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

Assessing functional novelty of PSI structures via structure-function analysis of large and diverse superfamilies

The structural genomics initiatives have had as one of their aims to improve our understanding of protein function by providing representative structures for many structurally uncharacterised protein families. As suggested by the recent assessment of the Protein Structure Initiative (Structural Genomics Initiative, funded by the NIH), doubts have arisen as to whether Structural Genomics as initially planned were really beneficial to our understanding of biological issues, and in particular of protein function.
A few protein domain superfamilies have been shown to account for unexpectedly large numbers of proteins encoded in fully sequenced genomes. These large superfamilies are generally very diverse, spanning a wide range of functions, both in terms of molecular activities and biological processes. Some of these superfamilies, such as the Rossmann-fold P-loop nucleotide hydrolases or the TIM-barrel glycosidases, have been the subject of extensive structural studies which in turn have shed light on how evolution of the sequence and structure properties produce functional diversity amongst homologues. Recently, the Structure-Function Linkage Database (SFLD) has been setup with the aim of helping the study of structure-function correlations in such superfamilies. Since the evolutionary success of these large superfamilies suggests biological importance, several Structural Genomics Centers have focused on providing full structural coverage for representatives of all sequence families in these superfamilies.
In this work we evaluate structure/function diversity in a set of these large superfamilies and attempt to assess the quality and quantity of biological information gained from Structural Genomics.
&#xa

Yeast cytochrome c oxidase: a model system to study mitochondrial forms of the haem-copper oxidase superfamily.

The known subunits of yeast mitochondrial cytochrome c oxidase are reviewed. The structures of all eleven of its subunits are explored by building homology models based on the published structures of the homologous bovine subunits and similarities and differences are highlighted, particularly of the core functional subunit I. Yeast genetic techniques to enable introduction of mutations into the three core mitochondrially-encoded subunits are reviewed

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

Neural-Based Nonlinear Device Models for Intermodulation Analysis

A new procedure to learn a nonlinear model together with its derivative parameters using a composite neural network is presented.So far neural networks have never been used to extract large-signal device model accounting for distortion parameters.Applying this method to FET devices leads to nonlinear models for current- voltage functions which allow improved prediction of weak and mildly device nonlinearities in the whole bias region. The resulting models have demonstrated to be suitable for both small-signal and large-signal analyses,including intermodulation distortion prediction

Simulating communication routes in Mediterranean alluvial plains

Societies exchange knowledge, ideas and merchandise throughout their territories. Topography plays a fundamental role in the trajectory of such movements whilst helping to explain the distribution of human constructions. Standard GIS functions have been employed widely to simulate communication routes between settlements, but the straight application of published least cost route models proved inadequate for Mediterranean alluvial plain areas in which seasonal floods become an important factor to acknowledge. The objective of this study is the production of a new model, using topographic and hydrologic factors as variables from which it would be possible to simulate a route, and test it against known Roman itineraries. The selected Roman stretches are Girona – Coll de Pannisars and Tarragona – Montblanc. The new model shows the need to consider each case individually but also stresses the hydrologic factor, expressed in seasonal floods, as being of prime importance in the creation and development of Roman roads in Mediterranean alluvial plains

The Augustan temple and forum of the colony of Barcino: a 90 degree turn

The Augustan Roman temple at Barcino has been a key element during the last 60 years in the research of the colony's urban development. Its peculiar elongated and narrow plan, first proposed in 1835, and its location at the highest point of the ancient city have dictated our understanding of the urban layout of Barcino by conditioning the shape of the city's forum and affecting the interpretation of the archaeological excavations carried out in the area since then. This paper proposes an alternative plan of the temple, based on data drawn from recent archaeological excavations, topographical analysis, typological comparisons, and the study of written sources. Our alternative hypothesis for the temple permits an in-depth reinterpretation of the plan of the forum and the evolution of the urban plan

Reconstructing the Roman London flavourscape: new insights into the exotic food plant trade using network and spatial analyses

Using archaeobotanical data and examining them with a novel combination of density interpolation surfaces and social and spatial network analyses, this study has brought together exotic food plants in Roman London to outline the changing ‘face’ of its flavourscape, and contextualise it within the broader exotics commerce in Britannia. Consumption of a variety of exotics appeared to be widespread since the very first stages of London's establishment and their presence was maintained throughout although later on, as life in the town developed and its character changed, the focus of their distribution also changed. The emphasis shifted from the core of the city in its early days towards its outer zones, such as the upper Walbrook valley and Southwark in the Middle Roman, and the western and eastern sectors in the Late Roman phase. These changes appeared to largely reflect the changes in the overall commerce network of exotics in Britannia. In this network London starts as a mainly consumption place in the Early Roman phase to become the main redistribution centre in the Middle Roman and the necessary intermediate node in the transport system that had been established by the Late Roman phase, connecting the south to the north

The application of 3D reconstruction techniques in the analysis of ancient Tarraco's urban topography

The widespread implementation of GIS-based 3D topographical models has been a great aid in the development and testing of archaeological hypotheses. In this paper, a topographical reconstruction of the ancient city of Tarraco, the Roman capital of the Tarraconensis province, is presented. This model is based on topographical data obtained through archaeological excavations, old photographic documentation, georeferenced archive maps depicting the pre-modern city topography, modern detailed topographical maps and differential GPS measurements. The addition of the Roman urban architectural features to the model offers the possibility to test hypotheses concerning the ideological background manifested in the city shape. This is accomplished mainly through the use of 3D views from the main city accesses. These techniques ultimately demonstrate the ‘theatre-shaped’ layout of the city (to quote Vitrubius) as well as its southwest oriented architecture, whose monumental character was conceived to present a striking aspect to visitors, particularly those arriving from the sea