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Results for “Heterogeneity Mapping”

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PubMed2006

Genetic heterogeneity of synpolydactyly: a novel locus SPD3 maps to chromosome 14q11.2-q12.

Syndactyly type II or synpolydactyly (SPD) is the second most frequent syndactyly type and is inherited in an autosomal dominant fashion. The cardinal features of this malformation are the cutaneous or bony fusion of third and fourth fingers, and fourth and fifth toes associated with additional digital elements within the web. It shows incomplete penetrance and high inter- and intrafamilial phenotypic variability. Two loci are known for SPD (MIM 186000, MIM 608180) associated with mutations in HOXD13 and FBLN1, respectively. Here, we report further genetic heterogeneity for SDP. Employing a whole genomic screen, we demonstrate, in a large Pakistani kindred, that the classical phenotype of SPD maps on a new locus at chromosome 14q11.2-q12. The highest LOD score (Z(max) = 4.06) was obtained with microsatellite marker D14S264, and the multipoint LOD score reached a maximum of 5.01. Haplotype analysis revealed that the disease interval is flanked by microsatellite markers D14S283 and D14S1060, encompassing a physical distance of 10.72 Mb. We propose to allocate to this locus the symbol SPD3 (synpolydactyly 3), and to name the loci associated with HOXD13 or FBLN1 mutations SPD1 and SPD2, respectively.

Chromosome Mapping↗

PubMed2006

Tumor microvascular architecture phenotype (T-MAP) as a new concept for studies of angiogenesis and oncology.

Heterogeneities exist in endothelial cells and microvascular architecture during tumor angiogenesis. We found significantly variable expression profiles of EC markers, including ephrinB2 and its receptor EphB4, and various types of the architecture. We propose a new concept of tumor microvascular architecture phenotype (T-MAP), reflecting the density, morphology, structure and the three-dimensional distribution of newly formed vessels. The pattern of T-MAP may represent the invasiveness of the tumor therefore predict the outcome of therapy. The presence of T-MAP heterogeneity (T-MAPH) may be utilized as additional diagnostic criteria and for therapeutic designs for antiangiogenesis.

Brain Neoplasms↗

PubMed1998

Mapping quantitative trait loci for binary traits using a heterogeneous residual variance model: an application to Marek's disease susceptibility in chickens.

A typical problem in mapping quantitative trait loci (QTLs) comes from missing QTL genotype. A routine method for parameter estimation involving missing data is the mixture model maximum likelihood method. We developed an alternative QTL mapping method that describes a mixture of several distributions by a single model with a heterogeneous residual variance. The two methods produce similar results, but the heterogeneous residual variance method is computationally much faster than the mixture model approach. In addition, the new method can automatically generate sampling variances of the estimated parameters. We derive the new method in the context of QTL mapping for binary traits in a F2 population. Using the heterogeneous residual variance model, we identified a QTL on chromosome IV that controls Marek's disease susceptibility in chickens. The QTL alone explains 7.2% of the total disease variation.

Algorithms↗

PubMed1992

Mapping of neurofibrillary degeneration in Alzheimer's disease: evaluation of heterogeneity using the quantification of abnormal tau proteins.

A biochemical mapping of neurofibrillary degeneration was performed in Brodmann areas of the brains of five patients with senile dementia of the Alzheimer type (AD). To quantify the degenerating process, we used an immunoblot method with antibodies directed against the abnormally phosphorylated tau proteins named Tau 55, 64 and 69, known to be early and reliable markers of the degenerating process in AD. The detection intensities were assessed using a numerical rating scale for each area and scores were grouped by lobe. In all cases, the detection of Tau 55, 64 and 69 was positive in all areas except in primary visual cortex (area 17) for two patients. The detections were especially strong in temporal neocortical and limbic areas and were higher in associative cortex than in primary sensory cortex. Scores from the occipital and frontal lobes differed strongly between patients as compared to the uniform degree of detection in the limbic, temporal and parietal lobes. Despite a relatively identical duration of the disease and an apparently global involvement of the cerebral cortex, the distribution of neurofibrillary degeneration in AD varies significantly across cortical areas and displays striking heterogeneity patterns along the rostrocaudal axis. The immunodetection of abnormal tau proteins using the Western blot method may provide complete and rapid quantitative data of the degenerating process in AD.

Aged↗

PubMed1984

Structure of the heterogeneous L-S junction region of human cytomegalovirus strain AD169 DNA.

The genome of human cytomegalovirus strain AD169 contains a region of heterogeneity located at the junction between the long (L) and short (S) components of the viral DNA. Twelve cloned L-S junction fragments were studied by using the restriction enzymes HaeII and XhoI. The region of heterogeneity was localized within a single HaeII restriction fragment. The enzyme XhoI was used to subdivide this region and revealed the presence of three types of heterogeneity within the junction fragments. Each of the cloned junction fragments contained one of the following fragments: 0.553, 0.95, or 1.35 kilobase pairs (referred to as class I heterogeneity). Class II heterogeneity was defined as the presence of tandem duplications of class I fragments. In addition, a variable number (0 to 5) of a 0.2-kbp fragment (class III heterogeneity) was observed. Mapping of these fragments with partial XhoI digestions revealed that the class I and class III heterogeneous fragments were adjacent. The DNA sequence of the smallest cloned L-S junction fragment was determined and analyzed. This junction fragment contained a single 0.553-kbp XhoI fragment and no copies of the 0.2-kbp fragment. The 0.553-kbp XhoI fragment was similar in structure to the a-sequences of herpes simplex virus types 1 and 2. In addition, a region of homology was found between the a sequences of herpes simplex virus types 1 and 2 and the 0.553-kbp XhoI fragment from the human cytomegalovirus junction.

Base Sequence↗

PubMed1991

Marfan syndrome: no evidence for heterogeneity in different populations, and more precise mapping of the gene.

Marfan syndrome is a dominantly inherited connective tissue disorder with manifestations in the cardiovascular, ocular, and skeletal systems. The diagnosis is hampered by both high variability in the phenotypic expression and late manifestation of symptoms. The cause of Marfan syndrome remains unknown, but our group has recently reported the genetic linkage of Marfan syndrome to a polymorphic marker on chromosome 15. To analyze the possible heterogeneity behind Marfan syndrome, we have performed linkage analyses for four chromosome 15 markers in 17 families from five different populations: Scottish, English, Swiss, American, and Finnish. By combining the linkage data of all the studied families into a LINKMAP analysis we obtained a maximal LOD score of 11.2, which maps the Marfan syndrome locus between D15S25 and D15S45 on the long arm of chromosome 15. The data reveal no evidence for genetic heterogeneity behind Marfan syndrome and provide us with a more precise location of both the Marfan syndrome locus and flanking markers. This information will provide the basis for the DNA diagnostics of Marfan syndrome in the future.

Chromosome Mapping↗

PubMed1993

Assessing genetic heterogeneity in production cell lines: detection by peptide mapping of a low level Tyr to Gln sequence variant in a recombinant antibody.

A recombinant antibody directed against the human epidermal growth factor receptor-2 extracellular domain was subjected to detailed structural characterization. Heterogeneity in the heavy chain was demonstrated by recovery of two forms of a tryptic peptide, with either glutamine or the expected tyrosine at residue 376. Subsequent experiments indicated that the Y376Q variant developed during transfection of the antibody heavy and light chain genes into Chinese hamster ovary cells. Levels of the Y376Q variant (range: 27% to 1%) in the purified antibody were inversely proportional to cell age. The established cell line was subcloned and found to be heterogeneous by polymerase chain reaction analysis of cell extracts and protein analysis of the purified antibody. Ten percent of subclones produced high levels of the Y376Q variant while 90% of the subclones produced antibody with only the expected heavy chain sequence. This report demonstrates the utility of peptide mapping as a sensitive tool for assessing genetic heterogeneity of recombinant cell lines.

Amino Acid Sequence↗

PubMed2003

Altered atrial electrical restitution and heterogeneous sympathetic hyperinnervation in hearts with chronic left ventricular myocardial infarction: implications for atrial fibrillation.

BACKGROUND: The substrates for the increased incidence of atrial fibrillation (AF) in hearts with chronic left ventricular myocardial infarction (MI) remain poorly defined. We hypothesized that chronic MI is associated with atrial electrical and neural remodeling that enhances AF vulnerability. METHODS AND RESULTS: We created MI in 8 dogs by permanent occlusion of the left anterior descending (LAD) coronary artery. Seven dogs (3 with thoracotomy) that had no LAD occlusion served as controls. Eight weeks after surgery, the incidence and duration of pacing-induced AF in the open chest anesthetized state were significantly (P<0.05) higher in the MI than in control dogs. Multisite biatrial monophasic action potential (MAP) recordings showed increased heterogeneity of MAP duration (MAPD) and MAPD restitution slope. AF in the MI groups was preceded by significantly higher MAPD (P<0.01) and MAP amplitude (P<0.05) alternans in both atria compared with controls. Epicardial mapping using 1792 bipolar electrodes (1-mm spatial resolution) showed multisite wavebreaks of the paced wavefronts leading to AF in MI but not in control dogs. Multiple wavelets in MI dogs were associated with significantly higher incidence and longer duration of AF compared with control. The density of biatrial tyrosine hydroxylase (TH) and growth-associated protein43 (GAP43) nerves were 5- to 8-fold higher and were more heterogeneous in MI compared with control dogs. CONCLUSIONS: Chronic ventricular MI with no atrial involvement causes heterogeneous alteration of atrial electrical restitution and atrial sympathetic hyperinnervation that might provide important substrates for the observed increased AF vulnerability.

Action Potentials↗

PubMed1992

Analysis of genetic heterogeneity within the type strain of satellite tobacco mosaic virus reveals variants and a strong bias for G to A substitution mutations.

Satellite tobacco mosaic virus (STMV) is a small plant virus that is dependent for its replication on the presence of a helper tobamovirus. RNase protection analysis of genomic RNA of the STMV type strain revealed that it was composed of two major genome types which differed at a single detectable site near nucleotide 753. Analyses of 42 full-length STMV clones for sequence heterogeneity resulted in the identification of 16 variants distinguishable by unique RNase protection assay patterns. Characterization of these variants confirmed the presence of a major heterogeneity site at nucleotide 751 and identified several sites of sequence microheterogeneity typical of an RNA quasispecies population. Mapping of the heterogeneity sites revealed an apparently random distribution along the length of the STMV genome, with no significant clustering or preference for noncoding regions. Infectivity experiments in tobacco showed that RNA transcripts of 13 of the 16 variant clones were infectious, indicating that most of the variants represent functional genomes coexisting in the type strain with the two major genome types. Sequence analyses revealed that most of the heterogeneity sites detected, including the major site of heterogeneity, were single base differences. Assessment of all the heterogeneity sites found in the total of 10,545 nt sequenced allowed us to estimate that the RNase protection assays detected approximately 50% of the differences present in the 16 clones studied. The nature of these differences was highly biased in that 18 of the 29 single base differences characterized (62%) were G to A substitutions.

Base Sequence↗

PubMed2004

Ordered subset analysis in genetic linkage mapping of complex traits.

Etiologic heterogeneity is a fundamental feature of complex disease etiology; genetic linkage analysis methods to map genes for complex traits that acknowledge the presence of genetic heterogeneity are likely to have greater power to identify subtle changes in complex biologic systems. We investigate the use of trait-related covariates to examine evidence for linkage in the presence of heterogeneity. Ordered-subset analysis (OSA) identifies subsets of families defined by the level of a trait-related covariate that provide maximal evidence for linkage, without requiring a priori specification of the subset. We propose that examining evidence for linkage in the subset directly may result in a more etiologically homogeneous sample. In turn, the reduced impact of heterogeneity will result in increased overall evidence for linkage to a specific region and a more distinct lod score peak. In addition, identification of a subset defined by a specific trait-related covariate showing increased evidence for linkage may help refine the list of candidate genes in a given region and suggest a useful sample in which to begin searching for trait-associated polymorphisms. This method provides a means to begin to bridge the gap between initial identification of linkage and identification of the disease predisposing variant(s) within a region when mapping genes for complex diseases. We illustrate this method by analyzing data on breast cancer age of onset and chromosome 17q [Hall et al., 1990, Science 250:1684-1689]. We evaluate OSA using simulation studies under a variety of genetic models.

Breast Neoplasms↗

PubMed2006

Genomewide linkage scan for obsessive-compulsive disorder: evidence for susceptibility loci on chromosomes 3q, 7p, 1q, 15q, and 6q.

Obsessive-compulsive disorder (OCD) is the tenth most disabling medical condition worldwide. Twin and family studies implicate a genetic etiology for this disorder, although specific genes have yet to be identified. Here, we present the first large-scale model-free linkage analysis of both extended and nuclear families using both 'broad' (definite and probable diagnoses) and 'narrow' (definite only) definitions of OCD. We conducted a genome-scan analysis of 219 families collected as part of the OCD Collaborative Genetics Study. Suggestive linkage signals were revealed by multipoint analysis on chromosomes 3q27-28 (P=0.0003), 6q (P=0.003), 7p (P=0.001), 1q (P=0.003), and 15q (P=0.006). Using the 'broad' OCD definition, we observed the strongest evidence for linkage on chromosome 3q27-28. The maximum overall Kong and Cox LODall score (2.67) occurred at D3S1262 and D3S2398, and simulation based P-values for these two signals were 0.0003 and 0.0004, respectively, although for both signals, the simulation-based genome-wide significance levels were 0.055. Covariate-linkage analyses implicated a possible role of gene(s) on chromosome 1 in increasing the risk for an earlier onset form of OCD. We are currently pursuing fine mapping in the five regions giving suggestive signals, with a particular focus on 3q27-28. Given probable etiologic heterogeneity in OCD, mapping gene(s) involved in the disorder may be enhanced by replication studies, large-scale family-based linkage studies, and the application of novel statistical methods.

Chromosomes, Human↗

PubMed1996

Evidence of genetic heterogeneity of Leber's congenital amaurosis (LCA) and mapping of LCA1 to chromosome 17p13.

Leber's congenital amaurosis (LCA) is an autosomal recessive disease responsible for congenital blindness. It is the earliest and most severe inherited retinal dystrophy in human and its genetic heterogeneity has long been recognised. We have recently reported on the first localisation of a disease gene (LCA1) to the short arm of chromosome 17 by homozygosity mapping in five families of North African origin. Here, we refine the genetic mapping of LCA1 to chromosome 17p13 between loci D17S938 and D17S1353 and provide strong support for the genetic heterogeneity of this condition (maximum likelihood for heterogeneity, 17.20 in InL; heterogeneity versus homogeneity, P = 0.0002, heterogeneity versus no linkage, P < 0.0001)

Blindness↗

PubMed2000

Evidence for a nonallelic heterogeneity of epidermodysplasia verruciformis with two susceptibility loci mapped to chromosome regions 2p21-p24 and 17q25.

Epidermodysplasia verruciformis is a rare genodermatosis associated with a high risk of skin cancer. This condition is characterized by an abnormal susceptibility to specific related human papillomavirus genotypes, including the oncogenic HPV5. Epidermodysplasia verruciformis is usually considered as an autosomal recessive disease. We recently mapped a susceptibility locus for epidermodysplasia verruciformis (EV1) to chromosome 17qter within the 1 cM interval between markers D17S939 and D17S802. We report here the genotyping for 10 microsatellite markers spanning 29 cM around EV1 in two consanguineous epidermodysplasia verruciformis families from Colombia (C2) and France (F1) comprising five patients and two patients, respectively. Using homozygosity mapping, linkage with 17qter markers was observed for family C2 only. Multipoint linkage analysis yielded maximum multipoint LOD-score values above 10 between markers D17S1839 and D17S802 encompassing the EV1 locus. A genome-wide search performed in family F1 yielded evidence for linkage between epidermodysplasia verruciformis and the chromosomal 2p marker D2S365. Nine additional microsatellite markers spanning 15 cM in this region were analyzed. Assuming an autosomal recessive inheritance with a complete penetrance, the expected maximum two-point LOD-score value of 1.8 was obtained for three markers and multipoint linkage analysis yielded a maximum LOD-score value of 3. 51 between markers D2S2144 and D2S392. Haplotype analysis allowed to map a candidate region for a second epidermodysplasia verruciformis susceptibility locus (EV2) within the 8 cM interval between markers D2S171 and D2S2347 of the 2p21-p24 region. In contrast, linkage with 2p markers was excluded for family C2 and for the three families in which we mapped EV1 previously. The disclosure of two susceptibility loci for epidermodysplasia verruciformis provides evidence for a nonallelic heterogeneity in this disease.

Adolescent↗

PubMed1977

Intramolecular heterogeneity of mitochondrial DNA of Drosophila melanogaster.

DNA from purified mitochondria of Drosophila melanogaster can be isolated as supercoiled molecules which when nicked have a contour length of 5.9 micron. Partial denaturation mapping shows regional heterogeneity of base composition with one early denaturing region, with a calculated GC content close to zero, extending over 20% of the genome. DNA isolated from unfertilized eggs shows nuclear and mitochondrial DNA in equal proportions; we found no evidence of other cytoplasmic species.

Animals↗

PubMed1996

Does the renin-angiotensin system determine the renal and systemic hemodynamic response to sodium in patients with essential hypertension?

Many patients with essential hypertension respond to a high dietary sodium intake with a rise in blood pressure. Experimental evidence suggests that the renal hemodynamic response to sodium determines, at least partially, this rise in blood pressure. Our aim was to clarify the role of the renin-angiotensin system in the renal and systemic adaptation to a change in dietary sodium. We studied changes in mean arterial pressure (MAP) (millimeters of mercury), effective renal plasma flow (ERPF), body weight, and immunoreactive renin in 17 patients with essential hypertension and 15 normotensive control subjects, randomly crossing over between a 3-week sodium-restricted (50 mmol/24 h) and a sodium-replete (200 mmol/24 h) diet period. In addition, the effects of renin inhibition by remikiren (600 mg, single oral dose) were studied during the high sodium period. In normotensive control subjects, high sodium intake had no effect on MAP or body weight, whereas ERPF increased (490 +/- 19 to 535 +/- 21 mL/min, P < .05) and immunoreactive renin decreased (32 +/- 6 to 14 +/- 1 pg/mL). In hypertensive subjects, high sodium intake induced a heterogeneous response of MAP (median change, 2.6 mm Hg; range, -4.7 to +21.2; P = NS) and ERPF (median change, 21 mL/min; range, -33 to +98; P = NS). Body weight increased from 81.3 +/- 1.9 to 82.5 +/- 2.0 kg (P < .05), and immunoreactive renin decreased from 18 +/- 3 to 10 +/- 1 pg/mL (P < .05). Interestingly, the patients with a distinct rise in MAP showed a blunted ERPF response to high sodium intake (r = -.70, P < .01) and an increase in body weight (r = .76, P < .001). Moreover, the increase of ERPF was more pronounced in patients with a larger fall in immunoreactive renin (r = .77, P < .001). After administration of remikiren, a heterogeneous response in ERPF was observed: the patients with the blunted ERPF response to high sodium intake showed the largest ERPF rise (r = .70, P < .01). The remikiren-induced rise in ERPF correlated (r = .68, P < .01) with the fall in MAP (114 +/- 2 to 110 +/- 2 mm Hg). In conclusion, in patients with essential hypertension a rise in blood pressure in response to high sodium intake appears to partially be the result of insufficient renal vasodilatation. This seems to be due to an inadequate (intrarenal?) renin-angiotensin system response to increased sodium intake.

Adult↗

PubMed2003

Multipoint linkage-disequilibrium mapping narrows location interval and identifies mutation heterogeneity.

Single-nucleotide polymorphism (SNP) genotypes were recently examined in an 890-kb region flanking the human gene CYP2D6. Single-marker and haplotype-based analyses identified, with genomewide significance (P < 10-7), a 403-kb interval displaying strong linkage disequilibrium (LD) with predicted poor-metabolizer phenotype. However, the width of this interval makes the location of causal variants difficult: for example, the interval contains seven known or predicted genes in addition to CYP2D6. We have developed the Bayesian fine-mapping software coldmap, which, applied to these genotype data, yields a 95% location interval covering only 185 kb and establishes genomewide significance for a causal locus within the region. Strikingly, our interval correctly excludes four SNPs, which individually display association with genomewide significance, including the SNP showing strongest LD (P < 10-34). In addition, coldmap distinguishes homozygous cases for the major CYP2D6 mutation from those bearing minor mutations. We further investigate a selection of SNP subsets and find that previously reported methods lead to a 38% savings in SNPs at the cost of an increase of <20% in the width of the location interval.

Bayes Theorem↗

PubMed2000

Markov chain Monte Carlo for mapping a quantitative trait locus in outbred populations.

A Bayesian approach is presented for mapping a quantitative trait locus (QTL) using the 'Fernando and Grossman' multivariate Normal approximation to QTL inheritance. For this model, a Bayesian implementation that includes QTL position is problematic because standard Markov chain Monte Carlo (MCMC) algorithms do not mix, i.e. the QTL position gets stuck in one marker interval. This is because of the dependence of the covariance structure for the QTL effects on the adjacent markers and may be typical of the 'Fernando and Grossman' model. A relatively new MCMC technique, simulated tempering, allows mixing and so makes possible inferences about QTL position based on marginal posterior probabilities. The model was implemented for estimating variance ratios and QTL position using a continuous grid of allowed positions and was applied to simulated data of a standard granddaughter design. The results showed a smooth mixing of QTL position after implementation of the simulated tempering sampler. In this implementation, map distance between QTL and its flanking markers was artificially stretched to reduce the dependence of markers and covariance. The method generalizes easily to more complicated applications and can ultimately contribute to QTL mapping in complex, heterogeneous, human, animal or plant populations.

Animals↗

PubMed1998

Molecular analysis of glycogen storage disease type Ib: identification of a prevalent mutation among Japanese patients and assignment of a putative glucose-6-phosphate translocase gene to chromosome 11.

Glycogen storage disease type Ib (GSD-Ib) is an inborn error of metabolism with autosomal recessive inheritance, caused by defects in microsomal transport of glucose-6-phosphate. Recently, Gerin et al isolated a human cDNA encoding a putative transporter homologous to bacterial transporters of hexose-6-phosphate, and identified two mutations in its gene in two patients with GSD-Ib (9). Independently, a linkage analysis mapped the GSD-Ib gene on chromosome 11q23 (10). It remains to be elucidated whether the two genes are identical or GSD-Ib is genetically heterogeneous. We first mapped the transporter gene on chromosome 11 by using a DNA panel of human/hamster hybridoma cells. The result suggested that the GSD-Ib genes identified by the two distinct approaches may be identical and GSD-Ib was allelic. We then studied four unrelated Japanese families with GSD-Ib, and found three novel mutations: a four-base deletion/two-base insertion, a point mutation within a consensus splicing donor site, and a missense mutation (W118R). The W118R mutation was found in 4 out of 8 mutant alleles, suggesting that it is prevalent among Japanese patients.

Amino Acid Sequence↗