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Computational Genomics

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http://hdl.handle.net/10400.7/37

We are interested in the evolutionary mechanisms underlying the origins and evolution of cellular life and the complex structures within the cell, the transitions to multi-cellularity, and the medical applications of evolutionary genomics. Our research encompasses themes that are broadly classified as evolutionary cell biology, systems biology, pathogenomics, and translational or medical bioinformatics

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  • 2006Review Restricted access Show more
  • 3D complex: a structural classification of protein complexes
    Publication . Levy, E.D.; Pereira-Leal, J.B.; Chothia, C.; Teichmann, S.A.
    Most of the proteins in a cell assemble into complexes to carry out their function. It is therefore crucial to understand the physicochemical properties as well as the evolution of interactions between proteins. The Protein Data Bank represents an important source of information for such studies, because more than half of the structures are homo- or heteromeric protein complexes. Here we propose the first hierarchical classification of whole protein complexes of known 3-D structure, based on representing their fundamental structural features as a graph. This classification provides the first overview of all the complexes in the Protein Data Bank and allows nonredundant sets to be derived at different levels of detail. This reveals that between one-half and two-thirds of known structures are multimeric, depending on the level of redundancy accepted. We also analyse the structures in terms of the topological arrangement of their subunits and find that they form a small number of arrangements compared with all theoretically possible ones. This is because most complexes contain four subunits or less, and the large majority are homomeric. In addition, there is a strong tendency for symmetry in complexes, even for heteromeric complexes. Finally, through comparison of Biological Units in the Protein Data Bank with the Protein Quaternary Structure database, we identified many possible errors in quaternary structure assignments. Our classification, available as a database and Web server at http://www.3Dcomplex.org, will be a starting point for future work aimed at understanding the structure and evolution of protein complexes
    2006-11Journal article Restricted access Show more
  • The evolution of protein complexes by duplication of homomeric interactions
    Publication . Pereira Leal, J.B.; Levy, E.D.; Kamp, C.; Teichmann, S.A.
    BACKGROUND: Cellular functions are accomplished by the concerted actions of functional modules. The mechanisms driving the emergence and evolution of these modules are still unclear. Here we investigate the evolutionary origins of protein complexes, modules in physical protein-protein interaction networks. RESULTS: We studied protein complexes in Saccharomyces cerevisiae, complexes of known three-dimensional structure in the Protein Data Bank and clusters of pairwise protein interactions in the networks of several organisms. We found that duplication of homomeric interactions, a large class of protein interactions, frequently results in the formation of complexes of paralogous proteins. This route is a common mechanism for the evolution of complexes and clusters of protein interactions. Our conclusions are further confirmed by theoretical modelling of network evolution. We propose reasons for why this is favourable in terms of structure and function of protein complexes. CONCLUSION: Our study provides the first insight into the evolution of functional modularity in protein-protein interaction networks, and the origins of a large class of protein complexes.
    2007Journal article Open access Show more
  • Multiple domain insertions and losses in the evolution of the Rab prenylation complex
    Publication . Rasteiro, R.; Pereira Leal, J.B.
    BACKGROUND: Rab proteins are regulators of vesicular trafficking, requiring a lipid modification for proper function, prenylation of C-terminal cysteines. This is catalysed by a complex of a catalytic heterodimer (Rab Geranylgeranyl Transferase - RabGGTase) and an accessory protein (Rab Escort Protein. REP). Components of this complex display domain insertions relative to paralogous proteins. The function of these inserted domains is unclear. RESULTS: We profiled the domain architecture of the components of the Rab prenylation complex in evolution. We identified the orthologues of the components of the Rab prenylation machinery in 43 organisms, representing the crown eukaryotic groups. We characterize in detail the domain structure of all these components and the phylogenetic relationships between the individual domains. CONCLUSION: We found different domain insertions in different taxa, in alpha-subunits of RGGTase and REP. Our results suggest that there were multiple insertions, expansions and contractions in the evolution of this prenylation complex
    2007-08Journal article Open access Show more
  • The Ypt/Rab family and the evolution of trafficking in Fungi
    Publication . Pereira-Leal, J.B.
    The evolution of the eukaryotic endomembrane system and the transport pathways of their vesicular intermediates are poorly understood. A common set of organelles and pathways seems to be present in all free-living eukaryotes, but different branches of the tree of life have a variety of diverse, specialized organelles. Rab/Ypt proteins are small guanosine triphosphatases with tissue-specific and organelle-specific localization that emerged as markers for organelle diversity. Here, I characterize the Rab/Ypt family in the kingdom Fungi, a sister kingdom of Animals. I identify and annotate these proteins in 26 genomes representing near one billion years of evolution, multiple lifestyles and cellular types. Surprisingly, the minimal set of Rab/Ypt present in fungi is similar to, perhaps smaller than, the predicted eukaryotic ancestral set. This suggests that the saprophytic fungal lifestyle, multicellularity as well as the highly polarized secretion associated with hyphal growth did not require any major innovation in the molecular machinery that regulates protein trafficking. The Rab/Ypt and other protein traffic-related families are kept small, not paralleling increases in genome size, in contrast to the expansion of such components observed in other branches of the tree of life, such as the animal and plant kingdoms. This analysis suggests that multicellularity and cellular diversity in fungi followed different routes from those followed by plants and metazoa
    2008Journal article Restricted access Show more
  • A Genomic Signature and the Identification of New Sporulation Genes
    Publication . Abecasis, A. B.; Serrano, M.; Alves, R.; Quintais, L.; Pereira-Leal, J. B.; Henriques, A. O.
    Bacterial endospores are the most resistant cell type known to humans, as they are able to withstand extremes of temperature, pressure, chemical injury, and time. They are also of interest because the endospore is the infective particle in a variety of human and livestock diseases. Endosporulation is characterized by the morphogenesis of an endospore within a mother cell. Based on the genes known to be involved in endosporulation in the model organism Bacillus subtilis, a conserved core of about 100 genes was derived, representing the minimal machinery for endosporulation. The core was used to define a genomic signature of about 50 genes that are able to distinguish endospore-forming organisms, based on complete genome sequences, and we show this 50-gene signature is robust against phylogenetic proximity and other artifacts. This signature includes previously uncharacterized genes that we can now show are important for sporulation in B. subtilis and/or are under developmental control, thus further validating this genomic signature. We also predict that a series of polyextremophylic organisms, as well as several gut bacteria, are able to form endospores, and we identified 3 new loci essential for sporulation in B. subtilis: ytaF, ylmC, and ylzA. In all, the results support the view that endosporulation likely evolved once, at the base of the Firmicutes phylum, and is unrelated to other bacterial cell differentiation programs and that this involved the evolution of new genes and functions, as well as the cooption of ancestral, housekeeping functions.
    2013Journal article Open access Show more
  • Genome of a Gut Strain of Bacillus subtilis
    Publication . Schyns, G.; Serra, C. R.; Lapointe, T.; Pereira-Leal, J. B.; Potot, S.; Fickers, P.; Perkins, J. B.; Wyss, M.; Henriques, A. O.
    Bacillus subtilis is a Gram-positive, rod-shaped, spore-forming bacterium. We present the genome sequence of an undomesticated strain, BSP1, isolated from poultry. The sequence of the BSP1 genome supports the view that B. subtilis has a biphasic lifestyle, cycling between the soil and the animal gastrointestinal tract, and it provides molecular-level insight into the adaptation of B. subtilis to life under laboratory conditions.
    2013-02-14Journal article Open access Show more
  • Aurora at the pole and equator: overlapping functions of Aurora kinases in the mitotic spindle
    Publication . Hochegger, H.; Hegarat, N.; Pereira-Leal, J. B.
    The correct assembly and timely disassembly of the mitotic spindle is crucial for the propagation of the genome during cell division. Aurora kinases play a central role in orchestrating bipolar spindle establishment, chromosome alignment and segregation. In most eukaryotes, ranging from amoebas to humans, Aurora activity appears to be required both at the spindle pole and the kinetochore, and these activities are often split between two different Aurora paralogues, termed Aurora A and B. Polar and equatorial functions of Aurora kinases have generally been considered separately, with Aurora A being mostly involved in centrosome dynamics, whereas Aurora B coordinates kinetochore attachment and cytokinesis. However, double inactivation of both Aurora A and B results in a dramatic synergy that abolishes chromosome segregation. This suggests that these two activities jointly coordinate mitotic progression. Accordingly, recent evidence suggests that Aurora A and B work together in both spindle assembly in metaphase and disassembly in anaphase. Here, we provide an outlook on these shared functions of the Auroras, discuss the evolution of this family of mitotic kinases and speculate why Aurora kinase activity may be required at both ends of the spindle microtubules.
    2013-03-20Journal article Open access Show more
  • inTB - a data integration platform for molecular and clinical epidemiological analysis of tuberculosis
    Publication . Soares, Patrícia; Alves, Renato J; Abecasis, Ana B; Penha-Gonçalves, Carlos; Gomes, M Gabriela M; Pereira-Leal, José B
    Tuberculosis is currently the second highest cause of death from infectious diseases worldwide. The emergence of multi and extensive drug resistance is threatening to make tuberculosis incurable. There is growing evidence that the genetic diversity of Mycobacterium tuberculosis may have important clinical consequences. Therefore, combining genetic, clinical and socio-demographic data is critical to understand the epidemiology of this infectious disease, and how virulence and other phenotypic traits evolve over time. This requires dedicated bioinformatics platforms, capable of integrating and enabling analyses of this heterogeneous data.
    2013-08-30Journal article Open access Show more
  • A comprehensive assessment of the transcriptome of cork oak (Quercus suber) through EST sequencing
    Publication . Pereira-Leal, José B; Abreu, Isabel A; Alabaça, Cláudia S; Almeida, Maria; Almeida, Paulo; Almeida, Tânia; Amorim, Maria; Araújo, Susana; Azevedo, Herlânder; Badia, Aleix; Batista, Dora; Bohn, Andreas; Capote, Tiago; Carrasquinho, Isabel; Chaves, Inês; Coelho, Ana; Costa, Maria; Costa, Rita; Cravador, Alfredo; Egas, Conceição; Faro, Carlos; Fortes, Ana M; Fortunato, Ana S; Gaspar, Maria; Gonçalves, Sónia; Graça, José; Horta, Marília; Inácio, Vera; Leitão, José M; Lino-Neto, Teresa; Marum, Liliana; Matos, José; Mendonça, Diogo; Miguel, Andreia; Miguel, Célia M; Morais-Cecílio, Leonor; Neves, Isabel; Nóbrega, Filomena; Oliveira, Maria; Oliveira, Rute; Pais, Maria; Paiva, Jorge A; Paulo, Octávio S; Pinheiro, Miguel; Raimundo, João AP; Ramalho, José C; Ribeiro, Ana I; Ribeiro, Teresa; Rocheta, Margarida; Rodrigues, Ana; Rodrigues, José C; Saibo, Nelson JM; Santo, Tatiana E; Santos, Ana; Sá-Pereira, Paula; Sebastiana, Mónica; Simões, Fernanda; Sobral, Rómulo S; Tavares, Rui; Teixeira, Rita; Varela, Carolina; Veloso, Maria; Ricardo, Cândido PP
    Cork oak (Quercus suber) is one of the rare trees with the ability to produce cork, a material widely used to make wine bottle stoppers, flooring and insulation materials, among many other uses. The molecular mechanisms of cork formation are still poorly understood, in great part due to the difficulty in studying a species with a long life-cycle and for which there is scarce molecular/genomic information. Cork oak forests are of great ecological importance and represent a major economic and social resource in Southern Europe and Northern Africa. However, global warming is threatening the cork oak forests by imposing thermal, hydric and many types of novel biotic stresses. Despite the economic and social value of the Q. suber species, few genomic resources have been developed, useful for biotechnological applications and improved forest management.
    2014-05-15Journal article Open access Show more