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Results for “Heterogeneity Mapping”

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PubMed2004

Confirmation of the HPCX prostate cancer predisposition locus in large Utah prostate cancer pedigrees.

Several genetic predisposition loci for prostate cancer have been identified through linkage analysis, and it is now generally recognized that no single gene is responsible for more than a small proportion of prostate cancers. However, published confirmations of these loci have been few, and failures to confirm have been frequent. The genetic etiology of prostate cancer is clearly complex and includes significant genetic heterogeneity, phenocopies, and reduced penetrance. Powerful analyses that involve robust statistics and methods to reduce genetic heterogeneity are therefore necessary. We have performed linkage analysis on 143 Utah pedigrees for the previously published Xq27-28 (HPCX) prostate cancer susceptibility locus. We employed a robust multipoint statistic (TLOD) and a novel splitting algorithm to reduce intra-familial heterogeneity by iteratively removing the top generation from the large Utah pedigrees. In a dataset containing pedigrees having no more than five generations, we observed a multipoint TLOD of 2.74 (P=0.0002), which is statistically significant after correction for multiple testing. For both the full-structure pedigrees (up to seven generations) and the smaller sub-pedigrees, the linkage evidence was much reduced. This study thus represents the first significant confirmation of HPCX (Xq27-28) and argues for the continued utility of large pedigrees in linkage analyses for complex diseases.

Chromosome Mapping↗

PubMed1995

Heterogeneity of genome sizes among natural isolates of Escherichia coli.

Comparisons of the genetic maps of Escherichia coli K-12 and Salmonella typhimurium LT2 suggest that the size and organization of bacterial chromosomes are highly conserved. Employing pulsed-field gel electrophoresis, we have estimated the extent of variation in genome size among 14 natural isolates of E. coli. The BlnI and NotI restriction fragment patterns were highly variable among isolates, and genome sizes ranged from 4,660 to 5,300 kb, which is several hundred kilobases larger than the variation detected between enteric species. Genome size differences increase with the evolutionary genetic distance between lineages of E. coli, and there are differences in genome size among the major subgroups of E. coli. In general, the genomes of natural isolates are larger than those of laboratory strains, largely because of the fact that laboratory strains were derived from the subgroup of E. coli with the smallest genomes.

Biological Evolution↗

PubMed1987

Purification and RNA binding properties of a C-type hnRNP protein from HeLa cells.

A protein of the C group, most likely C3 (Mr approximately 42,000, pI approximately 6, corresponding to IEF 48m,n of the HeLa protein catalogue (Celis, J. E., Bravo, R., Arenstorf, H. P., and LeStourgeon, W. M. (1986) FEBS Lett. 194, 101-109)), a minor hnRNP protein was purified to near homogeneity under nondenaturing conditions from 40 S heterogeneous nuclear ribonucleoprotein particles. Type C protein stoichiometrically disrupts the residual secondary structure of natural and synthetic RNAs, e.g. HeLa hnRNA, coliphage MS2 RNA, and poly(rU)-spermine, and decreases the Tm of duplex structures, e.g. poly[r(A + U)], by about 30 degrees C. Binding of the protein to polynucleotides is not highly cooperative and has a stoichiometry of one protein per about 10 nucleotides. Binding experiments with a variety of synthetic and natural poly- and oligonucleotides, including those containing consensus splice site sequences, indicate that the protein has a high affinity for G-rich and U-rich regions, G-rich regions being preferred. Base analogs I and T have affinities for the protein that are similar to G and U. There is little or no affinity for A- and C-rich regions. The presence of A residues in a G- or U-rich sequence does not interfere with binding while C-rich regions decrease or prevent the binding of the protein. The nucleotide specificity of type C protein, e.g. selective binding to an oligonucleotide from the 3' end of an intron, is discussed in relationship to the abundance of G and U and the relative scarcity of C residues in the processing signals in pre-mRNA.

Circular Dichroism↗

PubMed1991

[Studies of mtDNA of Ustilago maydis. I. Cloning and gene mapping].

This paper covers the following studies of mtDNA of Ustilago maydis. (1) By inserting the Bam HI and Pst I fragments of the mtDNA into the corresponding sites of pBR322, we cloned a unique sequence of 49.6 kb, accounting for 89.3% of the mitochondrial genome (60.7 kb). (2) With heterogenous genes from plants or fungi as probes, we identified seven genes, and mapped them onto the restriction map of the mt DNA. The genes were arranged in such an order: -UmCOB-UmOXII-S-rR NA-UmOXIII-L-rRNA-UmATPase6-UmOXI-. (3) We tried to express the three cloned genes, UmOXII, UmOXIII, and Um-ATPase 6, in E. coli maxcel expression system, but no specific protein was observed.

Chromosome Mapping↗

PubMed2004

A novel locus for autosomal dominant non-syndromic hearing loss, DFNA31, maps to chromosome 6p21.3.

BACKGROUND: Non-syndromic hearing loss is the most genetically heterogeneous trait known in humans. To date, 51 loci for autosomal dominant non-syndromic sensorineural hearing loss (NSSHL) have been identified by linkage analysis. OBJECTIVE: To investigate the genes involved in a Dutch family with NSSHL. METHODS: Linkage analysis in a large Dutch pedigree with progressive bilateral loss of the mid and high frequencies, in which a novel dominant locus for postlingual NSSHL (DFNA31) has been identified. RESULTS: DFNA31 was found to be located in a 7.5 cM region of chromosome 6p21.3 between D6S276 (telomeric) and D6S273 (centromeric), with a maximum two point LOD score of 5.99 for D6S1624. DNA sequencing of coding regions and exon/intron boundaries of two candidate genes (POU5F1, GABBR1) in this interval did not reveal disease causing mutations. CONCLUSIONS: Haplotype analysis indicated that the genetic defect in this family does not overlap the DFNA13 and DFNA21 regions that are also located on 6p. Identification of the disease gene will be of major importance in understanding the pathophysiology of hearing impairment.

Age of Onset↗

PubMed2000

Effects of stratification in the analysis of affected-sib-pair data: benefits and costs.

The benefits and costs of stratification of affected-sib-pair (ASP) data were examined in three situations: (1) when there is no difference in identity-by-descent (IBD) allele sharing between stratified and unstratified ASP data sets; (2) when there is an increase in IBD allele sharing in one of the stratified groups; and (3) when the data are stratified on the basis of IBD allele-sharing status at one locus, and the stratified ASPs are then analyzed for linkage at a second locus. When there is no difference in IBD sharing between strata, a penalty is always paid for stratifying the data. The loss of power to detect linkage in the stratified ASP data sets is the result of multiple testing and the smaller sample size within individual strata. In the case in which etiologic heterogeneity (i.e., severity of phenotype, age at onset) represents genetic heterogeneity, the power to detect linkage can be increased by stratifying the ASP data. This benefit is obtained when there is sufficient IBD allele sharing and sample sizes. Once linkage has been established for a given locus, data can be stratified on the basis of IBD status at this locus and can be tested for linkage at a second locus. When the relative risk is in the vicinity of 1, the power to detect linkage at the second locus is always greater for the unstratified ASP data set. Even for values of the relative risk that diverge sufficiently from 1, with adequate sample sizes and IBD allele sharing, the benefits of stratifying ASP data are minimal.

Age of Onset↗

PubMed2002

A novel form of autosomal recessive pure hereditary spastic paraplegia maps to chromosome 13q14.

BACKGROUND: Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous disorder characterized by a progressive weakening and spasticity of the lower limbs. HSP is classified according to the presence or absence of accompanying neurologic problems and by the mode of inheritance. Currently, 17 loci have been linked to the various forms of HSP. OBJECTIVE: To determine the chromosomal location of a gene causing pure autosomal recessive spastic paraplegia. METHODS: Genotyping using fluorescently labeled microsatellite markers was performed on three affected individuals and three unaffected individuals from a family displaying pure autosomal recessive HSP (ARHSP) and sensorineural deafness. All family members were then included in the analysis to narrow the genetic interval. Candidate genes were screened for the presence of mutations by heteroduplex analysis. RESULTS: The paraplegic trait linked to a 1.8-Mb region of chromosome 13q14 flanked by the FLJ11712 gene and the microsatellite marker D13S270. The deafness did not link to this region and did not cosegregate with the paraplegic trait. CONCLUSION: The HSP that this family had represents a novel genetic form of pure ARHSP as no other form of HSP (autosomal dominant or recessive) has been linked to chromosome 13.

Abnormalities, Multiple↗

PubMed1998

QTL mapping of genotype-environment interaction for fitness in Drosophila melanogaster.

A fundamental assumption of models for the maintenance of genetic variation by environmental heterogeneity is that selection favours alternative alleles in different environments. It is not clear, however, whether such antagonistic pleiotropy is common. We mapped quantitative trait loci (QTLs) causing variation for reproductive performance in each of three environmental treatments among a set of 98 recombinant inbred (RI) lines derived from a cross between two D. melanogaster laboratory strains. The three treatments were standard medium at 25 degrees C, ethanol-supplemented medium at 25 degrees C, and standard medium at 18 degrees C. The RI lines showed highly significant genotype-environment interaction for the fitness measure. Of six QTLs with significant effects on fitness in at least one of the environments, five had significantly different effects at the different temperatures. In each case, the QTL by temperature interaction arose because the QTL had stronger effects at one temperature than at the other. No evidence for QTLs with opposite fitness effects in different environments was found. These results, together with those of recent studies of crop plants, suggest that antagonistic pleiotropy is a relatively uncommon form of genotype-environment interaction for fitness, but additional studies of natural populations are needed to confirm this conclusion.

Animals↗

PubMed2001

Genetic heterogeneity and clonal evolution in neuroblastoma.

Tumour heterogeneity and clonal evolution at the genetic level may explain the development of malignant or resistant disease during clinical progression of neuroblastoma (NB). In this report we use 1p allelic analysis and DNA ploidy to evaluate clonal heterogeneity and clonal selection in vivo. We studied a total of 69 tumours from 29 patients with NB. To evaluate tumour heterogeneity and clonal evolution in vivo we used a panel of polymorphic allelic markers mapping to chromosome 1. 33 tumours from 12 patients (group 1) were obtained from different sites during the same surgery or at sequential surgeries without intervening chemotherapy to evaluate genetic heterogeneity. Paired samples from 10 patients (group 2) were used to evaluate clonal selection before and after chemotherapy. In 6 cases paired tumours and derived cell lines were studied. Analysis of DNA ploidy changes by karyotype, FISH and flow cytometry was performed in 15 tumours from 6 multiply recurred local-regional (LR) NB patients. Allelotype study revealed that 66% (8/12) of group 1 samples were heterogeneous, with distinct allelic patterns in tumour samples separated by time or location. In group 2 allelic patterns were different in post-chemotherapy specimens in 60% (6/10). DNA ploidy analysis showed that pre-chemotherapy samples contained 2 distinct ploidy clones, one diploid and one triploid, whereas all post-chemotherapy tumor samples were 100% diploid. These findings suggest that NB exhibits a high degree of clonal heterogeneity and clonal evolution occurs during the course of therapy and clinical progression.

Chromosomes, Human, Pair 1↗

PubMed2003

Spectrally driven classification of high spatial resolution, hyperspectral imagery: a tool for mapping in-stream habitat.

Streams represent an essential component of functional ecosystems and serve as sensitive indicators of disturbance. Accurate mapping and monitoring of these features is therefore critical, and this study explored the potential to characterize aquatic habitat with remotely sensed data. High spatial resolution, hyperspectral imagery of the Lamar River, Wyoming, USA, was used to examine the relationship between spectrally defined classes and field-mapped habitats. Advantages of this approach included enhanced depiction of fine-scale heterogeneity and improved portrayal of gradational zones between adjacent features. Certain habitat types delineated in the field were strongly associated with specific image classes, but most included areas of diverse spectral character; spatially buffering the field map polygons strengthened this association. Canonical discriminant analysis (CDA) indicated that the ratio of the variability among groups to that within a group was an order of magnitude greater for spectrally defined image classes (20.84) than for field-mapped habitat types (1.82), suggesting that unsupervised image classification might more effectively categorize the fluvial environment. CDA results also suggested that shortwave-infrared wavelengths were valuable for distinguishing various in-stream habitats. Although hyperspectral stream classification seemed capable of identifying more features than previously recognized, the technique also suggested that the intrinsic complexity of the Lamar River would preclude its subdivision into a discrete number of classes. Establishing physically based linkages between observed spectral patterns and ecologically relevant channel characteristics will require additional research, but hyperspectral stream classification could provide novel insight into fluvial systems while emerging as a potentially powerful tool for resource management.

Ecosystem↗

PubMed1993

Genetic mapping of three GABAA receptor-subunit genes in the mouse.

GABAA receptors are a heterogeneous group of heterooligomeric ligand-gated anion channels that represent the main means of synaptic inhibition in neuronal tissue. At least 14 distinct GABAA subunit proteins representing 5 different classes have been identified. Using rat brain cDNAs for the GABAA receptor beta 1-, alpha 2-, and alpha 4-subunits, we have assigned the corresponding murine genes Gabrb-1, Gabra-2, and Gabra-4 to specific chromosomes with somatic cell hybrids, and we have positioned these genes by analysis of the progeny of three genetic crosses. Gabrb-1 and Gabra-2 are tightly linked on mouse Chromosome 5 between the markers Pgm-1 and Kit, and Gabra-4 maps to proximal mouse Chromosome 7 in apparent proximity to the previously mapped Gabrb-3. The Gabrb-1, Gabra-2 pair of genes on Chr 5 maps near the mouse "circling mutation" pi (pirouette).

Alleles↗

PubMed2005

Frequency map variations in squirrel monkey primary auditory cortex.

OBJECTIVE: The goal of this work is to understand the neural basis for cortical representation of hearing in highly vocal primates to gain insights into the substrates for communication. Variation patterns in frequency representation among animals are incorporated into an explanatory model to reconcile heterogeneous observations. STUDY DESIGN: Prospective. METHODS: Thirty-four squirrel monkeys underwent microelectrode mapping experiments in primary auditory cortex (AI) using tone pip stimuli. Characteristic frequency (CF) was extracted from the excitatory frequency receptive field. Frequency maps were reconstructed using Voronoi-Dirichlet tessellation. The spatial locations (rostral vs. caudal) of highest CF isofrequency contours (minimum length 1 mm) and highest CF neuronal clusters on the temporal gyral surface were analyzed. RESULTS: Isofrequency contours at least 1 mm long with CFs greater than 2.9 kHz (75% cases) are accessible on the temporal gyrus. Variability of the highest CF isofrequency contours accessible on the temporal gyrus has an interquartile range from 2.9 to 5.1 (mean 4.3) kHz. The highest CF isofrequency contours are located mainly in rostral AI, whereas the highest CF neuronal clusters flanking fully expressed isofrequency contours are equally distributed in rostral and caudal locations. CONCLUSIONS: Squirrel monkey AI frequency map variations are sizeable across animals and small within single animals (interhemispheric comparison). AI frequency map variations, modeled as translations and rotations relative to the lateral sulcus, are independent transfers. Caution must be exercised when interpreting nominal frequency map changes that are attributed to hearing loss and auditory learning effects.

Animals↗

PubMed2001

[Progress in researches on the molecular genetics of facioscapulohumeral muscular dystrophy].

Facioscapulohumeral muscular dystrophy(FSHD) is an autosomal dominant neuromuscular disorder characterized by progressive weakness of the facial, shoulder and upper arm muscles. The major gene involved has been mapped to chromosome 4q35. There is the evidence for genetic heterogeneity. The FSHD- associated DNA rearrangements are due to deletions of integral copies of the 3.3 kb tandem repeated unit from the subtelomeric region on chromosome 4q35. A valuable molecular diagnostic test for FSHD has been created with the use of p13E-11 probe to detect the EcoR I/Bln I double digestion fragment which is usually smaller in FSHD patient than in normal indivdual. Since the FSHD gene has not been identified yet, the exact molecular pathogenesis of FSHD remains unclear. The hypothesis of position effect variegation has been postulated as the underlying genetic mechanism of FSHD. FRG1 (FSHD region gene 1) from human chromosome 4q35 is identified as a candidate gene for FSHD. A significant correlation between the size of rearrangements associated with FSHD and the clinical phenotype has been found. The various rearrangement fragment size may explain the wide range of clinical severity in FSHD.

Chromosome Mapping↗

PubMed1987

Genetic linkage studies with neurofibromatosis: the question of heterogeneity.

Three new families are reported for standard gene linkage markers and classical peripheral neurofibromatosis (Von Reckling-hausen disease). Additional data are summarised for the exclusion map. One family gives slight evidence of close linkage with the Gc locus on chromosome 4, raising again the question of possible genetic heterogeneity in NF.

Chromosome Mapping↗

PubMed1995

Consanguineous nuclear families used to identify a new locus for recessive non-syndromic hearing loss on 14q.

Hearing impairment is inherited most frequently as an autosomal recessive isolated clinical finding (non-syndromic hearing loss, NSHL). Extreme heterogeneity and phenotypic variability in the audiometric profile preclude pooling of affected families and severely hamper gene mapping by conventional linkage analysis. However, in instances of consanguinity, homozygosity mapping can be used to identify disease loci in small nuclear families. This report demonstrates the power of this technique by identifying a locus for recessive NSHL on 14q (DFNB4).

Chromosome Mapping↗

PubMed2006

Localized attraction correlates with bacterial adhesion to glass and metal oxide substrata.

Bacterial adhesion to surfaces does not always proceed according to theoretical expectations. Discrepancies are often attributed to surface heterogeneities that provide localized, favorable sites for bacterial attachment. The presence of these favorable deposition sites for bacteria, however, has never been directly measured. Atomic force microscopy (AFM) was used to quantify the distribution of attractive sites on clean substrata. Surfaces of silica and three different metal oxides mapped by adhesion force with regular or colloidal AFM tips showed a heterogeneous distribution of adhesion forces. Adhesion forces were normally distributed based on a colloid probe, but regular tips revealed a proportionately larger number of relatively more adhesive sites. No correlation was found between the average adhesion force (tip or colloid) and macroscopic adhesion tests using five strains of bacteria. However, when AFM tip results were compared to bacterial adhesion data on the basis of only the stickiest sites (the 5% of sites with the largest adhesion force), there was a good correlation of AFM data with adhesion data. These results demonstrate for the first time how overall bacterial adhesion to a surface effectively correlates with a relatively small fraction of highly adhesive sites rather than averaged adhesion force as detected using AFM.

Adhesiveness↗

PubMed1987

Characterization of the Cephalosporium acremonium ribosomal RNA genes.

To investigate the organization of the ribosomal RNA genes in Cephalosporium acremonium, we cloned the whole r X DNA repeat in pBR322 and pNEO plasmids. Both the cloned and the genomic r X DNA fragments were characterized by restriction mapping. The r X DNA repeat unit was found to be 8.0 kb long and there was no significant heterogeneity among the individual repeats.

Acremonium↗

PubMed1997

Genetic heterogeneity of Meckel syndrome.

Meckel syndrome (MKS) is a lethal, autosomal recessive condition characterised by an occipital meningoencephalocele, enlarged kidneys with multicystic dysplasia, fibrotic changes of the liver in the portal area with ductal proliferation, and postaxial polydactyly. Recently, a MKS gene has been mapped to chromosome 17q21-q24 in Finnish families, with no evidence of locus heterogeneity in this population. Here, we report the exclusion of chromosome 17q21-q24 in eight typical MKS families of North African and Middle Eastern ancestry and provide evidence for genetic heterogeneity of this condition.

Abnormalities, Multiple↗