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PubMed1997

Dominant negative mutants of TRAF3 reveal an important role for the coiled coil domains in cell death signaling by the lymphotoxin-beta receptor.

Ligation of the lymphotoxin-beta receptor (LTbetaR) recruits tumor necrosis factor receptor-associated factor-3 (TRAF3) and initiates cell death in HT29 adenocarcinoma cells. The minimal receptor binding domain (TRAF-C) defined by two hybrid analyses is not sufficient for direct recruitment to the ligated receptor. A series of TRAF3 deletion mutants reveal that a subregion of the coiled coil motif is required for efficient recruitment to the LTbetaR. Furthermore, the ability of TRAF3 to self-associate maps to an adjacent subregion. A TRAF3 deletion mutant that lacks the N-terminal zinc RING and zinc finger motifs, but retains the coiled coil and TRAF-C motifs, competitively displaces endogenous TRAF3 from the LTbetaR. A second TRAF3 mutant that lacks the receptor binding domain, yet contains the TRAF3 self-association domain, prevents TRAF3 homodimers from being recruited to the LTbetaR. Both of these mutants have a dominant negative effect on cell death and demonstrate that the recruitment of TRAF3 oligomers is necessary to initiate signal transduction that activates the cell death pathway.

Apoptosis↗

PubMed2005

Lysophosphatidic acid mediates pleiotropic responses in skeletal muscle cells.

Lysophosphatidic acid (LPA) is a potent modulator of growth, cell survival, and apoptosis. Although all four LPA receptors are expressed in skeletal muscle, very little is known regarding the role they play in this tissue. We used RT-PCR to demonstrate that cultured skeletal muscle C2C12 cells endogenously express multiple LPA receptor subtypes. The demonstration that LPA mediates the activation of ERK1/2 MAP kinase and Akt/PKB in C2C12 cells is consistent with the widely observed mitogenic properties of LPA. In spite of these observations, LPA did not induce proliferation in C2C12 cells. Paradoxically, we found that prolonged treatment of C2C12 cells with LPA led to caspase 3 and PARP cleavage as well as the activation of stress-associated MAP kinases JNK and p38. In spite of these typically pro-apoptotic responses, LPA did not induce cell death. Blocking ERK1/2 and Akt/PKB activation with specific pharmacological inhibitors, nevertheless, stimulated LPA-mediated apoptosis. Taken together, these results suggest that both mitogenic and apoptotic responses serve to counterbalance the effects of LPA in cultured C2C12 cells.

Animals↗

PubMed2004

An integrated auditory-comprehension process augmented through topographical maps and a new eigensystem study.

The algorithm developed in this study integrates a frequency analysis of key frequency bands (Alpha, Beta, Delta, and Theta) with the principal component analysis (PCA) in order to validate brain functional mappings associated with the characterization effects of an Auditory/Comprehension task. This study provides added insight to earlier findings involving the Wernicke and Broca's brain areas in relation to language comprehension. A thorough examination of the electroencephalograph (EEG) recordings through the PCA reveals that eigenvectors associated with the largest eigenvalues produce an interesting activity pattern directly attributable to those characteristic behaviors found in the Alpha, Beta, Delta, and Theta frequency bands. The clinical EEG data involved 9 patients at Miami Children's Hospital using the Electrical Source Imaging system with 256 electrodes. 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 PCA while results are validated through integration of EEG and PCA modalities. Such a representation allows us to bring new insight out on how different patients react under different circumstances, and be able to detect consequently the presence of potential neurological disorders by assessing similar/dissimilar behaviors with respects to all former patients already included in the database. The good results obtained are foreseen to extend the algorithm's application to other brain functional mapping tasks.

Algorithms↗

PubMed1997

The human gene encoding FKBP-rapamycin associated protein (FRAP) maps to chromosomal band 1p36.2.

FKBP-rapamycin associated protein (FRAP) is a phosphatidylinositol kinase (PIK)-related kinase implicated in the inhibition of progression through G1 of the cell cycle. The PIK-related kinases are a growing family of proteins involved in cell-cycle checkpoints, DNA repair and recombination. We have mapped the human FRAP gene to chromosome 1p36.2, a region consistently deleted in neuroblastomas.

Base Sequence↗

PubMed2002

Mutation screening and LD mapping in the VCFS deleted region of chromosome 22q11 in schizophrenia using a novel DNA pooling approach.

We examined whether variation within six genes from the VCFS critical region at 22q11 (DGSC, Stk22A1, DGSI, Gscl, Slc25A1 and Znf74) confers susceptibility to schizophrenia. We screened the exons and flanking intronic sequence of each gene for mutations in 14 individuals with DSM-IV schizophrenia using DHPLC. All polymorphisms identified were characterised and genotyped in a sample of 184 schizophrenics and matched controls, using novel DNA pooling methods. Of the polymorphisms identified, 17 were located within exons, six were within coding sequence, and two were non-synonymous. Pooled genotyping revealed no differences in the allele frequencies for any polymorphism between cases and controls that met our pre-defined criterion (P < or = 0.1). In a complementary approach we also attempted to define the location of a schizophrenia susceptibility locus more precisely by performing association mapping using seven microsatellites spanning the VCFS region with an average inter-marker distance of 450 kb. Conventional chi(2) analysis of genotypes in 368 cases and 368 controls revealed that none of the markers was significantly associated (P < 0.05) with schizophrenia. However, evidence for significant association (P = 0.003) was obtained for D22S944 when alleles were combined. TDT analysis of D22S944 genotyped in a further 278 cases of schizophrenia and their parents failed to find any overall allele-wise significant transmission disequilibrium (chi(2) = 18.3, P = 0.17). However, individual analysis of the alleles revealed that allele 12 was excessively non-transmitted and that this almost reached significance when corrected for multiple alleles (chi(2) = 7.35, P = 0.006, P = 0.078 corrected for 13 alleles).

Chromosome Deletion↗

PubMed2000

An optimized set of human telomere clones for studying telomere integrity and architecture.

Telomere-specific clones are a valuable resource for the characterization of chromosomal rearrangements. We previously reported a first-generation set of human telomere probes consisting of 34 genomic clones, which were a known distance from the end of the chromosome ( approximately 300 kb), and 7 clones corresponding to the most distal markers on the integrated genetic/physical map (1p, 5p, 6p, 9p, 12p, 15q, and 20q). Subsequently, this resource has been optimized and completed: the size of the genomic clones has been expanded to a target size of 100-200 kb, which is optimal for use in genome-scanning methodologies, and additional probes for the remaining seven telomeres have been identified. For each clone we give an associated mapped sequence-tagged site and provide distances from the telomere estimated using a combination of fiberFISH, interphase FISH, sequence analysis, and radiation-hybrid mapping. This updated set of telomeric clones is an invaluable resource for clinical diagnosis and represents an important contribution to genetic and physical mapping efforts aimed at telomeric regions.

Chromosomes, Artificial, Yeast↗

PubMed2006

A novel locus on the X chromosome regulates post-maturity bone density changes in mice.

Two mouse strains, AKR/J and SAMP6, were assessed longitudinally for bone mineral density of the spine. They displayed very different time courses of bone accrual, with the SAMP6 strain reaching a plateau for vertebral BMD at 3 months, whereas AKR/J mice continued to increase spine BMD for at least 8 months. Among 253 F(2) progeny of an AKR/JxSAMP6 cross, at 4 months of age, the BMD variance was 5-6% of the mean, vs. 15% for weight. Variance increased with age for every parameter measured, and was generally higher among males. The ratio of 6-month/4-month spine BMDs, termed DeltasBMD, had a normal distribution with 5.7% variance, and was largely independent of spine BMD (R=-0.23) or body weight (R=-0.12) at maturity. Heritability of the DeltasBMD trait was calculated at 0.59. Genetic mapping identified two significant loci, both distinct from those observed for BMD at maturity--implying that different genes regulate skeletal growth vs. remodeling. A locus on the X chromosome, replicated in two mouse F(2) populations (P<10(-4) for combined discovery and confirmation), affects age-dependent BMD change for both spine and the full skeleton. Its position agrees with a very narrow region identified by association mapping for effects on lumbar bone density in postmenopausal women [Parsons CA, Mroczkowski HJ, McGuigan FE, Albagha OM, Manolagas S, Reid DM, et al. Interspecies synteny mapping identifies a quantitative trait locus for bone mineral density on human chromosome Xp22. Hum Mol Genet 2005;14:3141-8]. A second locus, on chromosome 7, was observed in only one cross. Single-nucleotide polymorphisms (SNPs) are highly clustered near these loci, distinguishing the parental strains over only limited spans.

Absorptiometry, Photon↗

PubMed2026

IBAS: Interaction-bridged association studies discovering novel genes underlying complex traits.

Genetic contributions to complex traits are often mediated through coordinated gene-gene interaction networks, yet most existing association frameworks focus on marginal single-gene effects and overlook higher-order dependency structures. Direct modeling of interactions remains challenging due to combinatorial complexity and statistical instability. We introduce Interaction-Bridged Association Study (IBAS), a general framework that incorporates pathway-level interaction patterns into genotype-phenotype association analysis without explicitly enumerating interactions. IBAS leverages transcriptomic reference data to construct low-dimensional representations of pathway activity, which guide SNP-weighting and gene-level association testing within a kernel-based framework. In perturbation-based simulations, IBAS demonstrates improved stability and reproducibility compared to conventional TWAS and gene-based methods, while maintaining well-calibrated Type I error under phenotype permutation. Application to the WTCCC datasets identifies both known and novel genes across multiple complex diseases, including candidates with modest marginal effects missed by standard approaches. These findings are supported by replication in an independent cohort, and analyses across multiple reference tissues revealing both shared and tissue-specific signals. Overall, IBAS provides a statistically robust and computationally tractable framework for incorporating interaction effects into association mapping, extending beyond the single-gene paradigm and enabling more comprehensive characterization of complex trait. IBAS is available on GitHub at: https://github.com/QingrunZhangLab/IBAS.

Polymorphism, Single Nucleotide↗

PubMed2001

Prospects for association-based fine mapping of a susceptibility gene for a complex disease.

The potential of association studies for fine-mapping loci with common disease susceptibility alleles for complex genetic diseases in outbred populations is unclear. For a battery of tightly linked anonymous genetic markers spanning a candidate region centered around a disease locus, simulation methods based on a coalescent process with mutation, recombination, and genetic drift were used to study the spatial distribution of markers with large noncentrality parameters in a case-control study design. Simulations with a disease allele at intermediate frequency, presumably representing an old mutation, tend to exhibit the largest noncentrality parameter values at markers near the disease locus. In contrast, simulations with a disease allele at low frequency, presumably representing a young mutation, often exhibit the largest noncentrality parameter values at markers scattered over the candidate region. In the former case, sample sizes or marker densities sufficient to detect association are likely to lead to useful localization, whereas, in the latter case, localization of the disease locus within the candidate region is much less likely, regardless of the sample size or density of the map. The simulations suggest that for a single marker analysis, the simple strategy of choosing the marker with smallest associated P value to begin a laboratory search for the disease locus performs adequately for a common disease allele.

Alleles↗

PubMed1984

Activation sequence and potential distribution maps demonstrating multicentric atrial impulse origin in dogs.

We examined the onset of atrial epicardial excitation by recording unipolar potentials from 360 electrodes arranged in templates affixed to the superior vena cava and right atrium in dogs. Both activation sequence and potential distribution maps were obtained for the period of impulse origin beginning before the surface P wave and continuing through the first 15-20 msec of atrial depolarization. The activation maps demonstrated impulse origin from multiple widely separated sites, resulting in two to three individual wavefronts that merged to form a single widely disseminated wavefront spread over a 50 X 20 mm area by 10-15 msec. Atrial potential maps obtained for the same time periods revealed multiple sites of primary negativity corresponding to the points of impulse origin in the activation maps. The potential distributions and evolution of these maps also indicated the presence of multiple wavefronts originating from widely separated locations, and suggested an extensively dispersed source of impulse origin. One of these sites at the superior cavo-appendicular junction corresponded to the rostral portion of the sinus node and the site of classical unifocal origin. Additional sites of impulse origin and primary negativity distant to the sinus node were noted either concurrently in the same map or in other maps associated with different patterns of impulse initiation. Classical physiological and pharmacological interventions were used to alter adrenergic and cholinergic input to the atrium, and resulted in coincident changes of both the patterns of impulse origin and heart rate. In addition, we examined spontaneous changes in the patterns of impulse initiation which accompanied beat-to-beat changes in cycle length (sinus arrhythmia). There was close agreement between activation and potential maps over the entire steady state and dynamic range of impulse origin. The data can be explained by the concept of a widely distributed system of functionally differentiated but coordinated atrial pacemakers.

Action Potentials↗

PubMed2006

PDA: Pooled DNA analyzer.

BACKGROUND: Association mapping using abundant single nucleotide polymorphisms is a powerful tool for identifying disease susceptibility genes for complex traits and exploring possible genetic diversity. Genotyping large numbers of SNPs individually is performed routinely but is cost prohibitive for large-scale genetic studies. DNA pooling is a reliable and cost-saving alternative genotyping method. However, no software has been developed for complete pooled-DNA analyses, including data standardization, allele frequency estimation, and single/multipoint DNA pooling association tests. This motivated the development of the software, 'PDA' (Pooled DNA Analyzer), to analyze pooled DNA data. RESULTS: We develop the software, PDA, for the analysis of pooled-DNA data. PDA is originally implemented with the MATLAB language, but it can also be executed on a Windows system without installing the MATLAB. PDA provides estimates of the coefficient of preferential amplification and allele frequency. PDA considers an extended single-point association test, which can compare allele frequencies between two DNA pools constructed under different experimental conditions. Moreover, PDA also provides novel chromosome-wide multipoint association tests based on p-value combinations and a sliding-window concept. This new multipoint testing procedure overcomes a computational bottleneck of conventional haplotype-oriented multipoint methods in DNA pooling analyses and can handle data sets having a large pool size and/or large numbers of polymorphic markers. All of the PDA functions are illustrated in the four bona fide examples. CONCLUSION: PDA is simple to operate and does not require that users have a strong statistical background. The software is available at http://www.ibms.sinica.edu.tw/%7Ecsjfann/first%20flow/pda.htm.

Algorithms↗

PubMed2004

Effect of population stratification on case-control association studies. II. False-positive rates and their limiting behavior as number of subpopulations increases.

There has been considerable debate in the literature concerning bias in case-control association mapping studies due to population stratification. In this paper, we perform a theoretical analysis of the effects of population stratification by measuring the inflation in the test's type I error (or false-positive rate). Using a model of stratified sampling, we derive an exact expression for the type I error as a function of population parameters and sample size. We give necessary and sufficient conditions for the bias to vanish when there is no statistical association between disease and marker genotype in each of the subpopulations making up the total population. We also investigate the variation of bias with increasing subpopulations and show, both theoretically and by using simulations, that the bias can sometimes be quite substantial even with a very large number of subpopulations. In a companion simulation-based paper (Heiman et al., Part I, this issue), we have focused on the CRR (confounding risk ratio) and its relationship to the type I error in the case of two subpopulations, and have also quantified the magnitude of the type I error that can occur with relatively low CRR values.

Bias↗

PubMed1981

A protein kinase bound to the projection portion of MAP 2 (microtubule-associated protein 2).

In previous work we have demonstrated that the microtubule-associated protein 2 (MAP 2) molecule consists of two structural parts. One part of the molecule, referred to as the assembly-promoting domain, binds to the microtubule surface and is responsible for promoting microtubule assembly; the other represents a filamentous projection observed on the microtubule surface that may be involved in the interaction of microtubules with other cellular structures. MAP 2 is known to be specifically phosphorylated as the result of a protein kinase activity that is present in microtubule preparations. We have now found that the activity copurifies with the projection portion of MAP 2 itself. Kinase activity coeluted with MAP 2 when microtubule protein was subjected to either gel- filtration chromatography on bio-gel A-15m or ion-exchange chromatography on DEAE- Sephadex. The activity was released from microtubules by mild digestion with chymotrypsin in parallel with the removal by the protease of the MAP 2 projections from the microtubule surface. The association of the activity with the projection was demonstrated directly by gel filtration chromatography of the projections on bio-gel A-15m. Three protein species (M(r) = 39,000, 55,000, and 70,000) cofractionated with MAP 2, and two of these (M(r) = 39,000 and 55,000) may represent the subunits of an associated cyclic AMP- dependent protein kinase. The projection-associated activity was stimulated 10-fold by cyclic AMP and was inhibited more than 95 percent by the cyclic AMP-dependent protein kinase inhibitor from rabbit skeletal muscle. It appeared to represent the only significant activity associated with microtubules, almost no activity being found with tubulin, other MAPs, or the assembly-promoting domain of MAP 2, and was estimated to account for 7-22 percent of the total brain cytosolic protein kinase activity. The location of the kinase on the projection is consistent with a role in regulating the function of the projection, though other roles for the enzyme are also possible.

Animals↗

PubMed2005

Mapping autoimmune disease genes in humans: lessons from IBD and SLE.

The inflammatory bowel diseases (IBD) and systemic lupus erythematosus (SLE) are common autoimmune diseases that affect 2-3 million people in the USA alone. Crohn's disease (CD) and ulcerative colitis (UC), the inflammatory bowel diseases, are idiopathic, chronic inflammatory disorders of the gastrointestinal tract. SLE is a chronic, multi-system autoimmune disease that generally presents in women of childbearing age as fatigue, arthralgia and rash. Although the aetiology of these two diseases is not fully known, it is believed that genetic, hormonal and environmental influences contribute to susceptibility. Genomewide linkage scans in IBD have revealed significant loci that, upon comprehensive association mapping strategies, yield what are believed to be causal susceptibility alleles. Human linkage studies performed to date in SLE have not been as informative, although genetic mapping in mouse models of SLE as well as candidate gene approaches have provided important clues to the genetic susceptibility in humans. We will examine how some of the recent advances in our understanding of genetic variation in the human genome are greatly improving our ability to map autoimmune disease genes in humans.

Autoimmune Diseases↗

PubMed2005

The genetic basis of adaptation: lessons from concealing coloration in pocket mice.

Recent studies on the genetics of adaptive coat-color variation in pocket mice (Chaetodipus intermedius) are reviewed in the context of several on-going debates about the genetics of adaptation. Association mapping with candidate genes was used to identify mutations responsible for melanism in four different populations of C. intermedius. Here, I review four main results (i) a single gene, the melanocortin-1-receptor (Mc1r), appears to be responsible for most of the phenotypic variation in color in one population, the Pinacate site; (ii) four or fewer nucleotide changes at Mc1r appear to be responsible for the difference in receptor function; (iii) studies of migration-selection balance suggest that the selection coefficient associated with the dark Mc1r allele at the Pinacate site is large; and (iv) different (unknown) genes underlie the evolution of melanism on three other lava flows. These findings are discussed in light of the evolution of convergent phenotypes, the average size of phenotypic effects underlying adaptation, the evolution of dominance, and the distinction between adaptations caused by changes in gene dosage versus gene structure.

Adaptation, Biological↗

PubMed2004

Fetal magnetocardiographic mapping using independent component analysis.

Fetal magnetocardiography (fMCG) is the only noninvasive technique allowing effective assessment of fetal cardiac electrical activity during the prenatal period. The reconstruction of reliable magnetic field mapping associated with fetal heart activity would allow three-dimensional source localization. The efficiency of independent component analysis (ICA) in restoring reliable fetal traces from multichannel fMCG has already been demonstrated. In this paper, we describe a method of reconstructing a complete set of fetal signals hidden in multichannel fMCG preserving their correct spatial distribution, waveform, polarity and amplitude. Fetal independent components, retrieved with an ICA algorithm (FastICA), were interpolated (fICI method) using information gathered during FastICA iterations. The restored fetal signals were used to reconstruct accurate magnetic mapping for every millisecond during the average beat. The procedure was validated on fMCG recorded from the 22nd gestational week onward with a multichannel MCG system working in a shielded room. The interpolated traces were compared with those obtained with a standard technique, and the consistency of fetal mapping was checked evaluating source localizations relative to fetal echocardiographic information. Good magnetic field distributions during the P-QRS-T waves were attained with fICI for all gestational periods; their reliability was confirmed by three-dimensional source localizations.

Algorithms↗

PubMedDate not supplied

Surname distribution in France: a distance analysis by a distorted geographical map.

The distribution of surnames in 90 distinct regions in France during two successive periods, 1889-1915 and 1916-1940, is analysed from the civil birth registers of the 36,500 administrative units in France. A new approach, called 'Mobile Site Method' (MSM), is developed to allow representation of a surname distance matrix by a distorted geographical map. A surname distance matrix between the various regions in France is first calculated, then a distorted geographical map called the 'surname similarity map' is built up from the surname distances between regions. To interpret this map we draw (a) successive map contours obtained during the step-by-step distortion process, revealing zones of high surname dissimilarity, and (b) maps in grey levels representing the displacement magnitude, and allowing the segmentation of the geographical and surname maps into 'homogeneous surname zones'. By integrating geography and surname information in the same analysis, and by comparing results obtained for the two successive periods, the MSM approach produces convenient maps showing: (a) 'regionalism' of some peripheral populations such as Pays Basque, Alsace, Corsica and Brittany; (b) the presence of preferential axes of communications (Rhodanian corridor, Garonne valley); (c) barriers such as the Central Massif, Vosges; (d) the weak modifications of the distorted maps associated with the two periods studied suggest an extension (but limited) of the tendency of surname uniformity in France. These results are interpreted, in the nineteenth- and twentieth century context, as the consequences of a slow process of local migrations occurring over a long period of time.

France↗

PubMed1995

Functional topography of myelin-associated glycoprotein. II. Mapping of domains on molecular fragments.

The myelin-associated glycoprotein (MAG), an adhesion molecule of the immunoglobulin (Ig) superfamily with five Ig-like domains, was investigated with regard to its binding site(s) for the neuronal cell surface, collagen I, and heparin, using a panel of new monoclonal antibodies and cyanogen bromide cleavage fragments of MAG. All antibodies generated competed with each other for binding to MAG, indicating that they reacted with identical or closely related epitopes. Mapping of the reactive epitopes on recombinant deletion fragments of MAG expressed by Chinese hamster ovary (CHO) fibroblasts showed reactivity of monoclonal antibody 513 with domains I, II, and III, comprising the amino-terminal end of the extracellular domain. Monoclonal antibody 15 recognized domain III only. Binding of MAG-containing liposomes to neurons was blocked by antibodies 15 and 513. Cyanogen bromide (CNBr) fragments of domains I, II, and III bound to collagen type I under isotonic buffer conditions. CNBr fragments containing domains I and II were involved in binding to heparin. These observations suggest that domain III may be important for binding to the neuronal cell surface receptor for MAG, while domains I, II, and III interact with collagen type I and domains II and III with heparin.

3T3 Cells↗