Genomic epidemiology uncovers the timing and origin of the emergence of mpox in humans

Five years before the 2022–2023 global mpox outbreak Nigeria reported its first cases in nearly 40 years, with the ongoing epidemic since driven by sustained human-to-human transmission. However, limited genomic data has left questions about the timing and origin of the mpox virustextquoteright (MPXV) emergence. Here we generated 112 MPXV genomes from Nigeria from 2021-2023. We identify the closest zoonotic outgroup to the human epidemic in southern Nigeria, and estimate that the lineage transmitting from human-to-human emerged around July 2014, circulating cryptically until detected in September 2017. The epidemic originated in Southern Nigeria, particularly Rivers State, which also acted as a persistent and dominant source of viral dissemination to other states. We show that APOBEC3 activity increased MPXVtextquoterights evolutionary rate twenty-fold during human-to-human transmission. We also show how Delphy, a tool for near-real-time Bayesian phylogenetics, can aid rapid outbreak analytics. Our study sheds light on MPXVtextquoterights establishment in West Africa before the 2022–2023 global outbreak and highlights the need for improved pathogen surveillance and response.Competing Interest StatementThe authors have declared no competing interest.Funding StatementFlu Lab TEDs Audacious Project including the ELMA Foundation MacKenzie Scott the Skoll Foundation and Open Philanthropy This work was supported by grants from the National Institute of Allergy and Infectious Diseases grants: U01HG007480 U54HG007480 U01AI151812 U19AI135995 U19AI110818 R01AI153044 R01AI162611 This work was also supported by the World Bank grants projects ACE-019 and ACE-IMPACT The Rockefeller Foundation Grant $#$2021 HTH The Africa CDC through the African Society of Laboratory Medicine Grant $#$INV018978 Science for Africa Foundation Ifeanyi Omah is supported by the Wellcome Trust Hosts Pathogens & Global Health program Grant number 218471/Z/19/Z in partnership with Tackling infectious Disease to Benefit Africa TIBA PL is supported by the European Unions Horizon 2020 project MOOD grant agreement no 874850 and by the Research Foundation - Flanders Fonds voor Wetenschappelijk Onderzoek - Vlaanderen G0D5117N G005323N and G051322N We thank Advanced Micro Devices Inc for the donation of massively parallel computing hardwareAuthor DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Nigerian CDC.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.Yes

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