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Virus genomics and evolution: the transformative effect of new technologies and multidisciplinary collaboration… Ip, Camilla L C; Pybus, Oliver G; Gardy, Jennifer L Jul 25, 2016

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MEETING REPORTVirus genomics and evolueaa*demics. Several talks featured memorable accounts ofceptional levels of virus diversity and revealed the dy-sented by Darren Obbard (University of Edinburgh, UK).ted to humanrsity of Bonnemergence ofrvoir popula-n, UK).nceIp et al. Genome Biology  (2016) 17:159 DOI 10.1186/s13059-016-1019-84British Columbia Centre for Disease Control, Vancouver, BC V5Z 4R4, CanadaFull list of author information is available at the end of the articlepublic health. The surge of interest in this area is nodoubt due to the recent West African Ebola virus* Correspondence: jennifer.gardy@bccdc.ca3School of Population and Public Health, University of British Columbia,Vancouver, BC V6T 1Z9, CanadaPerhaps the strongest theme of the meeting was the useof viral sequencing for surveillance and diagnostics iningly, there was little discussion of sequencing technolo-gies themselves; rather the focus was on their practical,actionable applications.In this report, we highlight how genomics is beingused to explore viral origins and diversity and to under-stand transmission and pathogenesis. Additionally, wedescribe how real-time generation and analysis of viraltrated by the discovery of new viruses relahepatitis A virus (Jan Felix Drexler, UniveMedical Centre, Germany) and by the re-human noroviruses from unsampled resetions (Chris Ruis, University College LondoPublic health diagnostics and surveillathe use of genomics in practical settings, from WestAfrican field hospitals to European courtrooms. Interest-Uncharacterized or underappreciated viral diversity isequally apparent at smaller taxonomic scales, as illus-methods to interrogate these data.The meeting highlighted the broad temporal andspatial scales over which viral genetic data are having animpact, from understanding the trajectory of resistancemutations during a single infection to understanding thespatial expansion of viral lineages during large epi-ologists and bioinformaticians who are developingunusual arthropods to sharks—shows that we havetransformative effect of nand multidisciplinary collresearch and outbreak mCamilla L. C. Ip1, Oliver G. Pybus2 and Jennifer L. Gardy3,4AbstractThe first Virus Genomics and Evolution Conferencewas held at the Wellcome Genome Campus inHinxton, UK, 8–10 June 2016.IntroductionIn recognition of the increasingly important role thatgenomics plays in virology and public health epidemi-ology, the Wellcome Genome Campus hosted the inaug-ural conference on Virus Genomics and Evolution inJune 2016. This multidisciplinary conference brought to-gether public health researchers who are generating viralgenomic data from clinical samples and evolutionary bi-© 2016 The Author(s). Open Access This articInternational License (http://creativecommonsreproduction in any medium, provided you gthe Creative Commons license, and indicate if(http://creativecommons.org/publicdomain/zenamic nature of viral genome size and organization. Anovel approach for viral discovery, using small interfer-ing RNA (siRNA) as a marker of host response, was pre-w technologiesboration on virusnagementgenomic data are transforming outbreak surveillanceand management.Virus discoveryIan Lipkin (Columbia University, New York, USA)launched the meeting with tales of microbe-huntingacross many species and diseases, emphasizing that de-tection of a virus genome in a sample is simply the firststep in the process of linking an agent to disease. Viraldiscovery is fraught with false positives, and potentialassociations should be explored via multiple avenues,including serology and host response.The scale of the viral discovery problem washighlighted by Eddie Holmes (University of Sydney,Australia), whose virus-hunting in diverse species—from“barely scratched the surface of viral diversity”. Usingmetatranscriptomics, Holmes’ team demonstrated ex-Open Accesstion: thele is distributed under the terms of the Creative Commons Attribution 4.0.org/licenses/by/4.0/), which permits unrestricted use, distribution, andive appropriate credit to the original author(s) and the source, provide a link tochanges were made. The Creative Commons Public Domain Dedication waiverro/1.0/) applies to the data made available in this article, unless otherwise stated.Ip et al. Genome Biology  (2016) 17:159 Page 2 of 3(EBOV) epidemic, which provided the backdrop for sev-eral talks. Kristian Anderson (The Scripps ResearchInstitute, La Jolla, USA) explained how the BroadInstitute’s Lassa Fever genomics infrastructure in SierraLeone was quickly repurposed for Ebola virus sequen-cing and gave examples of epidemiological insightsdrawn from genomics during the outbreak. He cautionedthat real-time genomics must lead to real-time action.Specifically, he reported that genomic data could haveinfluenced public health conversations early in the out-break; sequencing indicated that ongoing EBOV trans-mission was not due to multiple spillovers from ananimal reservoir, yet messages about bushmeat con-sumption probably gave the opposite impression. Thework presented by Kristian also demonstrated the utilityof clinical metagenomics in an outbreak, revealing theassociations between co-infection with malaria andEbola mortality. Gustavo Palacios (US Army MedicalResearch Institute of Infectious Diseases (USAMRIID),Frederick, MD) described EBOV genomics in Liberia,where sequencing revealed the roles played by viral per-sistence in immune-privileged sites in transmission fromsurvivors as the outbreak waned.A glimpse of the future of surveillance was afforded byGytis Dudas’ (Fred Hutchinson Cancer Research Center,Seattle, USA) meta-analysis of around 1600 EBOVgenomes sequenced across the two-year outbreak. Hisphylogeographic analysis showed how EBOV lineagescrossed from one country to another, avoided extinctionby spreading within countries, and were magnified inurban areas. Access to a subset of these data during theoutbreak resulted in border closures that limited theepidemic, demonstrating that genomic information, ac-quired in real time, could help to contain future epi-demics. Ian Goodfellow (University of Cambridge, UK)set up an EBOV sequencing center in Sierra Leone anddescribed how the attendant logistical challenges of sucha project, from sourcing nitrogen canisters to managingsamples, must not be underestimated. Ian demonstratedthe benefits of sharing, whether it be of open-access datavia platforms like virological.org and nextflu.org or ofthe sequencing equipment itself, which was eventuallyrehomed at the University of Makeni. Hinting at asubject that might feature at the next edition of the con-ference, Oliver Pybus (University of Oxford, UK) intro-duced the ZiBRA project, which is using portablenanopore sequencing in the field in Brazil to explore thedynamics of the Zika virus epidemic.From transmission to epidemicsThe use of viral genomics as a tool to characterize trans-mission is not restricted to emerging epidemics, havingbeen applied widely to established human pathogens. Ex-amples presented at the meeting included reconstructionof a measles virus outbreak in Canada (Jennifer Gardy,University of British Columbia, Canada), communitytransmission of respiratory syncytial virus in Kenya(Charles Agoti, KEMRI-Wellcome Trust, Kenya), hospitaloutbreaks that were sequenced for infection controlas part of the ICONIC (InfeCtion respONse throughvIrus genomiCs) project (Paul Kellam, Sanger Institute,Hinxton, UK), and the use of HIV and hepatitis C virus(HCV) phylogenies to establish or disprove criminal trans-mission in court (Annemie Vandamme, KU Leuven,Belgium). Annemie explained why inferring the directionof transmission is not equivalent to inferring direct trans-mission and, through a series of real-world examples, sheestablished the conditions that must be met to argue fortransmission.At a larger epidemic scale, Marion Koopmans(Erasmus Medical Centre, The Netherlands) discussedglobal norovirus dynamics as captured by the Noronetsurveillance platform, including the recent emergence ofrecombinant strains that are undergoing rapid diversifi-cation and the association of excess mortality withnew variants. Talks from Philippe Lemey (KU Leuven,Belgium) and Kirstyn Brunker (University of Glasgow,UK) demonstrated how other data sources can bemerged with viral genomes to help us to understandepidemic dynamics, with examples showing how pre-dictors such as spatial distance and case counts af-fected the Ebola outbreak, and how human-mediatedconnectivity and spatial heterogeneity influence rabiesvirus transmission in Tanzania.Antiviral treatmentThe meeting also reflected a growing area of research inwhich virus genomics is used to guide the design of ef-fective antiviral drug interventions. Despite the approvalof new—but expensive—direct-acting antiviral drugs forHCV infection, we still do not know what determineswhether treatment will be successful against the diverserange of HCV genotypes. As Ellie Barnes and M. AzimAnsari (University of Oxford, UK) explained, large-scalesequencing of both HCV and human genomes, followedby genome-wide association studies (GWAS), is begin-ning to tease apart the host and virus genetic compo-nents of treatment response.Sequencing can also be used to observe the effectsof drugs on viral genomes directly. Daniel Goldhill(Imperial College London, UK) showed evidence sup-porting the hypothesis that the experimental com-pound favipiravir acts to increase the mutation rate ofinfluenza A viruses. Viral genomics is also being usedto plan and evaluate large-scale treatment programs.In the final keynote address, Christophe Fraser (ImperialCollege London, UK) showed how viral phylogenetics isbeing used to identify the source of new HIV infections inThe research activities of the authors were supported by Wellcome Trustgrant 090532/Z/09/Z (CLCI). JLG holds a Canada Research Chair in PublicHealth Genomics, and a Michael Smith Foundation for Health ResearchScholar Award.Authors’ contributionsAll authors wrote, edited, and approved the final manuscript.Competing interestsThe authors declare that they have no competing interests.Author details1Wellcome Trust Centre for Human Genetics, University of Oxford, OxfordOX37BN, UK. 2Department of Zoology, University of Oxford, Oxford OX1 3PS,UK. 3School of Population and Public Health, University of British Columbia,Vancouver, BC V6T 1Z9, Canada. 4British Columbia Centre for Disease Control,Vancouver, BC V5Z 4R4, Canada.Ip et al. Genome Biology  (2016) 17:159 Page 3 of 3the PopART community-randomized trial of HIV testingand treatment, which involves around 1.2 million peoplein sub-Saharan Africa. He described how the huge scale ofsuch a project requires the development of new, efficientmethods of evolutionary analysis, as well as rigorousthinking around sample size and power calculations fortests based on phylogenetic and molecular clock models.Evolutionary insights into pathogenesisThe importance of virus and host co-evolution was ap-preciated by the audience. Sunetra Gupta’s (University ofOxford, UK) dynamic models of the adaptive immunesystem indicated that decreasing levels of CD4+ T cellsdetermined HIV viral loads during the chronic phase ofinfection, which, in turn, determined the speed of dis-ease progression. Sarah Cobey (University of Chicago,USA) showed how influenza vaccines influence muta-tions in host B cells, and Andrea Tanzer (University ofVienna, Austria) asked whether, since Zika virus has beencirculating for decades, there are any genetic changes thatsparked the current outbreak in the Americas? By com-paring the structure and folding kinetics of flaviviral RNAelements involved in host response and virulence, sheidentified specific mutations leading to RNA structuralalterations and evidence for selective pressure by compen-satory mutations.Concluding remarksAlthough the conference focused on genomics andevolution—topics that might be considered more theor-etical than applied—it was notable that many speakerstalked as much about real people, some of whom havesuffered or died from viral disease, as they did aboutdata, theories, and technology. The frequency and scaleof viral outbreaks in recent years has emphasized the ur-gency of research in virus genomics. Further, it hasprompted efforts to shift academic culture towardscloser collaborations between clinicians, biologists,mathematicians, and computer scientists and towardsthe real-time, open release and analysis of data, with theshared aim of securing the health of our world’s popula-tion. The next meeting is provisionally scheduled forJune 2018.AbbreviationsEBOV, West African Ebola virus; HCV, hepatitis C virusAcknowledgementsWe thank the scientific organizing committee (Judith Breuer, AndrewRambaut and Emma Thomson) and the Wellcome Genome CampusScientific Conferences Team (Rebecca Twells, Laura Hubbard, JemmaBeard, Lucy Criddle, Emily Rees and Treasa Creavin), and apologize tothose speakers whose work could not be mentioned here due to a lackof space. This article was based on a collaborative note-taking initiativestarted by JLG in Etherpad (https://public.etherpad-mozilla.org/p/vge16),with contributions by CLCI, Chris Wymant, Christophe Fraser, M Azim Ansari,and others.Funding


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