Abstract
The complete genome of human cytomegalovirus (HCMV) was elucidated almost 25 years ago using a traditional cloning and Sanger sequencing approach. Analysis of the genetic content of additional laboratory and clinical isolates has lead to a better, albeit still incomplete, definition of the coding potential and diversity of wild-type HCMV strains. The introduction of a new generation of massively parallel sequencing technologies, collectively called next-generation sequencing, has profoundly increased the throughput and resolution of the genomics field. These increased possibilities are already leading to a better understanding of the circulating diversity of HCMV clinical isolates. The higher resolution of next-generation sequencing provides new opportunities in the study of intrahost viral population structures. Furthermore, deep sequencing enables novel diagnostic applications for sensitive drug resistance mutation detection. RNA-seq applications have changed the picture of the HCMV transcriptome, which resulted in proof of a vast amount of splicing events and alternative transcripts. This review discusses the application of next-generation sequencing technologies, which has provided a clearer picture of the intricate nature of the HCMV genome. The continuing development and application of novel sequencing technologies will further augment our understanding of this ubiquitous, but elusive, herpesvirus.
Highlights
Human cytomegalovirus (HCMV), the prototype member of the herpesvirus subfamilyBetaherpesvirinae, has a worldwide distribution and infections with this virus are extremely common.Seroprevalences in the adult population vary from 45% to 100%, increasing with age and varying with geographic location and socio-economic background [1]
AD169 and Towne had lost genome segments of 15 kb and 13 kb, respectively. These segments were situated at the 3‘ end of the UL region and were replaced by an inverted copy of the 5‘ end of the UL region, leading to an enlargement of the b repeats (Figure 1). This missing UL/b‘ segment was found to be present in an additional set of five low-passage clinical isolates like Toledo, confirming that it is a universal hallmark of wild-type HCMV strains and clearly contains factors that are dispensable for fibroblast replication, but essential for virulence in vivo [18,19]
The results showed that AD169 variant constituted a separate stock (varUC) was an AD169 variant with a nearly intact UL/b‘
Summary
Betaherpesvirinae, has a worldwide distribution and infections with this virus are extremely common. Reactivation, or reinfection of immunocompromised individuals, such as transplant recipients and AIDS patients, results in considerable morbidity and mortality [3]. The double-stranded DNA (dsDNA) genome of wild-type HCMV strains has a size of around 235 kb, which is longer than all other human herpesviruses and one of the longest genomes of all human viruses in general. It has the characteristic herpesvirus class E genome architecture, consisting of two unique regions (unique long UL and unique short US), both flanked by a pair of inverted repeats (terminal/internal repeat long TRL/IRL and internal/terminal repeat short IRS/TRS). We will highlight the recent progress that has contributed to the understanding of HCMV genomics through the application of NGS technologies
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