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    <h1 id="article-title-1" itemprop="headline">Evolution of Cocirculating Varicella-Zoster Virus Genotypes during a Chickenpox Outbreak in Guinea-Bissau</h1>
    <div class="contributors">
      <div class="contributor-list" id="contrib-group-1"> <span class="name" itemprop="name"><strong>Daniel P. Depledge</strong></span> <a id="xref-aff-1-1" class="xref-aff" href="#aff-1"><sup>1</sup></a>, <span class="name" itemprop="name"><strong>Eleanor R. Gray</strong></span> <a id="xref-aff-1-2" class="xref-aff" href="#aff-1"><sup>a</sup></a>, <span class="name" itemprop="name"><strong>Samit Kundu</strong></span> <a id="xref-aff-1-3" class="xref-aff" href="#aff-1"><sup>a</sup></a>, <span class="name" itemprop="name"><strong>Samantha Cooray</strong></span> <a id="xref-aff-1-4" class="xref-aff" href="#aff-1"><sup>a</sup></a>, <span class="name" itemprop="name"><strong>Anja Poulsen</strong></span> <a id="xref-aff-2-1" class="xref-aff" href="#aff-2"><sup>b</sup></a>, <a id="xref-aff-3-1" class="xref-aff" href="#aff-3"><sup>c</sup></a> <span class="name" itemprop="name"><strong>Peter Aaby</strong></span> <a id="xref-aff-2-2" class="xref-aff" href="#aff-2"><sup>b</sup></a>, <a id="xref-aff-4-1" class="xref-aff" href="#aff-4"><sup>d</sup></a> and <span class="name" itemprop="name"><strong>Judith Breuer</strong></span> <a id="xref-aff-1-5" class="xref-aff" href="#aff-1"><sup>a</sup></a> </div>
      <ol class="affiliation-list hideaffil">
        <li class="aff"><a id="aff-1" name="aff-1"></a>
          <address>
          <sup>a</sup>Division of Infection and Immunity, University College London, London, United Kingdom
          </address>
        </li>
        <li class="aff"><a id="aff-2" name="aff-2"></a>
          <address>
          <sup>b</sup>Bandim Health Project, INDEPTH Network, Bissau, Guinea-Bissau
          </address>
        </li>
        <li class="aff"><a id="aff-3" name="aff-3"></a>
          <address>
          <sup>c</sup>Child and Adolescent Clinic, Rigshospitalet, Copenhagen, Denmark
          </address>
        </li>
        <li class="aff"><a id="aff-4" name="aff-4"></a>
          <address>
          <sup>d</sup>Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark
          </address>
        </li>
      </ol>
    </div>
    <div class="section abstract" id="abstract-1" itemprop="description">
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            <li><a href="#abstract-1">Abstract</a></li>
            <li><a href="#sec-1">Introduction</a></li>
            <li><a href="#sec-2">Materials and Methods</a></li>
            <li><a href="#sec-10">Results</a></li>
            <li><a href="#sec-11">Discussion</a></li>
            <li><a href="#sec-11">Section misl</a></li>
            <li><a href="#ack-1">Acknowledgments</a></li>
            <li><a href="#fn-group-1">Footnotes</a></li>
            <li><a href="#ref-list-1">References</a></li>
          </ul>
        </div>
      </div>
      <h2>ABSTRACT</h2>
      <p>Varicella-zoster virus (VZV), a double-stranded DNA alphaherpesvirus, is associated with seasonal outbreaks of varicella in
        
        nonimmunized populations. Little is known about whether these outbreaks are associated with a single or multiple viral genotypes
        
        and whether new mutations rapidly accumulate during transmission. Here, we take advantage of a well-characterized population
        
        cohort in Guinea-Bissau and produce a unique set of 23 full-length genome sequences, collected over 7 months from eight households.
        
        Comparative sequence analysis reveals that four distinct genotypes cocirculated among the population, three of which were
        
        present during the first week of the outbreak, although no patients were coinfected, which indicates that exposure to infectious
        
        virus from multiple sources is common during VZV outbreaks. Transmission of VZV was associated with length polymorphisms in
        
        the R1 repeat region and the origin of DNA replication. In two cases, these were associated with the formation of distinct
        
        lineages and point to the possible coevolution of these loci, despite the lack of any known functional link in VZV or related
        
        herpesviruses. We show that these and all other sequenced clade 5 viruses possess a distinct R1 repeat motif that increases
        
        the acidity of an ORF11p protein domain and postulate that this has either arisen or been lost following divergence of the
        
        major clades. Thus, sequencing of whole VZV genomes collected during an outbreak has provided novel insights into VZV biology,
        
        transmission patterns, and (recent) natural history. </p>
      <p><strong>IMPORTANCE</strong> VZV is a highly infectious virus and the causative agent of chickenpox and shingles, the latter being particularly associated
        
        with the risk of painful complications. Seasonal outbreaks of chickenpox are very common among young children, yet little
        
        is known about the dynamics of the virus during person-to-person to transmission or whether multiple distinct viruses seed
        
        and/or cocirculate during an outbreak. In this study, we have sequenced chickenpox viruses from an outbreak in Guinea-Bissau
        
        that are supported by detailed epidemiological data. Our data show that multiple different virus strains seeded and were maintained
        
        throughout the 6-month outbreak period and that viruses transmitted between individuals accumulated new mutations in specific
        
        genomic regions. Of particular interest is the potential coevolution of two distinct parts of the genomes and our calculations
        
        of the rate of viral mutation, both of which increase our understanding of how VZV evolves over short periods of time in human
        
        populations. </p>
    </div>
    <div class="section intro" id="sec-1">
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            <li><a href="#abstract-1">Abstract</a></li>
            <li><a href="#sec-1">Introduction</a></li>
            <li><a href="#sec-2">Materials and Methods</a></li>
            <li><a href="#sec-10">Results</a></li>
            <li><a href="#sec-11">Discussion</a></li>
            <li><a href="#ack-1">Acknowledgments</a></li>
            <li><a href="#fn-group-1">Footnotes</a></li>
            <li><a href="#ref-list-1">References</a></li> 
          </ul>
        </div>
      </div>
      <h2>INTRODUCTION</h2>
      <p>Varicella-zoster virus (VZV; subfamily alphaherpesvirus), causes chickenpox (varicella), an infection mainly of childhood,
        
        and shingles (zoster), a painful dermatomal rash that follows reactivation of latent endogenous virus in sensory ganglia.
        
        The virus is transmitted in aerosols, resulting mainly from the rupture of fluid filled skin blisters which are characteristic
        
        of both chickenpox and shingles but also from virus shed from the respiratory tract. Virus inhaled by a susceptible contact
        
        replicates in the nasopharynx, spreading thereafter to cause the centripetal rash characteristic of chickenpox. Like other
        
        airborne virus infections, chickenpox is epidemic. Immunity is generally lifelong, with outbreaks mainly affecting susceptible
        
        birth cohorts. In temperate countries such as the United Kingdom and the United States, VZV is estimated to infect 60 to 90%
        
        of close and household contacts and, by age 10, more than 90% of the population are immune (<a id="xref-ref-1-1" class="xref-bibr" href="#ref-1">1</a>, <a id="xref-ref-2-1" class="xref-bibr" href="#ref-2">2</a>). In contrast, VZV household infectivity in Guinea-Bissau, a tropical African country close to the equator, is closer to
        
        16% (<a id="xref-ref-3-1" class="xref-bibr" href="#ref-3">3</a>). Unusually for a tropical climate, the mean age of chickenpox is similar to that of temperate countries, and this has been
        
        attributed to a higher population density which compensates for the reduced viral transmissibility (<a id="xref-ref-3-2" class="xref-bibr" href="#ref-3">3</a>). Possible explanations for the reduced infectivity of VZV in tropical countries include increased temperature, humidity,
        
        and UV light exposure, all of which have been shown <em>in vitro</em> to inactivate virus (<a id="xref-ref-4-1" class="xref-bibr" href="#ref-4">4</a>). However, prevalent viral genotypes circulating in Africa, India, and Sri Lanka differ from endogenous European genotypes,
        
        and this could also provide an explanation for different patterns of transmissibility (<a id="xref-ref-5-1" class="xref-bibr" href="#ref-5">5</a>). While more than 47 full-length VZV genomes have been sequenced to date (<a id="xref-ref-6-1" class="xref-bibr" href="#ref-6">6</a><a id="xref-ref-7-1" class="xref-bibr" href="#ref-7">–</a><a id="xref-ref-10-1" class="xref-bibr" href="#ref-10">10</a>), none are from viruses circulating in countries with low transmission rates. </p>
      <p>Here, we have sequenced and assembled whole VZV genomes from 23 individuals over the course of a seasonal varicella outbreak
        
        in Guinea Bissau. These viruses were collected from a well-characterized population cohort in the Bandim peri-urban area of
        
        Bissau, the capital of Guinea-Bissau, which has been studied for over 30 years as part of the Bandim Health Project (Statens
        
        Serum Institut, <a href="http://www.bandim.org">www.bandim.org</a>) (<a id="xref-ref-3-3" class="xref-bibr" href="#ref-3">3</a>, <a id="xref-ref-11-1" class="xref-bibr" href="#ref-11">11</a>, <a id="xref-ref-12-1" class="xref-bibr" href="#ref-12">12</a>). Epidemiological data were obtained for an outbreak of 1,419 cases occurring over a 7-month period during 2001, while samples
        
        of vesicle fluid were obtained from a subset of these (∼500). The data collected included house location, household structure
        
        (i.e., numbers of families and family members cohabiting), severity of disease, and the relationship of each infected person
        
        to the putative index patient who transmitted to them. While subgenomic regions (e.g., the origin of DNA replication [OriS])
        
        undergo rapid changes during an epidemic (<a id="xref-ref-3-4" class="xref-bibr" href="#ref-3">3</a>), the extent to which new mutations accumulate across the whole genome during transmission is not known, and thus VZV transmission
        
        chains remain poorly characterized at the whole-genome level. </p>
      <p>This study uses recently developed enrichment methods (<a id="xref-ref-13-1" class="xref-bibr" href="#ref-13">13</a>, <a id="xref-ref-14-1" class="xref-bibr" href="#ref-14">14</a>) which enable deep sequencing of pathogens directly from clinical samples and is the first study of herpesviruses that investigates
        
        the origins and subsequent evolution of viral genotypes during an outbreak and provides unique insights into the biology of
        
        these large double-stranded DNA viruses. Finally, we address the long-standing question of whether varicella strains circulating
        
        in tropical countries have specific genetic adaptations that result in reduced transmission rates. </p>
    </div>
    <div class="section materials-methods" id="sec-2">
      <div class="section-nav">  
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            <li><a href="#abstract-1">Abstract</a></li>
            <li><a href="#sec-1">Introduction</a></li>
            <li><a href="#sec-2">Materials and Methods</a></li>
            <li><a href="#sec-10">Results</a></li>
            <li><a href="#sec-11">Discussion</a></li>
            <li><a href="#ack-1">Acknowledgments</a></li>
            <li><a href="#fn-group-1">Footnotes</a></li>
            <li><a href="#ref-list-1">References</a></li> 
          </ul>
        </div>
      </div>
      <h2>MATERIALS AND METHODS</h2>
      <div id="sec-3" class="subsection">
        <p><span class="inline-l2-heading">Sample collection and ethics.</span>Ethical clearance for the study was obtained from the Ministry of Public Health in Guinea-Bissau and the East London and City
          
          Health Authority. Participation was voluntary. We selected eight putative transmission chains comprising two to four members
          
          of the same household collected during the start, middle, or end of the outbreak in 2001 (<a id="xref-table-wrap-1-1" class="xref-table" href="#T1">Table 1</a> and <a id="xref-fig-1-1" class="xref-fig" href="#F1">Fig. 1</a>). Putative transmissions were defined by the occurrence of a household member being diagnosed with varicella within 7 to
          
          21 days of another member of the same household and where typing of the OriS region showed a similar number of TA and GA repeats
          
          (±1) (<a id="xref-ref-3-5" class="xref-bibr" href="#ref-3">3</a>). We also selected three samples (Bandim 6, 7, and 18) where the OriS repeat structure differed from other infected persons
          
          of the same household in the same time period. Vesicular virus was obtained from a total of 24 subjects with varicella during
          
          the outbreak, placed in viral transport medium and stored at −80°C. </p>
      </div>
      
      <div id="F1">
      <iframe src="http://journalveterinaryvirology.com/urlbodies/figures.php?figureNumber=689662" name="figures" scrolling="no" width="520" marginheight="0" marginwidth="0" frameborder="0" height="470"></iframe>
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      <div id="sec-4" class="subsection">
        <p><span class="inline-l2-heading">DNA extraction, library construction, targeted enrichment, and sequencing.</span>Total DNA was extracted from each sample by using a QiaAMP DNA minikit (Qiagen) according to the manufacturer's instructions.
          
          DNA quantification was performed with a NanoDrop spectrophotometer, and samples with 260/280 ratios outside the range 1.7
          
          to 2.1 and 260/230 ratios outside the range 1.8 to 2.2 were further purified using a Zymoclean Genomic DNA Clean &amp; Concentrator
          
          (Zymo Research Corp.). Whole-genome amplification using GenomiPhi V2 (GE Healthcare) was performed using 10 ng of starting
          
          material. Libraries were constructed in accordance with the standard SureSelect XT v1.5 protocols (Agilent). Enrichment for
          
          VZV sequences was performed as described previously (<a id="xref-ref-13-2" class="xref-bibr" href="#ref-13">13</a>, <a id="xref-ref-14-2" class="xref-bibr" href="#ref-14">14</a>). Sequence libraries were multiplexed (Bandim 1 to 12 and Bandim 13 to 24) and sequenced using 300-bp and 500-bp paired-end
          
          kits (respectively) on an Illumina MiSeq. </p>
      </div>
      <div id="sec-5" class="subsection">
        <p><span class="inline-l2-heading">Genome assembly and variant calling.</span>Sequence data set where demultiplexed using BaseSpace and individual data sets were subsequently parsed through QUASR (<a id="xref-ref-15-1" class="xref-bibr" href="#ref-15">15</a>) for duplicate removal and read-trimming (-q 30, -l 50) and subsequently aligned against the VZV reference strain Dumas (<a href="/external-ref?link_type=GEN&amp;access_num=NC_001348">NC_001348</a>) using BWA (<a id="xref-ref-16-1" class="xref-bibr" href="#ref-16">16</a>). Resulting alignments were processed using SAMTools (<a id="xref-ref-17-1" class="xref-bibr" href="#ref-17">17</a>) to generate pileup files for each sample. A consensus sequence for each data set was called with the QUASR module “pileupConsensus”
          
          and a 50% frequency threshold (i.e., no ambiguities were included). Variant profiling for each data set was performed using
          
          VarScan v2.2.11 (<a id="xref-ref-18-1" class="xref-bibr" href="#ref-18">18</a>) with the following parameters: basecall quality, ≥20; read depth, ≥50; and independent reads supporting minor alleles, ≥2
          
          per strand. In addition, variant calls showing a directional strand bias of ≥0.85 were excluded from further analyses. Consensus
          
          sequences were generated for each rash sample, but iterative repeat regions R1, R2, R3, R4, and R5 (<a id="xref-ref-19-1" class="xref-bibr" href="#ref-19">19</a>, <a id="xref-ref-20-1" class="xref-bibr" href="#ref-20">20</a>), as well as the terminal repeat region, were trimmed prior to tree-building analyses. </p>
      </div>
      <div id="sec-6" class="subsection">
        <p id="p-16"><span class="inline-l2-heading">Consensus sequence analyses.</span>DNA sequences were aligned by using the program Mafft, v6 (<a id="xref-ref-21-1" class="xref-bibr" href="#ref-21">21</a>), with alignments checked manually; no insertions or deletions were inferred from the alignment. </p>
      </div>
      <div id="sec-7" class="subsection">
        <p id="p-17"><span class="inline-l2-heading">Substitution rates.</span>Estimates of substitution rates were inferred using the program Beast v1.7.5 (<a id="xref-ref-22-1" class="xref-bibr" href="#ref-22">22</a>). The Beast analyses were performed under a HKY+I model of nucleotide substitution (selected by jModeltest 2.1 [<a id="xref-ref-23-1" class="xref-bibr" href="#ref-23">23</a>, <a id="xref-ref-24-1" class="xref-bibr" href="#ref-24">24</a>]), strict and relaxed clock models (strict clock, relaxed lognormal, and relaxed exponential) and a variety or tree coalescent
          
          priors (constant, Bayesian skyline, and exponential). A Bayes factor analysis suggested that there was not sufficient evidence
          
          to reject a model of constant population size. The Monte Carlo Markov chain was run for 50,000,000 iterations, with a thinning
          
          of 50,000. We checked for convergence by ensuring that all parameters had an effective sample size (ESS) of at least 200.
          
          Finally, we assessed the molecular clock model by looking at the coefficient of variation histogram. The program Path-O-gen
          
          (<a href="http://tree.bio.ed.ac.uk/software/pathogen">http://tree.bio.ed.ac.uk/software/pathogen</a>), which regresses the root-to-tip distance against the sampling date, was used to assess the “clock-likeness” (the extent
          
          to which the sampling date is correlated with the total branch length) of the Guinea-Bissau VZV sequence data using neighbor-joined
          
          trees inferred by Mega v5.2 (<a id="xref-ref-25-1" class="xref-bibr" href="#ref-25">25</a>). To assess the level of the temporal structure (which measures the effect that the background mutation rate is having on
          
          the inferred substitution rate) we adopted the approach of Duffy and Holmes (<a id="xref-ref-43-1" class="xref-bibr" href="#ref-43">43</a>) whereby rate analyses were repeated, but with the sampling dates randomly shuffled among the tips. </p>
      </div>
      <div id="sec-8" class="subsection">
        <p id="p-18"><span class="inline-l2-heading">Amplification of VZV reiteration regions.</span>The VZV reiteration regions R1, R2, R4, and R5 were amplified and sequenced from Guinea-Bissau sample DNA using primers designed
          
          against the Dumas reference genome (<a href="/external-ref?link_type=GEN&amp;access_num=NC_001348">NC_001348</a>) as a template. All PCRs were carried out using Herculase II fusion DNA polymerase (Agilent Technologies) according to the
          
          manufacturer's instructions. The cycling conditions were as follows: denaturation at 95°C for 2 min, followed by 35 cycles
          
          of amplification (denaturation at 94°C for 20 s, annealing at 55 to 65°C for 20 s, and extension at 72°C for 30 s), and then
          
          a final extension step at 72°C for 3 min. PCR products were purified using a DNA Clean &amp; Concentrator-5 kit (Zymo Research)
          
          according to the manufacturer's instructions. Products were Sanger sequenced in the forward and reverse directions. </p>
      </div>
      <div id="sec-9" class="subsection">
        <p id="p-19"><span class="inline-l2-heading">GenBank accession numbers.</span>Consensus sequences for all samples sequenced in the present study are available in GenBank under the following accession
          
          numbers: KM355696 to KM355718. </p>
      </div>
    </div>
    <div class="section results" id="sec-10">
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            <li><a href="#abstract-1">Abstract</a></li>
            <li><a href="#sec-1">Introduction</a></li>
            <li><a href="#sec-2">Materials and Methods</a></li>
            <li><a href="#sec-10">Results</a></li>
            <li><a href="#sec-11">Discussion</a></li>
            <li><a href="#ack-1">Acknowledgments</a></li>
            <li><a href="#fn-group-1">Footnotes</a></li>
            <li><a href="#ref-list-1">References</a></li> 
          </ul>
        </div>
      </div>
      <h2>RESULTS</h2>
      <p id="p-20">VZV DNA was successfully enriched from 23 patient samples (<a id="xref-table-wrap-1-2" class="xref-table" href="#T1">Table 1</a>), with over 99.9% genome coverage by Illumina MiSeq sequencing (<a id="xref-table-wrap-2-1" class="xref-table" href="#T2">Table 2</a>). All 23 Guinea-Bissau viruses clustered within clade 5, and all Guinea-Bissau viruses were more closely related to each
        
        other than to other clade 5 viruses, although no single mutation differentiated them from other clade 5 viruses (<a id="xref-fig-2-2" class="xref-fig" href="#F2">Fig. 2</a>). Virus sequences segregated into two main genogroups, 5A and 5B, and these cocirculated throughout the epidemic although
        
        no coinfected samples were found (<a id="xref-table-wrap-1-3" class="xref-table" href="#T1">Table 1</a> and <a id="xref-fig-1-3" class="xref-fig" href="#F1">Fig. 1</a> and <a id="xref-fig-2-3" class="xref-fig" href="#F2">2</a>). Most viruses within each genogroup were genetically nearly identical. However, three viruses in genogroup 5B (Bandim 6,
        
        13, and 14) were more divergent than others compared to the consensus sequence for the genogroup. Bandim 6 differed from the
        
        consensus 5B sequence by 16 single-nucleotide polymorphisms (SNPs), and Bandim 13 and 14, although they were identical to
        
        each other, differed from the consensus 5B sequence by 11 SNPs (<a id="xref-fig-3-1" class="xref-fig" href="#F3">Fig. 3</a>). The paired Bandim 13/14 viruses were recovered at the end of the outbreak and may therefore have evolved during epidemic
        
        spread. In contrast, Bandim 6 cocirculated with 5A and 5B viruses in the first month of the outbreak. Based on the timing
        
        of the second infections (within 7 to 21 days of the putative index case), we identified 15 potential household transmissions
        
        (<a id="xref-table-wrap-1-4" class="xref-table" href="#T1">Table 1</a> and <a id="xref-fig-1-4" class="xref-fig" href="#F1">Fig. 1</a>). In nine of these, the SNP genotype of the transmitted virus sequence was identical to the index case, whereas in three
        
        they were identical apart from one (Bandim 1/2) or two SNP differences Bandim (11/12). However, for four putative household
        
        transmissions the viruses that appeared temporally linked were genetically distinct, indicating transmission from an external
        
        source (Bandim 4/6, 7/8, 16/17, and 16/18) (<a id="xref-fig-4-1" class="xref-fig" href="#F4">Fig. 4</a>). </p>
      <p id="p-29">In total, 44 SNP positions were identified within our sample set, 15 of which are nonsynonymous mutations (<a id="xref-fig-4-2" class="xref-fig" href="#F4">Fig. 4</a>). The majority of open reading frames (ORFs) contained either no SNP (<em>n</em> = 45) or a single SNP (<em>n</em> = 14). Four viruses—Bandim 6, 13, 14, and 17— had synonymous mutations at positions in ORF62. Three viruses—Bandim 15, 16,
        
        and 17—also shared a synonymous mutation in ORF64. Using the sampling dates for all 23 samples, we calculated the substitution
        
        rate (excluding the repeat regions) to be 1.82 × 10<sup>−5</sup> substitutions per site per year (<a id="xref-table-wrap-3-1" class="xref-table" href="#T3">Tables 3</a> and <a id="xref-table-wrap-4-1" class="xref-table" href="#T4">4</a>). Estimates of the substitution rate were also obtained using strict clock models (where a single substitution rate applies
        
        to all parts of a phylogenetic tree) and relaxed clock models (where substitution rates are allowed to differ across the phylogenetic
        
        tree). Although these rates varied only slightly between strict and relaxed clock models, there was only weak evidence for
        
        temporal signal (a measure of the degree of clock-like [i.e., constant] evolution in the data) (<a id="xref-table-wrap-3-2" class="xref-table" href="#T3">Tables 3</a> and <a id="xref-table-wrap-4-2" class="xref-table" href="#T4">4</a>). This can be attributed to the cocirculation of multiple genotypes during the outbreak and thus we also calculated a substitution
        
        rate separately for genogroup 5B, for which there was better evidence for temporal signal (<a id="xref-table-wrap-3-3" class="xref-table" href="#T3">Tables 3</a> and <a id="xref-table-wrap-4-3" class="xref-table" href="#T4">4</a>). No substitution rate could be calculated for genogroup 5A since the genetic diversity between the samples was too low.
        
        Overall, these substitution rate calculations are higher than have previously been estimated for VZV (e.g., 3.8 × 10<sup>−6</sup> substitutions per site per year [<a id="xref-ref-26-1" class="xref-bibr" href="#ref-26">26</a>]). To validate our estimate, the calculations were repeated after random shuffling of sampling dates between samples (<a id="xref-ref-27-1" class="xref-bibr" href="#ref-27">27</a>). Ideally, the mean evolutionary rate calculated from the true data should not coincide with the confidence intervals attached
        
        to the mean evolutionary rates calculated for any of the shuffled tips analyses (<a id="xref-fig-4-3" class="xref-fig" href="#F4">Fig. 4</a>). However, some overlap was observed in our analyses, which suggests that the background mutation rate may be slightly inflating
        
        our estimate of the evolutionary rate. This is consistent with the short time scale over which the viruses in the present
        
        study were sampled and suggests that some of the variation observed between samples may be from deleterious mutations which
        
        are yet to reach fixation. To estimate the time of divergence of genogroups 5A and 5B, we used three different calculations
        
        of the substitution rate, the one derived here from all 23 samples (1.82 × 10<sup>−5</sup> substitutions per site per year), one derived just from genogroup 5B samples (5.91 × 10<sup>−5</sup> substitutions per site per year), and one obtained from a previous studies by Firth et al. (3.80 × 10<sup>−6</sup> substitutions per site per year [<a id="xref-ref-26-2" class="xref-bibr" href="#ref-26">26</a>]). The dates of divergence, estimated from all three rates, for genogroups 5A and 5B, as well as the Bandim 6 and Bandim
        
        13/14 lineages, are shown in <a id="xref-table-wrap-4-4" class="xref-table" href="#T4">Table 4</a> and <a id="xref-fig-5-1" class="xref-fig" href="#F5">Fig. 5</a>. </p>
      <p id="p-36">In all but three cases, which differed by a single repeat unit (either TA or GA), the OriS sequences obtained by Illumina
        
        sequencing matched those previously obtained by PCR and Sanger sequencing (<a id="xref-ref-3-6" class="xref-bibr" href="#ref-3">3</a>) (see Table S1 in the supplemental material). The OriS and R4 repeat regions were present as two identical copies in all
        
        viruses (i.e., did not differ within a single sample but could still differ between samples). The OriS is the only region
        
        for which recombination could be postulated with a single genogroup 5A virus (Bandim 18) having a genogroup 5B-like OriS repeat
        
        structure. We were also able to amplify and sequence (by Sanger methodology) four of the five VZV tandem repeat regions (R1,
        
        R2, R4, and R5). Insufficient DNA remained to amplify the R3 repeat region. The repeat structures of the R2, R4, R5, and OriS
        
        sequences were similar to published sequences (see Table S2 in the supplemental material). However, the Guinea-Bissau viruses
        
        possess a hexamer repeat motif, termed ε, present at the 3′ end of the R1 repeat which has previously only been observed in
        
        four other clade 5 viruses (<a id="xref-table-wrap-5-1" class="xref-table" href="#T5">Table 5</a>) and is currently considered to be unique to clade 5 viruses (<a id="xref-ref-9-1" class="xref-bibr" href="#ref-9">9</a>, <a id="xref-ref-28-1" class="xref-bibr" href="#ref-28">28</a>). The hexamer repeat motif encodes a single aspartic and glutamic acid that serves to increase protein acidity at the C-terminal
        
        coiled/helical (end) region of the clade 5 R1 repeat. </p>
      <p id="p-39">Two R5 alleles were observed that segregated completely by genotype and did not vary throughout the outbreak (<a id="xref-fig-5-2" class="xref-fig" href="#F5">Fig. 5</a>). Although the other repeat regions appeared more variable, some evidence of conservation within each lineage was evident
        
        for R1, R4, and OriS, although less so for R2. (<a id="xref-fig-3-3" class="xref-fig" href="#F3">Fig. 3</a>; see Table S2 in the supplemental material). OriS was the most variable, although two main alleles, segregating with 5A (8xTA/14xGA)
        
        and 5B (5xTA/9xGA), were evident. Of the 11 samples that differed from the consensus for their genogroup, five (Bandim 7,
        
        11, 13, 23, and 24) differed by a single dinucleotide, of which four (Bandim 7, 11, 23, and 24) were otherwise identical.
        
        A single dinucleotide difference in OriS can occur even when resequencing the same sample and so may be considered an artifact
        
        in most cases. The six cases (Bandim 6 and Bandim 14 to 18) that differed by more than one dinucleotide repeat from the genogroup
        
        consensus coincided with six of the seven viruses that also had changes in R1 structure (<a id="xref-fig-5-3" class="xref-fig" href="#F5">Fig. 5</a>). The remaining virus with changes in the R1 region had a single dinucleotide change in OriS (Bandim 13). </p>
      <p id="p-40">Together, these data are consistent with a pattern of lineage coevolution involving the R1 repeat region and the OriS (<a id="xref-fig-5-4" class="xref-fig" href="#F5">Fig. 5</a>; see Table S1 in the supplemental material). In contrast, the R4 repeat region, which is noncoding and segregated according
        
        to lineage, does not vary or associate with the evolution of new lineages. Variation in the R2 repeat region located in ORF14,
        
        which codes for glycoprotein C, was lineage independent. </p>
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      </div>
      <h2>DISCUSSION</h2>
      <p id="p-41">We report here the first whole-genome sequencing of freely circulating uncultured VZV from an outbreak of chickenpox. The
        
        outbreak began in Bissau, the capital of Guinea-Bissau, at the beginning of January 2001 and ended 23 weeks later at the end
        
        of June 2001. All of the viruses sequenced belong to clade 5, which is thought to be endemic in Africa and parts of Southeast
        
        Asia. However, at least three distinct sublineages of 5A, 5B, and Bandim 6 were circulating during the first month of the
        
        outbreak, suggesting multiple viral origins. This finding corroborates a previous study that identified multiple clades among
        
        viruses cocirculating in time and geographical location during a chickenpox outbreak in the United Kingdom (<a id="xref-ref-29-1" class="xref-bibr" href="#ref-29">29</a>). We conclude that the most parsimonious explanation for this finding is that exposure to infectious virus from many sources
        
        is common and thus not a rate-limiting step to epidemic spread. Rather, as we and others have previously shown, it is probably
        
        the availability of sufficient susceptible hosts together with environmental conditions such as school gatherings (<a id="xref-ref-3-7" class="xref-bibr" href="#ref-3">3</a>). In the United Kingdom and United States, primary cases are typically school-aged children who become infected at school,
        
        and secondary infections are their cohabitants at home (<a id="xref-ref-1-2" class="xref-bibr" href="#ref-1">1</a>, <a id="xref-ref-2-2" class="xref-bibr" href="#ref-2">2</a>). In Guinea-Bissau, the ages of primary and secondary cases do not differ, probably due to extensive mixing of preschool-aged
        
        children with older children both inside and outside the home (<a id="xref-ref-3-8" class="xref-bibr" href="#ref-3">3</a>). It was shown in the present study that the infectivity rate falls coincidentally with the school holidays and that mixing
        
        at school is an important facilitator of transmission. Primary infections caused by Bandim 6 and 17 are from patients of school
        
        age (12 and 10 years old, respectively), but those caused by Bandim 7 and 18 are not (representing 2- and 4-year-old patients,
        
        respectively). We therefore have insufficient data to conclusively state from our samples whether transmission facilitated
        
        by mixing at school is an important primary transmission route of infection into a household or not, and so the origin of
        
        the index viruses in this outbreak remains uncertain. The Bandim Health Project collects detailed epidemiological data about
        
        households, their inhabitants, their health, and recent travel. Questionnaires administered to households affected early in
        
        the outbreak failed to identify contact with herpes zoster or sporadic chickenpox, including cases imported from outside the
        
        area. Asymptomatic oral shedding of virus is well described (<a id="xref-ref-30-1" class="xref-bibr" href="#ref-30">30</a><a id="xref-ref-31-1" class="xref-bibr" href="#ref-31">–</a><a id="xref-ref-32-1" class="xref-bibr" href="#ref-32">32</a>) and, in the absence of evidence for contact with chickenpox or zoster, the possibility that orally shed live virus seeded
        
        this outbreak cannot be excluded. </p>
      <p id="p-42">Whole-genome sequencing confirmed VZV to be extremely stable during transmission (<a id="xref-ref-4-2" class="xref-bibr" href="#ref-4">4</a>, <a id="xref-ref-8-1" class="xref-bibr" href="#ref-8">8</a>, <a id="xref-ref-11-2" class="xref-bibr" href="#ref-11">11</a>); for example, 8 of the 14 genogroup 5A viruses (Bandim 4, 5, 7, 11, 19, 20, 21, and 22) were identical (barring one OriS
        
        dinucleotide repeat in Bandim 7 and 11) despite, in some cases, being recovered several months apart. A further three—Bandim
        
        12, 15, and 16—differed by only a single SNP from the consensus sequence for their genogroup. There was more variation in
        
        the 5B genogroup, where at least two subsidiary divergent lineages appear to have arisen, at least one of which (Bandim 6)
        
        diverged prior to this outbreak. The substitution rates calculated from all of the sequences, excluding the repeat regions,
        
        and from just the 5B lineage, respectively, 1.82 × 10<sup>−5</sup> and 5.91 × 10<sup>−5</sup> substitutions per site per year, are significantly higher than previous estimates based on codivergence of the host and the
        
        virus (3.9 × 10<sup>−9</sup> substitutions per site per year) (<a id="xref-ref-9-2" class="xref-bibr" href="#ref-9">9</a>) but only slightly higher than a previous estimate using heterochronous data (3.8 × 10<sup>−6</sup> substitutions per site per year) (<a id="xref-ref-26-4" class="xref-bibr" href="#ref-26">26</a>). Previous analyses using time-stamped data in a range of other viruses have all inferred rates higher than that estimated
        
        by codivergence (<a id="xref-ref-33-1" class="xref-bibr" href="#ref-33">33</a><a id="xref-ref-34-1" class="xref-bibr" href="#ref-34">–</a><a id="xref-ref-36-1" class="xref-bibr" href="#ref-36">36</a>). Although the short sampling time may have inflated the estimates of substitution rates by including mutations that may
        
        be deleterious and become fixed over longer sampling times, the data are consistent with theories of VZV evolution that place
        
        the clade diversification of VZV some 20,000 to 50,000 years ago (<a id="xref-ref-37-1" class="xref-bibr" href="#ref-37">37</a>) rather than with the migrations out of Africa (<a id="xref-ref-26-5" class="xref-bibr" href="#ref-26">26</a>). Based on the substitution rates derived here and those derived by Firth et al. (<a id="xref-ref-26-6" class="xref-bibr" href="#ref-26">26</a>), we estimate that genogroups 5A and 5B diverged between 2 and 31 years prior to the outbreak, whereas the Bandim 6 lineage
        
        arose at least 1 and 14 years previously (<a id="xref-table-wrap-3-4" class="xref-table" href="#T3">Tables 3</a> and <a id="xref-table-wrap-4-5" class="xref-table" href="#T4">4</a> and <a id="xref-fig-6-1" class="xref-fig" href="#F6">Fig. 6</a>). We originally hypothesized that the Bandim 13/14 viruses, which were sampled toward the end of June, might have arisen
        
        by accumulation of mutations in genogroup 5B during the outbreak. However, even the fastest estimates of VZV mutation rate
        
        placed the date of divergence Bandim 13/14 from 5B as prior to the current outbreak (<a id="xref-table-wrap-3-5" class="xref-table" href="#T3">Tables 3</a> and <a id="xref-table-wrap-4-6" class="xref-table" href="#T4">4</a> and <a id="xref-fig-6-2" class="xref-fig" href="#F6">Fig. 6</a>). Sequencing of greater numbers of viruses from the outbreak is now required to corroborate (or refute) this finding. In
        
        addition, further sequencing should provide greater support for the mutation rate estimated here. The observation that length
        
        polymorphism in the R1, R4, and OriS is not random but rather lineage specific points to the possible coevolution of the R1
        
        repeat region and the OriS (<a id="xref-fig-6-3" class="xref-fig" href="#F6">Fig. 6</a>). However, no functional link between these two regions has been identified either in VZV or related herpesviruses. R1, which
        
        is located at the N terminus of the ORF11 protein (ORF11p), is upstream of a region of the ORF11p that has been predicted, <em>in silico</em>, to bind RNA (<a id="xref-ref-38-1" class="xref-bibr" href="#ref-38">38</a><a id="xref-ref-39-1" class="xref-bibr" href="#ref-39">–</a><a id="xref-ref-40-1" class="xref-bibr" href="#ref-40">40</a>). The R1 motif itself is predicted to form a hydrophobic alpha helix, which also typically binds to nucleic acid. It is unlikely
        
        that R1 directly binds to the OriS, since ORF11p is not known to be part of the DNA replication complex. </p>
      <p id="p-44">The structure and sequences of the Guinea-Bissau clade 5 repeat regions R2 to R5 and OriS overlap the repeat sequences found
        
        in other clades (see Table S2 in the supplemental material). The exception is the R1 tandem repeat, the C-terminal end of
        
        which contains densely repeating aspartic acid and glutamic acid residues, making it more acidic and hydrophobic than the
        
        R1 repeats found in clades 1 to 4 (see Table S2 in the supplemental material). ORF11 is expressed as an immediate-early protein
        
        in keratinocytes (<a id="xref-ref-18-2" class="xref-bibr" href="#ref-18">18</a>) and has been shown to be essential for replication in the SCID-Hu mouse skin xenograft model. As with its herpes simplex
        
        virus 1 homologue (UL47), the loss of ORF11p is associated with diminished expression of immediate-early proteins (<a id="xref-ref-38-2" class="xref-bibr" href="#ref-38">38</a>, <a id="xref-ref-41-1" class="xref-bibr" href="#ref-41">41</a>, <a id="xref-ref-42-1" class="xref-bibr" href="#ref-42">42</a>). Since clade 5 viruses are endemic to Africa and Southeast Asia (<a id="xref-ref-5-2" class="xref-bibr" href="#ref-5">5</a>), it is possible that the differences seen in clade 5 R1 represent adaptation to the host populations in these geographical
        
        regions. Further work is therefore needed to determine whether the R1 structure observed here is also found in clade 5 viruses
        
        from these regions and to determine whether this structure has an evolutionary or functional significance. </p>
      <p id="p-45">In summary, whole-genome sequencing of VZV has enabled us, for the first time, to study the dynamics of VZV transmission and
        
        evolution during a localized outbreak in Guinea-Bissau in 2001. These data have allowed us to accurately measure VZV short-term
        
        substitution rates and observe that all clade 5 viruses sequenced to date have a unique R1 repeat structure that codes for
        
        a more hydrophobic and acidic N terminus in the ORF11p. Guinea-Bissau clade 5 sequences cluster separately from clade 5 sequences
        
        obtained from European and U.S. subjects, suggesting a different evolutionary history, although sequencing of more African
        
        strains is needed to confirm this observation. Although most VZV remains highly conserved during epidemic transmission, our
        
        data imply that changes occurring in the R1 and OriS are associated with the evolution of new viral lineages. </p>
    </div>
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            <li><a href="#fn-group-1">Footnotes</a></li>
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          </ul>
        </div>
      </div>
      <h2>ACKNOWLEDGMENTS</h2>
      <p id="p-48">We thank Julianne Lockwood (Great Ormond Street Hospital) for assistance in processing of the samples and Horacio Semedo,
        
        Carlos da Silva, and Fernando Cabral for collecting the Bandim patient samples and gathering information about transmission. </p>
      <p id="p-49" class="financial-disclosure">We acknowledge the infrastructure support provided the <span class="funding-source">MRC Centre for Molecular Medical Virology</span> grant <span class="award-id" id="award-id-1">G0900950</span>, the <span class="funding-source">NIHR UCL/UCLH Biomedical Research Centre</span>, and the use of the UCL Legion High Performance Computing Facility, and associated support services, in the completion of
        
        this research. This study was also supported by <span class="funding-source">MRC</span> grant <span class="award-id" id="award-id-2">G0700814</span>, an MRF New Investigator Award to D.P.D., and the <span class="award-id" id="award-id-3">NIHR UCL/UCLH Biomedical Research Centre</span> (S.K., E.R.G., and J.B.). </p>
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      <h2>FOOTNOTES</h2>
      <ul>
        <ul class="history-list">
          <li xmlns:hwp="http://schema.highwire.org/Journal" class="received" hwp:start="2014-08-14"><span class="received-label">Received </span>14 August 2014. </li>
          <li xmlns:hwp="http://schema.highwire.org/Journal" class="accepted" hwp:start="2014-09-19"><span class="accepted-label">Accepted </span>19 September 2014. </li>
        </ul>
        <li class="corresp" id="corresp-1">Address correspondence to Daniel P. Depledge, <a href="mailto:d.depledge@ucl.ac.uk">d.depledge@ucl.ac.uk</a>. </li>
        <li class="fn-present-address" id="fn-1">
          <p id="p-1"><a class="rev-xref" href="#xref-fn-1-1">↵</a><span class="fn-label">*</span> Present address: Eleanor R. Gray, London Centre for Nanotechnology, University College London, London, United Kingdom. </p>
        </li>
        <li class="fn-equal" id="fn-2">
          <p id="p-2">D.P.D. and E.R.G. contributed equally to this article.</p>
        </li>
        <li class="fn-other" id="fn-13">
          <p id="p-46"><strong>Published ahead of print</strong> 1 October 2014 </p>
        </li>
        <li class="fn-supplementary-material" id="fn-14">
          <p id="p-47">Supplemental material for this article may be found at <a href="http://dx.doi.org/10.1128/JVI.02337-14">http://dx.doi.org/10.1128/JVI.02337-14</a>. </p>
        </li>
      </ul>
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        </div>
      </div>
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      <li class="fn" id="copyright-statement-1">Copyright © 2014 Depledge et al.</li>
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