Flicker image comparison of 2-D gel images for putative protein identification using the 2DWG meta-database

With the availability of two-dimensional (2-D) gel electrophoresis databases that have many characterized proteins, it may be possible to compare a researcher’s gel images with those in relevant databases. This may lead to the putative identification of unknown protein spots in a researcher’s gel with those characterized in a given database, saving the researcher time and money by suggesting monoclonal antibodies to try in confirming these identifications. We have developed two tools to help with this comparison: (1) Flicker, http://www.lecb.ncifcrf.gov/flicker/, a Java applet program running in the researcher’s Web browser, to visually compare their gels against gels on the Internet; and (2) the 2DWG meta-database, http://www.lecb.ncifcrf.gov/2dwgDB/, a searchable database of locations of 2-D electrophoretic gel images found on the Internet. Recent additions to Flicker allow users to click on a protein spot in a gel that is linked to a federated 2D gel database, such as SWISS-2DPAGE, and have it retrieve a report from that Web database for that protein.     

Genome-wide linkage analysis of population variation in high-density lipoprotein cholesterol

Lower plasma levels of high-density lipoprotein cholesterol (HDL-C) are associated with the metabolic syndrome (insulin resistance, obesity, hypertension) and higher cardiovascular risk. Recent association studies have suggested rare alleles responsible for very low HDL-C levels. However, for individual cardiovascular risk factors, the majority of population-attributable deaths are associated with average rather than extreme levels. Therefore, genetic factors that determine the population variation of HDL-C are particularly relevant. We undertook genome-wide and fine mapping to identify linkage to HDL-C in healthy adult nuclear families from the Victorian Family Heart Study. In 274 adult sibling pairs (average age 24 years, average plasma HDL-C 1.4 mmol/l), genome-wide mapping revealed suggestive evidence for linkage on chromosome 4 (Z score=3.5, 170 cM) and nominal evidence for linkage on chromosomes 1 (Z=2.1, 176 cM) and 6 (Z=2.6, 29 cM). Using genotypes and phenotypes from 932 subjects (233 of the sibling pairs and their parents), finer mapping of the locus on chromosome 4 strengthened our findings with a peak probability (Z score=3.9) at 169 cM. Our linkage data suggest that chromosome 4q32.3 is linked with normal population variation in HDL-C. This region coincides with previous reports of linkage to apolipoprotein AII (a major component of HDL) and encompasses the gene encoding the carboxypeptidase E, relevant to the metabolic syndrome and HDL-C. These findings are relevant for further understanding of the genetic determinants of cardiovascular risk at a population level.     

Analysis of the Candida albicans proteome. II. Protein information technology on the Net (update 2002)

Candida albicans is an important fungal model organism of noteworthy clinical interest in modern medicine. Different initiatives addressing its sequencing and physical mapping have been carried out. The C. albicans genome sequence is currently near to completion at Stanford University, heralding new challenges in proteomic research and functional analyses of its gene products. This review presents an update of the most relevant data resources that are available through the World Wide Web to scientists working in the area of the analysis of the C. albicans proteome. An overview of the current status of the main universal protein sequence databases and specialized data collections for C. albicans is given. Various issues of the single public C. albicans 2D-PAGE database are also described, highlighting the significance of setting up graphical query interface-based databanks to visualize 2D-PAGE images through the Net. Finally, we also emphasize the pressing need to create a "cyber-bioknowledge library" that will integrate all the databases developed at the different levels for the understanding of life processes as well as bioinformatic tools for interpreting this deluge of data generated through the Internet.     

Photosynthesis and the Web: 2008

The World Wide Web has become an important resource for public awareness and for educating the world’s population, including its political leaders, students, researchers, teachers, and ordinary citizens seeking information. Relevant information on photosynthesis-related web sites is grouped into several categories: (1) group sites, (2) sites by subject, (3) individual researcher’s sites, (4) sites for educators and students, and (5) other useful sites.     

Description and analysis of two internet-based databases of insect pathogens: EDWIP and VIDIL

In 1996, two searchable databases covering insect pathogens were posted on the World Wide Web: the Ecological Database of the World's Insect Pathogens (EDWIP) and the Viral Diseases of Insects in the Literature database (VIDIL). In this paper, we describe the format and contents of EDWIP and VIDIL on the World Wide Web. EDWIP contains over 9,400 pathogen-host association records, 677 negative test result or "no association" records, 4,454 host species, 2,285 pathogen species records, and 2,057 bibliographical references. Species of Coleoptera and Lepidoptera are the best represented groups in EDWIP. Lepidopteran species account for the most associations of any host order in EDWIP, over 2,500, or 27%. Of the pathogen groups, Protozoa (including microsporidia) accounted for nearly 66% of the pathogen species records and over 40% of the association records in EDWIP. Fungi account for only 18% of the pathogen species, but nearly 33% of the association records. Habitats dominated by human activities (e.g., crop, stored product, and human dwelling) account for most of the host habitats recorded in EDWIP. The United States and Japan are the most common locations and the Nearctic and Palearctic are the most common biogeographic regions reported in EDWIP. There are 4,801 annotated bibliographic records in VIDIL.     

A two-stage linkage analysis of Chinese schizophrenia pedigrees in 10 target chromosomes

We performed a two-stage linkage scan involving 25 Chinese schizophrenia families, focusing on 10 target chromosomes which have already been the subject of considerable research. We initially genotyped 237 individuals with 186 markers, five candidate regions were then chosen for fine mapping and 49 additional markers were genotyped. In region 1q21-23, a maximum multipoint HLOD (HLOD=2.38) was observed between D1S484 and D1S2705, under the dominant model. In region 5q35, dominant HOLD of 2.36, 2.04, and 2.31 were found at marker D5S2030, D5S408, and D5S2006, respectively. Consistent multipoint results also supported linkage to this region under the same dominant model, with a highest HOLD of 2.47. Furthermore, single-point HLODs (HLOD=1.95 at D22S274, and HLOD=1.91 at D22S1157) were found in region 22q13, under the dominant model. Evidence from these three regions satisfied the criteria for suggestive linkage and should help in identifying schizophrenia susceptibility genes.     

Computer simulation modelling of buoyancy change in Microcystis

This paper reviews the development of the SCUM seriesof models and presents additional algorithms forcalculating surface radiation flux and growth. Thefirst SCUM models used data obtained by laboratoryinvestigation of Oscillatoria agardhii byKromkamp & Walsby (1990). However when applied toother species the models became unstable. More recentattempts have taken a different and more theoreticalapproach combining lake mixing and modellingcomponents of SCUM with a buoyancy routine (CYANARA)developed at the Institute of Freshwater Ecology.Model algorithms and sample model results are brieflydescribed. The growing importance of the World Wide Webin modelling is highlighted and explained.     

Incorporating interference into linkage analysis for experimental crosses

The phenomenon of interference in genetic recombination is well-known and studied in a wide variety of organisms. Multilocus linkage analysis, which makes use of recombination patterns among all genetic markers simultaneously, is routinely used with data on humans and experimental organisms to build genetic maps. It is also used to try to determine the genes involved in traits of interest, such as common diseases. Most linkage analyses performed today ignore the occurrence of genetical interference. We present an extension to the Lander-Green algorithm for experimental crosses (backcross and intercross) to incorporate crossover interference according to the chi2 model. Simulation results show the impact of using this model on the accuracy of estimated genetic maps.     

Multivariate survival models induced by genetic frailties,with application to linkage analysis

We derive a multivariate survival model for age of onset data of a sibship from an additive genetic gamma frailty model constructed basing on the inheritance vectors, and investigate the properties of this model. Based on this model, we propose a retrospective likelihood approach for genetic linkage analysis using sibship data. This test is an allele-sharing-based test, and does not require specification of genetic models or the penetrance functions. This new approach can incorporate both affected and unaffected sibs, environmental covariates and age of onset or age at censoring information and, therefore, provides a practical solution for mapping genes for complex diseases with variable age of onset. Small simulation study indicates that the proposed method performs better than the commonly used allele-sharing-based methods for linkage analysis, especially when the population disease rate is high. We applied this method to a type 1 diabetes sib pair data set and a small breast cancer data set. Both simulated and real data sets also indicate that the method is relatively robust to the misspecification to the baseline hazard function.     

QoS-based Architectures for Geographically Replicated Web Servers

In this paper, we discuss strategies for providing World Wide Web service users with adequate Quality of Service (QoS). We argue that QoS can be provided by distributing the service requests processing load among replicated Web servers (WSs), that can be geographically distributed across the Internet. In order to support our argument, we compare and contrast several load distribution strategies, and assess their effectivness when deployed within the context of a geographically replicated Web service; the principal figure of merit we use in this assessment is the response time experienced by the users of that service. As a result of this comparison, we propose a specific strategy, named QoS-based, that implements load distribution among WS replicas by binding a user to the replica that provides the shortest user response time. We examine several architectures that exploit our QoS-based strategy. Two of these architectures, named, respectively, Browser-based and Load Distribution-based, are described in detail as they are particularly appropriate for implementing our strategy.     

Software for analysis and manipulation of genetic linkage data.

We present eight computer programs written in the C programming language that are designed to analyze genotypic data and to support existing software used to construct genetic linkage maps. Although each program has a unique purpose, they all share the common goals of affording a greater understanding of genetic linkage data and of automating tasks to make computers more effective tools for map building. The PIC/HET and FAMINFO programs automate calculation of relevant quantities such as heterozygosity, PIC, allele frequencies, and informativeness of markers and pedigrees. PREINPUT simplifies data submissions to the Centre d'Etude du Polymorphisme Humain (CEPH) data base by creating a file with genotype assignments that CEPH's INPUT program would otherwise require to be input manually. INHERIT is a program written specifically for mapping the X chromosome: by assigning a dummy allele to males, in the nonpseudoautosomal region, it eliminates falsely perceived noninheritances in the data set. The remaining four programs complement the previously published genetic linkage mapping software CRI-MAP and LINKAGE. TWOTABLE produces a more readable format for the output of CRI-MAP two-point calculations; UNMERGE is the converse to CRI-MAP's merge option; and GENLINK and LINKGEN automatically convert between the genotypic data file formats required by these packages. All eight applications read input from the same types of data files that are used by CRI-MAP and LINKAGE. Their use has simplified the management of data, has increased knowledge of the content of information in pedigrees, and has reduced the amount of time needed to construct genetic linkage maps of chromosomes.     

Doubled haploids for estimating genetic variances in presence of linkage and gene association

Summary The effect of gene association (or dispersion) and linkage on the estimation of genetic variances in a diallel experiment involving doubled haploid lines is evaluated. It is shown that the estimates of the additive and the additive X additive genetic variances, as obtained by Choo et al. (1979), are biased if genes are linked or are not independently distributed in the parents. However, this bias only occurs in the presence of interaction between homozygous loci. Gene association (or dispersion) and linkage, if present, can be detected by comparing the parental vs the crosses mean, the parental vs the doubled haploid lines variance, and the among vs the within crosses variance.     

Addition of glycerol for improved methylation linkage analysis of polysaccharides

A presolubilization procedure with the use of glycerol is shown to be applicable for the structural analysis of polysaccharides. Neutral, acidic, high-molecular-weight and low-molecular-weight polysaccharides were solubilized in glycerol prior to methylation and subsequent linkage analysis by GC-MS. All four types of polysaccharides showed significant increases in derivatization following presolubilization as measured by recovery of partially methylated alditol acetates.     

Optimal structure of protocol designs for building genetic linkage maps in livestock

We investigated protocol designs for gene mapping in livestock. The optimization of the population structure was based on the empirical variance of the recombination rate estimator. We concluded that a mixture of half-sib and full-sib families is preferred to half-sib families; a knowledge of parental phases does not improve the quality of the estimation for typical livestock families with five offspring or more; and measurements of the genotype of the mates in half-sib families are not useful. Graphs and algebraic approximations for the practical choice of family size and structure are given.     

Bayesian analysis of linkage between genetic markers and quantitative trait loci. I. Prior knowledge

Summary Prior information on gene effects at individual quantitative trait loci (QTL) and on recombination rates between marker loci and QTL is derived. The prior distribution of QTL gene effects is assumed to be exponential with major effects less likely than minor ones. The prior probability of linkage between a marker and another single locus is a function of the number and length of chromosomes, and of the map function relating recombination rate to genetic distance among loci. The prior probability of linkage between a marker locus and a quantitative trait depends additionally on the number of detectable QTL, which may be determined from total additive genetic variance and minimum detectable QTL effect. The use of this prior information should improve linkage tests and estimates of QTL effects.     

Conditional likelihood score functions for mixed models in linkage analysis

In this paper, we develop a general strategy for linkage analysis, applicable for arbitrary pedigree structures and genetic models with one major gene, polygenes and shared environmental effects. Extending work of Whittemore (1996), McPeek (1999) and Hossjer (2003d), the efficient score statistic is computed from a conditional likelihood of marker data given phenotypes. The resulting semiparametric linkage analysis is very similar to nonparametric linkage based on affected individuals. The efficient score S depends not only on identical-by-descent sharing and phenotypes, but also on a few parameters chosen by the user. We focus on (1) weak penetrance models, where the major gene has a small effect and (2) rare disease models, where the major gene has a possibly strong effect but the disease causing allele is rare. We illustrate our results for a large class of genetic models with a multivariate Gaussian liability. This class incorporates one major gene, polygenes and shared environmental effects in the liability, and allows e.g. binary, Gaussian, Poisson distributed and life-length phenotypes. A detailed simulation study is conducted for Gaussian phenotypes. The performance of the two optimal score functions S(wpairs) and S(normdom) are investigated. The conclusion is that (i) inclusion of polygenic effects into the score function increases overall performance for a wide range of genetic models and (ii) score functions based on the rare disease assumption are slightly more powerful.     

WWW and the aerobiologist: operating instructions

For several years now, the World Wide Web (WWW) has left the realm of information technology and represents a fundamental everyday working tool for a wide variety of disciplines. Aerobiology, though a newcomer in this virtual space, is proceeding at a fast pace towards the creation of an easily accessible and effective information network. The web gives access to text, imagery, movie and sound with relatively low-cost and user-friendly interfaces conceived as graphical magazines. A practical way to start navigating and looking for information is to operate a ‘search engine’ which is a large database containing addresses on a wide spectrum of subjects. As an alternative, a few selected sites exist that can initialize your search by providing a thematic list of addresses. After leaving the entry ‘port’ you are directed from site to site and eventually end up with a lot more information than you initially thought. Excerpts: information on public and private institutions, access to databases and image catalogs, bibliographical information, overview of monitoring networks, directions on national and international research programs, news (calendar of meetings, courses, etc.). Information is provided for the non-expert user who asks himself the key questions: ‘Where do I start to browse the net?’ or ‘Can I become a provider of information on the net and, if so, is it terribly difficult?’ The idea is that everybody can in principle become a ‘surfer’ or a ‘provider’ dedicating a reasonable amount of time and effort to the task. What one ends up with is an easy-to-use and powerful tool that is already helping the whole aerobiological community to pursue its goals and reach out for necessary interdisciplinary approaches to unsolved scientific issues. The server AEROBIOLOGY INTERNATIONAL (http://www.fisbat.bo.cnr.it/AERO/) is presented as an example on how to proceed with the creation of a new server and its management.     

A score test for linkage analysis of ordinal traits based on IBD sharing

Statistical methods for linkage analysis are well established for both binary and quantitative traits. However, numerous diseases including cancer and psychiatric disorders are rated on discrete ordinal scales. To analyze pedigree data with ordinal traits, we recently proposed a latent variable model which has higher power to detect linkage using ordinal traits than methods using the dichotomized traits. The challenge with the latent variable model is that the likelihood is usually very complicated, and as a result, the computation of the likelihood ratio statistic is too intensive for large pedigrees. In this paper, we derive a computationally efficient score statistic based on the identity-by-decent sharing information between relatives. Using simulation studies, we examined the asymptotic distribution of the test statistic and the power of our proposed test under various levels of heritability. We compared the computing time as well as power of the score test with the likelihood ratio test. We then applied our method for the Collaborative Study on the Genetics of Alcoholism and performed a genome scan to map susceptibility genes for alcohol dependence. We found a strong linkage signal on chromosome 4.     

A roadmap for the genetic analysis of renal aging

Several studies show evidence for the genetic basis of renal disease, which renders some individuals more prone than others to accelerated renal aging. Studying the genetics of renal aging can help us to identify genes involved in this process and to unravel the underlying pathways. First, this opinion article will give an overview of the phenotypes that can be observed in age‐related kidney disease. Accurate phenotyping is essential in performing genetic analysis. For kidney aging, this could include both functional and structural changes. Subsequently, this article reviews the studies that report on candidate genes associated with renal aging in humans and mice. Several loci or candidate genes have been found associated with kidney disease, but identification of the specific genetic variants involved has proven to be difficult. CUBN, UMOD, and SHROOM3 were identified by human GWAS as being associated with albuminuria, kidney function, and chronic kidney disease (CKD). These are promising examples of genes that could be involved in renal aging, and were further mechanistically evaluated in animal models. Eventually, we will provide approaches for performing genetic analysis. We should leverage the power of mouse models, as testing in humans is limited. Mouse and other animal models can be used to explain the underlying biological mechanisms of genes and loci identified by human GWAS. Furthermore, mouse models can be used to identify genetic variants associated with age‐associated histological changes, of which Far2, Wisp2, and Esrrg are examples. A new outbred mouse population with high genetic diversity will facilitate the identification of genes associated with renal aging by enabling high‐resolution genetic mapping while also allowing the control of environmental factors, and by enabling access to renal tissues at specific time points for histology, proteomics, and gene expression.