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Bioinformatique des gènes chevauchants; application à la protéine antisens ASP du VIH-1

Abstract : The hypothesis of overlapping genes encoded by the antisense strand of the retrovirus is an old concept. However, this one has been really demonstrated that with the discovery of the HBZ protein of HTLV-1 virus, a dozen of years ago and the recent results on the ASP protein of HIV-1. New research on this protein has demonstrated its expression in vivo, but its functionality is still unknown. We performed here, from a data set of more than 20,000 sequences, the first bioinformatic analyses on the evolution of this overlapping gene. We showed that the asp gene is conserved only in the M group sequences corresponding to the pandemic group of HIV-1. Moreover, we demonstrated a correlation between the presence of the ASP ORF and the prevalence of the various groups and subtypes. Our phylogenetic analyses showed that the appearance of the ASP ORF is concomitant with the emergence of the pandemic M group. Because of the overlapping of the genes, the analysis of the selection pressure induced by the ASP protein involved the use of models and specific analysis methods. Located in the frame -2, this overlap induces a correspondence of the third base codon of each gene. If we consider a "fixed" gene, the mechanical constraints induced by this "fixed" gene are very important and the overlapping gene has very little flexibility. Then, it is important to identify the selection pressure of the gene which is in the frame -2 and show that its presence and conservation are not only due to mechanical constraints induced by the "fixed" gene. For this, we first demonstrated by sequence simulation analysis, using a codon model, that the presence of the ASP ORF is not due to chance. Then, we developed a method of evolutionary analysis based on the study of synonymous mutations in the "fixed" gene (here the env gene) causes the appearance or disappearance of start and stop codons in the overlapping gene. When we applied this method to the asp gene, it showed that there is a selection pressure induced by the ASP protein.
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Elodie Cassan. Bioinformatique des gènes chevauchants; application à la protéine antisens ASP du VIH-1. Médecine humaine et pathologie. Université Montpellier, 2016. Français. ⟨NNT : 2016MONTT068⟩. ⟨tel-01556634⟩

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