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Rare Haplotypes (rare + haplotype)
Selected AbstractsFunctional analysis of promoter variants in the microsomal triglyceride transfer protein (MTTP) gene,HUMAN MUTATION, Issue 1 2008Diana Rubin Abstract The microsomal triglyceride transfer protein (MTTP) is required for the assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins from the intestine and liver. According to this function, polymorphic sites in the MTTP gene showed associations to low-density lipoprotein (LDL) cholesterol and related traits of the metabolic syndrome. Here we studied the functional impact of common MTTP promoter polymorphisms rs1800804:T>C (,164T>C), rs1800803:A>T (,400A>T), and rs1800591:G>T (,493G>T) using gene-reporter assays in intestinal Caco-2 and liver Huh-7 cells. Significant results were obtained in Huh-7 cells. The common MTTP promoter haplotype ,164T/,400A/,493G showed about two-fold lower activity than the rare haplotype ,164C/,400T/,493T. MTTP promoter mutant constructs ,164T/,400A/,493T and ,164T/,400T/,493T exhibited similar activity than the common haplotype. Activities of mutants ,164C/,400A/,493G and ,164C/,400A/,493T resembled the rare MTTP promoter haplotype. Electrophoretic mobility shift assays (EMSAs) revealed higher binding capacity of the transcriptional factor Sterol regulatory element binding protein1a (SREBP1a) to the ,164T probe in comparison to the ,164C probe. In conclusion, our study indicates that the polymorphism ,164T>C mediates different activities of common MTTP promoter haplotypes via SREBP1a. This suggested that the already described SREBP-dependent modulation of MTTP expression by diet is more effective in ,164T than in ,164C carriers. Hum Mutat 29(1), 123,129, 2008. © 2007 Wiley-Liss, Inc. [source] D90A- SOD1 mediated amyotrophic lateral sclerosis: A single founder for all cases with evidence for a Cis -acting disease modifier in the recessive haplotype,,HUMAN MUTATION, Issue 6 2002Matthew J. Parton Abstract More than 100 different heterozygous mutations in copper/zinc superoxide dismutase (SOD1) have been found in patients with amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. Uniquely, D90A- SOD1 has been identified in recessive, dominant and apparently sporadic pedigrees. The phenotype of homozygotes is stereotyped with an extended survival, whereas that of affected heterozygotes varies. The frequency of D90A- SOD1 is 50 times higher in Scandinavia (2.5%) than elsewhere, though ALS prevalence is not raised there. Our earlier study indicated separate founders for recessive and dominant/sporadic ALS and we proposed a disease-modifying factor linked to the recessive mutation. Here we have doubled our sample set and employed novel markers to characterise the mutation's origin and localise any modifying factor. Linkage disequilibrium analysis indicates that D90A homozygotes and heterozygotes share a rare haplotype and are all descended from a single ancient founder (alpha 0.974) c.895 generations ago. Homozygotes arose subsequently only c.63 generations ago (alpha 0.878). Recombination has reduced the region shared by recessive kindreds to 97-265 kb around SOD1, excluding all neighbouring genes. We propose that a cis -acting regulatory polymorphism has arisen close to D90A- SOD1 in the recessive founder, which decreases ALS susceptibility in heterozygotes and slows disease progression. © 2002 Wiley-Liss, Inc. [source] Genome-wide association studies using haplotype clustering with a new haplotype similarityGENETIC EPIDEMIOLOGY, Issue 6 2010Lina Jin Abstract Association analysis, with the aim of investigating genetic variations, is designed to detect genetic associations with observable traits, which has played an increasing part in understanding the genetic basis of diseases. Among these methods, haplotype-based association studies are believed to possess prominent advantages, especially for the rare diseases in case-control studies. However, when modeling these haplotypes, they are subjected to statistical problems caused by rare haplotypes. Fortunately, haplotype clustering offers an appealing solution. In this research, we have developed a new befitting haplotype similarity for "affinity propagation" clustering algorithm, which can account for the rare haplotypes primely, so as to control for the issue on degrees of freedom. The new similarity can incorporate haplotype structure information, which is believed to enhance the power and provide high resolution for identifying associations between genetic variants and disease. Our simulation studies show that the proposed approach offers merits in detecting disease-marker associations in comparison with the cladistic haplotype clustering method CLADHC. We also illustrate an application of our method to cystic fibrosis, which shows quite accurate estimates during fine mapping. Genet. Epidemiol. 34: 633,641, 2010. © 2010 Wiley-Liss, Inc. [source] Quantifying bias due to allele misclassification in case-control studies of haplotypesGENETIC EPIDEMIOLOGY, Issue 7 2006Usha S. Govindarajulu Abstract Objectives Genotyping errors can induce biases in frequency estimates for haplotypes of single nucleotide polymorphisms (SNPs). Here, we considered the impact of SNP allele misclassification on haplotype odds ratio estimates from case-control studies of unrelated individuals. Methods We calculated bias analytically, using the haplotype counts expected in cases and controls under genotype misclassification. We evaluated the bias due to allele misclassification across a range of haplotype distributions using empirical haplotype frequencies within blocks of limited haplotype diversity. We also considered simple two- and three-locus haplotype distributions to understand the impact of haplotype frequency and number of SNPs on misclassification bias. Results We found that for common haplotypes (>5% frequency), realistic genotyping error rates (0.1,1% chance of miscalling an allele), and moderate relative risks (2,4), the bias was always towards the null and increases in magnitude with increasing error rate, increasing odds ratio. For common haplotypes, bias generally increased with increasing haplotype frequency, while for rare haplotypes, bias generally increased with decreasing frequency. When the chance of miscalling an allele is 0.5%, the median bias in haplotype-specific odds ratios for common haplotypes was generally small (<4% on the log odds ratio scale), but the bias for some individual haplotypes was larger (10,20%). Bias towards the null leads to a loss in power; the relative efficiency using a test statistic based upon misclassified haplotype data compared to a test based on the unobserved true haplotypes ranged from roughly 60% to 80%, and worsened with increasing haplotype frequency. Conclusions The cumulative effect of small allele-calling errors across multiple loci can induce noticeable bias and reduce power in realistic scenarios. This has implications for the design of candidate gene association studies that utilize multi-marker haplotypes. Genet. Epidemiol. 2006. © 2006 Wiley-Liss, Inc. [source] Evolutionary-based grouping of haplotypes in association analysisGENETIC EPIDEMIOLOGY, Issue 3 2005Jung-Ying Tzeng Abstract Haplotypes incorporate more information about the underlying polymorphisms than do genotypes for individual SNPs, and are considered as a more informative format of data in association analysis. To model haplotypes requires high degrees of freedom, which could decrease power and limit a model's capacity to incorporate other complex effects, such as gene-gene interactions. Even within haplotype blocks, high degrees of freedom are still a concern unless one chooses to discard rare haplotypes. To increase the efficiency and power of haplotype analysis, we adapt the evolutionary concepts of cladistic analyses and propose a grouping algorithm to cluster rare haplotypes to the corresponding ancestral haplotypes. The algorithm determines the cluster bases by preserving common haplotypes using a criterion built on the Shannon information content. Each haplotype is then assigned to its appropriate clusters probabilistically according to the cladistic relationship. Through this algorithm, we perform association analysis based on groups of haplotypes. Simulation results indicate power increases for performing tests on the haplotype clusters when compared to tests using original haplotypes or the truncated haplotype distribution. Genet. Epidemiol. © 2005 Wiley-Liss, Inc. [source] Genetic variation in the Desert Springsnail (Tryonia porrecta): implications for reproductive mode and dispersalMOLECULAR ECOLOGY, Issue 6 2005R. HERSHLER Abstract Allozymes and mitochondrial cytochrome c oxidase subunit I (mtCOI) sequences were analysed to determine whether populations of the western North American gastropod Tryonia porrecta (from California, Nevada, Utah, and northwest Mexico) are strongly differentiated in accordance with traditional interpretation of regional fauna as ancient relicts inhabiting isolated fragments of late Tertiary palaeodrainages. These data were also used to assess whether this species, for which males have not been recorded, is a rare example of a molluscan parthenogen. Both data sets strongly supported monophyly of T. porrecta populations. Five of the nine sampled populations consisted of a single monoallelic allozyme genotype while the others contained two to 10 distinct genotypes. Allozymic data for genetically diverse Utah populations provided evidence of clonal and sexual reproduction. mtCOI haplotypes of T. porrecta formed two subgroups which differed by 1.99,2.60%. The common haplotype was found in seven populations with rare haplotypes observed in single populations. Based on these results and an available mtCOI molecular clock for related hydrobiid snails, T. porrecta is interpreted as a primarily parthenogenetic species that undergoes occasional sexual reproduction and has accumulated substantial diversity following its mid-Pliocene to mid-Pleistocene origin. Our results also suggest that the distribution of present-day populations of these gill-breathing snails did not result from fragmentation of an ancient, well-integrated drainage but instead reflects overland colonization of habitats which only recently became available following desiccation of late Quaternary pluvial lakes. [source] Genetic heterogeneity in regional populations of Quebec,Parental lineages in the Gaspe PeninsulaAMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY, Issue 4 2009Claudia Moreau Abstract Stable colonization of the Gaspe Peninsula by Europeans started in the middle of the 18th century at the time of the British conquest of New France. The earliest settlers were Acadians, escaping British deportation policies, followed by Loyalists from the US, who preferred to remain under British rule after the Declaration of Independence. In the 19th century, the developing fishing industry attracted French Canadians from the St. Lawrence Valley and newcomers from Europe including Channel Islanders from Jersey and Guernsey. We analyzed parental lineages of the self-declared descendants of these four groups of settlers by mtDNA D-loop sequencing and Y-chromosome genotyping and compared them with French, British, and Irish samples. Their representation in terms of haplotype frequency classes reveals different signatures of founder effects, such as a loss of rare haplotypes, modification of intermediate frequency haplotypes, reduction in genetic diversity (seen in Acadians), but also enrichment by admixture. Parental lineages correlate with group identity. Descendants of early settlers, Acadians and Loyalists, preserved their identity more than those of French Canadian and Channel Islander "latecomers." Although overall genetic diversity among Gaspesians is comparable with their European source populations, FST analysis indicated their greater differentiation. Distinct settlement history, a limited number of founders and relative genetic isolation contributed to the regionalization of the Quebec gene pool that appears less homogenous than usually anticipated. Am J Phys Anthropol, 2009. © 2009 Wiley-Liss, Inc. [source] | ||||||||||