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At least 253 records · Page 14Linked to original sources
PubMed2004

Phylogenomic inference of protein molecular function: advances and challenges.

MOTIVATION: Protein families evolve a multiplicity of functions through gene duplication, speciation and other processes. As a number of studies have shown, standard methods of protein function prediction produce systematic errors on these data. Phylogenomic analysis--combining phylogenetic tree construction, integration of experimental data and differentiation of orthologs and paralogs--has been proposed to address these errors and improve the accuracy of functional classification. The explicit integration of structure prediction and analysis in this framework, which we call structural phylogenomics, provides additional insights into protein superfamily evolution. RESULTS: Results of protein functional classification using phylogenomic analysis show fewer expected false positives overall than when pairwise methods of functional classification are employed. We present an overview of the motivations and fundamental principles of phylogenomic analysis, new methods developed for the key tasks, benchmark datasets for these tasks (when available) and suggest procedures to increase accuracy. We also discuss some of the methods used in the Celera Genomics high-throughput phylogenomic classification of the human genome. AVAILABILITY: Software tools from the Berkeley Phylogenomics Group are available at http://phylogenomics.berkeley.edu

Algorithms↗
PubMed2005

What can functional neuroimaging tell the experimental psychologist?

I argue here that functional neuroimaging data--which I restrict to the haemodynamic techniques of fMRI and PET--can inform psychological theorizing, provided one assumes a "systematic" function-structure mapping in the brain. In this case, imaging data simply comprise another dependent variable, along with behavioural data, that can be used to test competing theories. In particular, I distinguish two types of inference: function-to-structure deduction and structure-to-function induction. With the former inference, a qualitatively different pattern of activity over the brain under two experimental conditions implies at least one different function associated with changes in the independent variable. With the second type of inference, activity of the same brain region(s) under two conditions implies a common function, possibly not predicted a priori. I illustrate these inferences with imaging studies of recognition memory, short-term memory, and repetition priming. I then consider in greater detail what is meant by a "systematic" function-structure mapping and argue that, particularly for structure-to-function induction, this entails a one-to-one mapping between functional and structural units, although the structural unit may be a network of interacting regions and care must be taken over the appropriate level of functional/structural abstraction. Nonetheless, the assumption of a systematic function-structure mapping is a "working hypothesis" that, in common with other scientific fields, cannot be proved on independent grounds and is probably best evaluated by the success of the enterprise as a whole. I also consider statistical issues such as the definition of a qualitative difference and methodological issues such as the relationship between imaging and behavioural data. I finish by reviewing various objections to neuroimaging, including neophrenology, functionalism, and equipotentiality, and by observing some criticisms of current practice in the imaging literature.

Arousal↗
PubMed2006

Similar gene expression profiles do not imply similar tissue functions.

Although similarities in gene expression among tissues are commonly inferred to reflect functional constraints, this has never been formally tested. Furthermore, it is unclear which evolutionary processes are responsible for the observed similarities. When examining genome-wide expression data in mouse, we found that patterns of expression similarity between tissues extend to genes that are unlikely to function in the tissues. Thus, ectopic expression can seem coordinated across tissues. This indicates that knowledge of gene expression patterns per se is insufficient to infer gene function. Ectopic expression is possibly explained as expression leakage, caused by spreading of chromatin modifications or the transcription apparatus into neighboring genes.

Animals↗
PubMed2006

A systematic analysis of disease-associated variants in the 3' regulatory regions of human protein-coding genes II: the importance of mRNA secondary structure in assessing the functionality of 3' UTR variants.

In an attempt both to catalogue 3' regulatory region (3' RR)-mediated disease and to improve our understanding of the structure and function of the 3' RR, we have performed a systematic analysis of disease-associated variants in the 3' RRs of human protein-coding genes. We have previously analysed the variants that have occurred in two specific domains/motifs of the 3' untranslated region (3' UTR) as well as in the 3' flanking region. Here we have focused upon 83 known variants within the upstream sequence (USS; between the translational termination codon and the upstream core polyadenylation signal sequence) of the 3' UTR. To place these variants in their proper context, we first performed a comprehensive survey of known cis-regulatory elements within the USS and the mechanisms by which they effect post-transcriptional gene regulation. Although this survey supports the view that RNA regulatory elements function within the context of specific secondary structures, there are no general rules governing how secondary structure might exert its influence. We have therefore addressed this question by systematically evaluating both functional and non-functional (based upon in vitro reporter gene and/or electrophoretic mobility shift assay data) USS variant-containing sequences against known cis-regulatory motifs within the context of predicted RNA secondary structures. This has allowed us not only to establish a reliable and objective means to perform secondary structure prediction but also to identify consistent patterns of secondary structural change that could potentiate the discrimination of functional USS variants from their non-functional counterparts. The resulting rules were then used to infer potential functionality in the case of some of the remaining functionally uncharacterized USS variants, from their predicted secondary structures. This not only led us to identify further patterns of secondary structural change but also several potential novel cis-regulatory motifs within the 3' UTRs studied.

3' Untranslated Regions↗
PubMed2005

Protein molecular function prediction by Bayesian phylogenomics.

We present a statistical graphical model to infer specific molecular function for unannotated protein sequences using homology. Based on phylogenomic principles, SIFTER (Statistical Inference of Function Through Evolutionary Relationships) accurately predicts molecular function for members of a protein family given a reconciled phylogeny and available function annotations, even when the data are sparse or noisy. Our method produced specific and consistent molecular function predictions across 100 Pfam families in comparison to the Gene Ontology annotation database, BLAST, GOtcha, and Orthostrapper. We performed a more detailed exploration of functional predictions on the adenosine-5'-monophosphate/adenosine deaminase family and the lactate/malate dehydrogenase family, in the former case comparing the predictions against a gold standard set of published functional characterizations. Given function annotations for 3% of the proteins in the deaminase family, SIFTER achieves 96% accuracy in predicting molecular function for experimentally characterized proteins as reported in the literature. The accuracy of SIFTER on this dataset is a significant improvement over other currently available methods such as BLAST (75%), GeneQuiz (64%), GOtcha (89%), and Orthostrapper (11%). We also experimentally characterized the adenosine deaminase from Plasmodium falciparum, confirming SIFTER's prediction. The results illustrate the predictive power of exploiting a statistical model of function evolution in phylogenomic problems. A software implementation of SIFTER is available from the authors.

Adenosine Deaminase↗
PubMed2004

Live viral vaccines in patients with partial DiGeorge syndrome: clinical experience and cellular immunity.

Partial DiGeorge syndrome (pDGS) is an inherited primary immunodeficiency syndrome (incidence, 1:3000 live births) primarily affecting cellular immune function; partial, infers thymic hypoplasia with detectable circulating T-lymphocytes and adequate function. No guidelines exist regarding the recommendations for use of live viral vaccines (LVVs) in this extensive population of pediatric patients. We reviewed the experience with live viral vaccines in our cohort of patients with pDGS. Of 53 patients, 25 (47%) had received a live viral vaccine. No significant adverse events were recorded in association with administration of live viral vaccines. There was no statistically significant difference between cellular immune function at initial presentation between those patients that received live viral vaccines and those that did not. Adequate cellular immune function was documented for 15 of the 25 LVV recipients at the time of vaccine administration without significant change from baseline. These observations suggest that live viral vaccines appear safe in patients with pDGS and stable immune function.

Adolescent↗
PubMed2004

Missense mutations in cancer suppressor gene TP53 are colocalized with exonic splicing enhancers (ESEs).

Mutation databases can be viewed as footprints of functional organization of a gene and thus can be used to infer its functional organization. We studied the association of exonic splicing enhancers (ESEs) with missense mutations in the tumor suppressor gene TP53 using the International Agency for Research on Cancer (IARC) mutation database. The goals of the study were: (i) to verify the hypothesis that deleterious missense mutations are colocalized with ESEs; (ii) to identify potentially functional ESE sites in the open reading frame (ORF) of the TP53. If some sequence functions as a splicing enhancer, then nucleotide substitutions in the site will disturb splicing, abrogate p53 function, and cause an increased susceptibility to cancer. Therefore, among cancers showing p53 mutations, more missense mutations are expected within functional ESE sites as compared to non-functional ESE motifs. Using several statistical tests, we found that missense mutations in TP53 are strongly colocalized with ESEs, and that only a small fraction of ESE sites contributes to the association. There are usually one or two ESEs per exon showing a statistically significant association with missense mutations--so-called significant ESE sites. In many respects significant ESE sites are different from those that do not show association with missense mutations. We found that positions of significant ESE sites are codon-dependent--significant ESEs preferentially start from the first position of a codon, whereas non-significant ESEs show no position dependence. Significant ESEs showed a more limited set of sequences compared to non-significant ESEs. These findings suggest that there is a limited number of missense mutations that influence ESE sites and our analysis provides further insight into the types of sites that harbor exonic enhancer elements.

CpG Islands↗
PubMed2006

Retinotopic organization of primary visual cortex in glaucoma: Comparing fMRI measurements of cortical function with visual field loss.

Primary open angle glaucoma (POAG) is a progressive optic neuropathy characterized by retinal ganglion cell loss. Experimental primate glaucoma indicates neuronal degeneration of the lateral geniculate nucleus (LGN) and activity changes in the visual cortex (V1). Neuronal degeneration has also been shown in a post-mortem human study of the optic nerve, LGN and visual cortex. Functional magnetic resonance imaging (fMRI), a non-invasive means of inferring function-specific neuronal activity, provides an opportunity to evaluate glaucomatous changes in neuronal activity throughout the visual pathway in vivo. The purpose of this study is to demonstrate that the relationship between visual field loss in human POAG and the functional organization of V1 can be measured using novel fMRI analysis methods. Visual field defects were measured using standard automated perimetry (SAP). A retinotopic map of visual space was obtained for V1, and the retinotopy data was fit with a template. The template was used to project regions within the visual field onto a flattened representation of V1. Viewing through the glaucomatous vs. fellow eye was compared by alternately presenting each eye with a scotoma-mapping stimulus. The resulting blood oxygen level dependent (BOLD) fMRI response was compared to interocular differences in thresholds for corresponding regions of the visual field. The spatial pattern of activity observed in the flattened representation agreed with the pattern of visual field loss. Furthermore, the amplitude of the BOLD response was correlated on a pointwise basis with the difference in sensitivity thresholds between the glaucomatous and fellow eyes (r = 0.53, p < 0.0001). The BOLD signal in human V1 is altered for POAG patients in a manner consistent with the loss of visual function. FMRI of visual brain areas is a potential means for quantifying glaucomatous changes in neuronal activity. This should enhance our understanding of glaucoma, and could lead to new diagnostic techniques and therapies.

Animals↗
PubMed2002

Homologous (beta/alpha)8-barrel enzymes that catalyze unrelated reactions: orotidine 5'-monophosphate decarboxylase and 3-keto-L-gulonate 6-phosphate decarboxylase.

The 3-keto-L-gulonate 6-phosphate decarboxylase (KGPDC) encoded by the ulaD gene in the Escherichia coli genome [Yew, W. S., and Gerlt, J. A. (2002) J. Bacteriol. 184, 302-306] and orotidine 5'-monophosphate decarboxylase (OMPDC) are homologous (derived from a common ancestor) but catalyze different reactions. The metal-independent decarboxylation reaction catalyzed by OMPDC avoids the formation of a vinyl anion intermediate; the Mg2+-dependent decarboxylation reaction catalyzed by KGPDC involves the formation of an enediolate anion intermediate. Based on the available structures of OMPDC, a sequence alignment allows the predictions that (1) KGPDC is a dimer of (beta/alpha)8-barrels, with the active sites located at the dimer interface; (2) KGPDC and OMPDC share an aspartate residue at the end of the first beta-strand and an Asp-x-Lys-x-x-Asp motif at the end of the third beta-strand with OMPDC; but (3) KGPDC has a Glu instead of a Lys at the end of the second beta-strand. The structure of KGPDC has been determined in the presence of Mg2+ and the substrate analogue L-gulonate 6-phosphate and confirms these predictions. The carboxylate functional groups at the ends of the first, second, and third beta-strands in KGPDC are ligands of the Mg2+; in OMPDC, the homologues of these residues participate in a hydrogen-bonded network that facilitates the decarboxylation reaction. The 3-OH group of the substrate analogue is coordinated to the Mg2+, supporting the hypothesis that the mechanism of the decarboxylation catalyzed by KGPDC involves stabilization of an enediolate anion intermediate. These structural studies establish the existence of the OMPDC "suprafamily," in which members catalyze reactions that occur in different metabolic pathways and share no mechanistic relationship. The existence of this suprafamily demonstrates that divergent evolution can be opportunistic, conscripting active site features of a progenitor to catalyze unrelated functions. Accordingly, sequence or structure homology alone cannot be used to infer the functions of new proteins discovered in genome projects.

Amino Acid Sequence↗
PubMed1997

An instrument for the non-invasive objective assessment of velar function during speech.

This paper describes the development of a non-invasive, computer-based, clinical instrument that infers velar function by way of the measurement of nasal and oral airflow. The design criteria of the instrument were based upon a wide ranging review of current practice and available techniques. The instrument measures and displays both nasal and oral airflow, along with the envelope of the speech sound waveform. This allows the clinician to determine whether airflow is associated with oral or nasal airflow and, hence, to infer the position of the velum. Preliminary clinical trials suggest that the instrument provides valuable objective information about the movement of the soft palate, particularly within the time domain. Hence, it is believed that the device provides additional information for the assessment of velar function, complementing those techniques currently employed.

Biomedical Engineering↗
PubMed2002

Numerous potentially functional but non-genic conserved sequences on human chromosome 21.

The use of comparative genomics to infer genome function relies on the understanding of how different components of the genome change over evolutionary time. The aim of such comparative analysis is to identify conserved, functionally transcribed sequences such as protein-coding genes and non-coding RNA genes, and other functional sequences such as regulatory regions, as well as other genomic features. Here, we have compared the entire human chromosome 21 with syntenic regions of the mouse genome, and have identified a large number of conserved blocks of unknown function. Although previous studies have made similar observations, it is unknown whether these conserved sequences are genes or not. Here we present an extensive experimental and computational analysis of human chromosome 21 in an effort to assign function to sequences conserved between human chromosome 21 (ref. 8) and the syntenic mouse regions. Our data support the presence of a large number of potentially functional non-genic sequences, probably regulatory and structural. The integration of the properties of the conserved components of human chromosome 21 to the rapidly accumulating functional data for this chromosome will improve considerably our understanding of the role of sequence conservation in mammalian genomes.

Animals↗
PubMed2001

The InterPro database, an integrated documentation resource for protein families, domains and functional sites.

Signature databases are vital tools for identifying distant relationships in novel sequences and hence for inferring protein function. InterPro is an integrated documentation resource for protein families, domains and functional sites, which amalgamates the efforts of the PROSITE, PRINTS, Pfam and ProDom database projects. Each InterPro entry includes a functional description, annotation, literature references and links back to the relevant member database(s). Release 2.0 of InterPro (October 2000) contains over 3000 entries, representing families, domains, repeats and sites of post-translational modification encoded by a total of 6804 different regular expressions, profiles, fingerprints and Hidden Markov Models. Each InterPro entry lists all the matches against SWISS-PROT and TrEMBL (more than 1,000,000 hits from 462,500 proteins in SWISS-PROT and TrEMBL). The database is accessible for text- and sequence-based searches at http://www.ebi.ac.uk/interpro/. Questions can be emailed to interhelp@ebi.ac.uk.

Databases, Factual↗
PubMed2004

Prolinks: a database of protein functional linkages derived from coevolution.

The advent of whole-genome sequencing has led to methods that infer protein function and linkages. We have combined four such algorithms (phylogenetic profile, Rosetta Stone, gene neighbor and gene cluster) in a single database--Prolinks--that spans 83 organisms and includes 10 million high-confidence links. The Proteome Navigator tool allows users to browse predicted linkage networks interactively, providing accompanying annotation from public databases. The Prolinks database and the Proteome Navigator tool are available for use online at http://dip.doe-mbi.ucla.edu/pronav.

ATP Synthetase Complexes↗
PubMed1997

Cell cycle and apoptosis: possible roles of Gadd45 and MyD118 proteins inferred from their homology to ribosomal proteins.

The function and structure of many disease gene products are currently poorly understood, and the easiest way to proceed is to search databases for homologous proteins to infer function or structure from the closest database match. Bioinformatics provides a variety of methods that reach beyond the standard database searches with single query sequences. The identification of a large superfamily of ribosome-associated proteins by computer analysis enabled Eugene Koonin to infer functional information for Gadd45, which is part of a cell-cycle checkpoint pathway defective in ataxia-telangiectasia.

Amino Acid Sequence↗
PubMed2006

Annually reoccurring bacterial communities are predictable from ocean conditions.

Factors influencing patterns in the distribution and abundance of plant and animal taxa modulate ecosystem function and ecosystem response to environmental change, which is often taken to infer low functional redundancy among such species, but such relationships are poorly known for microbial communities. Using high-resolution molecular fingerprinting, we demonstrate the existence of extraordinarily repeatable temporal patterns in the community composition of 171 operational taxonomic units of marine bacterioplankton over 4.5 years at our Microbial Observatory site, 20 km off the southern California coast. These patterns in distribution and abundance of microbial taxa were highly predictable and significantly influenced by a broad range of both abiotic and biotic factors. These findings provide statistically robust demonstration of temporal patterning in marine bacterial distribution and abundance, which suggests that the distribution and abundance of bacterial taxa may modulate ecosystem function and response and that a significant subset of the bacteria exhibit low levels of functional redundancy as documented for many plant and animal communities.

Bacteria↗
PubMed2005

FIGENIX: intelligent automation of genomic annotation: expertise integration in a new software platform.

BACKGROUND: Two of the main objectives of the genomic and post-genomic era are to structurally and functionally annotate genomes which consists of detecting genes' position and structure, and inferring their function (as well as of other features of genomes). Structural and functional annotation both require the complex chaining of numerous different software, algorithms and methods under the supervision of a biologist. The automation of these pipelines is necessary to manage huge amounts of data released by sequencing projects. Several pipelines already automate some of these complex chaining but still necessitate an important contribution of biologists for supervising and controlling the results at various steps. RESULTS: Here we propose an innovative automated platform, FIGENIX, which includes an expert system capable to substitute to human expertise at several key steps. FIGENIX currently automates complex pipelines of structural and functional annotation under the supervision of the expert system (which allows for example to make key decisions, check intermediate results or refine the dataset). The quality of the results produced by FIGENIX is comparable to those obtained by expert biologists with a drastic gain in terms of time costs and avoidance of errors due to the human manipulation of data. CONCLUSION: The core engine and expert system of the FIGENIX platform currently handle complex annotation processes of broad interest for the genomic community. They could be easily adapted to new, or more specialized pipelines, such as for example the annotation of miRNAs, the classification of complex multigenic families, annotation of regulatory elements and other genomic features of interest.

Automation↗