ABSTRACT
The genomic characteristics of human cytomegalovirus (HCMV) strains sequenced directly from clinical material were investigated, focusing on variation, multiple-strain infection, recombination and natural mutation. A total of 207 datasets generated in this and other studies using target enrichment and high-throughput sequencing were analysed, in the process facilitating the determination of genome sequences for 91 strains. Key findings were that (i) it is vital to monitor sequence data quality, especially when analysing intrahost diversity, (ii) intrahost diversity in single-strain infections is much less than that in multiple strain infections, (iii) many recombinant strains have been generated and transmitted during HCMV evolution, and some have survived for thousands of years without further recombination, (iv) mutants lacking gene functions have been circulating and recombining for long periods and can cause congenital infection and resulting clinical sequelae. Future studies in general populations are likely to continue illuminating the evolution, epidemiology and pathogenesis of HCMV.
Footnotes
Conflict of interest statement Dr. Davison reports grants from the Medical Research Council and the Wellcome Trust. Dr. Ganzenmueller reports grants from the Deutsche Forschungsgemeinschaft Collaborative Research Centre 900 and from Niedersächsische Ministerium für Wissenschaft und Kultur. Dr. Hubáček reports a grant from the Ministry of Health of the Czech Republic for the conceptual development of University Hospital, Motol, Prague, Czech Republic, personal fees and non-financial support from MSD and from Chimaerix, and personal fees from Dynex that are outside the scope of the submitted work. Dr. Lilieri reports a grant from the Fondazione Regionale per la Ricerca Biomedica, Regione Lombardia. Dr. Schulz reports grants from the Deutsche Forschungsgemeinschaft Collaborative Research Centre 900 and from the German Federal Ministry of Education and Research. Dr. Wilkinson reports a grant from the Wellcome Trust. Dr. Wilkie reports that his part in the submitted work was completed prior to his employment by Illumina.
Funding statement This work was funded by the Medical Research Council (MC_UU_12014/3 and MC_UU_12014/12), the Wellcome Trust (204870/Z/16/Z and WT090323MA), the Ministry of Health of the Czech Republic for conceptual development of research organization 00064203 (University Hospital, Motol, Prague, Czech Republic), the Fondazione Regionale per la Ricerca Biomedica, Regione Lombardia (FRRB 2015-043), the Deutsche Forschungsgemeinschaft Collaborative Research Centre 900 (core project Z1, grant SFB-9001), the German Center of Infection Research TTU Infections of the Immunocompromised Host, and the Niedersächsische Minis terium für Wissenschaft und Kultur (grant COALITION – Communities Allied in Infection). A. Dhingra and E. Hage were supported by the Infection Biology graduate program of Hannover Biomedical Research School.
Presentation at conferences Parts of this work have been presented on multiple occasions, most recently at the German Society for Virology (14-17 March 2018) and the UK Microbiology Society (10-13 April 2018).