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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,7,25]]},"abstract":"<jats:p>Human cytomegalovirus (CMV) has infected humans since the origin of our species and currently infects most of the world\u2019s population. Variability between CMV genomes is the highest of any human herpesvirus, yet large portions of the genome are conserved. Here, we show that the genome encodes 74 regions of relatively high variability each with 2 to 8 alleles. We then identified two patterns in the CMV genome. Conserved parts of the genome and a minority (32) of variable regions show geographic population structure with evidence for African or European clustering, although hybrid strains are present. We find no evidence that geographic segregation has been driven by host immune pressure affecting known antigenic sites. Forty-two variable regions show no geographical structure, with similar allele distributions across different continental populations. These \u201cnongeographical\u201d regions are significantly enriched for genes encoding immunomodulatory functions suggesting a core functional importance. We hypothesize that at least two CMV founder populations account for the geographical differences that are largely seen in the conserved portions of the genome, although the timing of separation and direction of spread between the two are not clear. In contrast, the similar allele frequencies among 42 variable regions of the genome, irrespective of geographical origin, are indicative of a second evolutionary process, namely balancing selection that may preserve properties critical to CMV biological function. Given that genetic differences between CMVs are postulated to alter immunogenicity and potentially function, understanding these two evolutionary processes could contribute important information for the development of globally effective vaccines and the identification of novel drug targets.<\/jats:p>","DOI":"10.1073\/pnas.2221797120","type":"journal-article","created":{"date-parts":[[2023,7,17]],"date-time":"2023-07-17T15:12:34Z","timestamp":1689606754000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":36,"title":["Genomic and geographical structure of human cytomegalovirus"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2578-5193","authenticated-orcid":false,"given":"Oscar J.","family":"Charles","sequence":"first","affiliation":[{"name":"Department of Infection, Immunity and Inflammation, University College London, Great Ormond Street Institute of Child Health, London WC1N 1EH, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4769-7912","authenticated-orcid":false,"given":"Cristina","family":"Venturini","sequence":"additional","affiliation":[{"name":"Department of Infection, Immunity and Inflammation, University College London, Great Ormond Street Institute of Child Health, London WC1N 1EH, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5743-3606","authenticated-orcid":false,"given":"Soren","family":"Gantt","sequence":"additional","affiliation":[{"name":"Research Centre of the Sainte-Justine University Hospital and Department of Microbiology, Infectious Diseases and Immunology, University of Montr\u00e9al, Montr\u00e9al, Quebec H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Atkinson","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity, Institute for Immunity and Transplantation, University College London, London NW3 2PP, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9317-5915","authenticated-orcid":false,"given":"Paul","family":"Griffiths","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity, Institute for Immunity and Transplantation, University College London, London NW3 2PP, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5148-4672","authenticated-orcid":false,"given":"Richard A.","family":"Goldstein","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8246-0534","authenticated-orcid":false,"given":"Judith","family":"Breuer","sequence":"additional","affiliation":[{"name":"Department of Infection, Immunity and Inflammation, University College London, Great Ormond Street Institute of Child Health, London WC1N 1EH, United Kingdom"},{"name":"Great Ormond Street Hospital for Children National Health Service Foundation Trust, London WC1N 1LE, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,7,17]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.2034"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI136225"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00705-008-0278-4"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20112666"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13052-017-0358-8"},{"key":"e_1_3_4_6_2","volume-title":"Vaccines for the 21st Century: A Tool for Decisionmaking","author":"Institute of Medicine (US) Committee to Study Priorities for Vaccine Development","year":"2000","unstructured":"Institute of Medicine (US) Committee to Study Priorities for Vaccine Development, K. 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