On the relative roles of background selection and genetic hitchhiking in shaping human cytomegalovirus genetic diversity

Renzette, Nicholas; Kowalik, Timothy F.; Jensen, Jeffrey D.

doi:10.1111/mec.13331

Cited by 34 publications

(41 citation statements)

References 72 publications

(135 reference statements)

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“…All of these factors, except the distribution of fitness effects, have been studied and inferred in HCMV intrahost populations (10)(11)(12). The DFE characterizing HCMV intrahost populations is inferred here using two methods.…”

Section: Resultsmentioning

confidence: 99%

“…The parameters included the mean effective population size (N e ), as well as mutation and recombination rates. Further, four additional sets of simulations were performed, following previous reports suggesting that background selection and demography alter the patterns of polymorphism of in vivo HCMV populations (10). These simulations are identified as strong constraint, demography, demography/strong constraint, and demography/strong and weak constraint.…”

Section: Resultsmentioning

confidence: 99%

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On the Analysis of Intrahost and Interhost Viral Populations: Human Cytomegalovirus as a Case Study of Pitfalls and Expectations

Renzette

Pfeifer

Matuszewski

et al. 2017

J Virol

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Intrahost and interhost assessments of viral diversity are often treated as measures of separate and distinct evolutionary processes, with numerous investigations reporting seemingly incompatible results between the two. For example, in human cytomegalovirus, the nucleotide diversity estimates are 10-fold higher for interhost data, while the number of segregating (i.e., polymorphic) sites is 6-fold lower. These results have been interpreted as demonstrating that sampled intrahost variants are strongly deleterious. In reality, however, these observations are fully consistent with standard population genetic expectations. Here, we analyze published intra-and interhost data sets within this framework, utilizing statistical inference tools to quantify the fitness effects of segregating mutations. Further, we utilize population level simulations to clarify expectations under common evolutionary models. Contrary to common claims in the literature, these results suggest that most observed polymorphisms are likely nearly neutral with regard to fitness and that standard population genetic models in fact well predict observed levels of both intra-and interhost variability.IMPORTANCE With the increasing number of evolutionary virology studies examining both intrahost and interhost patterns of genomic variation, a number of seemingly incompatible results have emerged, revolving around the far greater level of observed intrahost than interhost variation. This has led many authors to suggest that the great majority of sampled within-host polymorphisms are strongly deleterious. Here, we demonstrate that there is in fact no incompatibility of these results and, indeed, that the vast majority of sampled within-host variation is likely neutral. These results thus represent a major shift in the current view of observed viral variation.KEYWORDS human cytomegalovirus, interhost diversity, intrahost diversity, population genetics T he majority of evolutionary studies in the virus literature are divided into those examining intrahost data and those examining interhost data. Broadly speaking, intrahost studies deeply sample viral diversity from a limited number of biological samples (e.g., plasma, urine, or saliva), while interhost studies sample viral diversity from a large number of hosts, but with a shallow perspective of variation within each host. These studies are often treated as separate analyses of viral diversity. For example, studies of intrahost human cytomegalovirus (HCMV) populations report per-site nucleotide diversity values of ϳ0.002, with approximately 160,000 segregating (i.e., polymorphic) sites in the ϳ235,000-bp genome, while analyses of interhost data report

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

On the Analysis of Intrahost and Interhost Viral Populations: Human Cytomegalovirus as a Case Study of Pitfalls and Expectations

Renzette

Pfeifer

Matuszewski

et al. 2017

J Virol

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“…This could be indicative of mixed viral populations or changes in polymerase fidelity (24,22). As in congenital HCMV infections (25,28,30), these data suggested that patients experiencing neonatal infection with HSV-2 may harbor mixed or diverse viral populations that are distinct from those observed in adult infections. These minor genotypes may be selected or genetically isolated in particular niches (e.g.…”

Section: Discussionmentioning

confidence: 87%

“…Each isolate was cultured once as part of the diagnostic process with expansion only for the experiments shown here. Although this is a relatively small group of samples due to the constraints discussed previously, it is the largest group of neonatal HSV samples ever compared genotypically or phenotypically, and is similar in size to prior studies of HCMV-infected neonates (25)(26)(27)(28)(29)(30).…”

Section: Neonatal Hsv-2 Samples Represent a Diverse Clinical Populationmentioning

confidence: 82%

“…http://dx.doi.org/10.1101/262055 doi: bioRxiv preprint first posted online Feb. 8, 2018; therapy (23,24). In HTSeq studies of congenital infections by the beta-herpesvirus human cytomegalovirus (HCMV), Renzette et al found evidence for heterogeneous viral populations both within and between hosts (25)(26)(27)(28)(29)(30), which far exceeded the levels of diversity observed in adult HCMV infections (31)(32)(33). Examination of vaccine-associated rashes for varicella zoster virus (VZV; an alpha-herpesvirus) has demonstrated that adult skin vesicles contained a subset of the viral population introduced during vaccination, and found at least 11 VZV genomic loci that were linked to rash formation (34).…”

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confidence: 99%

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Genotypic and phenotypic diversity within the neonatal HSV-2 population

Akhtar

Bowen

Renner

et al. 2018

Preprint

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Neonates infected with herpes simplex virus (HSV) at the time of birth can have different courses of clinical disease. Approximately half of those infected display manifestations limited to the skin, eyes, or mouth (SEM disease, 45%). However, others develop invasive infections that spread systemically (disseminated, 25%) or to the central nervous system (CNS, 30%); both of which are associated with significant morbidity and mortality. The viral and/or host factors that predispose a neonate to these invasive forms of HSV infection are not known. To define the level of viral diversity within the neonatal population we evaluated ten HSV-2 isolates cultured from neonates with a range of clinical presentations. To assess viral fitness independent of host immune factors, we measured viral growth characteristics of each isolate in cultured cells. We found that HSV-2 isolates displayed diverse in vitro phenotypes. Isolates from neonates with CNS disease were associated with larger average plaque size and enhanced spread through culture, with isolates derived directly from the cerebrospinal fluid (CSF) exhibiting the most robust growth characteristics. We then sequenced the complete viral genomes of all ten neonatal HSV-2 isolates, providing the first insights into HSV genomic diversity in this clinical setting.We found extensive inter-host variation between isolates distributed throughout the HSV-2

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Disentangling Types of Linked Selection Using Patterns of Nucleotide Variation in Drosophila pseudoobscura

Korunes

Samuk

Noor

2021

Population Genomics

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On the relative roles of background selection and genetic hitchhiking in shaping human cytomegalovirus genetic diversity

Cited by 34 publications

References 72 publications

On the Analysis of Intrahost and Interhost Viral Populations: Human Cytomegalovirus as a Case Study of Pitfalls and Expectations

On the Analysis of Intrahost and Interhost Viral Populations: Human Cytomegalovirus as a Case Study of Pitfalls and Expectations

Genotypic and phenotypic diversity within the neonatal HSV-2 population

Disentangling Types of Linked Selection Using Patterns of Nucleotide Variation in Drosophila pseudoobscura

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