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At least 235 records · Page 13Linked to original sources
PubMed2006

Exploiting large scale computing to construct high resolution linkage disequilibrium maps of the human genome.

UNLABELLED: Linkage disequilibrium (LD) maps increase power and precision in association mapping, define optimal marker spacing and identify recombination hot-spots and regions influenced by natural selection. Phase II of HapMap provides approximately 2.8-fold more single nucleotide polymorphisms (SNPs) than phase I for constructing higher resolution maps. LDMAP-cluster, is a parallel program for rapid map construction in a Linux environment used here to construct genome-wide LD maps with >8.2 million SNPs from the phase II data. AVAILABILITY: The LD maps, LDMAP-cluster and documentation are available from: http://www.som.soton.ac.uk/research/geneticsdiv/epidemiology/LDMAP. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Algorithms↗
PubMed2005

Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP).

OBJECTIVE: To investigate the contribution of MYH associated polyposis coli (MAP) among polyposis families in the Netherlands, and the prevalence of colonic and extracolonic manifestations in MAP patients. METHODS: 170 patients with polyposis coli, who previously tested negative for APC mutations, were screened by denaturing gradient gel electrophoresis and direct sequencing to identify MYH germline mutations. RESULTS: Homozygous and compound heterozygous MYH mutations were identified in 40 patients (24%). No difference was found in the percentage of biallelic mutation carriers between patients with 10-99 polyps or 100-1000 polyps (29% in both groups). Colorectal cancer was found in 26 of the 40 patients with MAP (65%) within the age range 21 to 67 years (median 45). Complete endoscopic reports were available for 16 MAP patients and revealed five cases with gastro-duodenal polyps (31%), one of whom also presented with a duodenal carcinoma. Breast cancer occurred in 18% of female MAP patients, significantly more than expected from national statistics (standardised morbidity ratio = 3.75). CONCLUSIONS: Polyp numbers in MAP patients were equally associated with the attenuated and classical polyposis coli phenotypes. Two thirds of the MAP patients had colorectal cancer, 95% of whom were older than 35 years, and one third of a subset of patients had upper gastrointestinal lesions. Endoscopic screening of the whole intestine should be carried out every two years for all MAP patients, starting from age 25-30 years. The frequent occurrence of additional extraintestinal manifestations, such as breast cancer among female MAP patients, should be thoroughly investigated.

Adenomatous Polyposis Coli↗
PubMed2004

Mapping of AFLP markers linked to seed coat colour loci in Brassica juncea (L.) Czern.

Association mapping of the seed-coat colour with amplified fragment length polymorphism (AFLP) markers was carried out in 39 Brassica juncea lines. The lines had genetically diverse parentages and varied for seed-coat colour and other morphological characters. Eleven AFLP primer combinations were used to screen the 39 B. juncea lines, and a total of 335 polymorphic bands were detected. The bands were analysed for association with seed-coat colour using multiple regression analysis. This analysis revealed 15 markers associated with seed-coat colour, obtained with eight AFLP primer combinations. The marker E-ACA/M-CTG(350 )explained 69% of the variation in seed-coat colour. This marker along with markers E-AAC/M-CTC(235 )and E-AAC/M-CTA(250) explained 89% of the total variation. The 15 associated markers were validated for linkage with the seed-coat colour loci using a recombinant inbred line (RIL) mapping population. Bands were amplified with the eight AFLP primer combinations in 54 RIL progenies. Of the 15 associated markers, 11 mapped on two linkage groups. Eight markers were placed on linkage group 1 at a marker density of 6.0 cM, while the remaining three were mapped on linkage group 2 at a marker density of 3.6 cM. Marker E-ACA/M-CTG(350 )co-segregated with Gene1 controlling seed-coat colour; it was specific for yellow seed-coat colour and mapped to linkage group 1. Marker E-AAC/M-CTC(235) (AFLP8), which had been studied previously, was present on linkage group 2; it was specific for brown seed-coat colour. Since AFLP markers are not adapted for large-scale applications in plant breeding, it is important to convert these to sequence-characterised amplified region (SCAR) markers. Marker E-AAC/M-CTC(235) (AFLP8) had been previously converted into a SCAR. Work is in progress to convert the second of the linked markers, E-ACA/M-CTG(350), to a SCAR. The two linked AFLP markers converted to SCARs will be useful for developing yellow-seeded B. juncea lines by means of marker-assisted selection.

Chromosome Mapping↗
PubMed2006

Statistical methods in genetics.

In recent years, a very large variety of statistical methodologies, at various levels of complexity, have been put forward to analyse genotype data and detect genetic variations that may be responsible for increasing the susceptibility to disease. This review provides a concise account of a number of selected statistical methods for population-based association mapping, from single-marker tests of association to multi-marker data mining techniques for gene-gene interaction detection.

Genetic Markers↗
PubMed2005

Cognitive flexibility and decision-making in a model of conditional visuomotor associations.

Arbitrary visuomotor associations map a stimulus onto a particular response upon reinforcing rewards. Changes in the associations between stimuli and responses require the neural networks to discard the already learned mappings and build new ones. This is a key aspect of cognitive flexibility. In addition, learning within this experimental paradigm requires a trial-and-error exploration strategy of the available stimulus-response associations. A system performing this task must be able to both build up mappings for stimulus-response associations and at the same time perform non-deterministically to explore the behavioural space until it reaches certainty. We hypothesize an integrate-and-fire network model that accounts for the neurophysiological data of a conditional visuomotor association task and is able to show non-deterministic behaviour. We aim at identifying multistable attractor regimes in the network dynamics, which intrinsically enable the system to make errors and thereby to perform trial-and-error exploration. Our model combines cognitive flexibility with multistable attractors in neurodynamical systems, believed to be the basis of decision-making. If multistable attractors support the exploration of the behavioural space, then our model predicts that the brain should respond stochastically with correct or incorrect activity to visuomotor associations until it has reached certainty. This should be visible not only in the corresponding activity in the premotor area, but also in activity corresponding to other associations or even other stimuli in the prefrontal cortex.

Algorithms↗
PubMed1999

Intracellular signalling pathways of okadaic acid leading to mitogenesis in Rat1 fibroblast overexpressing insulin receptors: okadaic acid regulates Shc phosphorylation by mechanisms independent of insulin.

Okadaic acid is a powerful inhibitor of serine/threonine protein phosphatases 1 and 2A. Although it is known as a potent tumour promoter, the intracellular mechanism by which okadaic acid mediates its mitogenic effect remains to be clarified. We investigated the effect of okadaic acid on the activation of mitogenesis in Rat1 fibroblasts overexpressing insulin receptors. As previously reported, insulin induced Shc phosphorylation, Shc-Grb2 association, MAP kinase activation, and BrdU incorporation. Okadaic acid also stimulated tyrosine phosphorylation of Shc and its subsequent association with Grb2 in a time- and dose-dependent manner without affecting tyrosine phosphorylation of insulin receptor beta-subunit and IRS. However, to a lesser extent, okadaic acid stimulated MAP kinase activity and BrdU incorporation. Interestingly, preincubation of okadaic acid potentiated insulin stimulation of tyrosine phosphorylation of Shc (213% of control), Shc-Grb2 association (150%), MAP kinase activity (152%), and BrdU incorporation (148%). These results further confirmed the important role of Shc, but not IRS, in cell cycle progression in Rat1 fibroblasts. Furthermore, serine/ threonine phosphorylation appears to be involved in the regulation of Shc tyrosine phosphorylation leading to mitogenesis by mechanisms independent of insulin signalling.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Principles of haplotype mapping and potential applications to attention-deficit/hyperactivity disorder.

Approaches to the study of common, complex genetic disorders like attention-deficit/hyperactivity disorder (ADHD) are evolving rapidly. Traditional linkage and association mapping each have distinct roles to play. Rapid advances in genomic information and technologies make association studies more attractive, including the possibility in the near future of whole genome association scans. This review covers the following broad topics: 1) the principles of linkage and association analyses as they apply to ADHD, and 2) the implications of genome architecture for association studies of complex diseases like ADHD. The structure of linkage disequilibrium is approached through review of the statistical measures of allelic associations and their relationship to observed haplotypes. The patterns of haplotypes across the human genome are discussed, as well as the implications of linkage disequilibrium mapping for association studies in general and ADHD specifically. Finally, the extent to which the allelic architecture of a candidate ADHD gene is publicly available and the web resources to access this information are covered. Today, the wealth of polymorphism data available on the worldwide web enables researchers to focus powerful methodologic tools on candidate genes and regions of interest. Coupling this with larger patient collections and more refined phenotyping will move forward the identification of disease-associated polymorphisms and ultimately the development of genetically based pharmaceuticals and diagnostic tests.

Attention Deficit Disorder with Hyperactivity↗
PubMed2004

Linkage disequilibrium mapping of yield and yield stability in modern spring barley cultivars.

Associations between markers and complex quantitative traits were investigated in a collection of 146 modern two-row spring barley cultivars, representing the current commercial germ plasm in Europe. Using 236 AFLP markers, associations between markers were found for markers as far apart as 10 cM. Subsequently, for the 146 cultivars the complex traits mean yield, adaptability (Finlay-Wilkinson slope), and stability (deviations from regression) were estimated from the analysis of variety trial data. Regression of those traits on individual marker data disclosed marker-trait associations for mean yield and yield stability. Support for identified associations was obtained from association profiles, i.e., from plots of P-values against chromosome positions. In addition, many of the associated markers were located in regions where earlier QTL were found for yield and yield components. To study the oligogenic genetic base of the traits in more detail, multiple linear regression of the traits on markers was carried out, using stepwise selection. By this procedure, 18-20 markers that accounted for 40-58% of the variation were selected. Our results indicate that association mapping approaches can be a viable alternative to classical QTL approaches based on crosses between inbred lines, especially for complex traits with costly measurements.

Bayes Theorem↗
PubMed2006

Functional characterization of human MutY homolog (hMYH) missense mutation (R231L) that is linked with hMYH-associated polyposis.

The MutY homolog (MYH) can excise adenines misincorporated opposite to guanines or 7,8-dihydro-8-oxo-guanines (8-oxoG) during DNA replication; thereby preventing G:C to T:A transversions. Germline mutations in the human MYH gene are associated with recessive inheritance of colorectal adenomatous polyposis (MAP). Here, we characterize one newly identified MAP-associated MYH missense mutation (R231L) that lies adjacent to the putative hMSH6 binding domain. The R231L mutant protein has severe defects in A/GO binding and in adenine glycosylase activities. The mutant fails to complement mutY-deficiency in Escherichia coli, but does not affect binding to hMSH6. These data support the role of the hMYH pathway in carcinogenesis.

Adenomatous Polyposis Coli↗
PubMed1997

Hardness of flip-cut problems from optical mapping.

Optical mapping is a new technology for constructing restriction maps. Associated computational problems include aligning multiple partial restriction maps into a single "consensus" restriction map, and determining the correct orientation of each molecule, which was formalized as the Exclusive Binary Flip Cut (EBFC) Problem in (Muthukrishnan and Parida, 1997). Here we prove that the EBFC problem, as well as a number of its variants, are NP-complete. Therefore, they do not have efficient, that is, polynomial time solutions unless P = NP.

Algorithms↗
PubMed2004

Isolation and mapping of resistance gene analogs from the Avena strigosa genome.

Degenerate primers based on conserved regions of the nucleotide binding site (NBS) domain (encoded by the largest group of cloned plant disease resistance genes) were used to isolate a set of 15 resistance gene analogs (RGA) from the diploid species Avena strigosa Schreb. These were grouped into seven classes on the basis of 60% or greater nucleic acid sequence identity. Representative clones were used for genetic mapping in diploid and hexaploid oats. Two RGAs were mapped at two loci of the linkage group AswBF belonging to the A. strigosa x A. wiestii Steud map, and ten RGAs were mapped at 15 loci in eight linkage groups belonging to the A. byzantina C. Koch cv. Kanota x A. sativa L. cv. Ogle map. A similar approach was used for targeting genes encoding receptor-like kinases. Three different sequences were obtained and mapped to two linkage groups of the hexaploid oat map. Associations were explored between already known disease resistance loci mapped in different populations and the RGAs. Molecular markers previously linked to crown rust and barley yellow dwarf resistance genes or quantitative trait loci were found in the Kanota x Ogle map linked to RGAs at a distance ranging from 0 cM to 20 cM. Homoeologous RGAs were found to be linked to loci either conferring resistance to different isolates of the same pathogen or to different pathogens. This suggests that these RGAs identify genome regions containing resistance gene clusters.

Amino Acid Sequence↗
PubMed2006

Identification of EFHC2 as a quantitative trait locus for fear recognition in Turner syndrome.

One-third of women with Turner syndrome (45,X) have autism-like social and communication difficulties, despite normal verbal IQ. Deletion mapping of the X-chromosome implicated 5 Mb of Xp11.3-4 as critical for recognition of facial fear, a quantitative measure of social cognition. Variability in fear recognition accuracy in Turner syndrome suggested the existence of a quantitative trait locus (QTL) revealed by X-monosomy. We aimed to identify the gene(s) influencing fear recognition by dense mapping of the 5 Mb region. Initial regression-based association mapping of fear recognition in 93 women with Turner syndrome across the critical region was performed, using genotype data at 242 single nucleotide polymorphisms (SNPs). We identified three regions of interest, in which 52 additional SNPs were genotyped. The third region then contained four SNPs associated with fear recognition (0.0030 > P > 0.00046). We obtained an independent sample of 77 Turner syndrome females that we genotyped for 77 SNPs in the initial regions of interest. Region three showed association in the same direction, maximal at SNPs rs7055196 and rs7887763 (P = 0.022 each). Four SNPs in strong linkage disequilibrium (LD), including this pair, span 40 kb within a novel transcript, EF-hand domain containing 2 (EFHC2). In the combined Turner syndrome samples, the most strongly associated SNP (P = 0.00007) has frequency of 8.8% and an estimated effect size accounting for over 13% of the variance in fear recognition. EFHC2 shows genealogy and extended LD consistent with directional selection. This novel QTL may influence social cognition in the general population and in autism.

Chromosome Mapping↗
PubMed1986

Vasopressin excess: relative contribution of volume retention versus direct actions on renin secretion and sodium excretion.

Three groups of dogs were studied to determine to what extent the suppression of plasma renin activity (PRA), natriuresis, and hyponatremia, seen with chronic elevations of plasma vasopressin (AVP), were caused by volume expansion or some other more direct actions of AVP. The dogs of group 1 (n = 7) were infused with AVP (0.36 ng/kg/min, i.v.) for 2 weeks, while water intake was maintained at a constant level. The dogs of group 2 (n = 6) were permitted to drink ad libitum during AVP infusion. The dogs of group 3 (n = 7) were infused with AVP while total body weight and volume were maintained at a constant level by use of an electronically servocontrolled water infusion system. Group 1, with fixed water intake, retained a large fluid volume (1.4 L), with an associated 36 mm Hg rise in mean arterial blood pressure (MAP). Associated with this hypertension and increased volume were a suppression of PRA and substantial decreases in plasma sodium concentration with increased excretion of sodium. With ad libitum drinking (group 2), only mild volume expansion occurred, with no significant elevations of MAP or changes in sodium excretion. With a volume expansion of 300-400 ml, there was a significant decrease of PRA and plasma sodium concentration. Group 3, servocontrolled dogs, exhibited no change in MAP, plasma sodium concentration, or PRA throughout the 2-week period of AVP infusion. Sodium excretion was mildly elevated only on the first day of AVP infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Association of microtubule-associated protein 2 (MAP 2) with microtubules and intermediate filaments in cultured brain cells.

The classification of MAP 2 as a microtubule-associated protein is based on its affinity for microtubules in vitro and its filamentous distribution in cultured cells. We sought to determine whether MAP 2 is also able to bind in situ to organelles other than microtubules. For this purpose, primary cultures of rat brain cells were stained for immunofluorescence microscopy with a rabbit anti-MAP 2 antibody prepared in our laboratory, as well as with antibodies to vimentin, an intermediate filament protein, and to tubulin, the major subunit of microtubules. MAP 2 was present on cytoplasmic fibers in neurons and in a subpopulation of the flat cells present in the cultures. Our observations were concentrated on the flat cells because of their suitability for high-resolution immunofluorescence microscopy. Double antibody staining revealed co-localization of MAP 2 with both tubulin and vimentin in the flat cells. Pretreatment of the cultures with vinblastine resulted in the redistribution of MAP 2 into perinuclear cables that contained vimentin. Tubulin paracrystals were not stained by anti-MAP 2. In cells extracted with digitonin, the normal fibrillar distribution of MAP 2 was resistant to several treatments (PIPES buffer plus 10 mM Ca++, phosphate buffer at pH 7 or 9) that induced depolymerization of microtubules, but not intermediate filaments. Staining of the primary brain cells was not observed with preimmune serum nor with immune serum adsorbed prior to use with pure MAP 2. We detected MAP 2 on intermediate filaments not only with anti-MAP 2 serum, but also with affinity purified anti-MAP 2 and with a monoclonal anti-MAP 2 prepared in another laboratory. We conclude from these experiments that material recognized by anti-MAP 2 antibodies associates with both microtubules and intermediate filaments. We propose that one function of MAP 2 is to cross-link the two types of cellular filaments.

Animals↗
PubMed1989

Characterization of proteins immunologically related to brain microtubule-associated protein MAP-1B in non-neural cells.

Brain microtubule-associated protein MAP-1 is composed of at least two polypeptides, MAP-1A and MAP-1B, which are among the main components of the neural cytoskeleton. Specific monoclonal and polyclonal antibodies against MAP-1B stain nuclei, mitotic spindles, centrosomes and the cytoplasmic microtubule network of different non-neural cells studied by immunofluorescence microscopy. It appears that these cells contain two proteins of 325K and 220K (K = 10(3) Mr), which are immunologically related to brain MAP-1B. The 325K protein, which is localized to the cytoplasmic microtubule network, the centrosome and the mitotic spindle, seems to be structurally related to the neural MAP-1B, as judged from their similar peptide maps and phosphorylation patterns. The 220K protein, which is localized to the nuclear matrix in interphase cells and to the mitotic spindle in dividing cells, has a proteolytic profile different from that of neural MAP-1B and is phosphorylated to a much lesser extent than the 325K protein. Both proteins bind tubulin in vitro, which suggests that they may participate in microtubule assembly in vivo; the 325K protein could perform such a role during the entire cell cycle, while the 220K protein could be implicated in the formation of the mitotic spindle.

Amino Acids↗
PubMed1999

Upregulation and redistribution of E-MAP-115 (epithelial microtubule-associated protein of 115 kDa) in terminally differentiating keratinocytes is coincident with the formation of intercellular contacts.

Microtubules are involved in the positioning and movement of organelles and vesicles and therefore play fundamental roles in cell polarization and differentiation. Their organization and properties are cell-type specific and are controlled by microtubule-associated proteins (MAP). E-MAP-115 (epithelial microtubule-associated protein of 115 kDa) has been identified as a microtubule-stabilizing protein predominantly expressed in epithelial cells. We have used human skin and primary keratinocytes as a model to assess a putative function of E-MAP-115 in stabilizing and reorganizing the microtubule network during epithelial cell differentiation. Immunolabeling of skin sections indicated that E-MAP-115 is predominantly expressed in the suprabasal layers of the normal epidermis and, in agreement with this observation, is relatively abundant in squamous cell carcinomas but barely detectable in basal cell carcinomas. In primary keratinocytes whose terminal differentiation was induced by increasing the Ca2+ concentration of the medium, E-MAP-115 expression significantly increased during the first day, as observed by northern and western blot analysis. Parallel immunofluorescence studies showed an early redistribution of E-MAP-115 from microtubules with a paranuclear localization to cortical microtubules organized in spike-like bundles facing intercellular contacts. This phenomenon is transient and can be reversed by Ca2+ depletion. Treatment of cells with cytoskeleton-active drugs after raising the Ca2+ concentration indicated that E-MAP-115 is associated with a subset of stable microtubules and that the cortical localization of these microtubules is dependent on other microtubules but not on strong interactions with the actin cytoskeleton or the plasma membrane. The mechanism whereby E-MAP-115 would redistribute to and stabilize cortical microtubules used for the polarized transport of vesicles towards the plasma membrane, where important reorganizations take place upon stratification, is discussed.

Humans↗
PubMed2001

Linkage disequilibrium in humans: models and data.

In this review, we describe recent empirical and theoretical work on the extent of linkage disequilibrium (LD) in the human genome, comparing the predictions of simple population-genetic models to available data. Several studies report significant LD over distances longer than those predicted by standard models, whereas some data from short, intergenic regions show less LD than would be expected. The apparent discrepancies between theory and data present a challenge-both to modelers and to human geneticists-to identify which important features are missing from our understanding of the biological processes that give rise to LD. Salient features may include demographic complications such as recent admixture, as well as genetic factors such as local variation in recombination rates, gene conversion, and the potential segregation of inversions. We also outline some implications that the emerging patterns of LD have for association-mapping strategies. In particular, we discuss what marker densities might be necessary for genomewide association scans.

Chromosome Mapping↗
PubMed1999

Multipoint linkage disequilibrium mapping with particular reference to the African-American population.

A new approach to scanning the genome is presented to detect linkage disequilibrium caused specifically by population admixture. In contrast to current linkage genome scanning methods to find causal genes for complex diseases, this new method should be powerful to find genes for multilocus traits, particularly those genes that lead to the highest population attributable risk. Such a scan using the African-American population is generally feasible for mapping common diseases. A conservative threshold is also provided for such association mapping.

Alleles↗