CpG-creating mutations are costly in many human viruses

Caudill, Victoria; Qin, Sarina; Winstead, Ryan; Kaur, Jasmeen; Tisthammer, Kaho H.; Pineda, E. Geo; Solis, Caroline; Cobey, Sarah; Bedford, Trevor; Carja, Oana; Eggo, Rosalind M; Koelle, Katia; Lythgoe, Katrina A.; Regoes, Roland R.; Roy, Scott William; Allen, Nicole; Aviles, Milo; Baker, Brittany A.; Bauer, William R.; Bermudez, Shannel; Carlson, Corey M.; Castellanos, Edgar; Catalan, Francisca; Chemel, Angeline Katia; Elliot, Jacob; Evans, Dwayne; Fiutek, Natalie; Fryer, Emily; Goodfellow, Samuel M; Hecht, Mordecai; Hopp, Kellen; Hopson, E. Deshawn; Jaberi, Amirhossein; Kinney, Christen; Lao, Derek; Le, Adrienne; Lo, Jacky; Lopez, Alejandro G.; López, Andrea; Lorenzo, Fernando G.; Luu, Gordon T; Mahoney, Andrew R.; Melton, Rebecca; Nascimento, Gabriela Do; Pradhananga, Anjani; Rodrigues, Nicole S.; Shieh, Annie W.; Sims, Jasmine; Singh, Rima; Sulaeman, Hasan; Thu, Ricky; Tran, Khanh Van; Tran, Livia; Winters, Elizabeth J.; Wong, Albert H.C.; Pennings, Pleuni S.

doi:10.1007/s10682-020-10039-z

Cited by 14 publications

(13 citation statements)

References 31 publications

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“…We also compared the consensus (majority nucleotide) sequences of all viral populations to gain further insights into the genetic variability between hosts. The overall sequence similarity (the average pairwise identity of consensus sequences) was relatively high (91.8%), and was within the range of the expected values (> 90% within a subtype) [17,29,30]. These results indicate that the number of sites excluded from the analysis was quite small, and the filtering step probably did not bias our results.…”

Section: Validation Of Our Frequency-based Approachsupporting

confidence: 67%

“…However, CpG-creating mutations and mutations that cause drastic amino acid changes, which have large effects on fitness costs in the HIV pol gene (∼50% reduction in mutation frequencies), showed markedly smaller effects in HCV, suggesting that the magnitude of these effects likely vary between viruses. Many RNA and DNA viruses display suppressed frequencies of CpG creating mutations, indicating that CpG creating mutations are costly to a variety of viruses [17], and the magnitude of such effects appear to vary greatly among viruses [16]. Here, we show an additional difference: Interestingly, in HCV, CpG creating mutations come with a modest cost, whereas they are much costlier in HIV.…”

Section: Discussionmentioning

confidence: 70%

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Assessingin vivomutation frequencies and creating a high-resolution genome-wide map of fitness costs of Hepatitis C virus

Tisthammer

Dong

Joy

et al. 2020

Preprint

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Studying in vivo fitness costs of mutations in viruses provides important insights into their evolutionary dynamics, which can help decipher how they adapt to host immune systems and develop drug resistance. However, studying fitness costs in natural populations is difficult, and is often conducted in vitro where evolutionary dynamics differ from in vivo. We aimed to understand in vivo fitness costs of mutations in Hepatitis C virus using next generation sequencing data. Hepatitis C virus is a positive-sense single-stranded RNA virus, and like many RNA viruses, has extremely high mutation and replication rates, making it ideal for studying mutational fitness costs. Using the ‘frequency-based approach’, we estimated genome-wide in vivo mutation frequencies at mutation-selection equilibrium, and inferred fitness costs (selection coefficients) at every genomic position using data from 195 patients. We applied a beta regression model to estimate the effects and the magnitudes of different factors on fitness costs. We generated a high-resolution genome-wide map of fitness costs in Hepatitis C virus for the first time. Our results revealed that costs of nonsynonymous mutations are three times higher than those of synonymous mutations, and mutations at nucleotides A/T have higher costs than those at C/G. Genome location had a modest effect, which is a clear contrast from previously reported in vitro findings, and highlights host immune selection. We inferred the strongest negative selection on the Core and NS5B proteins. We also found widespread natural prevalence of known drug resistance-associated variants in treatment naive patients, despite high fitness costs of these resistance sites. Our results indicate that in vivo evolutionary patterns and associated mutational costs are dynamic and can be virus specific, reinforcing the utility of constructing in vivo fitness cost maps of viral genomes.Author SummaryUnderstanding how viruses evolve within patients is important for combatting viral diseases, yet studying viruses within patients is difficult. Laboratory experiments are often used to understand the evolution of viruses, in place of assessing the evolution in natural populations (patients), but the dynamics will be different. In this study, we aimed to understand the within-patient evolution of Hepatitis C virus, which is an RNA virus that replicates and mutates extremely quickly, by taking advantage of high-throughput next generation sequencing. Here, we describe the evolutionary patterns of Hepatitis C virus from 195 patients: We analyzed mutation frequencies and estimated how costly each mutation was. We also assessed what factors made a mutation more costly, including the costs associated with drug resistance mutations. We were able to create a genome-wide fitness map of within-patient mutations in Hepatitis C virus which proves that, with technological advances, we can deepen our understanding of within-patient viral evolution, which can contribute to develop better treatments and vaccines.

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Section: Validation Of Our Frequency-based Approachsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 70%

Assessingin vivomutation frequencies and creating a high-resolution genome-wide map of fitness costs of Hepatitis C virus

Tisthammer

Dong

Joy

et al. 2020

Preprint

Self Cite

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“…In HCV, removal of CpG dinucleotides enhanced the replication of subtypes 1b and 2a in vitro [ 42 ]. Our study, therefore, confirms that CpG-creating mutations in HCV also come with a statistically significant, yet small fitness cost compared to other human viruses [ 41 ].…”

Section: Discussionsupporting

confidence: 83%

“…Throughout the genome, mutation frequencies were reduced by ≧50% for nonsynonymous mutations (as expected), and there was a small effect of whether mutations created CpG dinucleotides, which reduced mutation frequencies by 7.5–11.4% ( p -value = 4.6 × 10 −9 − 0.0002, Figure 6 , Table S3 ). CpG dinucleotides are underrepresented, and CpG-creating mutations are costly in many human viruses [ 39 , 40 , 41 ]. In HCV, removal of CpG dinucleotides enhanced the replication of subtypes 1b and 2a in vitro [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Comparative Analysis of Within-Host Mutation Patterns and Diversity of Hepatitis C Virus Subtypes 1a, 1b, and 3a

Tisthammer

Dong

Joy

et al. 2021

Viruses

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Understanding within-host evolution is critical for predicting viral evolutionary outcomes, yet such studies are currently lacking due to difficulty involving human subjects. Hepatitis C virus (HCV) is an RNA virus with high mutation rates. Its complex evolutionary dynamics and extensive genetic diversity are demonstrated in over 67 known subtypes. In this study, we analyzed within-host mutation frequency patterns of three HCV subtypes, using a large number of samples obtained from treatment-naïve participants by next-generation sequencing. We report that overall mutation frequency patterns are similar among subtypes, yet subtype 3a consistently had lower mutation frequencies and nucleotide diversity, while subtype 1a had the highest. We found that about 50% of genomic sites are highly conserved across subtypes, which are likely under strong purifying selection. We also compared within-host and between-host selective pressures, which revealed that Hyper Variable Region 1 within hosts was under positive selection, but was under slightly negative selection between hosts, which indicates that many mutations created within hosts are removed during the transmission bottleneck. Examining the natural prevalence of known resistance-associated variants showed their consistent existence in the treatment-naïve participants. These results provide insights into the differences and similarities among HCV subtypes that may be used to develop and improve HCV therapies.

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“…Strikingly, the deform rate of CG dinucleotides and formation of UU dinucleotides is extremely high. This phenomenon, which was observed in most human viruses (Caudill et al, 2020), was previously associated with the reduction of the hydrogen bonds between strands to achieve more efficient gene expression (Wang et al, 2020).…”

Section: Discussionmentioning

confidence: 93%

The mutation profile of SARS-CoV-2 is primarily shaped by the host antiviral defense

Azgari

Kilinc

Turhan

et al. 2021

Preprint

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Understanding SARS-CoV-2 evolution is a fundamental effort in coping with the COVID-19 pandemic. The virus genomes have been broadly evolving due to the high number of infected hosts world-wide. Mutagenesis and selection are the two inter-dependent mechanisms of virus diversification. However, which mechanisms contribute to the mutation profiles of SARS-CoV-2 remain under-explored. Here, we delineate the contribution of mutagenesis and selection to the genome diversity of SARS-CoV-2 isolates. We generated a comprehensive phylogenetic tree with representative genomes. Instead of counting mutations relative to the reference genome, we identified each mutation event at the nodes of the phylogenetic tree. With this approach, we obtained the mutation events that are independent of each other and generated the mutation profile of SARS-CoV-2 genomes. The results suggest that the heterogeneous mutation patterns are mainly reflections of host (i) antiviral mechanisms that are achieved through APOBEC, ADAR, and ZAP proteins and (ii) probable adaptation against reactive oxygen species.

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CpG-creating mutations are costly in many human viruses

Cited by 14 publications

References 31 publications

Assessingin vivomutation frequencies and creating a high-resolution genome-wide map of fitness costs of Hepatitis C virus

Assessingin vivomutation frequencies and creating a high-resolution genome-wide map of fitness costs of Hepatitis C virus

Comparative Analysis of Within-Host Mutation Patterns and Diversity of Hepatitis C Virus Subtypes 1a, 1b, and 3a

The mutation profile of SARS-CoV-2 is primarily shaped by the host antiviral defense

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