On the Mutation Rate of Herpes Simplex Virus Type 1

Abstract

All seven DNA-based microbes for which carefully established mutation rates and mutational spectra were previously available displayed a genomic mutation rate in the neighborhood of 0.003 per chromosome replication. The pathogenic mammalian DNA virus herpes simplex type 1 has an estimated genomic mutation rate compatible with that value.A LL microbes with chromosomes composed of DNA, However, recently reported data can be used to fill this gap. The wild-type KOS strain of herpes simplex virus and for which both spontaneous mutation rates and mutational spectra have been determined, display type 1 (HSV-1) cannot form plaques in the presence of various nucleoside analogs, while thymidine kinase (tk) a mutation rate in the laboratory of ‫300.0ف‬ per genome replication, with a range of 0.0018-0.0046 and boundary mutants defective in the synthesis of thymidine kinase can do so. Ganciclovir is a guanosine analog that bevalues experimentally indistinguishable from 0.003 (Drake et al. 1998; Grogan et al. 2001). The DNA-based comes strongly cytotoxic when phosphorylated. Using ganciclovir as the selective agent provided a HSV-1 tk Ϫ microbes that support this value are phage M13 with single-stranded DNA and a temperate mode of infection; mutant frequency of 6 ϫ 10 Ϫ5 and a mutation spectrum (Lu et al. 2002). To calculate a genomic mutation rate, phage with double-stranded DNA and alternating bethis value must first be corrected for tk mutations that tween lysogenic and lytic modes of infection; phages T2were not detected. A preferred way to do this (Drake and T4 with double-stranded DNA and a strictly lytic 1991) is to assume that indels (insertions and deletions mode of infection; the eubacterium Escherichia coli growof base pairs) within the coding sequence are detected ing optimally at ‫73ف‬Њ; the archaeon Sulfolobus acidocaldwith high efficiency and that the total number of BPSs arius growing optimally at ‫08ف‬Њ; the yeast Saccharomyces can be estimated from the number that produce intercerevisiae; and the filamentous fungus Neurospora crassa.nal stop codons (UAG, UGA, and UAA), which are These organisms vary by nearly four orders of magniusually null mutations; this is done by multiplying by 64/3 tude in genome size, and the average gene or base-pair the number of chain-terminating codons produced by mutation rate varies reciprocally by the same amount.BPSs. In the present experiment, the mutational specAnother generality holds in most but not all DNAtrum comprised 67 mutations of which 45 were indels and based organisms: on average, the majority of mutations 5 were chain-terminating BPSs; this proportion (5/22 ϭ are base-pair substitutions (BPSs) (Grogan et al. 2001). 23%) of BPSs that produce chain-terminating codons The exceptions are thermophiles, which appear to have falls in the center of the range (5-50%, average 20%) lower rates of BPSs than do mesophiles (Grogan et al.found for DNA-based microbes (Grogan et al. 2001(Grogan et al. ). 2001 Friedman et al. 2004), perhaps because the averThe correcte...

The Rate and Character of Spontaneous Mutation in Thermus thermophilus

“…Third, the set of mesophiles that forms a basis for comparison have genomic mutation rates of 0.0025, 0.0027, 0.0027, 0.0030, 0.0038, 0.0040, 0.0045, and 0.0046 (mean ¼ 0.0035 6 0.00097) for Escherichia coli, S. cerevisiae, Herpes simplex virus 1, Neurospora crassa, bacteriophage l, bacteriophage T2/T4, Schizosaccharomyces pombe, and bacteriophage M13, respectively, estimated using the historical correction factor (Drake et al 1998;Fraser et al 2003;Drake and Hwang 2005). All but one of these values are based on only one or two reporter genes but the range of values resulting from the same methods of calculation is nevertheless less than twofold.…”

DNA Replication Fidelity of Herpes Simplex Virus

“…It is estimated that the TK mutagenesis assay can detect less than 50% of all possible substitutions of tk mutations (Hwang, Liu, and Hwang, 2002). Despite this, an extensive study (Lu, Hwang, and Hwang, 2002a) of tk mutants derived from wild-type HSV-1 strain KOS found that HSV replicates DNA with a genomic mutation rate similar to those of other DNA-based microbes (Drake and Hwang, 2005). However, earlier studies (Hall et al, 1984;Hall et al, 1985;Parris and Harrington, 1982;Hwang and Chen, 1995) demonstrated a roughly 10-fold higher mutation frequency than those (Hwang et al, 1997;Lu, Hwang, and Hwang, 2002a) used to calculate the mutation rate.…”

“…It is reasonable to predict that microorganisms also replicate under tight regulations to accomplish the required DNA replication fidelity for selection and fitness. This notion also applies to herpes simplex virus type 1 (HSV-1), which replicates DNA with a genomic mutation rate similar to those of other DNA-based microbes examined (Drake and Hwang, 2005). Since the HSV-1 genome can be easily manipulated, it offers a good model for a variety of studies, including the study of DNA replication (reviewed in (Coen, 1996)).…”

An Unusual Pattern of Spontaneous Mutations Recovered in the Halophilic Archaeon Haloferax volcanii

“…Sequencing of representative mutants then reveals a spectrum of mutation, which enables the efficiency of mutation detection and other parameters to be estimated. Such analyses have shown that all mesophilic micro-organisms examined (including DNA viruses) share two mutational characteristics: (i) the rates of mutation per genome fall near 0.003/replication, despite large differences in mutation rates per base pair (Drake 1991;Drake et al 1998;Drake and Hwang 2005), and (ii) $70% of the observed mutations are base-pair substitutions (BPSs) (Grogan et al 2001). However, extending this analysis to an archaeon from a geothermal environment revealed an apparently lower genomic rate (#0.0018) and a lower proportion of BPSs (33%) (Grogan et al 2001).…”

“…rates display a genomic mutation rate of m g % 0.0034 (range 0.0025-0.0046)/chromosome replication (Drake 1991;Drake et al 1998;Drake and Hwang 2005). On the basis of an H. volcanii pyrE2 mutation rate of (1.93-5.87) 310 À8 and the coding sequence of 531 bp (including the termination codon), the midrange mutation rate per base pair is 7.34 3 10 À11 .…”