Next-generation sequencing unravels hidden genomic complexity of the giant Mimivirus

06-Apr-2010 - France

The giant virus Mimivirus, the genome of which is already the largest known for a virus, has proven to be even more complex following the first application of next-generation sequencing (NGS) to study the viral replication cycle. This is the main result reported in an article to be published in Genome Research by the Structural & Genomic Information (SGI) Laboratory (UPR2589-CNRS, University of the Mediterranée). In addition to confirming 910 previously predicted protein-coding genes, deep sequencing of RNAs expressed by infected amoebas throughout the Mimivirus replication cycle allowed the discovery of 75 additional genes, including 26 non-coding RNAs. Prior to this work, only a handful of such genes were known in viruses. The study also reports a new type of viral promoter, which Mimivirus shares with its unique parasite, the recently discovered Sputnik “virophage.”

Since its discovery and the deciphering of its genome in 2004, the giant virus Mimivirus, which infects ubiquitous amoebae of the genus Acanthamoeba, has been the focus of a vehement debate among virologists and evolutionists. Larger and genetically more complex than many bacteria, Mimivirus blurs the traditional frontier between viruses and “living” cellular organisms. Metagenomic studies suggested that Mimivirus could also be the prototype of numerous marine viruses infecting a variety of planktonic microorganisms, participating in the regulation of their population (and exerting geochemical effects) at the planetary scale. Mimivirus is thus both of fundamental and environmental interest, and a specific program is devoted to a search for its marine relatives in the ongoing international TARAOceans expedition that will circumnavigate the world’s oceans for the next three years.

In the past couple of years, a team led by Chantal Abergel undertook the elucidation of the mechanisms at work during intracellular replication of this atypical virus, in the hope that they may glimpse at the way ancestral eukaryotic cells might have operated. The unique blend of bioinformaticians and experimentalists found in the SGI laboratory allowed them to perform the first NGS-based (454 Life Sciences [Roche]-FLX) analysis of the transcriptome of a virus-infected cell over an entire replication cycle.

The article reports a variety of results. First, all previously predicted Mimivirus genes were validated by detection of corresponding transcripts. Moreover, the beginning and end of most transcripts were mapped to single nucleotide resolution. In turn, this mapping allowed the precise delineation of most promoter regions and the identification of the sequence motif governing the early vs. late expression of Mimivirus genes. As expected from a true parasite relying on the transcriptional machinery of its host, Mimivirus, the virophage Sputnik exhibits a newly found late promoter element in front of many of its own genes.

But perhaps the most unexpected finding was the discovery of 75 new genes, in the already plethoric Mimivirus genome. Most of them are strongly expressed, including the 26 non coding RNAs, the existence (and unknown function) of which could radically change our current understanding of the way large DNA virus genomes operate. Overall, there are now 991 known Mimivirus genes.

Original publication: M. Legendre, S. Audic, O. Poirot, P.Hingamp, D. Byrne, A. Lartigue, M. Lescot, A. Bernadac, J. Poulain, C. Abergel, J.-M. Claverie; "mRNA Deep Sequencing Reveals 75 New Genes and a Complex Transcriptional Landscape in Mimivirus."; Genome Research 2010.

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