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PubMed1993

Early systemic and renal responses to nephrectomy in normotensive kidney donors.

The present studies were designed to assess the effect of uninephrectomy (UNX) on arterial pressure and renal excretory function in normal subjects. Baseline values of arterial pressure, renal function, parameters of the renin-angiotensin and renal kallikrein-kinin systems and the response to acute saline loading (VE, 1800 ml in 3 h) were estimated in 18 kidney donors prior to and 1 year following UNX. Within the follow-up period of 14 +/- 1 months mean arterial pressure (MAP) increased by 7 +/- 2 mmHg, creatinine clearance decreased by 38 +/- 4%, plasma renin activity (PRA) decreased, urinary kallikrein remained unchanged, and the renal response to VE was blunted. According to individual changes in MAP associated with UNX, subjects were classified as responders (R, increase in MAP > or = 10%, n = 8) and non-responders (NR, n = 10). Age, incidence of a family history of hypertension, decrease in creatinine clearance, and predonation PRA, urinary kallikrein, and the natriuretic response to VE were similar in the two groups. However, following UNX, PRA decreased whereas 24-h urinary sodium and thus sodium intake increased only in the R group. In conclusion, in normotensive subjects a 50% reduction in renal mass may result in a consistent increase in MAP and sometimes the development of de novo hypertension (4/18 subjects). Baseline characteristics as well as the predonation renal response to VE do not provide a means of detecting kidney donors in whom arterial pressure will increase consistently after UNX.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2006

Multipoint linkage-disequilibrium mapping with haplotype-block structure.

The HapMap Project is providing a great deal of new information on high-resolution haplotype structure in various human populations. This information has the potential to greatly increase the power of association mapping for a fixed amount of genotyping. A number of methods have been proposed for the identification of haplotype blocks, common haplotypes, and tagging single-nucleotide polymorphisms. Here, we build on this work by developing novel methods for case-control multipoint linkage-disequilibrium (LD) mapping that gain power and speed by making explicit use of the inferred block structure. Specifically, we developed a virtual-variant approach that uses the haplotype-block information to greatly increase power for detection of untyped common variants associated with a trait. Because full multipoint LD mapping can be slow, we exploited the haplotype-block information to develop a fast single-block multipoint mapping method. Our methods are appropriate for genotype data and take into account the uncertainty in phase. We describe the methods in the context of case-parents trios, although they are also applicable to unrelated cases and controls. Our simulations indicate that the most important gains from taking into account the haplotype-block structure at the analysis stage of multipoint LD mapping come from (1) greatly increased power to detect association with untyped variants and (2) greatly improved localization of untyped variants associated with the trait. More-modest gains are obtained in improving power to detect association with a variant that is typed with a moderate amount of missing data. The methods are applied to a Crohn disease data set.

Algorithms↗
PubMed1971

An M-associated protein antigen (MAP) of group A streptococci.

A streptococcal antigen that is closely associated with the M-antigen, but is not type specific can be detected by means of a complement-fixation test in extracts of M-positive, but not of M-negative, variants of group A streptococci. Purification of acid extracts results in a concomitant increase in the purity both of the type-specific M-antigen and of the M-associated protein (MAP). Antibody to MAP is present in the sera of patients who have had streptococcal infection. The highest titres are found in patients with rheumatic fever.

Antigens↗
PubMed2006

Identification of genetic loci associated with ear-emergence in bread wheat.

A doubled haploid population constructed from a cross between the South Australian wheat cultivars 'Trident' and 'Molineux' was grown under winter field conditions, under field conditions over summer and under artificial light both with and without vernalisation. The duration from planting to ear-emergence was recorded and QTL associated with heading date were detected using a previously constructed genetic linkage map. Associations were shown with chromosomal regions syntenous to previously identified photoperiod (Ppd-B1) and vernalisation (Vrn-A1) sensitive loci. Additional QTL associated with time to heading were also identified on chromosomes 1A, 2A, 2B, 6D, 7A and 7B. Comparisons between the genetic associations observed under the different growing conditions allowed the majority of these loci to be classified as having either photoperiod-sensitive, vernalisation-sensitive or earliness per se actions. The identification of a photoperiod-sensitive QTL on chromosome 1A provides evidence for a wheat gene possibly homoeologous to Ppd-H2 previously identified on chromosome 1H of barley. The occurrence of a putative major gene for photoperiod sensitivity observed on chromosome 7A is presented. The combined additive effects at these loci accounted for more than half the phenotypic variance in the duration from planting to ear-emergence in this population. The possible role of these loci on the adaptation of wheat in Australia is discussed.

Chromosomes, Plant↗
PubMed2006

Phenotypic variation and natural selection at catsup, a pleiotropic quantitative trait gene in Drosophila.

Quantitative traits are shaped by networks of pleiotropic genes . To understand the mechanisms that maintain genetic variation for quantitative traits in natural populations and to predict responses to artificial and natural selection, we must evaluate pleiotropic effects of underlying quantitative trait genes and define functional allelic variation at the level of quantitative trait nucleotides (QTNs). Catecholamines up (Catsup), which encodes a negative regulator of tyrosine hydroxylase , the rate-limiting step in the synthesis of the neurotransmitter dopamine, is a pleiotropic quantitative trait gene in Drosophila melanogaster. We used association mapping to determine whether the same or different QTNs at Catsup are associated with naturally occurring variation in multiple quantitative traits. We sequenced 169 Catsup alleles from a single population and detected 33 polymorphisms with little linkage disequilibrium (LD). Different molecular polymorphisms in Catsup are independently associated with variation in longevity, locomotor behavior, and sensory bristle number. Most of these polymorphisms are potentially functional variants in protein coding regions, have large effects, and are not common. Thus, Catsup is a pleiotropic quantitative trait gene, but individual QTNs do not have pleiotropic effects. Molecular population genetic analyses of Catsup sequences are consistent with balancing selection maintaining multiple functional polymorphisms.

Animals↗
PubMed2004

Nucleotide polymorphism and linkage disequilibrium within and among natural populations of European aspen (Populus tremula L., Salicaceae).

Populus is an important model organism in forest biology, but levels of nucleotide polymorphisms and linkage disequilibrium have never been investigated in natural populations. Here I present a study on levels of nucleotide polymorphism, haplotype structure, and population subdivision in five nuclear genes in the European aspen Populus tremula. Results show substantial levels of genetic variation. Levels of silent site polymorphisms, pi(s), averaged 0.016 across the five genes. Linkage disequilibrium was generally low, extending only a few hundred base pairs, suggesting that rates of recombination are high in this obligate outcrossing species. Significant genetic differentiation was found at all five genes, with an average estimate of F(ST) = 0.116. Levels of polymorphism in P. tremula are 2- to 10-fold higher than those in other woody, long-lived perennial plants, such as Pinus and Cryptomeria. The high levels of nucleotide polymorphism and low linkage disequilibrium suggest that it may be possible to map functional variation to very fine scales in P. tremula using association-mapping approaches.

Genes, Plant↗
PubMed1992

The role of microtubule-associated protein 2 (MAP-2) in neuronal growth, plasticity, and degeneration.

Microtubule associated protein 2 (MAP-2) historically has been perceived primarily as a static, structural protein, necessary along with other cytoskeletal proteins to maintain neuroarchitecture but somewhat removed from the "mainstream" of neuronal response mechanisms. Quite to the contrary, MAP-2 is exquisitely sensitive to many inputs and recent investigations have revealed dynamic functions for MAP-2 in the growth, differentiation, and plasticity of neurons, with key roles in neuronal responses to growth factors, neurotransmitters, synaptic activity, and neurotoxins. These discoveries indicate that modification and rearrangement of MAP-2 is an early obligatory step in many processes which modify neuronal function.

Aging↗
PubMed1990

Hemodynamic status susceptible to slowing of heart rate during thermodilution cardiac output determination in anesthetized patients.

To identify hemodynamic variables that might indicate susceptibility to slowing of heart rate (HR) and to mean arterial pressure (MAP) decrease caused by cold injectate during thermodilution (TD) cardiac output determination, we measured hemodynamic variables in 32 anesthetized patients undergoing major surgery. A total of 608 cardiac output determinations were evaluated for any relationship between the magnitude of HR decreases and basal hemodynamic variables. The magnitude of HR decrease was pronounced in low cardiac index (CI), low mean pulmonary artery pressure (MPAP), and high systemic vascular resistance index (SVRI). Although there was some decrease in MAP associated with cold injectate, neither changes in SVRI nor those in the other hemodynamic variables correlated with the decreases in MAP. These results suggest that decreased CI and MPAP associated with elevated SVRI may be more susceptible to slowing of HR during cardiac output determination by TD in anesthetized patients.

Adult↗
PubMed2005

Integrated study of topographical functional maps based on an auditory comprehension paradigm using an eigensystem study and spectrum analysis.

This study integrates a spectral analysis of key frequency bands (Alpha, Beta, Delta, and Theta) with an eigensystem-based study in order to validate brain functional mappings associated with the characterization effects of an Auditory/Comprehension paradigm. This numerical characterization supported by topographic functional maps brings added insight in the involvement of the Wernicke and Broca's brain areas to language comprehension. A thorough examination of EEG recordings through the eigensystem reveals that eigenvectors associated with the largest eigenvalues produce an interesting activity pattern located in the frontal area of the brain directly attributable to those characteristic behaviors found in the Alpha, Beta, Delta, and Theta frequency bands. An evaluation of spectral arrays is performed using topographic maps of the induced brain activities during both listening and answering phases. This evaluation is then augmented with quantifying measures using the eigensystem study while results are validated through integration of EEG activity and eigensystem modalities. Such a representation can provide insightful information on how different patients react during an auditory and response phases, and in the ability to detect the presence of potential neurological disorders by assessing similar/dissimilar behaviors with respects to all former patients already included in the database. The algorithm as developed in this study could be extended in its application to other brain functional mapping tasks given its simple but effective practical mathematical foundation.

Acoustic Stimulation↗
PubMed2004

Mapping genes for common diseases: the case for genetic (LD) maps.

We examine the current effort to develop a haplotype map of the human genome and suggest an alternative approach which represents linkage disequilibrium patterns in the form of a metric LD map. LD maps have some of the useful properties of genetic linkage maps but have a much higher resolution which is optimal for SNP-based association mapping of common diseases. The studies that have been undertaken to date suggest that LD and recombination maps show some close similarities because of abundant, narrow, recombination hot spots. These hot spots are co-localised in all populations but, unlike linkage maps, LD maps differ in scale for different populations because of differences in population history. The prospects for developing optimized panels of SNPs and the use of linkage disequilibrium maps in disease gene localisation are assessed in the light of recent evidence.

Chromosome Mapping↗
PubMed1991

c-yes protein kinase is associated with a 38 kD protein in cerebellum.

p62c-yes, the protein product of the yes proto-oncogene, was found in association with a cellular protein of 38 kD in chicken cerebella. The complex was detected by immunoprecipitation of cerebellar membranes with affinity purified anti-yes IgG followed by in vitro phosphorylation of the immunocomplex. Both proteins were found to be phosphorylated exclusively on tyrosine. The sedimentation profile of the yes kinase indicated that a fraction of p62c-yes was complexed with the 38 kD protein and comigrated in the gradient with a molecular mass of approximately 150 kD. We have previously described the association of p60c-src with a 38 kD protein, referred to as p38 [Grandori, C. and Hanafusa, H., J. Cell Biol. (1988), 107: 2125-2135]. Comparison of the src-associated p38 with the yes-associated 38 kD protein indicates that they are indistinguishable by one-dimensional peptide mapping. Association of p38 with more than one member of the src-family of tyrosine kinases makes this protein an attractive probe to study the structural and functional aspects of these enzymes.

Animals↗
PubMed1989

Microtubule formation and neurite growth in cerebellar macroneurons which develop in vitro: evidence for the involvement of the microtubule-associated proteins, MAP-1a, HMW-MAP2 and Tau.

The relationship between the expression of microtubule-associated proteins (MAPs) and microtubule formation was studied in embryonic cerebellar macroneurons maintained in culture. The results obtained suggest that in these neurons high molecular weight-MAP2 (HMW-MAP2) acts as a promoter of tubulin assembly since its induction and pattern of distribution are highly correlated with the increase in microtubule mass which parallels axonal and dendritic growth; MAP-1a may have a similar role but restricted to the assembly of dendritic microtubules. On the other hand, Tau expression and accumulation follows a time course identical to that of the induction of stable microtubules; besides, at all stages of neurite differentiation and growth this protein seems to be preferentially associated with this subset of microtubules as opposed to the other MAPs, observations which suggest an important role for this protein in determining microtubule stability during axonal and dendritic elongation. Finally, the present results show that environmental stimuli are capable of regulating the expression of these MAPs; the induction of each of them varies as a function of the type of signal. Thus, while diffusable substances are able to dramatically induce HMW-MAP2, MAP-1a and Tau inductions depend on cell substrate attachment and/or cell-cell interactions.

Animals↗
PubMed2003

Behavioural and electrophysiological correlates of visuomotor learning during a visual search task.

Visuomotor association learning involves learning specific motor responses to arbitrary cues, and is dependent on a distributed and highly flexible network in the brain. We investigated the behavioural and electrophysiological correlates of arbitrary visuomotor learning in 20 normal participants. An experimental group learned an arbitrary association between a visual stimulus and a motor response during a training block. Their performance was compared with that of untrained controls on a subsequent visual discrimination task in which the learned association was a crucial element. Event-related brain potentials (ERPs) were recorded from the scalp of each participant during learning and discrimination blocks. Reaction times to stimuli in the discrimination task were significantly faster in the trained group compared to controls. There was a corresponding difference in the ERP waveforms recorded during the task, with larger P3b amplitude for the trained group over midline and centroparietal scalp areas. A latency difference in P3b was also observed for trained targets compared to distractors. RTs during the training block decreased in a manner consistent with learning effects. We conclude that training of a visuomotor association facilitates subsequent performance on a related task, and that the waveform correlates found here may reflect the involvement of parts of the network underlying arbitrary association mapping.

Adult↗
PubMed2002

A whole genome screen for linkage disequilibrium in multiple sclerosis confirms disease associations with regions previously linked to susceptibility.

Linkage analysis in multiplex families has provisionally identified several genomic regions where genes influencing susceptibility to multiple sclerosis are likely to be located. It is anticipated that association mapping will provide a higher degree of resolution, but this more powerful approach is limited by the substantial genotyping effort required. Here, we describe the first use of DNA pooling to screen the whole genome for association in multiple sclerosis based on a 0.5 cM map of microsatellite markers and using four DNA pools derived from cases (n = 216), controls (n = 219) and trio families (n = 745 affected individuals and their 1490 parents). The 10 markers showing the greatest evidence for association with multiple sclerosis that emerge from this analysis include three from the HLA region on chromosome 6p (D6S1615, D6S2444 and TNFa), providing a positive control for the method, four from regions previously identified by linkage analysis in UK multiplex families (two mapping to chromosome 17q GCT6E11 and D17S1535; one to chromosome 1p GGAA30B06; and one to 19q D19S585), and three from novel sites with respect to linkage analysis (D1S1590 at 1q; D2S2739 at 2p; and D4S416 at 4q). Our results thus provide further supporting evidence for the candidature of 6p, 17q, 19q and 1p as regions encoding susceptibililty genes for multiple sclerosis. The protocol used in this UK-based study is now being extended to 18 additional sites in Europe in order to search for susceptibility genes shared between populations of common ancestry, as well as those that exert ethnically more restricted effects.

Adult↗
PubMed2006

The effective size of the Icelandic population and the prospects for LD mapping: inference from unphased microsatellite markers.

Characterizing the extent of linkage disequilibrium (LD) in the genome is a pre-requisite for association mapping studies. Patterns of LD also contain information about the past demography of populations. In this study, we focus on the Icelandic population where LD was investigated in 12 regions of approximately 15 cM using regularly spaced microsatellite loci displaying high heterozygosity. A total of 1753 individuals were genotyped for 179 markers. LD was estimated using a composite disequilibrium measure based on unphased data. LD decreases with distance in all 12 regions and more LD than expected by chance can be detected over approximately 4 cM in our sample. Differences in the patterns of decrease of LD with distance among genomic regions were mostly due to two regions exhibiting, respectively, higher and lower proportions of pairs in LD than average within the first 4 cM. We pooled data from all regions, except these two and summarized patterns of LD by computing the proportion of pairs of loci exhibiting significant LD (at the 5% level) as a function of distance. We compared observed patterns of LD with simulated data sets obtained under scenarios with varying demography and intensity of recombination. We show that unphased data allow to make inferences on scaled recombination rates from patterns of LD. Patterns of LD in Iceland suggest a genome-wide scaled recombination rate of rho* = 200 (130-330) per cM (or an effective size of roughly 5000), in the low range of estimates recently reported in three populations from the HapMap project.

Biological Evolution↗
PubMed2026

Genetic architecture and evolution of stripe rust resistance uncovered using diverse panels of wheat lines and North American Puccinia striiformis f. sp. tritici isolates.

Screening global wheat germplasm with a diverse collection of pathogen races expands the catalog of novel Yr loci and identifies new sources of broad-spectrum resistance against evolving Pst populations. Newly emerging highly virulent races of Puccinia striiformis f. sp. tritici (Pst) often defeat deployed resistance genes (Yr), highlighting the need for novel sources of durable resistance. A global diversity panel of 377 spring wheat (Triticum aestivum L.) lines was screened for all-stage resistance (ASR) against a panel of diverse 20 Pst isolates at the seedling stage and for adult-plant-stage resistance (APR) against natural mix of field races. Genome-wide association mapping identified 77 unique Yr loci. Of these, 34 overlapped with the previously mapped 1150 Yr loci, confirming the robustness of our GWAS results, while 43 were likely novel. Comparison of the nine adult-plant-stage Yr loci mapped in our study with known APR genes identified only one overlap, with Yr29. Except for Yr29, APR genes Yr18 and Yr36 were detected at low frequencies, indicating that resistance in our panel may arise from less characterized or novel sources. Two wheat lines, lacking widely effective Yr5 and Yr15 alleles, exhibited resistance to all 20 Pst races at the seedling stage and natural field races at the adult stage, suggesting that they may carry novel, broad-spectrum ASR alleles. Wheat improvement had no effect on the frequency of ASR alleles but resulted in a threefold increase in the frequency of APR alleles, suggesting that the latter were subjected to more consistent breeding selection over time. Our findings underscore the value of combined screening of diverse germplasm with diverse pathogen races to identify novel sources of broad-spectrum resistance for breeding stripe rust resistant cultivars.

Triticum↗
PubMed2002

Plant molecular diversity and applications to genomics.

Surveys of nucleotide diversity are beginning to show how genomes have been shaped by evolution. Nucleotide diversity is also being used to discover the function of genes through the mapping of quantitative trait loci (QTL) in structured populations, the positional cloning of strong QTL, and association mapping.

Chromosome Mapping↗
PubMed2000

Obesity in young Europeans: genetic and environmental influences.

BACKGROUND: Nutrition, lifestyles and genetics are increasingly involved in the maintenance of health and the prevalence of several non-communicable diseases, such as cardiovascular illnesses, diabetes, cancer etc. In this context, obesity appears as a complex multi-factorial condition resulting from an imbalance between energy intake and expenditure, which has been associated with the genetic background (more than 50 genes have been located in the human gene map associated to obesity), but also with environmental forces such as reduced physical activity (more than 60% of Europeans spend more than 3 h sitting at work) and with the over-consumption of fat-rich and high energy yielding foods (fat oxidation is poorly regulated as compared with other fuel substrates). SUBJECTS: Furthermore, subject selection was quota-controlled to make the sample nationally representative by various socio-demographic factors based on the most recent official statistics (census data) in each member state. Overall, there were 15,239 subjects older than 15 y in the EU (17% of them were younger than 24 y old). RESULTS: The obesity problem appears to be increasing rapidly in children and adolescents as well as in adults with an average rate of obese subjects of about 10% in the European Union, however several factors should be taken into consideration, such as the cut-off references, the age group and the conditions of the data collection when processing the information about obesity prevalence. CONCLUSIONS: Management of the increasing epidemic of obesity in young people must involve prevention strategies concerning nutritional education and physical activity programmes.

Adolescent↗