Linkage disequilibrium between two highly polymorphic microsatellites.

The PCR was used to amplify genomic DNA from two microsatellite (dC-dA)n.(dG-dT)n sequences found to be present in the same chromosome 5 genomic clone. Analysis of the haplotype frequencies of these two interspersed repeat sequences in individuals showed strong allelic association or linkage disequilibrium. Six alleles were found for p599 (CA)n with a PIC value of 0.71 and 8 alleles were seen for lambda 599 (CA)n with a PIC value of 0.74. The two microsatellites are separated by approximately 7 kb. Analysis of the length variations for the two microsatellites showed that they were positively correlated, a finding that has no obvious explanation. The strong linkage disequilibrium found demonstrates stability during evolution for these novel markers. Therefore they should be powerful new tools for studying genetic drift and admixture of populations. Furthermore, disequilibrium data from microsatellites can be used in the fine mapping and cloning of disease genes.     

Algorithms versus models for analyzing data that contain misclassification errors.

Espeland and Hui (1987, Biometrics 43, 1001-1012) propose a methodology for analysing epidemiologic data contaminated by misclassification. They explicate their algorithm by a data set concerning cervical cancer and circumcision. We reanalyse these data using a conditional independence assumption different from theirs, and reach radically different conclusions. Espeland and Hui's methodology is a form of correlation analysis. We propose an alternative methodology based on the logic of regression analysis.     

Linkage and association between inflammatory bowel disease and a locus on chromosome 12.

Genetic epidemiological studies have shown that genetic factors are important in the pathogenesis of the idiopathic inflammatory bowel diseases (IBD), Crohn disease (CD), and ulcerative colitis (UC). A genome screen in the United Kingdom found linkage of IBD to a 41-cM region of chromosome 12, surrounding D12S83. We aimed to replicate this linkage and to narrow the region of interest. Nonparametric linkage analyses at microsatellites surrounding D12S83 were performed in 122 North American Caucasian families containing 208 genotyped IBD-affected relative pairs. Transmission/disequilibrium tests (TDTs) were also performed. We confirmed that IBD is linked to chromosome 12 (peak GENEHUNTER-PLUS LOD* score 2.76 [P = .00016] between D12S1724 and D12S90). The evidence for linkage is contributed by both the group of CD-affected relative pairs (peak GENEHUNTER-PLUS LOD* score 1.79 [P = .0021] between D12S1724 and D12S90) and the group of UC-affected relative pairs (peak GENEHUNTER-PLUS LOD* score 1.82 [P = .0019] at D12S335). The TDT is positive at the D12S83 locus (global chi2 = 16.41, 6 df, P = .012). In conclusion, we have independently confirmed linkage of IBD to the chromosome 12 region that we investigated. A positive TDT at D12S83 suggests that we have greatly narrowed the chromosome 12 region that contains an IBD locus.     

Evidence that intramolecular associations between presenilin domains are obligatory for endoproteolytic processing.

Mutations in genes encoding presenilins (PS1 and PS2) cosegregate with the majority of early onset cases of familial Alzheimer's disease. PS1 and PS2 are polytopic membrane proteins that undergo endoproteolytic cleavage to generate stable NH2- and COOH-terminal derivatives (NTF and CTF, respectively). Several lines of evidence suggest that the endoproteolytic derivatives are likely the functional units of PS in vivo. In the present report, we examine the disposition of PS NTF and CTF assemblies in stable mouse N2a neuroblastoma cell lines expressing human PS polypeptides. We show that exogenous expression of PS1 NTFs neither assemble with endogenous CTF nor exhibit dominant negative inhibitory effects on the endogenous PS1 cleavage and the accumulation of derivatives. In cells co-expressing PS1 and PS2, PS1- and PS2-derived fragments do not form mixed assemblies. In contrast, cells expressing a chimeric PS1/PS2 polypeptide form stable PS1 NTF-PS2 CTF assemblies. Moreover, expression of chimeric PS1/PS2 polypeptides harboring a familial early onset AD-linked mutation (M146L) elevates the production of Abeta42 peptides. Our results provide evidence that assembly of structural domains contained within NH2- and COOH-terminal regions of PS occur prior to endoproteolytic cleavage.     

Segregation analysis of congenital glaucoma: approach by two differential models.

To determine the mode of inheritance of congenital glaucoma, segregation analysis was performed using two different models: the transmission probability model and the mixed model. Whereas the latter, testing for monogenic inheritance in the presence of both monogenic and polygenic components, results in strong evidence for a major locus, the former, testing for Mendelian segregation at one locus, rejects this hypothesis. The differences in the results of these two models are discussed and are attributed to the underlying structure of each. Genetic heterogeneity of congenital glucoma is proposed.     

Ants versus spiders: interference competition between two social predators

Interference competition can profoundly influence the outcome of species interactions and may lead to either coexistence or exclusion. Our understanding of how interference can lead to coexistence remains incomplete, particularly when interference fails to result in resource partitioning. I document a novel form of interference competition between an ant (Myrmecia pyriformis) and a social spider (Delena cancerides) with similar foraging patterns. Of 120 nest boxes occupied by D. cancerides in the field, 7 (6 %) were invaded by M. pyriformis ants over a 2-month period. After eliminating spiders from the nest boxes, the ants proceeded to fill the boxes with debris, rendering them useless to the spiders. The ants do not occupy the nest boxes; thus, interference occurs at a resource that is necessary to one species, but not the other. I discuss how further research into this system may improve our understanding of how interference competition can support coexistence. I also suggest modeling exploitation and interference competition on multiple resources to align with this and other empirical examples where different forms of competition occur for different resources.     

Linkage analysis of schizophrenia: challenges and promise.

Schizophrenia is a serious mental illness affecting nearly 1 per cent of the general population. Family, twin, and adoption studies suggest that genetics plays a major role in the etiology of schizophrenia. The inheritance pattern appears complex, similar to that of other common conditions like heart disease. To uncover a causal genetic factor, researchers have recently begun to apply a linkage analysis strategy to schizophrenia. Early results suggest that there are many challenges facing scientists who undertake schizophrenia genetics research. While one study has shown significant linkage of schizophrenia to a region on chromosome 5, several other studies have not found linkage to this area. The likelihood that there are several major genes predisposing to the illness and uncertainties about inheritance patterns and diagnostic boundaries are potential difficulties to overcome. Many more families need to be studied, and creative complementary research strategies pursued, to achieve the potential success offered by a genetic linkage approach.     

Linkage analysis of two murine polycystic kidney disease genes, pcy and cpk.

Two murine models of polycystic kidney disease (PKD) in humans are currently available: the infant-type cpk in mice and the adult-type pcy mutation in mice. Our linkage analysis was to determine whether these genes are allelic forms of the same gene, or infant-type and adult-type PKD resulting from homozygous and heterozygous mutation, as in the rat Cy gene. We found that the pcy gene in the mice was linked with the d gene on chromosome 9, but the cpk gene was not. A segregation test indicated that the two genes are inherited independently. This indicates that the cpk and pcy genes are not alleles and that the genetic mechanism of PKD pathogenesis in the mouse is different from that in the Cy rat.     

An analysis of the association of collagen based on structural models.

The existence and distribution of vertical, interacting edges on cylindrical surfaces, which were derived from the basic structural features of the collagen molecule, have been examined as a function of the angle θ of the superhelix. Over the range θ = 26°–33° and near θ = 36°, the strongest intermolecular association was detected at 29.95°. This model exhibited three similar, self-interacting edges, separated by approximately 120°. The potential for three similar but nonidentical edges lies in the geometry of the collagen molecule, but the existence of such edges and their ability to self-associate is dependent upon the unique amino acid sequence. The relative strengths of association of each edge with itself and with the other edges are not identical, but the present analysis does not permit a judgment as to whether this variation could result in functional specificity in such interactions. All three chains participate in each edge though their contribution to the relative interaction strength is not identical. These edges showed distinct maxima when displaced past one another by integral intervals of D, where D = 233 residue positions (quarter-stagger). The strongest relative interaction occurs at a displacement of 1D.     

Linkage disequilibrium and population-structure analysis among Capsicum annuum L. cultivars for use in association mapping

Knowledge of population structure and linkage disequilibrium among the worldwide collections of peppers currently classified as hot, mild, sweet and ornamental types is indispensable for applying association mapping and genomic selection to improve pepper. The current study aimed to resolve the genetic diversity and relatedness of Capsicum annuum germplasm by use of simple sequence repeat (SSR) loci across all chromosomes in samples collected in 2011 and 2012. The physical distance covered by the entire set of SSRs used was 2,265.9 Mb from the 3.48-Gb hot-pepper genome size. The model-based program STRUCTURE was used to infer five clusters, which was further confirmed by classical molecular-genetic diversity analysis. Mean heterozygosity of various loci was estimated to be 0.15. Linkage disequilibrium (LD) was used to identify 17 LD blocks across various chromosomes with sizes from 0.154 Kb to 126.28 Mb. CAMS-142 of chromosome 1 was significantly associated with both capsaicin (CA) and dihydrocapsaicin (DCA) levels. Further, CAMS-142 was located in an LD block of 98.18 Mb. CAMS-142 amplified bands of 244, 268, 283 and 326 bp. Alleles 268 and 283 bp had positive effects on both CA and DCA levels, with an average R ² of 12.15 % (CA) and 12.3 % (DCA). Eight markers from seven different chromosomes were significantly associated with fruit weight, contributing an average effect of 15 %. CAMS-199, HpmsE082 and CAMS-190 are the three major quantitative trait loci located on chromosomes 8, 9, and 10, respectively, and were associated with fruit weight in samples from both years of the study. This research demonstrates the effectiveness of using genome-wide SSR-based markers to assess features of LD and genetic diversity within C. annuum.     

Temporal associations between weather and headache: analysis by empirical mode decomposition

Background

Patients frequently report that weather changes trigger headache or worsen existing headache symptoms. Recently, the method of empirical mode decomposition (EMD) has been used to delineate temporal relationships in certain diseases, and we applied this technique to identify intrinsic weather components associated with headache incidence data derived from a large-scale epidemiological survey of headache in the Greater Taipei area.

Methodology/Principal Findings

The study sample consisted of 52 randomly selected headache patients. The weather time-series parameters were detrended by the EMD method into a set of embedded oscillatory components, i.e. intrinsic mode functions (IMFs). Multiple linear regression models with forward stepwise methods were used to analyze the temporal associations between weather and headaches. We found no associations between the raw time series of weather variables and headache incidence. For decomposed intrinsic weather IMFs, temperature, sunshine duration, humidity, pressure, and maximal wind speed were associated with headache incidence during the cold period, whereas only maximal wind speed was associated during the warm period. In analyses examining all significant weather variables, IMFs derived from temperature and sunshine duration data accounted for up to 33.3% of the variance in headache incidence during the cold period. The association of headache incidence and weather IMFs in the cold period coincided with the cold fronts.

Conclusions/Significance

Using EMD analysis, we found a significant association between headache and intrinsic weather components, which was not detected by direct comparisons of raw weather data. Contributing weather parameters may vary in different geographic regions and different seasons.     

Equivalence of certain models in protein ligand equilibria and the possibility of distinguishing between them

Methods have been developed for analyzing the binding of ligand by a protein exhibiting allosteric properties. The procedure has been developed for the case of four subunits. The relationship to existing theoretical models has been discussed. The conditions under which a choice between models is feasible are described.