Ancestral Haplotype (ancestral + haplotype)

Distribution by Scientific Domains

Selected Abstracts

A recombined haplotype in the major histocompatibility region contains a cluster of genes conferring high susceptibility to ulcerative colitis in the Spanish population

Laura Fernández PhD
Abstract Background: The most consistently described associations in ulcerative colitis (UC) have been with human leukocyte antigen (HLA) class II alleles. Our aim was to look for associations among distinct genetic polymorphisms in the major histocompatibility complex (MHC) that might play a role in determining the susceptibility to UC and especially to the extensive form of the disease. Methods: A case-control study was performed with a total of 253 patients with UC and 315 healthy controls recruited from a single Spanish center. All the samples and 4 cell lines carrying DRB1*0103 or DRB1*1501 alleles were typed for the HLA-DRB1 class II gene and for a panel of HLA class III markers (D6S273, BAT_2, TNFa, b, c, d, e, IKBL+738, MICA). Results: The frequency of the alleles DRB1*0103, IKBL+738(C) (extending our previous results) and BAT_2-8 (newly typed) was increased in patients compared with controls (P = 0.00001, odds ratio [OR] = 5.90; P = 0.002, OR = 2.42; and P = 0.0001, OR = 3.04, respectively), and these associations were greatest in patients with extensive disease compared with patients with distal disease (P = 0.02, OR = 2.53; P = 0.002, OR = 3.06; and P = 0.03, OR = 2.08, respectively). The allelic combination DRB1*0103/D6S273-5/BAT_2-8/TNFa11b4c1d3e3/IKBL+738(C)/MICA5.1 that includes the telomeric class III markers of the 7.1 ancestral haplotype is highly increased in patients with UC (P = 0.0001, OR = 10.57), especially in those with the extensive form of the disease (P = 0.02, OR = 3.41 extensive versus distal). Conclusions: The above-mentioned pattern, most likely formed by recombination of the telomeric fragment of the MHC 7.1 ancestral haplotype, seems to be the most important genetic determinant of susceptibility to the extensive form of UC in our population. [source]

Phylogeographic relationships within the Mediterranean turbot inferred by mitochondrial DNA haplotype variation

N. Suzuki
The Mediterranean turbot Psetta maxima consists of two main genetically distinct lineages (western Mediterranean and ,eastern secluded Mediterranean' basins) as investigated by mitochondrial DNA analysis. Within the latter lineage, most haplotypes from the Sea of Azov were endemic and more than half of them derived from a single ancestral haplotype shared among all the eastern Mediterranean areas. There was no relation between morphotype variation in bony tubercles and mitochondrial genealogy. [source]

Homozygous Defects In Lmna, Encoding Lamin A/C Nuclear-Envelope Proteins, Cause Autosomal Recessive Axonal Neuropathy In Human (Charcot-Marie-Tooth Disorder Type 2) And Mouse

A De Sandre-Giovannoli
The Charcot-Marie-Tooth (CMT) disorders comprise a group of clinically and genetically heterogeneous hereditary motor and sensory neuropathies, which are mainly characterized by muscle weakness and wasting, foot deformities, and electrophysiological, as well as histological, changes. A subtype, CMT2, is defined by a slight or absent reduction of nerve-conduction velocities together with the loss of large myelinated fibers and axonal degeneration. CMT2 phenotypes are also characterized by a large genetic heterogeneity, although only two genes-NF-L and KIF1Bbeta-have been identified to date. Homozygosity mapping in inbred Algerian families with autosomal recessive CMT2 (AR-CMT2) provided evidence of linkage to chromosome 1q21.2-q21.3 in two families (Z(max) = 4.14). All patients shared a common homozygous ancestral haplotype that was suggestive of a founder mutation as the cause of the phenotype. A unique homozygous mutation in LMNA (which encodes lamin A/C, a component of the nuclear envelope) was identified in all affected members and in additional patients with CMT2 from a third, unrelated family. Ultrastructural explor- ation of sciatic nerves of LMNA null (i.e., ,/,) mice was performed and revealed a strong reduction of axon density, axonal enlargement, and the presence of nonmyelinated axons, all of which were highly similar to the phenotypes of human peripheral axonopathies. The finding of site-specific amino acid substitutions in limb-girdle muscular dystrophy type 1B, autosomal dominant Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy type 1A, autosomal dominant partial lipodystrophy, and, now, AR-CMT2 suggests the existence of distinct functional domains in lamin A/C that are essential for the maintenance and integrity of different cell lineages. To our knowledge, this report constitutes the first evidence of the recessive inheritance of a mutation that causes CMT2; additionally, we suggest that mutations in LMNA may also be the cause of the genetically overlapping disorder CMT2B1. [source]

Relationship of polymorphisms located in tumor necrosis factor region and HLA loci among Croatians

Katarina Stingl
Polymorphism of TNFa, TNFb, and TNFd microsatellites, linkage disequilibrium (LD) within TNF region as well as relationship of TNF microsatellites with alleles at HLA-A, - B, and - DRB1 loci was investigated on a sample of 160 Croatians, previously typed for HLA-A, - B, and - DRB1 loci. Analysis of the relationship of TNF alleles and HLA specificities revealed that very strong associations exist between TNFa2, TNFb3, and TNFd2 alleles and HLA-A*01, -B*08, and -DRB1*03 specificities, therefore placing them in the 8.1 ancestral haplotype. Similar findings were observed for TNFa11, TNFb4, and TNFd4 alleles and HLA specificities, which are a part of the 7.1 ancestral haplotype. Finally, multiple associations with significant P- values were also observed between TNFa10, TNFb4, and TNFd4 microsatellite alleles and HLA-A*02, -B*18, -DRB1*11 specificities which form the 18.3 ancestral hapolotype. Am. J. Hum. Biol. 2009. © 2008 Wiley-Liss, Inc. [source]

A population study of a mutation allele associated with cone,rod dystrophy in the standard wire-haired dachshund

A. C. Wiik
Summary Cone,rod dystrophy in the standard wire-haired dachshund (SWHD) is inherited as a simple autosomal recessive trait and the recently discovered mutation is widespread within the SWHD population in Norway and other Scandinavian countries. The gene frequency was estimated to be 4.8%. On the basis of the assumption that the size of the ancestral haplotype around a mutation is inversely correlated with the number of generations since the mutation arose, we have found that the mutation is of a relatively recent origin. The conserved haplotype was found to be 8 Mb in size and therefore we estimate that the mutation arose roughly eight generations (approximately 37 years) ago. This indicates that the mutation arose after breed separation. [source]

Founder Effect and Estimation of the Age of the c.892C>T (p.Arg298Cys) Mutation in LMNA Associated to Charcot-Marie-Tooth Subtype CMT2B1 in Families from North Western Africa

T. Hamadouche
Summary CMT2B1, an axonal subtype (MIM 605588) of the Charcot-Marie-Tooth disease, is an autosomal recessive motor and sensory neuropathy characterized by progressive muscular and sensory loss in the distal extremities with chronic distal weakness. The genetic defect associated with the disease is, to date, a unique homozygous missense mutation, p.Arg298Cys (c.892C>T), in the LMNA gene. So far, this mutation has only been found in affected individuals originating from a restricted region of North Western Africa (northwest of Algeria and east of Morocco), strongly suggesting a founder effect. In order to address this hypothesis, genotyping of both STRs and intragenic SNPs was performed at the LMNA locus, at chromosome 1q21.2-q21.3, in 42 individuals affected with CMT2B1 from 25 Algerian families. Our results indicate that the affected individuals share a common ancestral haplotype in a region of about 1.0 Mb (1 cM) and that the most recent common ancestor would have lived about 800,900 years ago (95% confidence interval: 550 to 1300 years). [source]

HLA polymorphisms in African Americans with idiopathic inflammatory myopathy: Allelic profiles distinguish patients with different clinical phenotypes and myositis autoantibodies

Terrance P. O'Hanlon
Objective To investigate possible associations of HLA polymorphisms with idiopathic inflammatory myopathy (IIM) in African Americans, and to compare this with HLA associations in European American IIM patients with IIM. Methods Molecular genetic analyses of HLA,A, B, Cw, DRB1, and DQA1 polymorphisms were performed in a large population of African American patients with IIM (n = 262) in whom the major clinical and autoantibody subgroups were represented. These data were compared with similar information previously obtained from European American patients with IIM (n = 571). Results In contrast to European American patients with IIM, African American patients with IIM, in particular those with polymyositis, had no strong disease associations with HLA alleles of the 8.1 ancestral haplotype; however, African Americans with dermatomyositis or with anti,Jo-1 autoantibodies shared the risk factor HLA,DRB1*0301 with European Americans. We detected novel HLA risk factors in African American patients with myositis overlap (DRB1*08) and in African American patients producing anti,signal recognition particle (DQA1*0102) and anti,Mi-2 autoantibodies (DRB1*0302). DRB1*0302 and the European American,, anti,Mi-2,associated risk factor DRB1*0701 were found to share a 4,amino-acid sequence motif, which was predicted by comparative homology analyses to have identical 3-dimensional orientations within the peptide-binding groove. Conclusion These data demonstrate that North American IIM patients from different ethnic groups have both shared and distinct immunogenetic susceptibility factors, depending on the clinical phenotype. These findings, obtained from the largest cohort of North American minority patients with IIM studied to date, add additional support to the hypothesis that the myositis syndromes comprise multiple, distinct disease entities, perhaps arising from divergent pathogenic mechanisms and/or different gene,environment interactions. [source]

Evolutionary-based grouping of haplotypes in association analysis

Jung-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]

Further characterization of MHC haplotypes demonstrates conservation telomeric of HLA-A: update of the 4AOH and 10IHW cell panels

S. K. Cattley
Cell panels have been used extensively in studies of polymorphism and disease associations within the major histocompatibility complex (MHC), but the results from these panels require continuous updates with the increasing availability of novel data. We present here an updated table of the typings of the 10IHW and 4AOH panels. Local data included are HFE, HERV-K(C4) and six microsatellites telomeric of HLA-A. Typings for class I, MICA (PERB11.1), MICB (PERB11.2), XA, XB, LMP2 and 10 microsatellites reported by others have also been consolidated in this table. The tabulation shows that the length of conservation in the human MHC is even more extensive than previously thought. Human MHC ancestral haplotypes are inherited as a conserved region of genomic sequence spanning some 6,8 megabases from the HLA class II region and beyond the HLA class I region up to and including the HFE gene. Numerous examples of historical recombinations were also observed. [source]

Genomewide SNP Screen to Detect Quantitative Trait Loci for Alcohol Preference in the High Alcohol Preferring and Low Alcohol Preferring Mice

ALCOHOLISM, Issue 3 2009
Paula Bice
Background:, The high and low alcohol preferring (HAP1 and LAP1) mouse lines were selectively bred for differences in alcohol intake. The HAP1 and LAP1 mice are essentially noninbred lines that originated from the outbred colony of HS/Ibg mice, a heterogeneous stock developed from intercrossing 8 inbred strains of mice. Methods:, A total of 867 informative SNPs were genotyped in 989 HAP1 × LAP1 F2, 68 F1s, 14 parents (6 LAP1, 8 HAP1), as well as the 8 inbred strains of mice crossed to generate the HS/Ibg colony. Multipoint genome wide analyses were performed to simultaneously detect linked QTLs and also fine map these regions using the ancestral haplotypes. Results:, QTL analysis detected significant evidence of association on 4 chromosomes: 1, 3, 5, and 9. The region on chromosome 9 was previously found linked in a subset of these F2 animals using a whole genome microsatellite screen. Conclusions:, We have detected strong evidence of association to multiple chromosomal regions in the mouse. Several of these regions include candidate genes previously associated with alcohol dependence in humans or other animal models. [source]

Founder Mutation(s) in the RSPH9 Gene Leading to Primary Ciliary Dyskinesia in Two Inbred Bedouin Families

Orit Reish
Summary A rare mutation in the RSPH9 gene leading to primary ciliary dyskinesia was previously identified in two Bedouin families, one from Israel and one from the United Arab Emirates (UAE). Herein we analyse mutation segregation in the Israeli family, present the clinical disease spectrum, and estimate mutation age in the two families. Mutation segregation was studied by restriction fragment length analysis. Mutation ages were estimated using a model of the decrease in the length of ancestral haplotypes. The mutations in each of the two families had a common ancestor less than 95 and less than 17 generations in the past. If the mutations in the two families are descended from a common ancestor, that mutation would have to have arisen at least 150 generations ago. If the Bedouin population has been roughly constant in size for at least 6000 years, it is possible that the mutations in the two families are identical by descent. If there were substantial fluctuations in the size of the Bedouin population, it is more likely that there were two independent mutations. Based on the available data, the population genetic analysis does not strongly favour one conclusion over the other. [source]

A Regression-based Association Test for Case-control Studies that Uses Inferred Ancestral Haplotype Similarity

Youfang Liu
Summary Association methods based on haplotype similarity (HS) can overcome power and stability issues encountered in standard haplotype analyses. Current HS methods can be generally classified into evolutionary and two-sample approaches. We propose a new regression-based HS association method for case-control studies that incorporates covariate information and combines the advantages of the two classes of approaches by using inferred ancestral haplotypes. We first estimate the ancestral haplotypes of case individuals and then, for each individual, an ancestral-haplotype-based similarity score is computed by comparing that individual's observed genotype with the estimated ancestral haplotypes. Trait values are then regressed on the similarity scores. Covariates can easily be incorporated into this regression framework. To account for the bias in the raw p-values due to the use of case data in constructing ancestral haplotypes, as well as to account for variation in ancestral haplotype estimation, a permutation procedure is adopted to obtain empirical p-values. Compared with the standard haplotype score test and the multilocus T2 test, our method improves power when neither the allele frequency nor linkage disequilibrium between the disease locus and its neighboring SNPs is too low and is comparable in other scenarios. We applied our method to the Genetic Analysis Workshop 15 simulated SNP data and successfully pinpointed a stretch of SNPs that covers the fine-scale region where the causal locus is located. [source]