46 research outputs found
The Recalcitrance and Resilience of Scientific Function
âFunctionâ is a vitally important concept in the scientific community. Scientists use it to describe and address a wide variety of research problems. In publications, however, scientists within and across disciplines interpret function differently. For example, intense controversy surrounds what percentage of the human genome should be deemed "functionalâ rather than âjunk DNA.â In this essay, we analyze the use of function in the research of de novo gene birth, a budding scientific field that studies how novel genes can emerge in non-genic sequences. Our research team, composed of a rhetorical scholar, philosopher, structural biologist and systems biologist, crafts a taxonomy of how âfunctionâ is variously constituted in de novo gene birth publications, including as expressions, capacities, interactions, physiological implications and evolutionary implications. We argue function is shaped by the diverse onto-epistemological perspectives of scientists and is both a recalcitrant and resilient concept of scientific practice. Informed by Gilles Deleuze and Felix Guattariâs writings on a scientific mode of thinking, functions are time-space scales of objects under investigation that make possible references to scientific measurements
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Genome-Wide Identification of Pseudomonas aeruginosa Virulence-Related Genes Using a Caenorhabditis elegans Infection Model
Pseudomonas aeruginosa strain PA14 is an opportunistic human pathogen capable of infecting a wide range of organisms including the nematode Caenorhabditis elegans. We used a non-redundant transposon mutant library consisting of 5,850 clones corresponding to 75% of the total and approximately 80% of the non-essential PA14 ORFs to carry out a genome-wide screen for attenuation of PA14 virulence in C. elegans. We defined a functionally diverse 180 mutant set (representing 170 unique genes) necessary for normal levels of virulence that included both known and novel virulence factors. Seven previously uncharacterized virulence genes (ABC transporters PchH and PchI, aminopeptidase PepP, ATPase/molecular chaperone ClpA, cold shock domain protein PA0456, putative enoyl-CoA hydratase/isomerase PA0745, and putative transcriptional regulator PA14_27700) were characterized with respect to pigment production and motility and all but one of these mutants exhibited pleiotropic defects in addition to their avirulent phenotype. We examined the collection of genes required for normal levels of PA14 virulence with respect to occurrence in P. aeruginosa strain-specific genomic regions, location on putative and known genomic islands, and phylogenetic distribution across prokaryotes. Genes predominantly contributing to virulence in C. elegans showed neither a bias for strain-specific regions of the P. aeruginosa genome nor for putatively horizontally transferred genomic islands. Instead, within the collection of virulence-related PA14 genes, there was an overrepresentation of genes with a broad phylogenetic distribution that also occur with high frequency in many prokaryotic clades, suggesting that in aggregate the genes required for PA14 virulence in C. elegans are biased towards evolutionarily conserved genes
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Interpreting Cancer Genomes Using Systematic Host Perturbations by Tumour Virus Proteins
Genotypic differences greatly influence susceptibility and resistance to disease. Understanding genotype-phenotype relationships requires that phenotypes be viewed as manifestations of network properties, rather than simply as the result of individual genomic variations. Genome sequencing efforts have identified numerous germline mutations associated with cancer predisposition and large numbers of somatic genomic alterations. However, it remains challenging to distinguish between background, or âpassengerâ and causal, or âdriverâ cancer mutations in these datasets. Human viruses intrinsically depend on their host cell during the course of infection and can elicit pathological phenotypes similar to those arising from mutations. To test the hypothesis that genomic variations and tumour viruses may cause cancer via related mechanisms, we systematically examined host interactome and transcriptome network perturbations caused by DNA tumour virus proteins. The resulting integrated viral perturbation data reflects rewiring of the host cell networks, and highlights pathways that go awry in cancer, such as Notch signalling and apoptosis. We show that systematic analyses of host targets of viral proteins can identify cancer genes with a success rate on par with their identification through functional genomics and large-scale cataloguing of tumour mutations. Together, these complementary approaches result in increased specificity for cancer gene identification. Combining systems-level studies of pathogen-encoded gene products with genomic approaches will facilitate prioritization of cancer-causing driver genes so as to advance understanding of the genetic basis of human cancer
Des protéines et de leurs interactions aux principes évolutifs des systÚmes biologiques
Darwin exposed to the world that living species continuously evolve. Yet the molecular mechanisms of evolution remain under intense research. Systems biology proposes that dynamic molecular networks underlie relationships between genotype, environment and phenotype, but the organization of these networks is mysterious. Combining established concepts from evolutionary and systems biology with protein interaction mapping and the study of genome annotation methodologies, I have developed new bioinformatics approaches that partially unveiled the composition and organization of cellular systems for three eukaryotic organisms: the bakerâs yeast, the nematode Caenorhabditis elegans and the plant Arabidopsis thaliana. My analyses led to insights into the evolution of biological systems. First, I propose that the translation of peptides from intergenic regions could lead to de novo birth of new protein-coding genes. Second, I show that the evolution of proteins originating from gene duplications and of their physical interaction repertoires are tightly interrelated. Lastly, I uncover signatures of the ancestral host-pathogen co-evolution in the topology of a host protein interaction network. My PhD work supports the thesis that molecular systems also evolve in a Darwinian fashion.Darwin a rĂ©vĂ©lĂ© au monde que les espĂšces vivantes ne cessent jamais dâĂ©voluer, mais les mĂ©canismes molĂ©culaires de cette Ă©volution restent le sujet de recherches intenses. La biologie systĂ©mique propose que les relations entre gĂ©notype, environnement et phĂ©notype soient sous-tendues par un ensemble de rĂ©seaux molĂ©culaires dynamiques au sein de la cellule, mais lâorganisation de ces rĂ©seaux demeure mystĂ©rieuse. En combinant des concepts Ă©tablis en biologie Ă©volutive et systĂ©mique avec la cartographie dâinteractions protĂ©iques et lâĂ©tude des mĂ©thodologies dâannotation de gĂ©nomes, jâai dĂ©veloppĂ© de nouvelles approches bioinformatiques qui ont en partie dĂ©voilĂ© la composition et lâorganisation des systĂšmes cellulaires de trois organismes eucaryotes : la levure de boulanger, le nĂ©matode Caenorhabditis elegans et la plante Arabidopsis thaliana. Lâanalyse de ces systĂšmes mâa conduit Ă proposer des hypothĂšses sur les principes Ă©volutifs des systĂšmes biologiques. En premier lieu, je propose une thĂ©orie selon laquelle la traduction fortuite de rĂ©gions intergĂ©niques produirait des peptides sur lesquels la sĂ©lection naturelle agirait pour aboutir occasionnellement Ă la crĂ©ation de protĂ©ines de novo. De plus, je montre que lâĂ©volution de protĂ©ines apparues par duplication de gĂšnes est corrĂ©lĂ©e avec celle de leurs profils dâinteractions. Enfin, jâai mis en Ă©vidence des signatures de la co-Ă©volution ancestrale hĂŽte-pathogĂšne dans lâorganisation topologique du rĂ©seau dâinteractions entre protĂ©ines de lâhĂŽte. Mes travaux confortent lâhypothĂšse que les systĂšmes molĂ©culaires Ă©voluent, eux aussi, de maniĂšre darwinienne
From proteins and their interactions to evolutionary principles of biological systems
Darwin a rĂ©vĂ©lĂ© au monde que les espĂšces vivantes ne cessent jamais dâĂ©voluer, mais les mĂ©canismes molĂ©culaires de cette Ă©volution restent le sujet de recherches intenses. La biologie systĂ©mique propose que les relations entre gĂ©notype, environnement et phĂ©notype soient sous-tendues par un ensemble de rĂ©seaux molĂ©culaires dynamiques au sein de la cellule, mais lâorganisation de ces rĂ©seaux demeure mystĂ©rieuse. En combinant des concepts Ă©tablis en biologie Ă©volutive et systĂ©mique avec la cartographie dâinteractions protĂ©iques et lâĂ©tude des mĂ©thodologies dâannotation de gĂ©nomes, jâai dĂ©veloppĂ© de nouvelles approches bioinformatiques qui ont en partie dĂ©voilĂ© la composition et lâorganisation des systĂšmes cellulaires de trois organismes eucaryotes : la levure de boulanger, le nĂ©matode Caenorhabditis elegans et la plante Arabidopsis thaliana. Lâanalyse de ces systĂšmes mâa conduit Ă proposer des hypothĂšses sur les principes Ă©volutifs des systĂšmes biologiques. En premier lieu, je propose une thĂ©orie selon laquelle la traduction fortuite de rĂ©gions intergĂ©niques produirait des peptides sur lesquels la sĂ©lection naturelle agirait pour aboutir occasionnellement Ă la crĂ©ation de protĂ©ines de novo. De plus, je montre que lâĂ©volution de protĂ©ines apparues par duplication de gĂšnes est corrĂ©lĂ©e avec celle de leurs profils dâinteractions. Enfin, jâai mis en Ă©vidence des signatures de la co-Ă©volution ancestrale hĂŽte-pathogĂšne dans lâorganisation topologique du rĂ©seau dâinteractions entre protĂ©ines de lâhĂŽte. Mes travaux confortent lâhypothĂšse que les systĂšmes molĂ©culaires Ă©voluent, eux aussi, de maniĂšre darwinienne.Darwin exposed to the world that living species continuously evolve. Yet the molecular mechanisms of evolution remain under intense research. Systems biology proposes that dynamic molecular networks underlie relationships between genotype, environment and phenotype, but the organization of these networks is mysterious. Combining established concepts from evolutionary and systems biology with protein interaction mapping and the study of genome annotation methodologies, I have developed new bioinformatics approaches that partially unveiled the composition and organization of cellular systems for three eukaryotic organisms: the bakerâs yeast, the nematode Caenorhabditis elegans and the plant Arabidopsis thaliana. My analyses led to insights into the evolution of biological systems. First, I propose that the translation of peptides from intergenic regions could lead to de novo birth of new protein-coding genes. Second, I show that the evolution of proteins originating from gene duplications and of their physical interaction repertoires are tightly interrelated. Lastly, I uncover signatures of the ancestral host-pathogen co-evolution in the topology of a host protein interaction network. My PhD work supports the thesis that molecular systems also evolve in a Darwinian fashion
Biological factors and statistical limitations prevent detection of most noncanonical proteins by mass spectrometry.
Ribosome profiling experiments indicate pervasive translation of short open reading frames (ORFs) outside of annotated protein-coding genes. However, shotgun mass spectrometry (MS) experiments typically detect only a small fraction of the predicted protein products of this noncanonical translation. The rarity of detection could indicate that most predicted noncanonical proteins are rapidly degraded and not present in the cell; alternatively, it could reflect technical limitations. Here, we leveraged recent advances in ribosome profiling and MS to investigate the factors limiting detection of noncanonical proteins in yeast. We show that the low detection rate of noncanonical ORF products can largely be explained by small size and low translation levels and does not indicate that they are unstable or biologically insignificant. In particular, proteins encoded by evolutionarily young genes, including those with well-characterized biological roles, are too short and too lowly expressed to be detected by shotgun MS at current detection sensitivities. Additionally, we find that decoy biases can give misleading estimates of noncanonical protein false discovery rates, potentially leading to false detections. After accounting for these issues, we found strong evidence for 4 noncanonical proteins in MS data, which were also supported by evolution and translation data. These results illustrate the power of MS to validate unannotated genes predicted by ribosome profiling, but also its substantial limitations in finding many biologically relevant lowly expressed proteins
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Of mice, men and immunity: a case for evolutionary systems biology
Animal models have been tremendously useful to translational research, but there is a need to maximize their predictive value to human disease. This Comment proposes novel strategies that consider evolutionary history and the presence, absence or modification of molecular networks in one species that are being studied in the other
Evolutionary Characterization of the Short Protein SPAAR
Microproteins (de novo emergence from a noncoding sequence. By integrating syntenic alignments and homology searches, we identify SPAAR orthologs in marsupials and monotremes, establishing that SPAAR has existed at least since the emergence of mammals. SPAAR shows substantial primary sequence divergence but retains a conserved protein structure. In primates, we infer two independent evolutionary events leading to the de novo origination of 5âČ elongated isoforms of SPAAR from a noncoding sequence and find evidence of adaptive evolution in this extended region. Thus, SPAAR may be of ancient origin, but it appears to be experiencing continual evolutionary innovation in mammals