Reports Genomic surveillance elucidates Ebola virus origin and transmission during the 2014 outbreak Stephen K Gire 1 2 Augustine Goba 3 Kristian G Andersen 1 2 Rachel S G Sealfon 2 4 Daniel J Park 2 Lansana Kanneh 3 Simbirie Jalloh 3 Mambu Momoh 3 5 Mohamed Fullah 3 5 Gytis Dudas 6 Shirlee Wohl 1 2 7 Lina M Moses 8 Nathan L Yozwiak 1 2 Sarah Winnicki 1 2 Christian B Matranga 2 Christine M Malboeuf 2 James Qu 2 Adrianne D Gladden 2 Stephen F Schaffner 1 2 Xiao Yang 2 Pan Pan Jiang 1 2 Mahan Nekoui 1 2 Andres Colubri 1 Moinya Ruth Coomber 3 Mbalu Fonnie 3 Alex Moigboi 3 Michael Gbakie 3 Fatima K Kamara 3 Veronica Tucker 3 Edwin Konuwa 3 Sidiki Saffa 3 Josephine Sellu 3 Abdul Azziz Jalloh 3 Alice Kovoma 3 James Koninga 3 Ibrahim Mustapha 3 Kandeh Kargbo 3 Momoh Foday 3 Mohamed Yillah 3 Franklyn Kanneh 3 Willie Robert 3 James L B Massally 3 Sin ad B Chapman 2 James Bochicchio 2 Cheryl Murphy 2 Chad Nusbaum 2 Sarah Young 2 Bruce W Birren 2 Donald S Grant 3 John S Scheiffelin 8 Eric S Lander 2 7 9 Christian Happi 10 Sahr M Gevao 11 Andreas Gnirke 2 Andrew Rambaut 6 12 13 Robert F Garry 8 S Humarr Khan 3 Pardis C Sabeti1 2 6 1 Center for Systems Biology Department of Organismic and Evolutionary Biology Harvard University Cambridge MA 02138 USA 2Broad Institute of MIT and Harvard Cambridge MA 02142 USA 3Kenema Government Hospital Kenema Sierra Leone 4Computer Science and Artificial Intelligence Laboratory Massachusetts Institute of Technology Cambridge MA 02139 USA 5Eastern Polytechnic College Kenema Sierra Leone 6Institute of Evolutionary Biology University of Edinburgh Edinburgh EH9 3JT UK 7 Systems Biology Harvard Medical School Boston MA 02115 USA 8Tulane University Medical Center New Orleans LA 70112 USA 9Department of Biology Massachusetts Institute of Technology Cambridge MA 02139 USA 10Redeemer s University Ogun State Nigeria 11University of Sierra Leone Freetown Sierra Leone 12Fogarty International Center National Institutes of Health Bethesda MD 20892 USA 13 Centre for Immunity Infection and Evolution University of Edinburgh Edinburgh EH9 3JT UK 7 3 8 These authors contributed equally to this work Corresponding author E mail andersen broadinstitute org K G A augstgoba yahoo com A G psabeti oeb harvard edu P C S Deceased These authors jointly supervised this work In its largest outbreak Ebola virus disease is spreading through Guinea Liberia Sierra Leone and Nigeria We sequenced 99 Ebola virus genomes from 78 patients in Sierra Leone to 2 000x coverage We observed a rapid accumulation of interhost and intrahost genetic variation allowing us to characterize patterns of viral transmission over the initial weeks of the epidemic This West African variant likely diverged from Middle African lineages 2004 crossed from Guinea to Sierra Leone in May 2014 and has exhibited sustained human to human transmission subsequently with no evidence of additional zoonotic sources Since many of the mutations alter protein sequences and other biologically meaningful targets they should be monitored for impact on diagnostics vaccines and therapies critical to outbreak response 6 9 6 1 2 3 Downloaded from www sciencemag org on August 28 2014 4 5 6 3 15 6 16 18 6 10 12 6 6 13 13 In memoriam References and Notes Biosecur Bioterror 3 9 Bull World Health Organ 14 56 et al N Engl J Med Med Sci 30 Science J Infect Dis 196 J Infect Dis 196 Nucleic Acids Res 41 Proc Natl Acad Sci U S A 93 Virology 214 Genome Res 21 Nucleic Acids Res 32 J Infect Dis 204 Drosophila PLOS Curr Outbreaks 6 Filoviruses A Compendium of 40 Years of Epidemiological Clinical and Laboratory Studies melanogaster Fly 6 Bioinformatics 21 Bioinformatics 19 Mol Biol Evol 29 J Virol 83 J Mol Evol 22 Mol Biol Evol 28 J Mol Evol 39 Mol Biol Evol 22 J Virol 77 Mol Biol Evol 30 PLOS Biol 4 BMC PLOS ONE 7 Bioinform 14 Antiviral Res 63 J Infect Dis 204 J Infect Dis 204 Nat Genet 40 Virology 403 J Virol 85 J Virol Methods 150 J Clin Microbiol 39 Am J Trop Med Hyg 82 Microbes Infect 1 PLOS ONE 7 J Infect Dis 179 Nat Methods 10 J Clin Acknowledgments Supplementary Materials 19 44 Virol 30 Fig 1 Ebola outbreaks historical and current A Historical EVD outbreaks colored by decade Circle area represents total number of cases RC Republic of the Congo DRC Democratic Republic of Congo B 2014 outbreak growth confirmed probable and suspected cases C Spread of EVD in Sierra Leone by district The gradient denotes number of cases and the arrows depict likely direction D EBOV samples from 78 patients were sequenced in two batches totaling 99 viral genomes Replication technical replicates 6 Mean coverage and median depth of coverage with range are shown E Combined normalized to the sample average coverage across sequenced EBOV genomes Fig 2 Relationship between outbreaks A Unrooted phylogenetic tree of EBOV samples each major clade corresponds to a distinct outbreak scale bar nucleotide substitutions site B Root to tip distance correlates better with 2 2 sample date when rooting on the 1976 branch R 0 92 top than on the 2014 branch R 0 67 bottom C Temporally rooted tree from A Fig 3 Molecular dating of the 2014 outbreak A BEAST dating of the separation of the 2014 lineage from Middle African lineages SL Sierra Leone GN Guinea DRC Democratic Republic of Congo tMRCA Sep 2004 95 HPD Oct 2002 May 2006 B BEAST dating of the tMRCA of the 2014 West African outbreak tMRCA Feb 23 95 HPD Jan 27 Mar 14 and the tMRCA of the Sierra Leone lineages tMRCA Apr 23 95 HPD Apr 2 May 13 probability distributions for both 2014 divergence events overlayed below Posterior support for major nodes is shown Fig 4 Viral dynamics during the 2014 outbreak A Mutations one patient sample per row beige identical to Kissidougou Guinean sequence accession KJ660346 The top row shows the type of mutation green synonymous pink nonsynonymous intergenic gray with genomic locations indicated above Clusters assignments are shown on left B Number of EVD confirmed patients per day colored by cluster arrow first appearance of the derived allele at position 10 218 distinguishing clusters 2 and 3 C Intrahost frequency of SNP 10 218 in all 78 patients absent in 28 patients polymorphic in 12 fixed in 38 D and E 12 patients carrying iSNV 10 218 cluster geographically and temporally HCW A unsequenced health care worker Driver drove HCW A from Kissi Teng to Jawie then continued alone to Mambolo HCW B treated HCW A F Substitution rates within the 2014 outbreak and between all EVD outbreaks G Proportion of
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