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Identification of Novel Viral Interacting Proteins through the Detection of Genetic INNovations (DGINN) combined with functional assays

Abstract : The identification of cellular proteins that interfere with virus replication is a key challenge in virology. Amongst them, finding those engaged in long-term virus-host interaction and co-evolution is of particular interest. In the host, such selective pressures induce diverse genetic innovations, such as site-specific positive selection, gene copy number variation, recombination, etc. Under the hypothesis that genetic innovations in innate immunity may particularly occur in viral interacting proteins, we developed a pipeline for retrieving orthologous sequences, aligning them and reconstructing their phylogeny, followed by the detection of genetic innovations. This streamlined procedure uniquely allows for the detection of paralogous genes, recombination breakpoints, and signatures of positive selection with several widely-used methods. We validated this evolutionary and predictive pipeline on genes with known selection profiles. Furthermore, we screened two datasets of candidate genes. The first one was composed of 56 genes which knock-downs impact the interferon response to viral infection. The second one was composed of 60 genes upregulated in macrophages resistant to HIV infection. We found numerous genes presenting important marks of genetic conflict, thus potentially encoding for novel Viral Interacting Proteins. Two of these candidates are undergoing functional characterization for their role in the HIV replicative cycle, and others are pending further investigation. Overall, we designed a complete and highly-flexible pipeline, available to the public, that can screen large datasets and allow researchers to rank candidate genes in order to prioritize their wet-lab experiments.
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https://tel.archives-ouvertes.fr/tel-03510332
Contributor : Abes Star :  Contact
Submitted on : Tuesday, January 4, 2022 - 2:39:48 PM
Last modification on : Sunday, April 3, 2022 - 3:31:43 AM

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  • HAL Id : tel-03510332, version 1

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Léa Picard. Identification of Novel Viral Interacting Proteins through the Detection of Genetic INNovations (DGINN) combined with functional assays. Molecular biology. Université de Lyon, 2020. English. ⟨NNT : 2020LYSEN031⟩. ⟨tel-03510332⟩

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