(2) haplotypes, respectively, and w.l.o.g. x(1)x(4) > or = x(2)x(3). Alternatively, Phi can be expressed in terms of the allele frequencies and the LD parameter delta. We also extend the formula to triads of two parents plus one child. We estimate our measure Phi for relevant SNPs in the published lipoprotein lipase (LPL) gene dataset [Clark et al., Am J Hum Genet 1998;63:595; Nickerson et al., Nat Genet 1998;19:233], obtaining values ranging from a low of 0 to a high of 0.11 among adjacent pairs of sites. In genome-wide LD studies to map common disease genes, a dense map of SNPs may be utilized to detect association between a marker and disease. Therefore, the measurement of ambiguity can potentially help investigators to determine a more efficient map, designed to minimize ambiguity and subsequent information loss.

Algorithms↗