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Results for “Haplotype structures”

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PubMed2004

Polymorphisms in multidrug resistance 1 (MDR1) gene are associated with refractory Crohn disease and ulcerative colitis.

We used coding and noncoding polymorphisms evenly spaced across the ABCB1/MDR1 gene to perform association analysis in Slovenian patients with inflammatory bowel diseases and to obtain haplotype structure and patterns of linkage disequilibrium (LD) in the MDR1 gene. A disease association study was performed in 307 IBD patients, including 144 patients with ulcerative colitis (UC) and 163 patients with Crohn's disease (CD), and 355 healthy controls. Here we report an association between MDR1 alleles, polymorphisms and haplotypes and refractory CD patients, who do not respond to standard therapy, including patients who develop fistulas. We also report an association with UC and MDR1 polymorphisms in a Slovenian population. Haplotypes significantly associated with diseases were defined by single-nucleotide polymorphisms (SNPs) in exons 12 (1236 C>A), 21(A893S), and 26 (3435 C>T). In addition, two intronic SNPs in LD with the disease haplotype, one in intron 13 (rs2235035) and another in intron 16 (rs1922242), were significantly associated with refractory Crohn (P=0.026, odds ratio (OR) 2.7 and P=0.025, OR 2.8, respectively), as well as with UC (P=0.006, OR 1.8 and P=0.026, OR 1.9, respectively). Our results suggest that MDR1 is a potential target for therapy in refractory CD patients and in patients with UC.

Adult↗

PubMed2026

Rice LSD1-like Genes: Genome-Wide Characterization and Evidence Linking OsLSD3 to Plant Height.

LSD1-like zinc-finger proteins participate in programmed cell death, redox homeostasis, and stress responses in plants, but their functional diversification and contributions to agronomic variation in rice remain poorly defined. This study aimed to characterize the rice LSD1-like gene family and evaluate the potential agronomic roles of selected members, with particular emphasis on OsLSD3. Genome-wide analyses were integrated with OsLSD3 natural variation and haplotype analyses in 4666 rice accessions, CRISPR/Cas9 mutant phenotyping in the ZH11 background, and subcellular localization assays. Seven LSD1-like genes were identified and showed substantial divergence in protein architecture, gene organization, promoter cis-element profiles, and tissue- and stress-responsive expression. OsLSD3 formed six population-structured haplotypes, and two common Japonica haplotypes differed significantly in plant height. Consistently, two independent oslsd3 mutant lines were taller than the wild type, whereas additional changes in grain-related traits were line-specific. OsLSD2 and OsLSD3 localized mainly to the nucleus, while OsLSD4 was predominantly nuclear with weak cytoplasmic localization. These results identify OsLSD3 as the strongest candidate among the examined members for further investigation of plant height- and grain-related traits, while OsLSD2 and OsLSD4 represent additional candidates for grain-trait regulation. Further validation using additional alleles and environments is required.

LSD1-like↗

PubMed2006

Evidence of gene conversion associated with a selective sweep in Drosophila melanogaster.

Since Drosophila melanogaster colonized Europe from tropical Africa 10 to 15 thousand years ago, it is expected that adaptation has played a major role in this species in recent times. A previously conducted multilocus scan of noncoding DNA sequences on the X chromosome in an ancestral and a derived population of D. melanogaster revealed that some loci have been affected by directional selection in the European population. We investigated if the pattern of DNA sequence polymorphism in a region surrounding one of these loci can be explained by a hitchhiking event. We found strong evidence that the studied region around the gene unc-119 was shaped by a recent selective sweep, including a valley of reduced heterozygosity of 83.4 kb, a skew in the frequency spectrum, and significant linkage disequilibrium on one side of the valley. This region, however, was interrupted by gene conversion events leading to a strong haplotype structure in the center of the valley of reduced variation.

Africa↗

PubMed2005

Investigation of malaria susceptibility determinants in the IFNG/IL26/IL22 genomic region.

Interferon-gamma, encoded by IFNG, is a key immunological mediator that is believed to play both a protective and a pathological role in malaria. Here, we investigate the relationship between IFNG variation and susceptibility to malaria. We began by analysing West African and European haplotype structure and patterns of linkage disequilibrium across a 100 kb genomic region encompassing IFNG and its immediate neighbours IL22 and IL26. A large case-control study of severe malaria in a West Africa population identified several weak associations with individual single-nucleotide polymorphisms in the IFNG and IL22 genes, and defined two IL22 haplotypes that are, respectively, associated with resistance and susceptibility. These data provide a starting point for functional and genetic analysis of the IFNG genomic region in malaria and other infectious and inflammatory conditions affecting African populations.

Black People↗

PubMed2004

Signatures of selection and gene conversion associated with human color vision variation.

Trichromatic color vision in humans results from the combination of red, green, and blue photopigment opsins. Although color vision genes have been the targets of active molecular and psychophysical research on color vision abnormalities, little is known about patterns of normal genetic variation in these genes among global human populations. The current study presents nucleotide sequence analyses and tests of neutrality for a 5.5-kb region of the X-linked long-wave "red" opsin gene (OPN1LW) in 236 individuals from ethnically diverse human populations. Our analysis of the recombination landscape across OPN1LW reveals an unusual haplotype structure associated with amino acid replacement variation in exon 3 that is consistent with gene conversion. Compared with the absence of OPN1LW amino acid replacement fixation since divergence from chimpanzee, the human population exhibits a significant excess of high-frequency OPN1LW replacements. Our results suggest that subtle changes in L-cone opsin wavelength absorption may have been adaptive during human evolution.

Africa↗

PubMed2004

Sequencing complex diseases With HapMap.

Determining the patterns of DNA sequence variation in the human genome is a useful first step toward identifying the genetic basis of a common disease. A haplotype map (HapMap), aimed at describing these variation patterns across the entire genome, has been recently developed by the International HapMap Consortium. In this article, we present a novel statistical model for directly characterizing specific sequence variants that are responsible for disease risk based on the haplotype structure provided by HapMap. Our model is developed in the maximum-likelihood context, implemented with the EM algorithm. We perform simulation studies to investigate the statistical properties of this disease-sequencing model. A worked example from a human obesity study with 155 patients was used to validate this model. In this example, we found that patients carrying a haplotype constituted by allele Gly16 at codon 16 and allele Gln27 at codon 27 genotyped within the beta2AR candidate gene display significantly lower body mass index than patients carrying the other haplotypes. The implications and extensions of our model are discussed.

Body Mass Index↗

PubMed2001

Sequence haplotypes revealed by sequence-tagged site fine mapping of the Ror1 gene in the centromeric region of barley chromosome 1H.

We describe the development of polymerase chain reaction-based, sequence-tagged site (STS) markers for fine mapping of the barley (Hordeum vulgare) Ror1 gene required for broad-spectrum resistance to powdery mildew (Blumeria graminis f. sp. hordei). After locating Ror1 to the centromeric region of barley chromosome 1H using a combined amplified fragment length polymorphism/restriction fragment-length polymorphism (RFLP) approach, sequences of RFLP probes from this chromosome region of barley and corresponding genome regions from the related grass species oat (Avena spp.), wheat, and Triticum monococcum were used to develop STS markers. Primers based on the RFLP probe sequences were used to polymerase chain reaction-amplify and directly sequence homologous DNA stretches from each of four parents that were used for mapping. Over 28,000 bp from 22 markers were compared. In addition to one insertion/deletion of at least 2.0 kb, 79 small unique sequence polymorphisms were observed, including 65 single nucleotide substitutions, two dinucleotide substitutions, 11 insertion/deletions, and one 5-bp/10-bp exchange. The frequency of polymorphism between any two barley lines ranged from 0.9 to 3.0 kb, and was greatest for comparisons involving an Ethiopian landrace. Haplotype structure was observed in the marker sequences over distances of several hundred basepairs. Polymorphisms in 16 STSs were used to generate genetic markers, scored by restriction enzyme digestion or by direct sequencing. Over 2,300 segregants from three populations were used in Ror1 linkage analysis, mapping Ror1 to a 0.2- to 0.5-cM marker interval. We discuss the implications of sequence haplotypes and STS markers for the generation of high-density maps in cereals.

Base Sequence↗

PubMed2006

Haplotype analysis of UDP-glucuronocyltransferase 2B7 gene (UGT2B7) polymorphisms in healthy Japanese subjects.

OBJECTIVES: UDP-glucuronocyltransferase 2B7 (UGT2B7) catalyzes glucuronidation of various types of endogenous compounds and drugs, but the genetic basis of interindividual variation in the metabolism of these substances has not yet been sufficiently elucidated. In addition, information about single nucleotide polymorphisms (SNPs) and haplotypes of the UGT2B7 gene that encode the enzyme in the Japanese population is still far from sufficient. DESIGN AND METHODS: We paid special attention to and performed an investigation on -327A > G, -161T > C, -138G > A, and -125T > C in the proximal promoter region, which is regarded as being important for the transcription of the UGT2B7 gene, and also on 211G > A and 802C > T, i.e., non-synonymous SNPs of exon 1 and exon 2 that encode the substrate binding domain. Their genotypes were determined by PCR-direct sequencing. RESULTS: As a result of genotyping, the minor allele frequencies in 160 Japanese individuals were found to be as follows: -327SNP A allele, 0.244; -161SNP T allele, 0.244; -138SNP A allele, 0; -125SNP C allele, 0.078; 211SNP T allele, 0.148 and 802SNP T allele, 0.244. By computational haplotype analysis, it was found that these regions formed a linkage disequilibrium block, and the presence of five haplotypes was demonstrated. CONCLUSIONS: These results suggest that the haplotype structure in the Japanese population is different from that of other ethnic groups.

Asian People↗

PubMed2006

Association between patterns of nucleotide variation across the three fibrinogen genes and plasma fibrinogen levels: the Coronary Artery Risk Development in Young Adults (CARDIA) study.

BACKGROUND: Previous genotype-phenotype association studies of fibrinogen have been limited by incomplete knowledge of genomic sequence variation within and between major ethnic groups in FGB, FGA, and FGG. METHODS: We characterized the linkage disequilibrium patterns and haplotype structure across the human fibrinogen gene locus in European- and African-American populations. We analyzed the association between common polymorphisms in the fibrinogen genes and circulating levels of both 'functional' fibrinogen (measured by the Clauss clotting rate method) and total fibrinogen (measured by immunonephelometry) in a large, multi-center, bi-racial cohort of young US adults. RESULTS: A common haplotype tagged by the A minor allele of the well-studied FGB-455 G/A promoter polymorphism (FGB 1437) was confirmed to be strongly associated with increased plasma fibrinogen levels. Two non-coding variants specific to African-American chromosomes, FGA 3845 A and FGG 5729 G, were each associated with lower plasma fibrinogen levels. In European-Americans, a common haplotype tagged by FGA Thr312Ala and several other variant alleles across the fibrinogen gene locus was strongly associated with decreased fibrinogen levels as measured by functional assay, but not by immunoassay. Overall, common polymorphisms within the three fibrinogen genes explain < 2% of the variability in plasma fibrinogen concentration. CONCLUSIONS: In young adults, fibrinogen multi-locus genotypes are associated with plasma fibrinogen levels. The specific single nucleotide polymorphism and haplotype patterns for these associations differ according to population and also according to phenotypic assay. It is likely that a substantial proportion of the heritable component of plasma fibrinogen concentration is due to genetic variation outside the three fibrinogen genes.

Adolescent↗

PubMed2006

Linkage disequilibrium across six prion gene regions spanning 20 kbp in U.S. sheep.

Single nucleotide polymorphisms (SNPs) and haplotype alleles within the prion gene (PRNP) coding sequence of domestic sheep (Ovis aries) are associated with genetic predisposition to scrapie, a transmissible spongiform encephalopathy disease of sheep. This report describes regions of linkage disequilibrium (LD) throughout the PRNP gene region in U.S. sheep and provides a genetic framework for identifying additional PRNP determinants associated with scrapie resistance. Four sequence tagged sites (i.e., STS or amplicons) totaling 3869 bp and spanning 20 kbp of genomic PRNP sequence were sequenced in a diverse panel of 90 sires representing ten popular U.S. breeds of sheep. Analysis of these sequences identified 36 previously unreported polymorphisms. In combination with two previously characterized STS, 62 polymorphisms were analyzed in a 20-kbp PRNP region in this panel of U.S. sheep. Two regions of strong LD and ten common haplotypes were identified. The haplotype encoding amino acid residues A, R, and Q at codons 136, 154, and 171, respectively, was observed on nine larger haplotypes spanning PRNP from the promoter region to the 3' untranslated region. The haplotype encoding VRQ was observed on two larger haplotypes, whereas ARR, ARH, and AHQ were each present on a single haplotype. The existence of multiple haplotypes encoding ARQ raises the question of whether sheep bearing these different haplotypes are equally susceptible to scrapie. The haplotype structure within the 20-kbp region of PRNP identified in this study is important for higher-resolution analysis of genetics contributions to scrapie susceptibility.

Animals↗

PubMed2005

Genetic linkage and association of the growth hormone secretagogue receptor (ghrelin receptor) gene in human obesity.

The growth hormone secretagogue receptor (GHSR) (ghrelin receptor) plays an important role in the regulation of food intake and energy homeostasis. The GHSR gene lies on human chromosome 3q26 within a quantitative trait locus strongly linked to multiple phenotypes related to obesity and the metabolic syndrome. Because the biological function and location of the GHSR gene make it an excellent candidate gene, we tested the relation between common single nucleotide polymorphisms (SNPs) in the GHSR gene and human obesity. We performed a comprehensive analysis of SNPs, linkage disequilibrium (LD), and haplotype structure across the entire GHSR gene region (99.3 kb) in 178 pedigrees with multiple obese members (DNA of 1,095 Caucasians) and in an independent sample of the general population (MONICA Augsburg left ventricular hypertrophy substudy; DNA of 1,418 Caucasians). The LD analysis revealed a disequilibrium block consisting of five SNPs, consistent in both study cohorts. We found linkage among all five SNPs, their haplotypes, and BMI. Further, we found suggestive evidence for transmission disequilibrium for the minor SNP alleles (P < 0.05) and the two most common haplotypes with the obesity affection status ("susceptible" P = 0.025, "nonsusceptible" P = 0.045) in the family cohort using the family-based association test program. Replication of these findings in the general population resulted in stronger evidence for an association of the SNPs (best P = 0.00001) and haplotypes with the disease ("susceptible" P = 0.002, "nonsusceptible" P = 0.002). To our knowledge, these data are the first to demonstrate linkage and association of SNPs and haplotypes within the GHSR gene region and human obesity. This linkage, together with significant transmission disequilibrium in families and replication of this association in an independent population, provides evidence that common SNPs and haplotypes within the GHSR region are involved in the pathogenesis of human obesity.

Body Mass Index↗

PubMed2002

The extent of linkage disequilibrium in Arabidopsis thaliana.

Linkage disequilibrium (LD), the nonrandom occurrence of alleles in haplotypes, has long been of interest to population geneticists. Recently, the rapidly increasing availability of genomic polymorphism data has fueled interest in LD as a tool for fine-scale mapping, in particular for human disease loci. The chromosomal extent of LD is crucial in this context, because it determines how dense a map must be for associations to be detected and, conversely, limits how finely loci may be mapped. Arabidopsis thaliana is expected to harbor unusually extensive LD because of its high degree of selfing. Several polymorphism studies have found very strong LD within individual loci, but also evidence of some recombination. Here we investigate the pattern of LD on a genomic scale and show that in global samples, LD decays within approximately 1 cM, or 250 kb. We also show that LD in local populations may be much stronger than that of global populations, presumably as a result of founder events. The combination of a relatively high level of polymorphism and extensive haplotype structure bodes well for developing a genome-wide LD map in A. thaliana.

Arabidopsis↗

PubMed2007

Nucleotide sequence variation within the human tyrosine kinase B neurotrophin receptor gene: association with antisocial alcohol dependence.

To identify sequence variants in genes that may have roles in neuronal responses to alcohol, we resequenced the 5' region of tyrosine kinase B neurotrophin receptor gene (NTRK2) and determined linkage disequilibrium (LD) values, haplotype structure, and performed association analyses using 43 single nucleotide polymorphisms (SNPs) covering the entire NTRK2 region in a Finnish Caucasian sample of 229 alcohol-dependent subjects with antisocial personality disorder (ASPD) and 287 healthy controls. Individually, three SNPs were associated with alcohol dependence and alcohol abuse (AD) (P-value from 0.0019 to 0.0059, significance level was set at P<or=0.01 corrected for multiple testing), whereas a common 18 locus haplotype within the largest LD block of NTRK2, a 119-kb region containing the 5' flanking region and exons 1-15, was marginally overrepresented in control subjects compared to AD individuals (global P=0.057). Taken together, these results support a role for the NTRK2 gene in addiction in a Caucasian population with AD and a subtype of ASPD.

5' Flanking Region↗

PubMed2005

Association analysis of the RGS4 gene in Han Chinese and Scottish populations with schizophrenia.

We investigated the RGS4 as a susceptibility gene for schizophrenia in Chinese Han (184 trios and 138 sibling pairs, a total of 322 families) and Scottish (580 cases and 620 controls) populations using both a family trio and case-control design. Both the samples had statistical power greater than 70% to detect a heterozygote genotype relative risk of >1.2 for frequent RGS4-risk alleles. We genotyped four single nucleotide polymorphisms (SNPs) which have previously been associated with schizophrenia as either individually or part of haplotypes. Allele frequencies and linkage disequilibrium between the SNPs was similar in the two populations. In the Chinese sample, no individual SNPs or any of their haplotypes were associated with schizophrenia. In the Scottish population, one SNP (SNP7) was significantly over-represented in the cases compared with the controls (0.44 vs. 0.38; A allele; chi(2) 7.08, P = 0.011 after correction for correlation between markers by permutation testing). One two-marker haplotype, composed of alleles T and A of SNP4 and SNP7, respectively, showed individual significance after correction by permutation testing (chi(2) 6.8; P = 0.04). None of the full four-marker haplotypes showed association, including the G-G-G-G haplotype previously associated with schizophrenia in more than one sample and the A-T-A-A haplotype. Thus, our data do not directly replicate previous associations of RGS4, but association with SNP 7 in the Scottish population provides some support for a role in schizophrenia susceptibility. We cannot conclusively exclude RGS4, as associated haplotypes are likely to be surrogates for unknown causative alleles, whose relationship with overlying haplotypes may differ between the population groups. Differences in the association seen across the two populations could result from methodological factors such as diagnostic differences but most likely result from ethnic differences in haplotype structures within RGS4.

Case-Control Studies↗

PubMed2006

Serious carbamazepine-induced hypersensitivity reactions associated with the HSP70 gene cluster.

OBJECTIVES: The use of carbamazepine (CBZ), the most commonly prescribed antiepileptic drug, is hampered by the occurrence of severe, potentially lethal hypersensitivity reactions. The pathogenesis of hypersensitivity is not yet known, but immune mechanisms are involved. Predisposition to CBZ hypersensitivity is likely to be genetically determined, and genes within the major histocompatibility complex (MHC) have been implicated. The heat shock protein (HSP70) gene cluster is located in the MHC class III region. METHODS: Using a case-control study design, we compared 61 patients with CBZ hypersensitivity (22 with a severe reaction) to 44 patients on CBZ with no signs of hypersensitivity and 172 healthy controls. The genotyping strategy involved identification of common and rare single nucleotide polymorphisms (SNPs) within the HSP70 gene cluster by sequencing, estimation of linkage disequilibrium (LD) and haplotype structure, and thereafter, analysis of SNP/haplotype frequencies in the cases and controls. Population substructure was evaluated by genotyping of 34 microsatellites. RESULTS: Twenty-five SNPs were detected across the three HSP70 genes. Analyses revealed that alleles G, T and C at the SNPs HSPA1A +1911 C/G, HSPA1A +438 C/T and HSPA1L +2437 T/C, respectively, were associated with protection from serious hypersensitivity reactions to CBZ, with the associated alleles falling on a common haplotype. We were unable to detect the presence of population stratification in our patients and controls. CONCLUSIONS: Our data show that HSP70 gene variants are associated with serious CBZ hypersensitivity reactions, but whether this is causal or reflects LD with another gene within the MHC requires further study.

Adolescent↗

PubMed2004

Hierarchical scaffolding with Bambus.

The output of a genome assembler generally comprises a collection of contiguous DNA sequences (contigs) whose relative placement along the genome is not defined. A procedure called scaffolding is commonly used to order and orient these contigs using paired read information. This ordering of contigs is an essential step when finishing and analyzing the data from a whole-genome shotgun project. Most recent assemblers include a scaffolding module; however, users have little control over the scaffolding algorithm or the information produced. We thus developed a general-purpose scaffolder, called Bambus, which affords users significant flexibility in controlling the scaffolding parameters. Bambus was used recently to scaffold the low-coverage draft dog genome data. Most significantly, Bambus enables the use of linking data other than that inferred from mate-pair information. For example, the sequence of a completed genome can be used to guide the scaffolding of a related organism. We present several applications of Bambus: support for finishing, comparative genomics, analysis of the haplotype structure of genomes, and scaffolding of a mammalian genome at low coverage. Bambus is available as an open-source package from our Web site.

Algorithms↗

PubMed2005

Y chromosome evidence for a founder effect in Ashkenazi Jews.

Recent genetic studies, based on Y chromosome polymorphic markers, showed that Ashkenazi Jews are more closely related to other Jewish and Middle Eastern groups than to their host populations in Europe. However, Ashkenazim have an elevated frequency of R-M17, the dominant Y chromosome haplogroup in Eastern Europeans, suggesting possible gene flow. In the present study of 495 Y chromosomes of Ashkenazim, 57 (11.5%) were found to belong to R-M17. Detailed analyses of haplotype structure, diversity and geographic distribution suggest a founder effect for this haplogroup, introduced at an early stage into the evolving Ashkenazi community in Europe. R-M17 chromosomes in Ashkenazim may represent vestiges of the mysterious Khazars.

Chromosomes, Human, Y↗

PubMed2006

A bivariate functional mapping model for identifying haplotypes that control drug response for systolic and diastolic blood pressures.

A bivariate functional mapping model has been proposed to detect haplotype-based DNA sequence variants that regulate the response curves of systolic and diastolic blood pressures (SBP and DBP) to a particular drug. This model capitalizes on the haplotype structure constructed by single nucleotide polymorphisms (SNPs) and incorporates the mathematical aspects of pharmacodynamic reactions into the estimation process, aimed to identify DNA sequence variants responsible for drug response. In this way, by estimating and testing the curve parameters that define drug response, many genetically and clinically meaningful hypotheses regarding the degree and pattern of the genetic control of SBP and DBP can be formulated, tested and disseminated. In a pharmacogenetic study composed of 107 subjects, our bivariate model has probed two haplotypes within the beta 2AR candidate gene that exert a significant effect on both SBP and DBP respond to dobutamine. With this candidate gene, two SNPs are genotyped, with allele Gly16 (G) and Arg16 (A) at codon 16 and alleles Glu27 (G) and Gln27 (C) at codon 27, respectively. The significant haplotypes are [AC] for SBP and [GG] for DBP. This model provides a powerful tool for elucidating the genetic variants of drug response and ultimately designing personalized medications based on each patient's genetic makeup.

Algorithms↗