scholarly journals Drivers of within-host genetic diversity in acute infections of viruses

2020 ◽  
Vol 16 (11) ◽  
pp. e1009029 ◽  
Author(s):  
Maoz Gelbart ◽  
Sheri Harari ◽  
Ya’ara Ben-Ari ◽  
Talia Kustin ◽  
Dana Wolf ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Viral Infection ◽  
Deep Sequencing ◽  
Low Frequency ◽  
Clinical Samples ◽  
Early Stages ◽  
Acute Infections ◽  
Host Genetic ◽  
Virus Genomes ◽  
Defective Virus

Genetic diversity is the fuel of evolution and facilitates adaptation to novel environments. However, our understanding of what drives differences in the genetic diversity during the early stages of viral infection is somewhat limited. Here, we use ultra-deep sequencing to interrogate 43 clinical samples taken from early infections of the human-infecting viruses HIV, RSV and CMV. Hundreds to thousands of virus templates were sequenced per sample, allowing us to reveal dramatic differences in within-host genetic diversity among virus populations. We found that increased diversity was mostly driven by presence of multiple divergent genotypes in HIV and CMV samples, which we suggest reflect multiple transmitted/founder viruses. Conversely, we detected an abundance of low frequency hyper-edited genomes in RSV samples, presumably reflecting defective virus genomes (DVGs). We suggest that RSV is characterized by higher levels of cellular co-infection, which allow for complementation and hence elevated levels of DVGs.

scholarly journals Accurate in vivo population sequencing uncovers drivers of within-host genetic diversity in viruses

2018 ◽  
Author(s):  
Maoz Gelbart ◽  
Sheri Harari ◽  
Ya’ara Ben-Ari ◽  
Talia Kustin ◽  
Dana Wolf ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Rare Variants ◽  
Single Point ◽  
Error Rates ◽  
Clinical Samples ◽  
Nonsense Mutations ◽  
Viral Loads ◽  
Host Genetic ◽  
Virus Genomes

ABSTRACTMutations fuel evolution and facilitate adaptation to novel environments. However, characterizing the spectrum of mutations in a population is obscured by high error rates of next generation sequencing. Here, we present AccuNGS, a novel in vivo sequencing approach that detects variants as rare as 1:10,000. Applying it to 46 clinical samples taken from early infections of the human-infecting viruses HIV, RSV and CMV, revealed large differences in within-host genetic diversity among virus populations. Haplotype reconstruction revealed that increased diversity was mostly driven by multiple transmitted/founder viruses in HIV and CMV samples. Conversely, we detected an abundance of defective virus genomes (DVGs) in RSV samples, including hyper-edited genomes, nonsense mutations and single point deletions. Higher proportions of DVGs correlated with increased viral loads, suggesting increased cellular co-infection rates, which enable DVG persistence. AccuNGS establishes a general platform that allows detecting DVGs, and in general, rare variants that drive evolution.

scholarly journals Deep Sequencing Reveals Potential Antigenic Variants at Low Frequencies in Influenza A Virus-Infected Humans

2016 ◽  
Vol 90 (7) ◽  
pp. 3355-3365 ◽  
Author(s):  
Jorge M. Dinis ◽  
Nicholas W. Florek ◽  
Omolayo O. Fatola ◽  
Louise H. Moncla ◽  
James P. Mutschler ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Influenza Virus ◽  
Deep Sequencing ◽  
Influenza A ◽  
Rapid Evolution ◽  
Low Frequency ◽  
Influenza Viruses ◽  
Influenza Vaccines ◽  
Host Genetic ◽  
Antigenic Evolution

ABSTRACTInfluenza vaccines must be frequently reformulated to account for antigenic changes in the viral envelope protein, hemagglutinin (HA). The rapid evolution of influenza virus under immune pressure is likely enhanced by the virus's genetic diversity within a host, although antigenic change has rarely been investigated on the level of individual infected humans. We used deep sequencing to characterize the between- and within-host genetic diversity of influenza viruses in a cohort of patients that included individuals who were vaccinated and then infected in the same season. We characterized influenza HA segments from the predominant circulating influenza A subtypes during the 2012-2013 (H3N2) and 2013-2014 (pandemic H1N1; H1N1pdm) flu seasons. We found that HA consensus sequences were similar in nonvaccinated and vaccinated subjects. In both groups, purifying selection was the dominant force shaping HA genetic diversity. Interestingly, viruses from multiple individuals harbored low-frequency mutations encoding amino acid substitutions in HA antigenic sites at or near the receptor-binding domain. These mutations included two substitutions in H1N1pdm viruses, G158K and N159K, which were recently found to confer escape from virus-specific antibodies. These findings raise the possibility that influenza antigenic diversity can be generated within individual human hosts but may not become fixed in the viral population even when they would be expected to have a strong fitness advantage. Understanding constraints on influenza antigenic evolution within individual hosts may elucidate potential future pathways of antigenic evolution at the population level.IMPORTANCEInfluenza vaccines must be frequently reformulated due to the virus's rapid evolution rate. We know that influenza viruses exist within each infected host as a “swarm” of genetically distinct viruses, but the role of this within-host diversity in the antigenic evolution of influenza has been unclear. We characterized here the genetic and potential antigenic diversity of influenza viruses infecting humans, some of whom became infected despite recent vaccination. Influenza virus between- and within-host genetic diversity was not significantly different in nonvaccinated and vaccinated humans, suggesting that vaccine-induced immunity does not exert strong selective pressure on viruses replicating in individual people. We found low-frequency mutations, below the detection threshold of traditional surveillance methods, in nonvaccinated and vaccinated humans that were recently associated with antibody escape. Interestingly, these potential antigenic variants did not reach fixation in infected people, suggesting that other evolutionary factors may be hindering their emergence in individual humans.

scholarly journals Within-Host Variations of Human Papillomavirus Reveal APOBEC Signature Mutagenesis in the Viral Genome

2018 ◽  
Vol 92 (12) ◽  
pp. e00017-18 ◽  
Author(s):  
Yusuke Hirose ◽  
Mamiko Onuki ◽  
Yuri Tenjimbayashi ◽  
Seiichiro Mori ◽  
Yoshiyuki Ishii ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Cervical Cancer ◽  
Deep Sequencing ◽  
Viral Genome ◽  
Reference Sequence ◽  
Characteristic Change ◽  
Whole Genome ◽  
Cervical Carcinogenesis ◽  
Genome Sequences ◽  
Host Genetic

ABSTRACTPersistent infection with oncogenic human papillomaviruses (HPVs) causes cervical cancer, accompanied by the accumulation of somatic mutations into the host genome. There are concomitant genetic changes in the HPV genome during viral infection; however, their relevance to cervical carcinogenesis is poorly understood. Here, we explored within-host genetic diversity of HPV by performing deep-sequencing analyses of viral whole-genome sequences in clinical specimens. The whole genomes of HPV types 16, 52, and 58 were amplified by type-specific PCR from total cellular DNA of cervical exfoliated cells collected from patients with cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC) and were deep sequenced. After constructing a reference viral genome sequence for each specimen, nucleotide positions showing changes with >0.5% frequencies compared to the reference sequence were determined for individual samples. In total, 1,052 positions of nucleotide variations were detected in HPV genomes from 151 samples (CIN1,n= 56; CIN2/3,n= 68; ICC,n= 27), with various numbers per sample. Overall, C-to-T and C-to-A substitutions were the dominant changes observed across all histological grades. While C-to-T transitions were predominantly detected in CIN1, their prevalence was decreased in CIN2/3 and fell below that of C-to-A transversions in ICC. Analysis of the trinucleotide context encompassing substituted bases revealed that TpCpN, a preferred target sequence for cellular APOBEC cytosine deaminases, was a primary site for C-to-T substitutions in the HPV genome. These results strongly imply that the APOBEC proteins are drivers of HPV genome mutation, particularly in CIN1 lesions.IMPORTANCEHPVs exhibit surprisingly high levels of genetic diversity, including a large repertoire of minor genomic variants in each viral genotype. Here, by conducting deep-sequencing analyses, we show for the first time a comprehensive snapshot of the within-host genetic diversity of high-risk HPVs during cervical carcinogenesis. Quasispecies harboring minor nucleotide variations in viral whole-genome sequences were extensively observed across different grades of CIN and cervical cancer. Among the within-host variations, C-to-T transitions, a characteristic change mediated by cellular APOBEC cytosine deaminases, were predominantly detected throughout the whole viral genome, most strikingly in low-grade CIN lesions. The results strongly suggest that within-host variations of the HPV genome are primarily generated through the interaction with host cell DNA-editing enzymes and that such within-host variability is an evolutionary source of the genetic diversity of HPVs.

scholarly journals Dynamics of Human Immunodeficiency Virus-1 Genetic Diversification During Acute Infection

2020 ◽  
Vol 7 (10) ◽  
Author(s):  
Hongshuo Song ◽  
Meera Bose ◽  
Suteeraporn Pinyakorn ◽  
Eric Sanders-Buell ◽  
Anne Marie O’Sullivan ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Human Immunodeficiency Virus ◽  
Acute Infection ◽  
Viral Dynamics ◽  
Virus Envelope ◽  
Acute Infections ◽  
Human Immunodeficiency Virus Envelope ◽  
Immunodeficiency Virus ◽  
Host Genetic ◽  
Human Immunodeficiency Virus 1

Abstract We analyzed human immunodeficiency virus envelope diversity in 98 acute infections. The within-host genetic diversity, divergence from transmitted/founder (T/F) strain, and the observed frequency of multiple T/F infections increased with Fiebig stage. These data identify rapid viral dynamics during acute infection with implications for clinical trials conducted in this setting.

scholarly journals Reconciling disparate estimates of viral genetic diversity during human influenza infections

2018 ◽  
Author(s):  
Katherine S. Xue ◽  
Jesse D. Bloom
Keyword(s):  
Genetic Diversity ◽  
Hong Kong ◽  
Deep Sequencing ◽  
Large Scale ◽  
Viral Diversity ◽  
Human Influenza ◽  
Sequencing Data ◽  
Viral Genetic Diversity ◽  
Host Genetic ◽  
Low Levels

AbstractDeep sequencing can measure viral genetic diversity within human influenza infections, but published studies disagree in their estimates of how much genetic diversity is typically present. One large-scale deep-sequencing study of human influenza reported high levels of shared viral genetic diversity among infected individuals in Hong Kong, but subsequent studies of other cohorts have reported little shared viral diversity. We re-analyze sequencing data from four studies of within-host genetic diversity encompassing more than 500 acute human influenza infections. We identify an anomaly in the Hong Kong data that provides a technical explanation for these discrepancies: read pairs from this study are often split between different biological samples, indicating that some reads are incorrectly assigned. These technical abnormalities explain the high levels of within-host variation and loose transmission bottlenecks reported by this study. Studies without these anomalies consistently report low levels of genetic diversity in acute human influenza infections.

scholarly journals Direct whole-genome deep-sequencing of human respiratory syncytial virus A and B from Vietnamese children identifies distinct patterns of inter- and intra-host evolution

2015 ◽  
Vol 96 (12) ◽  
pp. 3470-3483 ◽  
Author(s):  
Lien Anh Ha Do ◽  
Andreas Wilm ◽  
H. Rogier van Doorn ◽  
Ha Minh Lam ◽  
Shuzhen Sim ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Respiratory Syncytial Virus ◽  
Deep Sequencing ◽  
Human Respiratory Syncytial Virus ◽  
Whole Genome ◽  
M Gene ◽  
Upper Airways ◽  
Host Genetic ◽  
Syncytial Virus ◽  
Tract Infections

Human respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in children < 2 years of age. Little is known about RSV intra-host genetic diversity over the course of infection or about the immune pressures that drive RSV molecular evolution. We performed whole-genome deep-sequencing on 53 RSV-positive samples (37 RSV subgroup A and 16 RSV subgroup B) collected from the upper airways of hospitalized children in southern Vietnam over two consecutive seasons. RSV A NA1 and RSV B BA9 were the predominant genotypes found in our samples, consistent with other reports on global RSV circulation during the same period. For both RSV A and B, the M gene was the most conserved, confirming its potential as a target for novel therapeutics. The G gene was the most variable and was the only gene under detectable positive selection. Further, positively selected sites in G were found in close proximity to and in some cases overlapped with predicted glycosylation motifs, suggesting that selection on amino acid glycosylation may drive viral genetic diversity. We further identified hotspots and coldspots of intra-host genetic diversity in the RSV genome, some of which may highlight previously unknown regions of functional importance.

scholarly journals Dynamics of apomictic and sexual reproduction during primary succession on a glacier forefield in the Swiss Alps

2019 ◽  
Author(s):  
Christian Sailer ◽  
Jürg Stöcklin ◽  
Ueli Grossniklaus
Keyword(s):  
Genetic Diversity ◽  
Gene Flow ◽  
Primary Succession ◽  
Swiss Alps ◽  
Reproductive Assurance ◽  
Glacier Forefield ◽  
Early Stages ◽  
Hieracium Pilosella ◽  
Baker’S Law ◽  
Successional Stages

AbstractApomixis, the asexual reproduction through seeds, is thought to provide reproductive assurance when ploidy is not even and/or when population density is low. Therefore, apomicts are expected to be more abundant, and the frequency of apomictic offspring higher, at early stages of primary succession when mates are rare.To test this hypothesis, we sampled facultative apomictic Hieracium pilosella L. along the successional gradient on a glacier forefield and determined their ploidy, the level of apomixis in their offspring, and the genetic diversity of the entire meta-population and within subpopulations.We found that apomixis is more common in odd- and aneuploid cytotypes, which are more frequent at early stages of primary succession. However, apomixis was uncommon at all successional stages and sexual hexaploids were dominating throughout. Reproductive assurance was reflected in the higher fertility of all odd-ploid apomictic plants (3x, 5x) by avoiding meiosis, illustrating that apomixis provides an escape from sterility, as proposed by Darlington. Odd-ploid plants are supposedly better colonizers (Baker’s law), which is supported by their higher occurrence close to the glacier snout. Independent of succession, we found gene flow between apomicts and sexuals, which allows for the continuous creation of new apomictic and sexual genotypes.We conclude that apomixis in H. pilosella does indeed provide an escape from sterility, and therefore reproductive assurance, in aneuploid cytotypes. We further propose that apomixis preserves beneficial combinations of unlinked alleles in every generation for as long as apomictic genotypes persist in the population.

scholarly journals Genetic diversity of Collaborative Cross mice controls viral replication, clinical severity and brain pathology induced by Zika virus infection, independently of Oas1b

2019 ◽  
Author(s):  
Caroline Manet ◽  
Etienne Simon-Lorière ◽  
Grégory Jouvion ◽  
David Hardy ◽  
Matthieu Prot ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Viral Load ◽  
Viral Replication ◽  
Clinical Severity ◽  
Brain Pathology ◽  
Zikv Infection ◽  
Infected Cells ◽  
Host Genetic ◽  
Host Genes

ABSTRACTThe explosive spread of Zika virus (ZIKV) has been associated with major variations in severe disease and congenital afflictions among infected populations, suggesting an influence of host genes. We investigated how genome-wide variants could impact susceptibility to ZIKV infection in mice. We first describe that the susceptibility of Ifnar1 knockout mice is largely influenced by their genetic background. We then show that the broad genetic diversity of Collaborative Cross mice, which receptor to type I interferon (IFNAR) was blocked by anti-IFNAR antibody, expressed phenotypes ranging from complete resistance to severe symptoms and death with large variations in the peak and rate of decrease of plasma viral load, in brain viral load, in brain histopathology and in viral replication rate in infected cells. Differences of susceptibility between CC strains were correlated between Zika, Dengue and West Nile viruses. We identified highly susceptible and resistant mouse strains as new models to investigate the mechanisms of human ZIKV disease and other flavivirus infections. Genetic analyses revealed that phenotypic variations are driven by multiple genes with small effects, reflecting the complexity of ZIKV disease susceptibility in human population. Notably, our results rule out a role of the Oas1b gene in the susceptibility to ZIKV. Altogether, this study emphasizes the role of host genes in the pathogeny of ZIKV infection and lays the foundation for further genetic and mechanistic studies.IMPORTANCEIn recent outbreaks, ZIKV has infected millions of people and induced rare but potentially severe complications, including Guillain-Barré syndrome and encephalitis in adults. While several viral sequence variants were proposed to enhance the pathogenicity of ZIKV, the influence of host genetic variants in the clinical heterogeneity remains mostly unexplored. We have addressed this question using a mouse panel which models the genetic diversity of human population and a ZIKV strain from a recent clinical isolate. Through a combination of in vitro and in vivo approaches, we demonstrate that multiple host genetic variants determine viral replication in infected cells, and clinical severity, kinetics of blood viral load and brain pathology in mice. We describe new mouse models expressing high susceptibility or resistance to ZIKV and to other flaviviruses. These models will facilitate the identification and mechanistic characterization of host genes that influence ZIKV pathogenesis.

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