Unit: Genetics of Bacterial Genomes
Director: Danchin Antoine
The Genetics of Bacterial Genomes Unit makes use of the determination of the complete sequence of bacterial genomes to explore how the distribution of the genes along the chromosomes is (or is not) coupled to the distribution and/or function of genes in the cell. This study is focussed on sulfur metabolism. Because of the Severy Acute Respiratory Syndrome outbreak the Unit participated in a theoretical work meant to explore the SARS-CoV coronavirus, and its spread during the outbreak (the " double epidemic " hypothesis).
The genomics revolution that has recently transformed biology is steadily producing new spectacular discoveries. While the world of mass media tends to concentrate almost exclusively on the " Human Genome ", it is clearer and clearer that one will not be able to understand much in this genome in the absence of knowledge created by the study of powerful models, in particular microbes. This explains why all the major Genome Centres in the world are now developping the study of microbial genomes. It is also obviously with such organisms that the two major discoveries about genomes have been made in the past fifteen years (with a major contribution from the Unit of Regulation of Gene Expression, the ancestor of the present one). On the one hand a fair number of genes are not fixed, belonging to a given organism, but they tend to propagate from organism to organism (" horizontal " gene transfer). On the otehr hand, a very high proportion of the genes present in a genome, whatever the organism, do not have a known function. This is the more surprising because we now know one thousand genome sequences. In this context, the work in the Unit, in collaboration with the activity developed by its director at the HKU-Pasteur Research Centre (which he created in Hong Kong in 2000), consists in exploring these unknown functions. To this aim, experimental work at the bench is combined with work in silico (using computer programmes), in order to perform conceptual experiments that serve as references and predictions for experiments performed at the bench. The central conjecture explored in the Unit is to know whether, and if yes why, genes are distributed randomly in the chromosomes. It is obvious that the accidents that occur continuously during reproduction lead the genes either to be modified or disappear, or to change place. One would therefore expect that, after some time, a more or less random distribution of the genes should be observed. However the very idea that founded conceptual genomics, derived from the idea of the " genetic programme ", is that a cell behaves more or less as does a computer, where the machine is truly separated from the data and programmes it works with. However, one knows that a computer is not able to duplicate itself. What more is therefore needed? John von Neumann at the beginning of years 1960 made the hypothesis that, if this were to happen, then one should find somewhere an image of the machine. This drives the quest of the Unit: its scientists try to know whether the cell and its programme are organized structures. In concrete terms, is the order of the genes random in the genome? And, in paralle, where are located, in the cell, the gene products, does one find them everywhere?,
An important part of the work in the Unit will therefore consist, on the one hand, in organizing the data making biological knowledge (Ivan Moszer, and construction of the GenoList databases, until the time when he left to set up a new axis at the Genopole of the Institute), and, on the other hand, to analyse the genome structure (Eduardo Rocha and scientists from the HKU-Pasteur Research Centre, see http://bioinfo.hku.hk/genolist.html). The most surprising discovery during year 2003 has been that the genes that are essential to the life of bacteria are distributed along the replication leading strand of the DNA double helix, and that this is not directly correlated to a high level of expression. This is accounted for by the absence of conflict between transcription and replication for these genes, because the collisions that occur when the genes are located on the lagging replication strand must often create truncated messenger RNAs, and hence truncated proteins. Furthermore, this discovery indicates that the products of these essential genes systematically belong to complexes formed by the association of several proteins, for one would hardly explain the toxicity of a truncated product unless it destroys the complex it is forming (let us think of a building with truncated beams!). In parallel, the Unit participated in the deciphering of the complete genome sequence of three bacteria: Leptospira interrogans (in collaboration with the Genome Sequencing Centre of Shanghai), bacterium that is particularly dangerous and infects peasants working in rice paddies; Staphylococcus epidermidis (collaboration with the same Centre and Fudan University in Shanghai), bacterium present in the environnement and important for nosocomial infections; and Photorhabdus luminescens (sequenced in the Laboratory of Pathogenic Microorganisms Genomics in the Institute), highly virulent against insects, including against mosquito larvae (Jean-François Charles, Sylviane Derzelle and their coworkers).
At this stage, it is essential to understand where the gene products are located inside the cell. The study of uridylate kinase by a group that recently joined the Unit (Anne Marie Gilles et Octavian Barzu) will give interesting information in this domain. Another approach, developed in the Unit for several years, is to understand the organisation in the cell of the production of molecules containing sulfur. This is because of the extreme versatility of this atom in terms of oxido-reduction states. The study of sulfur metabolism has therefore been emphasized (Isabelle Martin-Verstraete in Paris and Agnieszka Sekowska in Hong Kong) in particular because the knowledge of this atom was often extremely limited because of the difficulty of the genetic and biochemical studies of sulfur-containing molecules. We have unravelled several new pathways in Bacillus subtilis (one of the two most studied bacteria) and further characterized the methionine salvage pathway that was unfolded in part during the past years..
Finally, year 2003 witnessed the dangerous development of the outbreak of atypical pneumonia (Severe Acute Respiratory Syndrome) and we judged important to participate in the fight against the disease, on the one hand with theoretical studies on the genomes of coronaviruses (at the HKU-Pasteur Research Centre), and on the other hand by an epidemiological model that was meant to get an idea about the origin of the disease and of its development (in collaboration with INRIA and the Deprtement of mathematics at the University of Hong Kong). The model proposed, that of a " double epidemic ", caused by a first innocuous virus, that can mutate in certain patients and lead to the phenomenon of SARS fits well with observations in the field (in particular the large difference between diverse regions in China). This model suggests that the initial virus could stay as an endemic mild pathogen, and might occasionally lead to a resurgence of the disease. It is also interesting in that it suggests that the primary infection caused by the ancestral virus can protect against the disease and proposes that a vaccine could be developped (at least a vaccine with a significant protective effect, if not a long-lasting one).
Keywords: entomopathogens, specialized microbial databases, sulfur, methionine salvage pathway, SARS