Alphaherpesvirus Genomics: Past, Present and Future

Kuny, Chad V.; Szpara, Moriah L.

doi:10.21775/cimb.042.041

Cited by 18 publications

(15 citation statements)

References 145 publications

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“…Others have employed high fidelity approaches such as duplex sequencing to reduce sequencing error associated with high-throughput sequencing [ 40 ] for estimating mutation rates of DNA viruses and finding mutation-prone sequence motifs and mutational hotspots [ 27 ]. High throughput sequencing has also enabled the characterization of genetic diversity within DNA virus populations and its functional implications [ 48 , 49 ]. Long-read sequencing has made it possible to study of evolutionary dynamics of adaptation by point mutations and gene-copy-number variation in poxviruses [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Empirical estimates of the mutation rate for an alphabaculovirus

et al. 2022

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Mutation rates are of key importance for understanding evolutionary processes and predicting their outcomes. Empirical mutation rate estimates are available for a number of RNA viruses, but few are available for DNA viruses, which tend to have larger genomes. Whilst some viruses have very high mutation rates, lower mutation rates are expected for viruses with large genomes to ensure genome integrity. Alphabaculoviruses are insect viruses with large genomes and often have high levels of polymorphism, suggesting high mutation rates despite evidence of proofreading activity by the replication machinery. Here, we report an empirical estimate of the mutation rate per base per strand copying (s/n/r) of Autographa californica multiple nucleopolyhedrovirus (AcMNPV). To avoid biases due to selection, we analyzed mutations that occurred in a stable, non-functional genomic insert after five serial passages in Spodoptera exigua larvae. Our results highlight that viral demography and the stringency of mutation calling affect mutation rate estimates, and that using a population genetic simulation model to make inferences can mitigate the impact of these processes on estimates of mutation rate. We estimated a mutation rate of μ = 1×10−7 s/n/r when applying the most stringent criteria for mutation calling, and estimates of up to μ = 5×10−7 s/n/r when relaxing these criteria. The rates at which different classes of mutations accumulate provide good evidence for neutrality of mutations occurring within the inserted region. We therefore present a robust approach for mutation rate estimation for viruses with stable genomes, and strong evidence of a much lower alphabaculovirus mutation rate than supposed based on the high levels of polymorphism observed.

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Section: Discussionmentioning

confidence: 99%

Empirical estimates of the mutation rate for an alphabaculovirus

et al. 2022

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“…HSV-2 exhibited greater rates of MVs accumulation than HSV-1, adds an extra degree of robustness to the confidence in our findings. These comprehensive analyses and quality controls, together with the benefits provided by an ultra-deep sequence coverage, are instrumental in confidently detecting very low MVs, thus overcoming the challenges presented by short-read sequencing of high G + C content repetitive genomes [ 42 , 59 ]. The integration of comparative genomic and reverse genetic approaches will improve our understanding of fundamental aspects of HSV biology, where studying the phenotypic effect of in vitro and in vivo generated variants can complement previous discoveries on gene roles, as well as explaining or predicting clinical outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…However, here for the first time, we have identified and characterized how the genetic diversity is differentially generated between human herpesviruses when serially passaged in cell culture. The effects that this differentially generated genetic diversity may have had on each aspect of HSV biology, as well as on the clinical outcomes of infections, is currently an active area of research [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

Herpes simplex virus 2 (HSV-2) evolves faster in cell culture than HSV-1 by generating greater genetic diversity

et al. 2021

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Herpes simplex virus type 1 and 2 (HSV-1 and HSV-2, respectively) are prevalent human pathogens of clinical relevance that establish long-life latency in the nervous system. They have been considered, along with the Herpesviridae family, to exhibit a low level of genetic diversity during viral replication. However, the high ability shown by these viruses to rapidly evolve under different selective pressures does not correlates with that presumed genetic stability. High-throughput sequencing has revealed that heterogeneous or plaque-purified populations of both serotypes contain a broad range of genetic diversity, in terms of number and frequency of minor genetic variants, both in vivo and in vitro. This is reminiscent of the quasispecies phenomenon traditionally associated with RNA viruses. Here, by plaque-purification of two selected viral clones of each viral subtype, we reduced the high level of genetic variability found in the original viral stocks, to more genetically homogeneous populations. After having deeply characterized the genetic diversity present in the purified viral clones as a high confidence baseline, we examined the generation of de novo genetic diversity under culture conditions. We found that both serotypes gradually increased the number of de novo minor variants, as well as their frequency, in two different cell types after just five and ten passages. Remarkably, HSV-2 populations displayed a much higher raise of nonconservative de novo minor variants than the HSV-1 counterparts. Most of these minor variants exhibited a very low frequency in the population, increasing their frequency over sequential passages. These new appeared minor variants largely impacted the coding diversity of HSV-2, and we found some genes more prone to harbor higher variability. These data show that herpesviruses generate de novo genetic diversity differentially under equal in vitro culture conditions. This might have contributed to the evolutionary divergence of HSV-1 and HSV-2 adapting to different anatomical niche, boosted by selective pressures found at each epithelial and neuronal tissue.

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“…Epigenetics is defined as the process by which a stably heritable phenotypic change results from changes in the chromosome without alterations in its DNA sequence [58]. However, stable phenotypic changes in alphaherpesviruses that are inherited across subsequent virus generations involve mutations of the virus genome [59,60]. Thus, the definition of epigenetics has been enlarged to describe a host-centered mechanism to control virus transcription, especially during the latent stage of the virus life cycle.…”

Section: Epigenetic Control Of Alphaherpesvirus Latencymentioning

confidence: 99%

Recent Issues in Varicella-Zoster Virus Latency

Kennedy

Mogensen

Cohrs

2021

Viruses

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Varicella-zoster virus (VZV) is a human herpes virus which causes varicella (chicken pox) as a primary infection, and, following a variable period of latency in neurons in the peripheral ganglia, may reactivate to cause herpes zoster (shingles) as well as a variety of neurological syndromes. In this overview we consider some recent issues in alphaherpesvirus latency with special focus on VZV ganglionic latency. A key question is the nature and extent of viral gene transcription during viral latency. While it is known that this is highly restricted, it is only recently that the very high degree of that restriction has been clarified, with both VZV gene 63-encoded transcripts and discovery of a novel VZV transcript (VLT) that maps antisense to the viral transactivator gene 61. It has also emerged in recent years that there is significant epigenetic regulation of VZV gene transcription, and the mechanisms underlying this are complex and being unraveled. The last few years has also seen an increased interest in the immunological aspects of VZV latency and reactivation, in particular from the perspective of inborn errors of host immunity that predispose to different VZV reactivation syndromes.

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Alphaherpesvirus Genomics: Past, Present and Future

Cited by 18 publications

References 145 publications

Empirical estimates of the mutation rate for an alphabaculovirus

Empirical estimates of the mutation rate for an alphabaculovirus

Herpes simplex virus 2 (HSV-2) evolves faster in cell culture than HSV-1 by generating greater genetic diversity

Recent Issues in Varicella-Zoster Virus Latency

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