Endogenous Retroviral elements in Disease: "PathoGenes" within the human genome.

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1 Endogenous Retroviral elements in Disease: "PathoGenes" within the human genome. H. Perron 1. Geneuro, Geneva, Switzerland 2. Geneuro-Innovation, Lyon-France 3. Université Claude Bernard, Lyon, France Declared conflict of interest: Hervé Perron is CSO of Geneuro.

2 Background Science we are dealing with pathogens that are : neither viruses, nor produced by regular genes.

3 From «Junk DNA» to Human Endogenous RetroViruses Normal genomic organization of Mobile genetic elements and HERVs Hancks DC, Kazazian HH. Roles for retrotransposon insertions in human disease. Mob. DNA 2016 Pace JK, Feschotte C. The evolutionary history of human DNA transposons: Evidence for intense activity in the primate lineage. Genome Res Marchi E, Kanapin A, Magiorkinis G, et al. Unfixed endogenous retroviral insertions in the human population. J. Virol. 2014

4 Retroviral germ infection and generation of Endogenous -line cell Retrovirus (ERV) Belshaw R, et al. Proc Natl Acad Sci U S A. 2004; Wildschutte JH Proc Natl Acad Sci U S A

5 Long Terminal Repeats (LTRs) of retroviral genomes repeat same sequences on each extremity Short reads Real 5 Locus 3 Locus genome Discarded as 5 flanking region AATTACCGTA redundant sequences AATTACCGT.3 flanking region Taken as overlapping sequences from the junction between 5 and 3 Loci Reconstituted Genome 5 Locus Solo LTR 3 Locus in databases Endogenous retroviral sequences have not been aligned: a solitary LTR only is taken as a single sequence from a mere junction between two flanking regions

6 Role in Health or Disease Friend or Foe? The enemy within: dormant retroviruses awaken Michael E Engel & Scott W Hiebert Nature Medicine 16, (2010)

7 «Emerging Scientific Domain» Mobile genetic elements >45% of the Human genome (Highly repeated, Transposable and Retrotransposable elements) Human Endogenous Retroviruses (HERV): 8% of the human genome Most are inactive, but active elements are persisting in human genomes The enemy within: dormant retroviruses awaken Michael E Engel & Scott W Hiebert Nature Medicine 16, (2010) Endogenous viruses: insights into viral evolution and impact on host biology Cédric Feschotte & Clément Gilbert Nature Reviews Genetics 13, (2012) distributed unequally in humans Jainy Thomas (Feschotte Lab/UTAH) The potential association with several diseases is beginning to be acknowledged Presentations in Sessions II, III & IV.

8 Locally activated by various environmental triggers, HERV-W may lead to different diseases Environmental triggers with different tropism for given cell type / organ Local MSRV-Env expression MSRV-Env Gray Matter CMV, Toxoplasma Inflammatory Psychoses % of cases? Peripheral Nerves CMV,? CIDP +/- 50% of cases? EBV, global priming effect on immune cells? White Matter HSV1, HHV6, VZV, Multiple Sclerosis % of cases TLR4 Inflammation Autoimmunity Cytotoxicity Other Diseases? Pancreas Enteroviruses, Coxsackie? Type 1 Diabetes % of cases?

9 Novel Domain & New Concepts: at the gene level 20th Century: Discovery of «environmental microbes» 21rst Century: Unraveling «genetic microbes»: endogenous viruses

10 Role in Health or Disease: MSRV versus Syncytin MSRV clone from MS retroviral particles Syncytin clone from Placenta RNA Cell surface (non-permeabilized) Transfected HEK cells Cytoplasm (permeabilized)

11 Amino acid differences in reference HERV-W envelopes Aligned Syncytin and MSRV-Env Protein amino-acid sequences Differences between Syncytin and MSRV HERV-W envelope proteins 4 amino acids deletion in Syncytin

12 Retroviral genomes phylogeny: gag-pol alignment

13 Retroviral genomes phylogeny: env gene alignment

14 Normal genomic organization of simple retroviruses and HERVs

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