Predicting protein function with hierarchical phylogenetic profiles: The Gene3D phylo-tuner method applied to eukaryotic Genomes

"Phylogenetic profiling'' is based on the hypothesis that during evolution functionally or physically interacting genes are likely to be inherited or eliminated in a codependent manner. Creating presence-absence profiles of orthologous genes is now a common and powerful way of identifying functionally associated genes. In this approach, correctly determining orthology, as a means of identifying functional equivalence between two genes, is a critical and nontrivial step and largely explains why previous work in this area has mainly focused on using presence-absence profiles in prokaryotic species. Here, we demonstrate that eukaryotic genomes have a high proportion of multigene families whose phylogenetic profile distributions are poor in presence-absence information content. This feature makes them prone to orthology mis-assignment and unsuited to standard profile-based prediction methods. Using CATH structural domain assignments from the Gene3D database for 13 complete eukaryotic genomes, we have developed a novel modification of the phylogenetic profiling method that uses genome copy number of each domain superfamily to predict functional relationships. In our approach, superfamilies are subclustered at ten levels of sequence identity from 30% to 100% - and phylogenetic profiles built at each level. All the profiles are compared using normalised Euclidean distances to identify those with correlated changes in their domain copy number. We demonstrate that two protein families will "auto-tune'' with strong co-evolutionary signals when their profiles are compared at the similarity levels that capture their functional relationship. Our method finds functional relationships that are not detectable by the conventional presence - absence profile comparisons, and it does not require a priori any fixed criteria to define orthologous genes

Protein function annotation using protein domain family resources

As a result of the genome sequencing and structural genomics initiatives, we have a wealth of protein sequence and structural data. However, only about 1% of these proteins have experimental functional annotations. As a result, computational approaches that can predict protein functions are essential in bridging this widening annotation gap. This article reviews the current approaches of protein function prediction using structure and sequence based classification of protein domain family resources with a special focus on functional families in the CATH-Gene3D resource

Large-scale, multi-temporal remote sensing of palaeo-river networks: A case study from Northwest India and its implications for the indus civilisation

© 2018 by the authors. Remote sensing has considerable potential to contribute to the identification and reconstruction of lost hydrological systems and networks. Remote sensing-based reconstructions of palaeo-river networks have commonly employed single or limited time-span imagery, which limits their capacity to identify features in complex and varied landscape contexts. This paper presents a seasonal multi-temporal approach to the detection of palaeo-rivers over large areas based on long-term vegetation dynamics and spectral decomposition techniques. Twenty-eight years of Landsat 5 data, a total of 1711 multi-spectral images, have been bulk processed using Google Earth Engine. © Code Editor and cloud computing infrastructure. The use of multi-temporal data has allowed us to overcome seasonal cultivation patterns and long-term visibility issues related to recent crop selection, extensive irrigation and land-use patterns. The application of this approach on the Sutlej-Yamuna interfluve (northwest India), a core area for the Bronze Age Indus Civilisation, has enabled the reconstruction of an unsuspectedly complex palaeo-river network comprising more than 8000 km of palaeo-channels. It has also enabled the definition of the morphology of these relict courses, which provides insights into the environmental conditions in which they operated. These new data will contribute to a better understanding of the settlement distribution and environmental settings in which this, often considered riverine, civilisation operated.ER

Diversity in protein domain superfamilies

Whilst ∼93% of domain superfamilies appear to be relatively structurally and functionally conserved based on the available data from the CATH-Gene3D domain classification resource, the remainder are much more diverse. In this review, we consider how domains in some of the most ubiquitous and promiscuous superfamilies have evolved, in particular the plasticity in their functional sites and surfaces which expands the repertoire of molecules they interact with and actions performed on them. To what extent can we identify a core function for these superfamilies which would allow us to develop a 'domain grammar of function' whereby a protein's biological role can be proposed from its constituent domains? Clearly the first step is to understand the extent to which these components vary and how changes in their molecular make-up modifies function

Identifying and characterising key alternative splicing events in Drosophila development

In complex Metazoans a given gene frequently codes for multiple protein isoforms, through processes such as alternative splicing. Large scale functional annotation of these isoforms is a key challenge for functional genomics. This annotation gap is increasing with the large numbers of multi transcript genes being identified by technologies such as RNASeq. Furthermore attempts to characterise the functions of splicing in an organism are complicated by the difficulty in distinguishing functional isoforms from those produced by splicing errors or transcription noise. Tools to help prioritise candidate isoforms for testing are largely absent

Characterization of pathogenic germline mutations in human Protein Kinases

Background: Protein Kinases are a superfamily of proteins involved in crucial cellular processes such as cell cycle regulation and signal transduction. Accordingly, they play an important role in cancer biology. To contribute to the study of the relation between kinases and disease we compared pathogenic mutations to neutral mutations as an extension to our previous analysis of cancer somatic mutations. First, we analyzed native and mutant proteins in terms of amino acid composition. Secondly, mutations were characterized according to their potential structural effects and finally, we assessed the location of the different classes of polymorphisms with respect to kinase-relevant positions in terms of subfamily specificity, conservation, accessibility and functional sites.Results: Pathogenic Protein Kinase mutations perturb essential aspects of protein function, including disruption of substrate binding and/or effector recognition at family-specific positions. Interestingly these mutations in Protein Kinases display a tendency to avoid structurally relevant positions, what represents a significant difference with respect to the average distribution of pathogenic mutations in other protein families.Conclusions: Disease-associated mutations display sound differences with respect to neutral mutations: several amino acids are specific of each mutation type, different structural properties characterize each class and the distribution of pathogenic mutations within the consensus structure of the Protein Kinase domain is substantially different to that for non-pathogenic mutations. This preferential distribution confirms previous observations about the functional and structural distribution of the controversial cancer driver and passenger somatic mutations and their use as a proxy for the study of the involvement of somatic mutations in cancer development. © 2011 Izarzugaza et al; licensee BioMed Central Ltd

VIDA: a virus database system for the organization of animal virus genome open reading frames

VIDA is a new virus database that organizes open reading frames (ORFs) from partial and complete genomic sequences from animal viruses. Currently VIDA includes all sequences from GenBank for Herpesviridae, Coronaviridae and Arteriviridae. The ORFs are organized into homologous protein families, which are identified on the basis of sequence similarity relationships, Conserved sequence regions of potential functional importance are identified and can be retrieved as sequence alignments. We use a controlled taxonomical and functional classification for all the proteins and protein families in the database. When available, protein structures that are related to the families have also been included. The database is available for online search and sequence information retrieval at http://www.biochem.ucl.ac.uk/bsm/virus-database/ VIDA.html

An integrated approach to the interpretation of Single Amino Acid Polymorphisms within the framework of CATH and Gene3D

Background: The phenotypic effects of sequence variations in protein-coding regions come about primarily via their effects on the resulting structures, for example by disrupting active sites or affecting structural stability. In order better to understand the mechanisms behind known mutant phenotypes, and predict the effects of novel variations, biologists need tools to gauge the impacts of DNA mutations in terms of their structural manifestation. Although many mutations occur within domains whose structure has been solved, many more occur within genes whose protein products have not been structurally characterized.Results: Here we present 3DSim (3D Structural Implication of Mutations), a database and web application facilitating the localization and visualization of single amino acid polymorphisms (SAAPs) mapped to protein structures even where the structure of the protein of interest is unknown. The server displays information on 6514 point mutations, 4865 of them known to be associated with disease. These polymorphisms are drawn from SAAPdb, which aggregates data from various sources including dbSNP and several pathogenic mutation databases. While the SAAPdb interface displays mutations on known structures, 3DSim projects mutations onto known sequence domains in Gene3D. This resource contains sequences annotated with domains predicted to belong to structural families in the CATH database. Mappings between domain sequences in Gene3D and known structures in CATH are obtained using a MUSCLE alignment. 1210 three-dimensional structures corresponding to CATH structural domains are currently included in 3DSim; these domains are distributed across 396 CATH superfamilies, and provide a comprehensive overview of the distribution of mutations in structural space.Conclusion: The server is publicly available at http://3DSim.bioinfo.cnio.es/. In addition, the database containing the mapping between SAAPdb, Gene3D and CATH is available on request and most of the functionality is available through programmatic web service access

A novel application method for wearable bend sensors

Bend sensors fundamental characteristic is to furnish an electrical resistance value related to the angle they are bent. This feature can be successfully exploited to realize wearable systems capable to measure human static and dynamic postures. In particular some efforts have been made to determine finger joint movements of human hands and it has been demonstrated the feasibility of using the so called data glove system as a goniometric device. The repeatability of such system is quite good for general purposes but it is still not sufficient for specific applications (for instance in virtual surgery). So here we introduce a novel application method of bend sensors and demonstrate how it can be useful to improve the system repeatabilit

VarSite: disease variants and protein structure

VarSite is a web server mapping known disease-associated variants from UniProt and ClinVar, together with natural variants from gnomAD, onto protein 3D structures in the Protein Data Bank (PDB). The analyses are primarily image-based and provide both an overview for each human protein, as well as a report for any specific variant of interest. The information can be useful in assessing whether a given variant might be pathogenic or benign. The structural annotations for each position in the protein include protein secondary structure, interactions with ligand, metal, DNA/RNA, or other protein, and various measures of a given variant's possible impact on the protein's function. The 3D locations of the disease-associated variants can be viewed interactively via the 3dmol.js JavaScript viewer, as well as in RasMol and PyMOL. Users can search for specific variants, or sets of variants, by providing the DNA coordinates of the base change(s) of interest. Additionally, various agglomerative analyses are given, such as the mapping of disease and natural variants onto specific Pfam or CATH domains. The server is freely accessible to all at: https://www.ebi.ac.uk/thornton-srv/databases/VarSite. This article is protected by copyright. All rights reserved