Islands of linkage in an ocean of pervasive recombination reveals two-speed evolution of human cytomegalovirus genomes

Journal article


Lassalle, F., Depledge, D.P., Reeves, M.B., Brown, A.C., Christiansen, M.T., Tutill, H.J., Williams, R.J., Einer-Jensen, K., Holdstock, J., Atkinson, C., Brown, J.R., van Loenen, F.B., Clark, D.A., Griffiths, P.D., Verjans, G.M.G.M., Schutten, M., Milne, R.S.B., Balloux, F., Breuer, J. and Fullerton, C. (2016). Islands of linkage in an ocean of pervasive recombination reveals two-speed evolution of human cytomegalovirus genomes. Virus Evolution. 2 (1). https://doi.org/10.1093/ve/vew017
AuthorsLassalle, F., Depledge, D.P., Reeves, M.B., Brown, A.C., Christiansen, M.T., Tutill, H.J., Williams, R.J., Einer-Jensen, K., Holdstock, J., Atkinson, C., Brown, J.R., van Loenen, F.B., Clark, D.A., Griffiths, P.D., Verjans, G.M.G.M., Schutten, M., Milne, R.S.B., Balloux, F., Breuer, J. and Fullerton, C.
Abstract

Human cytomegalovirus (HCMV) infects most of the population worldwide, persisting throughout the host's life in a latent state with periodic episodes of reactivation. While typically asymptomatic, HCMV can cause fatal disease among congenitally infected infants and immunocompromised patients. These clinical issues are compounded by the emergence of antiviral resistance and the absence of an effective vaccine, the development of which is likely complicated by the numerous immune evasins encoded by HCMV to counter the host's adaptive immune responses, a feature that facilitates frequent super-infections. Understanding the evolutionary dynamics of HCMV is essential for the development of effective new drugs and vaccines. By comparing viral genomes from uncultivated or low-passaged clinical samples of diverse origins, we observe evidence of frequent homologous recombination events, both recent and ancient, and no structure of HCMV genetic diversity at the whole-genome scale. Analysis of individual gene-scale loci reveals a striking dichotomy: while most of the genome is highly conserved, recombines essentially freely and has evolved under purifying selection, 21 genes display extreme diversity, structured into distinct genotypes that do not recombine with each other. Most of these hyper-variable genes encode glycoproteins involved in cell entry or escape of host immunity. Evidence that half of them have diverged through episodes of intense positive selection suggests that rapid evolution of hyper-variable loci is likely driven by interactions with host immunity. It appears that this process is enabled by recombination unlinking hyper-variable loci from strongly constrained neighboring sites. It is conceivable that viral mechanisms facilitating super-infection have evolved to promote recombination between diverged genotypes, allowing the virus to continuously diversify at key loci to escape immune detection, while maintaining a genome optimally adapted to its asymptomatic infectious lifecycle.

Year2016
JournalVirus Evolution
Journal citation2 (1)
PublisherOxford University Press (OUP)
ISSN2057-1577
Digital Object Identifier (DOI)https://doi.org/10.1093/ve/vew017
Web address (URL)http://dx.doi.org/10.1093/ve/vew017
Publication dates
Online15 Jun 2016
Publication process dates
Deposited15 May 2023
Accepted author manuscript
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Open
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