Résumé : Identifying the function of every gene in all sequenced organisms is the major challenge of the post-genomic era and an obligate step for any systems biology approach. This objective is far from reached. By various estimates, at least 30-50% of the genes of any given organism are of unknown function, incorrectly annotated, or have only a generic annotation such as “ATPase”. Moreover, with 8000 genomes sequenced and 80,000 in the pipeline (http://www.genomeson.line.org), the numbers of unknown genes are increasing, and annotation errors are proliferating rapidly. For some gene families, 40% of the annotations are wrong. On the other side of the coin, there are still 1,900 known enzyme activities for which no corresponding gene has been identified and these numbers are also increasing. This biochemical knowledge is yet to be captured in genome annotations.
Using mainly a comparative genomic approach, we have linked gene and function for around 50 families related mainly to the fields of coenzyme metabolism, tRNA modification, protein modification and more recently metabolite repair. This approach integrates several types of data and uses filters, sieves, and associations to make predictions that can then be tested experimentally. An unknown gene’s function may thus be predicted from those of its associates : the ‘guilt by association’ principle. Associations that can be derived from whole genome datasets include : gene clustering, gene fusion events, phylogenetic occurrence profiles or signatures and shared regulatory sites. Post-genomic experimental sources such as protein interaction networks, gene expression profiles and phenomics data can also be used to find associations. In practice it is often ‘guilt by multiple association’ as genes can be associated in several ways, and analyzing more than one of these improves the accuracy of predictions.
We have applied these methods to decipher the synthesis and salvage pathways for two azapurine modifications of tRNA, Queuosine (Q) and Archaeosine (G+), made from the same precursor molecule PreQ0. This has led to the discovery of many unforeseen roles for PreQ0 derivatives that will be discussed. These include : 1) the fact that the queuine base is a forgotten vitamin in Eukaryotes that has to be salvaged from the diet or microflora ; 2) the discovery of links between Q and metal homeostasis in different kingdoms of life ; 3) to the identification of 7-deazapurine in bacterial and phage DNA as well as novel secondary metabolite clusters by miming genomes for novel preQ0 synthesis gene clusters.
Invité par l’équipe Microbiologie Moléculaire des Actinomycètes
Lieu : Salle de séminaires - Bâtiment 400, Campus de gif