RIKEN IMS AnnualReport 2020
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We study the anamnestic responses of genomes upon exposure to mo-57bile genetic elements. We focus on endogenous viral elements (EVEs), which are virus-derived sequences integrated into the genomes of their hosts. EVEs are often transcribed and processed into small RNAs called PIWI-interacting RNAs (piRNAs), which can guide RNA interference (RNAi) against complementary sequences. We are testing if piRNA-guided RNAi functions as antiviral immunity in eukaryotes, similar to the CRISPR/Cas adaptive immune system in prokaryotes. We previously showed that human and mouse EVEs derived from relatives of Borna disease virus (BoDV) are transcribed and pro-cessed into piRNAs (Parrish NF et al., RNA. 2015). While piRNAs are known to guide RNAi against transposons, they have not been shown to function in antiviral immunity against exogenous viruses in mammals. We are using ge-nome engineering to test this hypothesis in a murine model of BoDV infection. Human herpesvirus 6 (HHV-6) infection was recently proposed to be influ-enced by piRNAs (Liu S et al., Cell. 2018). We have characterized EVEs derived from HHV-6 that have been stably co-evolving with human chromosomes since prehistory (Liu X et al., PLoS Genet. 2020; Aswad A et al., Mol Biol Evol. 2020). We are currently testing whether these EVEs make piRNAs and how they influ-ence human phenotypes. We have also developed new computational tools to determine the genotype of polymorphic human mobile genetic elements, in-cluding EVEs derived from human endogenous retroviruses (HERVs) (Kojima et al., bioRxiv. 2020). In collaboration with several laboratories in IMS, we are using these tools to probe the influence of variation in EVEs and other mobile genetic elements on human phenotypes, including responses to coronavirus in-fection.Figure: Virus-derived variation in 3,332 diverse human genomesWe analyzed 3,332 whole genome sequencing datasets for sequences derived from viruses. The heatmap shows read depth of seven viruses with abundant reads in at least one dataset, as well as variation in reads mapping to a HERV. The column colors represent the human pop-ulations present in two databases, the 1,000 Genomes Project (1kGP) and the Human Genome Diversity Project (HGDP). AFR: African; AMR: American; EAS: East Asian; EUR: European; SAS: South Asian.Recent Major PublicationsSakashita A, Maezawa S, Takahashi K, Alavattam KG, Yukawa M, Hu YC, Kojima S, Parrish NF, Barski A, Pav-licev M, Namekawa SH. Endogenous retroviruses drive species-specific germline transcriptomes in mammals. Nat Struct Mol Biol 27, 967-977 (2020)Liu X, Kosugi S, Koide R, Kawamura Y, Ito J, Miura H, Matoba N, Matsuzaki M, Fujita M, Kamada AJ, Nak-agawa H, Tamiya G, Matsuda K, Murakami Y, Kubo M, Sato K, Momozawa Y, Ohashi J, Terao C, Yoshikawa T, Parrish NF, Kamatani Y. Endogenization and excision of human herpesvirus 6 in human genomes. PLoS Genet 16, e1008915 (2020)Ophinni Y, Palatini U, Hayashi Y, Parrish NF. piRNA-Guided CRISPR-like Immunity in Eukaryotes. Trends Immunol 40, 998-1010 (2019)Invited presentationsParrish NF. “Immunity Induced by Endogenous Viral Elements” The 24th Annual Meeting of the Japanese Society for Vaccinology (Aichi, Japan/Online) December 2020Parrish NF. “Virus-derived structural variation in human genomes: new phenotypes from old viruses” The 43rd Annual Meeting of the Molecular Biology Society of Japan (Online) December 2020Parrish NF. “Human genome plasticity via horizontal gene transfer from human herpesvirus 6” Society for Molecular Biology and Evolution Annual Meeting (On-line) June 2020Genome Immunobiology RIKEN Hakubi Research TeamHakubi Team Leader: Nicholas Parrish

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