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Haplotype Structure (haplotype + structure)
Selected AbstractsStudy of Regions of Extended Homozygosity Provides a Powerful Method to Explore Haplotype Structure of Human PopulationsANNALS OF HUMAN GENETICS, Issue 2 2008D. Curtis Summary Previous investigations have reported linkage disequilibrium occurring between nearby polymorphisms, a block-like structure for such relationships, some instances where surprisingly few haplotypes are found and regions of extended homozygosity which are especially marked around centromeres and which are especially common on the X chromosome. We investigated the distribution and nature of regions of extended homozygosity in a sample of 1411 subjects included in a genome wide association study. Regions of extended homozygosity over 1Mb are common, with an average of 35.9 occurring per subject, and containing on average 73 homozygous markers. They have a markedly non-random distribution. They are relatively common on the X chromosome and are seen at centromeres but are also concentrated at other chromosomal regions where presumably recombination is rare. They seem to be a consequence of some haplotypes being very common in the population and although sometimes this reflects the effect of a very common haplotype we also note that there are examples of two or three common haplotypes, each very different from each other, underlying this effect. Regions of extended homozygosity are commoner than previously appreciated. They result from the presence of extended haplotypes with high population frequency. Such regions concentrate in particular locations. The haplotypes involved are sometimes markedly disparate from each other. These regions offer a valuable opportunity for further investigation, in particular with regard to their ancestral history. [source] Mutation and evolutionary analyses identify NR2E1- candidate-regulatory mutations in humans with severe cortical malformationsGENES, BRAIN AND BEHAVIOR, Issue 6 2007R. A. Kumar Nuclear receptor 2E1 (NR2E1) is expressed in human fetal and adult brains; however, its role in human brain,behavior development is unknown. Previously, we have corrected the cortical hypoplasia and behavioral abnormalities in Nr2e1,/, mice using a genomic clone spanning human NR2E1, which bolsters the hypothesis that NR2E1 may similarly play a role in human cortical and behavioral development. To test the hypothesis that humans with abnormal brain,behavior development may have null or hypomorphic NR2E1 mutations, we undertook the first candidate mutation screen of NR2E1 by sequencing its entire coding region, untranslated, splice site, proximal promoter and evolutionarily conserved non-coding regions in 56 unrelated patients with cortical disorders, namely microcephaly. We then genotyped the candidate mutations in 325 unrelated control subjects and 15 relatives. We did not detect any coding region changes in NR2E1; however, we identified seven novel candidate regulatory mutations that were absent from control subjects. We used in silico tools to predict the effects of these candidate mutations on neural transcription factor binding sites (TFBS). Four candidate mutations were predicted to alter TFBS. To facilitate the present and future studies of NR2E1, we also elucidated its molecular evolution, genetic diversity, haplotype structure and linkage disequilibrium by sequencing an additional 94 unaffected humans representing Africa, the Americas, Asia, Europe, the Middle East and Oceania, as well as great apes and monkeys. We detected strong purifying selection, low genetic diversity, 21 novel polymorphisms and five common haplotypes at NR2E1. We conclude that protein-coding changes in NR2E1 do not contribute to cortical and behavioral abnormalities in the patients examined here, but that regulatory mutations may play a role. [source] BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitisHEPATOLOGY, Issue 3 2004Christiane Pauli-Magnus Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are characterized by a cholestatic pattern of liver damage, also observed in hereditary or acquired dysfunction of the canalicular membrane transporters bile salt export pump (BSEP, ABCB11) and multidrug resistance protein type 3 (MDR3, ABCB4). Controversy exists whether a genetically determined dysfunction of BSEP and MDR3 plays a pathogenic role in PBC and PSC. Therefore, 149 healthy Caucasian control individuals (control group) were compared to 76 PBC and 46 PSC patients with respect to genetic variations in BSEP and MDR3. Sequencing spanned ,10,000 bp including promoter and coding regions as well as 50,350 bp of flanking intronic regions. In all, 46 and 45 variants were identified in BSEP and MDR3, respectively. No differences between the groups were detected either in the total number of variants (BSEP: control group: 37, PBC: 37, PSC: 31; and MDR3: control group: 35; PBC: 32, PSC: 30), or in the allele frequency of the common variable sites. Furthermore, there were no significant differences in haplotype distribution and linkage disequilibrium. In conclusion, this study provides an analysis of BSEP and MDR3 variant segregation and haplotype structure in a Caucasian population. Although an impact of rare variants on BSEP and MDR3 function cannot be ruled out, our data do not support a strong role of BSEP and MDR3 genetic variations in the pathogenesis of PBC and PSC. (HEPATOLOGY 2004;39:779,791.) [source] Comparison of genetic polymorphisms of the NAT2 gene between Korean and four other ethnic groupsJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 6 2009T. S. Kang MS Summary Background and objective:,N -acetyltransferase 2 (NAT2) is responsible for the acetylation of numerous drugs and in the transformation of aromatic and heterocyclinc amines into carcinogenic intermediates. Polymorphism of NAT2 may contribute to interindividual variability in such acetylation. The aim of this study was to determine the allele frequencies of polymorphisms of the NAT2 gene, analyse linkage disequilibrium (LD) block and haplotypes in Koreans and compare them with those of other ethnic groups. Methods:, We analysed genetic polymorphisms in all functional promoter and exons of the NAT2 gene by direct sequencing of genomic DNA from 192 healthy Korean subjects. The LD and haplotype blocks of these subjects were constructed from genotype data using an expectation,maximization algorithm. We compared these allele frequencies, LD block and haplotype structure with those of other ethnic groups registered on the International HapMap database. Results and discussion:, We identified 33 polymorphisms including six novel single nucleotide polymorphisms, ,10778T>C, ,10777A>G, ,10351A>G, ,10199C>T and ,10104G>T in promoter and 578C>T in exon2 (T193M) in the Korean subjects tested. All allele frequencies reported in the Koreans were similar to those of Asians except for one allele (rs4345600, ,9306A>G), whereas African and European groups had different frequencies in exon2. The haplotype structure and LD block among the five groups also revealed significant differences. Conclusion:, Ethnic differences in the NAT2 genotype frequencies may be one of the important factors explaining variability in cancer incidence and drug toxicity. Our observations could be useful in assessing the susceptibility of different populations to cancer and contribute to better predictions of the pharmacokinetics and pharmacodynamics of drugs that are metabolized by NAT2, in different populations. [source] High population differentiation and unusual haplotype structure in a shade-intolerant pioneer tree species, Zanthoxylum ailanthoides (Rutaceae) revealed by analysis of DNA polymorphism at four nuclear lociMOLECULAR ECOLOGY, Issue 10 2008K. KAMIYA Abstract Differences in demographic history, life-history traits, and breeding systems affect nucleotide variation patterns. It is expected that shade-intolerant pioneer tree species have different patterns of genetic polymorphism and population structure than climax species. We studied patterns of nucleotide polymorphism at four putative starch pathway loci (agpSA, agpSB, agpL, and GBSSI) in Zanthoxylum ailanthoides, a shade-intolerant pioneer tree species that occupies forest gaps in warm-temperate forests of East Asia. Genetic diversity was lower within each population than among populations, and differentiation among populations was high across the loci (FST = 0.32,0.64), as expected from the insect-pollinated breeding system and the metapopulation structure of this pioneer species. Numbers of haplotypes were smaller than those expected from the observed numbers of segregating sites. Single haplotypes accounted for more than 47% of all the sampled genes at the respective loci. These variation patterns were incompatible with neutral predictions for populations of a finite island model. Complex population dynamics, such as bottleneck and/or admixture, in the history of this pioneer tree species might have resulted in the observed patterns of genetic variation and population structure, which are different from those of climax wind-pollinated tree species, such as conifers. In contrast to the other loci investigated in this study, agpL showed nearly no variation in Z. ailanthoides (one singleton only), but there was some extent of variation in a closely related species, Zanthoxylum schinifolium. This suggests possibly a recent selective sweep at or near the locus in Z. ailanthoides. [source] Sequence diversity and haplotype associations with phenotypic responses to crowding: GIGANTEA affects fruit set in Arabidopsis thalianaMOLECULAR ECOLOGY, Issue 14 2007MARCUS T. BROCK Abstract Identifying the molecular genetic basis of intraspecific variation in quantitative traits promises to provide novel insight into their evolutionary history as well as genetic mechanisms of adaptation. In an attempt to identify genes responsible for natural variation in competitive responses in Arabidopsis thaliana, we examined DNA sequence diversity at seven loci previously identified as members of the phytochrome B signalling network. For one gene, GIGANTEA (GI), we detected significant haplotype structure. To test for GI haplogroup,phenotype associations, we genotyped 161 A. thaliana accessions at GI and censused the same accessions for total fruit set and the expression of three phenotypic traits (days to flowering, petiole length, and inflorescence height) in a greenhouse experiment where plants were grown in crowded and uncrowded environments. We detected a significant association between GI and total fruit set that resulted in a 14% difference in average fruit set among GI haplogroups. Given that fruit set is an important component of fitness in this species and given the magnitude of the effect, the question arises as to how variation at this locus is maintained. Our observation of frequent and significant epistasis between GI and background single nucleotide polymorphisms (SNP), where the fitness ranking of the GI allele either reverses or does not differ depending on the allele at the interacting SNP, suggests that epistatic selection may actively maintain or at least slow the loss of variation at GI. This result is particularly noteworthy in the light of the ongoing debate regarding the genetic underpinnings of phenotypic evolution and recent observations that epistasis for phenotypic traits and components of fitness is common in A. thaliana. [source] The pattern of linkage disequilibrium in German Holstein cattleANIMAL GENETICS, Issue 4 2010S. Qanbari Summary This study presents a second generation of linkage disequilibrium (LD) map statistics for the whole genome of the Holstein,Friesian population, which has a four times higher resolution compared with that of the maps available so far. We used DNA samples of 810 German Holstein,Friesian cattle genotyped by the Illumina Bovine SNP50K BeadChip to analyse LD structure. A panel of 40 854 (75.6%) markers was included in the final analysis. The pairwise r2 statistic of SNPs up to 5 Mb apart across the genome was estimated. A mean value of r2 = 0.30 ± 0.32 was observed in pairwise distances of <25 kb and it dropped to 0.20 ± 0.24 at 50,75 kb, which is nearly the average inter-marker space in this study. The proportion of SNPs in useful LD (r2 , 0.25) was 26% for the distance of 50 and 75 kb between SNPs. We found a lower level of LD for SNP pairs at the distance ,100 kb than previously thought. Analysis revealed 712 haplo-blocks spanning 4.7% of the genome and containing 8.0% of all SNPs. Mean and median block length were estimated as 164 ± 117 kb and 144 kb respectively. Allele frequencies of the SNPs have a considerable and systematic impact on the estimate of r2. It is shown that minimizing the allele frequency difference between SNPs reduces the influence of frequency on r2 estimates. Analysis of past effective population size based on the direct estimates of recombination rates from SNP data showed a decline in effective population size to Ne = 103 up to ,4 generations ago. Systematic effects of marker density and effective population size on observed LD and haplotype structure are discussed. [source] Nucleotide variability and linkage disequilibrium patterns at the porcine FABP5 geneANIMAL GENETICS, Issue 5 2008A. Ojeda Summary Fatty acid binding protein 5 (FABP5) is a major positional and physiological candidate gene for the porcine FAT1 QTL on SSC4. Here we characterize the nucleotide polymorphism and haplotype variability of FABP5 and we compare it with that of FABP4, given their close physical location and similar metabolic roles. DNA resequencing of the FABP5 gene region in 29 pigs from 14 breeds and in European and Japanese wild boars revealed 36 polymorphisms in 5.2 kb, and a nucleotide diversity of 0.19%, comparable to values reported in other domestic species but sixfold lower than that previously found for FABP4. Remarkably, both the nucleotide variability and the haplotype structure of FABP5 and FABP4 were dramatically different, and the Hudson,Kreitman,Aguadé test was highly significant. Nevertheless, both genes also had similarities. The neighbour-joining trees of their haplotypes did not show a geographical arrangement for any of the genes. Besides, both genes presented a similar extent and pattern of linkage disequilibrium. Haplotype blocks did not extend for large stretches (,1 kb in both genes), and the number of tag SNPs required to capture all variability was higher than previously expected. Our findings indicate that FABP4 and FABP5 have undergone different selective or evolutive processes. The fact that haplotype blocks were so small may require us to increase the number of SNPs in prospective whole-genome association studies in the pig. [source] SNP Discovery and Haplotype Analysis in the Segmentally Duplicated DRD5 Coding RegionANNALS OF HUMAN GENETICS, Issue 3 2009Donna J. E. Housley Summary The dopamine receptor 5 gene (DRD5) holds much promise as a candidate locus for contributing to neuropsychiatric disorders and other diseases influenced by the dopaminergic system, as well as having potential to affect normal behavioral variation. However, detailed analyses of this gene have been complicated by its location within a segmentally duplicated chromosomal region. Microsatellites and SNPs upstream from the coding region have been used for association studies, but we find, using bioinformatics resources, that these markers all lie within a previously unrecognized second segmental duplication (SD). In order to accurately analyze the DRD5 locus for polymorphisms in the absence of contaminating pseudogene sequences, we developed a fast and reliable method for sequence analysis and genotyping within the DRD5 coding region. We employed restriction enzyme digestion of genomic DNA to eliminate the pseudogenes prior to PCR amplification of the functional gene. This approach allowed us to determine the DRD5 haplotype structure using 31 trios and to reveal additional rare variants in 171 unrelated individuals. We clarify the inconsistencies and errors of the recorded SNPs in dbSNP and HapMap and illustrate the importance of using caution when choosing SNPs in regions of suspected duplications. The simple and relatively inexpensive method presented herein allows for convenient analysis of sequence variation in DRD5 and can be easily adapted to other duplicated genomic regions in order to obtain good quality sequence data. [source] Resampling-based multiple hypothesis testing procedures for genetic case-control association studies,GENETIC EPIDEMIOLOGY, Issue 6 2006Bingshu E. Chen Abstract In case-control studies of unrelated subjects, gene-based hypothesis tests consider whether any tested feature in a candidate gene,single nucleotide polymorphisms (SNPs), haplotypes, or both,are associated with disease. Standard statistical tests are available that control the false-positive rate at the nominal level over all polymorphisms considered. However, more powerful tests can be constructed that use permutation resampling to account for correlations between polymorphisms and test statistics. A key question is whether the gain in power is large enough to justify the computational burden. We compared the computationally simple Simes Global Test to the min,P test, which considers the permutation distribution of the minimum p -value from marginal tests of each SNP. In simulation studies incorporating empirical haplotype structures in 15 genes, the min,P test controlled the type I error, and was modestly more powerful than the Simes test, by 2.1 percentage points on average. When disease susceptibility was conferred by a haplotype, the min,P test sometimes, but not always, under-performed haplotype analysis. A resampling-based omnibus test combining the min,P and haplotype frequency test controlled the type I error, and closely tracked the more powerful of the two component tests. This test achieved consistent gains in power (5.7 percentage points on average), compared to a simple Bonferroni test of Simes and haplotype analysis. Using data from the Shanghai Biliary Tract Cancer Study, the advantages of the newly proposed omnibus test were apparent in a population-based study of bile duct cancer and polymorphisms in the prostaglandin-endoperoxide synthase 2 (PTGS2) gene. Genet. Epidemiol. 2006. Published 2006 Wiley-Liss, Inc. [source] Characterization of a QTL region affecting clinical mastitis and protein yield on BTA6ANIMAL GENETICS, Issue 5 2009H. Nilsen Summary Quantitative trait loci affecting clinical mastitis were detected and fine mapped to a narrow region on bovine chromosome 6 in the Norwegian Red cattle population. The region includes the casein gene cluster and several candidate genes thought to influence clinical mastitis. The most significant results were found for SNPs within the Mucin 7 gene. This gene encodes an antimicrobial peptide and constitutes part of the first line of defence for the mucosal immune system. Detection of long haplotypes extending several Mb may indicate that artificial selection has influenced the haplotype structures in the region. A search for selection sweeps supports this observation and coincides with association results found both by single SNP and haplotype analyses. Our analyses identified haplotypes carrying quantitative trait loci alleles associated with high protein yield and simultaneously fewer incidences of clinical mastitis. The fact that such haplotypes are found in relative high frequencies in Norwegian Red may reflect the combined breeding goal that is characterized by selection for both milk production and disease resistance. The identification of these haplotypes raises the possibility of overcoming the unfavourable genetic correlation between these traits through haplotype-assisted selection. [source] | |||||||||||||