Evolution and Genetic Diversity of Primate Cytomegaloviruses

Abstract

Cytomegaloviruses (CMVs) infect many mammals, including humans and non-human primates (NHPs). Human cytomegalovirus (HCMV) is an important opportunistic pathogen among immunocompromised patients and represents the most common infectious cause of birth defects. HCMV possesses a large genome and very high genetic diversity. NHP-infecting CMVs share with HCMV a similar genomic organization and coding content, as well as the course of viral infection. Recent technological advances have allowed the sequencing of several HCMV strains from clinical samples and provided insight into the diversity of NHP-infecting CMVs. The emerging picture indicates that, with the exclusion of core genes (genes that have orthologs in all herpesviruses), CMV genomes are relatively plastic and diverse in terms of gene content, both at the inter- and at the intra-species level. Such variability most likely underlies the strict species-specificity of these viruses, as well as their ability to persist lifelong and with relatively little damage to their hosts. However, core genes, despite their strong conservation, also represented a target of adaptive evolution and subtle changes in their coding sequence contributed to CMV adaptation to different hosts. Indubitably, important knowledge gaps remain, the most relevant of which concerns the role of viral genetics in HCMV-associated human disease.

Keywords: cytomegalovirus; genome organization; non–human primates; positive selection; species–specificity.

Figure 1

Primate CMV genome organization. A schematic representation of the HCMV genome is shown in the upper panel. Annotated coding regions are represented as boxes (white: core genes, gray: non–core genes); repetitive elements are shown as orange boxes. Colored similarity plots with primate CMV genomes are also shown. The whole–genome CMV alignment was obtained with progressive MAUVE [16,17]. Each genome is laid out in a horizontal track and each colored block delimits a genome region that aligns to part of another genome (presumably homologous and free from internal rearrangements) and thus represents a locally collinear block. When the similarity plot points downward it indicates an alignment to the reverse strand of the genome. Genome IDs: HCMV, NC_006273; CCMV, NC_003521; SMCV, NC_012783; RhCMV, NC_006150; CyCMV, NC_033176; BaCMV, NC_027016; OMCMV, NC_016447; SMCMV, NC_016448.

Figure 2

Genetic diversity of human herpesviruses. Neighbor–net split networks of 84 unpassaged HCMV (Supplementary Table S1), 140 HSV–1 [79], and 110 VZV [80] genomes. A phylogenetic network is a graph to visualize the evolutionary relationships (edges) among taxa (nodes). In particular, a split network represents incompatibilities within a data set by combining the results of different phylogenetic trees. Neighbor–net split networks of all whole genome sequences were constructed with SplitsTree v4.13.1 [81] using uncorrected p–distances and all polymorphic sites, after removing gap sites.

Figure 3

Gene disrupting mutations in HCMV strains. Neighbor–net split network of 233 HCMV genome sequences. (A) Strains are color–coded on the basis of the number of mutated genes. (B) Strains are color–coded depending on the type of US9 mutation (Supplementary Table S1). Neighbor–net split networks of genomic sequences were constructed with SplitsTree v4.13.1 [81] using uncorrected p–distances and all polymorphic sites, after removing gap sites.