Mechanisms of viral mutation

Sanjuán R, Nebot MR, Chirico N, Mansky LM, Belshaw R (2010) Viral mutation rates. J Virol 84:9733–9748 Duffy S, Shackelton LA, Holmes EC (2008) Rates of evolutionary change in viruses: patterns and determinants. Nat Rev Genet 9:267–276 Sanjuán R (2012) From molecular genetics to phylodynamics: evolutionary relevance of mutation rates across viruses. PLoS Pathog 8:e1002685 Perelson AS (2002) Modelling viral and immune system dynamics. Nat Rev Immunol 2:28–36 Pawlotsky JM (2016) Hepatitis C virus resistance to direct-acting antiviral drugs in interferon-fee regimens. Gastroenterology 151:70–86 Cao Y, Bao Y, Xia W, Wu H, Wei F, Zhang Y, Zhang R, Xu X (2016) Resistance-associated mutations to HCV protease inhibitors naturally pre-existed in HIV/HCV coinfected, treatment-naive patients. Clin Res Hepatol Gastroenterol. doi:10.1016/j.clinre.2016.02.004 Coppola N, Onorato L, Minichini C, Di CG, Starace M, Sagnelli C, Sagnelli E (2015) Clinical significance of hepatitis B surface antigen mutants. World J Hepatol 7:2729–2739 Schotsaert M, García-Sastre A (2014) Influenza vaccines: a moving interdisciplinary field. Viruses 6:3809–3826 Roberts JD, Bebenek K, Kunkel TA (1988) The accuracy of reverse transcriptase from HIV-1. Science 242:1171–1173 Steinhauer DA, Domingo E, Holland JJ (1992) Lack of evidence for proofreading mechanisms associated with an RNA virus polymerase. Gene 122:281–288 Smith EC, Sexton NR, Denison MR (2014) Thinking outside the triangle: replication fidelity of the largest RNA viruses. Annu Rev Virol 1:111–132 Hong YB, Choi Y, Jung G (2004) Increased DNA polymerase fidelity of the Lamivudine resistant variants of human hepatitis B virus DNA polymerase. J Biochem Mol Biol 37:167–176 Menéndez-Arias L (2009) Mutation rates and intrinsic fidelity of retroviral reverse transcriptases. Viruses 1:1137–1165 Biek R, Pybus OG, Lloyd-Smith JO, Didelot X (2015) Measurably evolving pathogens in the genomic era. Trends Ecol Evol 30:306–313 Shackelton LA, Parrish CR, Truyen U, Holmes EC (2005) High rate of viral evolution associated with the emergence of carnivore parvovirus. Proc Natl Acad Sci USA 102:379–384 Shackelton LA, Holmes EC (2006) Phylogenetic evidence for the rapid evolution of human B19 erythrovirus. J Virol 80:3666–3669 Duffy S, Holmes EC (2008) Phylogenetic evidence for rapid rates of molecular evolution in the single-stranded DNA begomovirus tomato yellow leaf curl virus. J Virol 82:957–965 Sarker S, Patterson EI, Peters A, Baker GB, Forwood JK, Ghorashi SA, Holdsworth M, Baker R, Murray N, Raidal SR (2014) Mutability dynamics of an emergent single stranded DNA virus in a naive host. PLoS One 9:e85370 Michaud V, Randriamparany T, Albina E (2013) Comprehensive phylogenetic reconstructions of African swine fever virus: proposal for a new classification and molecular dating of the virus. PLoS One 8:e69662 Renzette N, Pokalyuk C, Gibson L, Bhattacharjee B, Schleiss MR, Hamprecht K, Yamamoto AY, Mussi-Pinhata MM, Britt WJ, Jensen JD, Kowalik TF (2015) Limits and patterns of cytomegalovirus genomic diversity in humans. Proc Natl Acad Sci USA 112:E4120–E4128 Seronello S, Montanez J, Presleigh K, Barlow M, Park SB, Choi J (2011) Ethanol and reactive species increase basal sequence heterogeneity of hepatitis C virus and produce variants with reduced susceptibility to antivirals. PLoS One 6:e27436 Jiricny J (2013) Postreplicative mismatch repair. Cold Spring Harb Perspect Biol 5:a012633 Cuevas JM, Duffy S, Sanjuán R (2009) Point mutation rate of bacteriophage ΦX174. Genetics 183:747–749 Deschavanne P, Radman M (1991) Counterselection of GATC sequences in enterobacteriophages by the components of the methyl-directed mismatch repair system. J Mol Evol 33:125–132 Luftig MA (2014) Viruses and the DNA damage response: activation and antagonism. Annu Rev Virol 1:605–625 Weitzman MD, Lilley CE, Chaurushiya MS (2010) Genomes in conflict: maintaining genome integrity during virus infection. Annu Rev Microbiol 64:61–81 Blackford AN, Patel RN, Forrester NA, Theil K, Groitl P, Stewart GS, Taylor AM, Morgan IM, Dobner T, Grand RJ, Turnell AS (2010) Adenovirus 12 E4orf6 inhibits ATR activation by promoting TOPBP1 degradation. Proc Natl Acad Sci USA 107:12251–12256 Lynch M (2010) Evolution of the mutation rate. Trends Genet 26:345–352 Bradwell K, Combe M, Domingo-Calap P, Sanjuán R (2013) Correlation between mutation rate and genome size in riboviruses: mutation rate of bacteriophage Qβ. Genetics 195:243–251 Dahl J, You J, Benjamin TL (2005) Induction and utilization of an ATM signaling pathway by polyomavirus. J Virol 79:13007–13017 Gillespie KA, Mehta KP, Laimins LA, Moody CA (2012) Human papillomaviruses recruit cellular DNA repair and homologous recombination factors to viral replication centers. J Virol 86:9520–9526 Luo Y, Qiu J (2013) Parvovirus infection-induced DNA damage response. Future Virol 8:245–257 Weiden MD, Ginsberg HS (1994) Deletion of the E4 region of the genome produces adenovirus DNA concatemers. Proc Natl Acad Sci USA 91:153–157 Ciccia A, Elledge SJ (2010) The DNA damage response: making it safe to play with knives. Mol Cell 40:179–204 Bordería AV, Rozen-Gagnon K, Vignuzzi M (2015) Fidelity variants and RNA quasispecies. Curr Top Microbiol Immunol 392:303–322 Pfeiffer JK, Kirkegaard K (2003) A single mutation in poliovirus RNA-dependent RNA polymerase confers resistance to mutagenic nucleotide analogs via increased fidelity. Proc Natl Acad Sci USA 100:7289–7294 Sadeghipour S, Bek EJ, McMinn PC (2013) Ribavirin-resistant mutants of human enterovirus 71 express a high replication fidelity phenotype during growth in cell culture. J Virol 87:1759–1769 Meng T, Kwang J (2014) Attenuation of human enterovirus 71 high-replication-fidelity variants in AG129 mice. J Virol 88:5803–5815 Levi LI, Gnadig NF, Beaucourt S, McPherson MJ, Baron B, Arnold JJ, Vignuzzi M (2010) Fidelity variants of RNA dependent RNA polymerases uncover an indirect, mutagenic activity of amiloride compounds. PLoS Pathog 6:e1001163 Coffey LL, Beeharry Y, Bordería AV, Blanc H, Vignuzzi M (2011) Arbovirus high fidelity variant loses fitness in mosquitoes and mice. Proc Natl Acad Sci USA 108:16038–16043 Cheung PP, Watson SJ, Choy KT, Fun SS, Wong DD, Poon LL, Kellam P, Guan Y, Malik Peiris JS, Yen HL (2014) Generation and characterization of influenza A viruses with altered polymerase fidelity. Nat Commun 5:4794 Van Slyke GA, Arnold JJ, Lugo AJ, Griesemer SB, Moustafa IM, Kramer LD, Cameron CE, Ciota AT (2015) Sequence-specific fidelity alterations associated with West Nile virus attenuation in mosquitoes. PLoS Pathog 11:e1005009 Gong P, Peersen OB (2010) Structural basis for active site closure by the poliovirus RNA-dependent RNA polymerase. Proc Natl Acad Sci USA 107:22505–22510 Korneeva VS, Cameron CE (2007) Structure-function relationships of the viral RNA-dependent RNA polymerase: fidelity, replication speed, and initiation mechanism determined by a residue in the ribose-binding pocket. J Biol Chem 282:16135–16145 Arnold JJ, Vignuzzi M, Stone JK, Andino R, Cameron CE (2005) Remote site control of an active site fidelity checkpoint in a viral RNA-dependent RNA polymerase. J Biol Chem 280:25706–25716 Stapleford KA, Rozen-Gagnon K, Das PK, Saul S, Poirier EZ, Blanc H, Vidalain PO, Merits A, Vignuzzi M (2015) Viral polymerase-helicase complexes regulate replication fidelity to overcome intracellular nucleotide depletion. J Virol 89:11233–11244 Mansky LM, Cunningham KS (2000) Virus mutators and antimutators: roles in evolution, pathogenesis and emergence. Trends Genet 16:512–517 Mufti S (1979) Mutator effects of alleles of phage T4 genes 32, 41, 44, and 45 in the presence of an antimutator polymerase. Virology 94:1–9 Hwang YT, Liu BY, Coen DM, Hwang CB (1997) Effects of mutations in the Exo III motif of the herpes simplex virus DNA polymerase gene on enzyme activities, viral replication, and replication fidelity. J Virol 71:7791–7798 Tian W, Hwang YT, Lu Q, Hwang CB (2009) Finger domain mutation affects enzyme activity, DNA replication efficiency, and fidelity of an exonuclease-deficient DNA polymerase of herpes simplex virus type 1. J Virol 83:7194–7201 Smith EC, Blanc H, Vignuzzi M, Denison MR (2013) Coronaviruses lacking exoribonuclease activity are susceptible to lethal mutagenesis: evidence for proofreading and potential therapeutics. PLoS Pathog 9:e1003565 Andino R, Domingo E (2015) Viral quasispecies. Virology 479–480C:46–51 Harris RS, Dudley JP (2015) APOBECs and virus restriction. Virology 479–480C:131–145 Munk C, Willemsen A, Bravo IG (2012) An ancient history of gene duplications, fusions and losses in the evolution of APOBEC3 mutators in mammals. BMC Evol Biol 12:71 Harris RS, Bishop KN, Sheehy AM, Craig HM, Petersen-Mahrt SK, Watt IN, Neuberger MS, Malim MH (2003) DNA deamination mediates innate immunity to retroviral infection. Cell 113:803–809 Lecossier D, Bouchonnet F, Clavel F, Hance AJ (2003) Hypermutation of HIV-1 DNA in the absence of the Vif protein. Science 300:1112 Mangeat B, Turelli P, Caron G, Friedli M, Perrin L, Trono D (2003) Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts. Nature 424:99–103 Desimmie BA, Delviks-Frankenberrry KA, Burdick RC, Qi D, Izumi T, Pathak VK (2014) Multiple APOBEC3 restriction factors for HIV-1 and one Vif to rule them all. J Mol Biol 426:1220–1245 Suspène R, Guetard D, Henry M, Sommer P, Wain-Hobson S, Vartanian JP (2005) Extensive editing of both hepatitis B virus DNA strands by APOBEC3 cytidine deaminases in vitro and in vivo. Proc Natl Acad Sci USA 102:8321–8326 Vartanian JP, Guétard D, Henry M, Wain-Hobson S (2008) Evidence for editing of human papillomavirus DNA by APOBEC3 in benign and precancerous lesions. Science 320:230–233 Suspène R, Aynaud MM, Koch S, Pasdeloup D, Labetoulle M, Gaertner B, Vartanian JP, Meyerhans A, Wain-Hobson S (2011) Genetic editing of herpes simplex virus 1 and Epstein-Barr herpesvirus genomes by human APOBEC3 cytidine deaminases in culture and in vivo. J Virol 85:7594–7602 Holtz CM, Sadler HA, Mansky LM (2013) APOBEC3G cytosine deamination hotspots are defined by both sequence context and single-stranded DNA secondary structure. Nucleic Acids Res 41:6139–6148 Cuevas JM, Geller R, Garijo R, López-Aldeguer J, Sanjuán R (2015) Extremely high mutation rate of HIV-1 in vivo. PLoS Biol 13:e1002251 Monajemi M, Woodworth CF, Zipperlen K, Gallant M, Grant MD, Larijani M (2014) Positioning of APOBEC3G/F mutational hotspots in the human immunodeficiency virus genome favors reduced recognition by CD8 + T cells. PLoS One 9:e93428 Sadler HA, Stenglein MD, Harris RS, Mansky LM (2010) APOBEC3G contributes to HIV-1 variation through sublethal mutagenesis. J Virol 84:7396–7404 Fourati S, Malet I, Lambert S, Soulie C, Wirden M, Flandre P, Fofana DB, Sayon S, Simon A, Katlama C, Calvez V, Marcelin AG (2012) E138K and M184I mutations in HIV-1 reverse transcriptase coemerge as a result of APOBEC3 editing in the absence of drug exposure. AIDS 26:1619–1624 Tomaselli S, Galeano F, Locatelli F, Gallo A (2015) ADARs and the balance game between virus infection and innate immune cell response. Curr Issues Mol Biol 17:37–51 Kuttan A, Bass BL (2012) Mechanistic insights into editing-site specificity of ADARs. Proc Natl Acad Sci USA 109:E3295–E3304 Cattaneo R, Schmid A, Eschle D, Baczko K, ter Meulen V, Billeter MA (1988) Biased hypermutation and other genetic changes in defective measles viruses in human brain infections. Cell 55:255–265 Murphy DG, Dimock K, Kang CY (1991) Numerous transitions in human parainfluenza virus 3 RNA recovered from persistently infected cells. Virology 181:760–763 Martínez I, Melero JA (2002) A model for the generation of multiple A to G transitions in the human respiratory syncytial virus genome: predicted RNA secondary structures as substrates for adenosine deaminases that act on RNA. J Gen Virol 83:1445–1455 Zahn RC, Schelp I, Utermohlen O, von Laer D (2007) A-to-G hypermutation in the genome of lymphocytic choriomeningitis virus. J Virol 81:457–464 Suspène R, Renard M, Henry M, Guetard D, Puyraimond-Zemmour D, Billecocq A, Bouloy M, Tangy F, Vartanian JP, Wain-Hobson S (2008) Inversing the natural hydrogen bonding rule to selectively amplify GC-rich ADAR-edited RNAs. Nucleic Acids Res 36:e72 Cuevas JM, Combe M, Torres-Puente M, Garijo R, Guix S, Buesa J, Rodríguez-Díaz J, Sanjuán R (2016) Human norovirus hyper-mutation revealed by ultra-deep sequencing. Infect Genet Evol 41:233–239 Chen R, Le RE, Kearney JA, Mansky LM, Benichou S (2004) Vpr-mediated incorporation of UNG2 into HIV-1 particles is required to modulate the virus mutation rate and for replication in macrophages. J Biol Chem 279:28419–28425 Mansky LM, Preveral S, Selig L, Benarous R, Benichou S (2000) The interaction of vpr with uracil DNA glycosylase modulates the human immunodeficiency virus type 1 in vivo mutation rate. J Virol 74:7039–7047 Diamond TL, Roshal M, Jamburuthugoda VK, Reynolds HM, Merriam AR, Lee KY, Balakrishnan M, Bambara RA, Planelles V, Dewhurst S, Kim B (2004) Macrophage tropism of HIV-1 depends on efficient cellular dNTP utilization by reverse transcriptase. J Biol Chem 279:51545–51553 Holtz CM, Mansky LM (2013) Variation of HIV-1 mutation spectra among cell types. J Virol 87:5296–5299 Sardanyés J, Solé RV, Elena SF (2009) Replication mode and landscape topology differentially affect RNA virus mutational load and robustness. J Virol 83:12579–12589 Sardanyés J, Elena SF (2011) Quasispecies spatial models for RNA viruses with different replication modes and infection strategies. PLoS One 6:e24884 Thébaud G, Chadoeuf J, Morelli MJ, McCauley JW, Haydon DT (2010) The relationship between mutation frequency and replication strategy in positive-sense single-stranded RNA viruses. Proc Biol Sci 277:809–817 Chao L, Rang CU, Wong LE (2002) Distribution of spontaneous mutants and inferences about the replication mode of the RNA bacteriophage ϕ6. J Virol 76:3276–3281 Garcia-Villada L, Drake JW (2012) The three faces of riboviral spontaneous mutation: spectrum, mode of genome replication, and mutation rate. PLoS Genet 8:e1002832 Martínez F, Sardanyés J, Elena SF, Daròs JA (2011) Dynamics of a plant RNA virus intracellular accumulation: stamping machine vs. geometric replication. Genetics 188:637–646 Schulte MB, Draghi JA, Plotkin JB, Andino R (2015) Experimentally guided models reveal replication principles that shape the mutation distribution of RNA viruses. Elife 4. doi:10.7554/eLife.03753 Combe M, Garijo R, Geller R, Cuevas JM, Sanjuán R (2015) Single-cell analysis of RNA virus infection identifies multiple genetically diverse viral genomes within single infectious units. Cell Host Microbe 18:424–432 Gillam S, Astell CR, Jahnke P, Hutchison CA III, Smith M (1984) Construction and properties of a ribosome-binding site mutation in gene E of ϕX174 bacteriophage. J Virol 52:892–896 Hutchison CA III, Sinsheimer RL (1966) The process of infection with bacteriophage ϕX174. X. Mutations in a ϕX lysis gene. J Mol Biol 18:429–447 Bull JJ, Pfennig DW, Wang IN (2004) Genetic details, optimization and phage life histories. Trends Ecol Evol 19:76–82 Chantranupong L, Heineman RH (2012) A common, non-optimal phenotypic endpoint in experimental adaptations of bacteriophage lysis time. BMC Evol Biol 12:37 Heineman RH, Bull JJ (2007) Testing optimality with experimental evolution: lysis time in a bacteriophage. Evolution 61:1695–1709 Domingo-Calap P, Pereira-Gómez M, Sanjuán R (2012) Nucleoside analogue mutagenesis of a single-stranded DNA virus: evolution and resistance. J Virol 86:9640–9646 Pereira-Gómez M, Sanjuán R (2014) Delayed lysis confers resistance to the nucleoside analogue 5-fluorouracil and alleviates mutation accumulation in the single-stranded DNA bacteriophage ϕX174. J Virol 88:5042–5049 Kunkel TA (1985) The mutational specificity of DNA polymerase-beta during in vitro DNA synthesis. Production of frameshift, base substitution, and deletion mutations. J Biol Chem 260:5787–5796 Yamanaka R, Termini J (2007) Nucleotide sequence context influences HIV replication fidelity by modulating reverse transcriptase binding and product release. Biosci Trends 1:52–61 Pathak VK, Temin HM (1992) 5-Azacytidine and RNA secondary structure increase the retrovirus mutation rate. J Virol 66:3093–3100 Galetto R, Moumen A, Giacomoni V, Veron M, Charneau P, Negroni M (2004) The structure of HIV-1 genomic RNA in the gp120 gene determines a recombination hot spot in vivo. J Biol Chem 279:36625–36632 Simon-Loriere E, Galetto R, Hamoudi M, Archer J, Lefeuvre P, Martin DP, Robertson DL, Negroni M (2009) Molecular mechanisms of recombination restriction in the envelope gene of the human immunodeficiency virus. PLoS Pathog 5:e1000418 Geller R, Domingo-Calap P, Cuevas JM, Rossolillo P, Negroni M, Sanjuán R (2015) The external domains of the HIV-1 envelope are a mutational cold spot. Nat Commun 6:8571 Rawson JM, Landman SR, Reilly CS, Bonnac L, Patterson SE, Mansky LM (2015) Lack of mutational hotspots during decitabine-mediated HIV-1 mutagenesis. Antimicrob Agents Chemother 59:6834–6843 Armitage AE, Katzourakis A, de Oliveira T, Welch JJ, Belshaw R, Bishop KN, Kramer B, McMichael AJ, Rambaut A, Iversen AK (2008) Conserved footprints of APOBEC3G on Hypermutated human immunodeficiency virus type 1 and human endogenous retrovirus HERV-K(HML2) sequences. J Virol 82:8743–8761 Kijak GH, Janini LM, Tovanabutra S, Sanders-Buell E, Arroyo MA, Robb ML, Michael NL, Birx DL, McCutchan FE (2008) Variable contexts and levels of hypermutation in HIV-1 proviral genomes recovered from primary peripheral blood mononuclear cells. Virology 376:101–111 Watts JM, Dang KK, Gorelick RJ, Leonard CW, Bess JW Jr, Swanstrom R, Burch CL, Weeks KM (2009) Architecture and secondary structure of an entire HIV-1 RNA genome. Nature 460:711–716 Giguère T, Adkar-Purushothama CR, Perreault JP (2014) Comprehensive secondary structure elucidation of four genera of the family Pospiviroidae. PLoS One 9:e98655 Geller R, Estrada U, Peris JB, Andreu I, Bou J-V, Garijo R, Cuevas JM, Sabariegos R, Mas A, Sanjuán R (2016) Highly heterogeneous mutation rates in the hepatitis C virus genome. Nat Microbiol 1:16045 Kwong PD, Mascola JR, Nabel GJ (2013) Broadly neutralizing antibodies and the search for an HIV-1 vaccine: the end of the beginning. Nat Rev Immunol 13:693–701 Bankwitz D, Steinmann E, Bitzegeio J, Ciesek S, Friesland M, Herrmann E, Zeisel MB, Baumert TF, Keck ZY, Foung SK, Pecheur EI, Pietschmann T (2010) Hepatitis C virus hypervariable region 1 modulates receptor interactions, conceals the CD81 binding site, and protects conserved neutralizing epitopes. J Virol 84:5751–5763 Elde NC, Child SJ, Eickbush MT, Kitzman JO, Rogers KS, Shendure J, Geballe AP, Malik HS (2012) Poxviruses deploy genomic accordions to adapt rapidly against host antiviral defenses. Cell 150:831–841 Bikard D, Marraffini LA (2012) Innate and adaptive immunity in bacteria: mechanisms of programmed genetic variation to fight bacteriophages. Curr Opin Immunol 24:15–20 Guo H, Arambula D, Ghosh P, Miller JF (2014) Diversity-generating retroelements in phage and bacterial genomes. Microbiol Spectr 2:10–2014 Liu M, Deora R, Doulatov SR, Gingery M, Eiserling FA, Preston A, Maskell DJ, Simons RW, Cotter PA, Parkhill J, Miller JF (2002) Reverse transcriptase-mediated tropism switching in Bordetella bacteriophage. Science 295:2091–2094 Medhekar B, Miller JF (2007) Diversity-generating retroelements. Curr Opin Microbiol 10:388–395 Minot S, Grunberg S, Wu GD, Lewis JD, Bushman FD (2012) Hypervariable loci in the human gut virome. Proc Natl Acad Sci USA 109:3962–3966 Arambula D, Wong W, Medhekar BA, Guo H, Gingery M, Czornyj E, Liu M, Dey S, Ghosh P, Miller JF (2013) Surface display of a massively variable lipoprotein by a Legionella diversity-generating retroelement. Proc Natl Acad Sci USA 110:8212–8217 Doulatov S, Hodes A, Dai L, Mandhana N, Liu M, Deora R, Simons RW, Zimmerly S, Miller JF (2004) Tropism switching in Bordetella bacteriophage defines a family of diversity-generating retroelements. Nature 431:476–481 Paul BG, Bagby SC, Czornyj E, Arambula D, Handa S, Sczyrba A, Ghosh P, Miller JF, Valentine DL (2015) Targeted diversity generation by intraterrestrial archaea and archaeal viruses. Nat Commun 6:6585 Baroudy BM, Moss B (1982) Sequence homologies of diverse length tandem repetitions near ends of vaccinia virus genome suggest unequal crossing over. Nucleic Acids Res 10:5673–5679 Moss B, Winters E, Cooper N (1981) Instability and reiteration of DNA sequences within the vaccinia virus genome. Proc Natl Acad Sci USA 78:1614–1618 Munir M, Berg M (2013) The multiple faces of proteinkinase R in antiviral defense. Virulence 4:85–89 Elde NC, Child SJ, Geballe AP, Malik HS (2009) Protein kinase R reveals an evolutionary model for defeating viral mimicry. Nature 457:485–489 Rothenburg S, Seo EJ, Gibbs JS, Dever TE, Dittmar K (2009) Rapid evolution of protein kinase PKR alters sensitivity to viral inhibitors. Nat Struct Mol Biol 16:63–70 Kerr PJ, Hone J, Perrin L, French N, Williams CK (2010) Molecular and serological analysis of the epidemiology of myxoma virus in rabbits. Vet Microbiol 143:167–178 Pérez-Losada M, Arenas M, Galán JC, Palero F, González-Candelas F (2015) Recombination in viruses: mechanisms, methods of study, and evolutionary consequences. Infect Genet Evol 30:296–307 Tromas N, Zwart MP, Poulain M, Elena SF (2014) Estimation of the in vivo recombination rate for a plant RNA virus. J Gen Virol 95:724–732 Gerrish PJ, Lenski RE (1998) The fate of competing beneficial mutations in an asexual population. Genetica 102–103:127–144 Xiao Y, Rouzine IM, Bianco S, Acevedo A, Goldstein EF, Farkov M, Brodsky L, Andino R (2016) RNA recombination enhances adaptability and is required for virus spread and virulence. Cell Host Microbe 19:493–503 Poirier EZ, Mounce BC, Rozen-Gagnon K, Hooikaas PJ, Stapleford KA, Moratorio G, Vignuzzi M (2015) Low-fidelity polymerases of alphaviruses recombine at higher rates to overproduce defective interfering particles. J Virol 90:2446–2454 Malpica JM, Fraile A, Moreno I, Obies CI, Drake JW, García-Arenal F (2002) The rate and character of spontaneous mutation in an RNA virus. Genetics 162:1505–1511 Wang W, Lee WM, Mosser AG, Rueckert RR (1998) WIN 52035-dependent human rhinovirus 16: assembly deficiency caused by mutations near the canyon surface. J Virol 72:1210–1218 Heinz BA, Rueckert RR, Shepard DA, Dutko FJ, McKinlay MA, Fancher M, Rossmann MG, Badger J, Smith TJ (1989) Genetic and molecular analyses of spontaneous mutants of human rhinovirus 14 that are resistant to an antiviral compound. J Virol 63:2476–2485 de la Torre JC, Giachetti C, Semler BL, Holland JJ (1992) High frequency of single-base transitions and extreme frequency of precise multiple-base reversion mutations in poliovirus. Proc Natl Acad Sci USA 89:2531–2535 Drake JW, Holland JJ (1999) Mutation rates among RNA viruses. Proc Natl Acad Sci USA 96:13910–13913 de la Torre JC, Wimmer E, Holland JJ (1990) Very high frequency of reversion to guanidine resistance in clonal pools of guanidine-dependent type 1 poliovirus. J Virol 64:664–671 Vignuzzi M, Stone JK, Arnold JJ, Cameron CE, Andino R (2006) Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population. Nature 439:344–348 Sanjuán R, Agudelo-Romero P, Elena SF (2009) Upper-limit mutation rate estimation for a plant RNA virus. Biol Lett 5:394–396 Tromas N, Elena SF (2010) The rate and spectrum of spontaneous mutations in a plant RNA virus. Genetics 185:983–989 Cuevas JM, González-Candelas F, Moya A, Sanjuán R (2009) The effect of ribavirin on the mutation rate and spectrum of hepatitis C virus in vivo. J Virol 83:5760–5764 Ribeiro RM, Li H, Wang S, Stoddard MB, Learn GH, Korber BT, Bhattacharya T, Guedj J, Parrish EH, Hahn BH, Shaw GM, Perelson AS (2012) Quantifying the diversification of hepatitis C virus (HCV) during primary infection: estimates of the in vivo mutation rate. PLoS Pathog 8:e1002881 Eckerle LD, Lu X, Sperry SM, Choi L, Denison MR (2007) High fidelity of murine hepatitis virus replication is decreased in nsp14 exoribonuclease mutants. J Virol 81:12135–12144 Holland JJ, de la Torre JC, Steinhauer DA, Clarke DK, Duarte EA, Domingo E (1989) Virus mutation frequencies can be greatly underestimated by monoclonal antibody neutralization of virions. J Virol 63:5030–5036 Drake JW (1993) Rates of spontaneous mutation among RNA viruses. Proc Natl Acad Sci USA 90:4171–4175 Furió V, Moya A, Sanjuán R (2005) The cost of replication fidelity in an RNA virus. Proc Natl Acad Sci USA 102:10233–10237 Combe M, Sanjuán R (2014) Variation in RNA virus mutation rates across host cells. PLoS Pathog 10:e1003855 Parvin JD, Moscona A, Pan WT, Leider JM, Palese P (1986) Measurement of the mutation rates of animal viruses: influenza A virus and poliovirus type 1. J Virol 59:377–383 Nobusawa E, Sato K (2006) Comparison of the mutation rates of human influenza A and B viruses. J Virol 80:3675–3678 Stech J, Xiong X, Scholtissek C, Webster RG (1999) Independence of evolutionary and mutational rates after transmission of avian influenza viruses to swine. J Virol 73:1878–1884 Wong KK, Bull RA, Rockman S, Scott G, Stelzer-Braid S, Rawlinson W (2011) Correlation of polymerase replication fidelity with genetic evolution of influenza A/Fujian/411/02(H3N2) viruses. J Med Virol 83:510–516 Zhang X, Rennick LJ, Duprex WP, Rima BK (2013) Determination of spontaneous mutation frequencies in measles virus under nonselective conditions. J Virol 87:2686–2692 Schrag SJ, Rota PA, Bellini WJ (1999) Spontaneous mutation rate of measles virus: direct estimation based on mutations conferring monoclonal antibody resistance. J Virol 73:51–54 Pult I, Abbott N, Zhang YY, Summers J (2001) Frequency of spontaneous mutations in an avian hepdnavirus infection. J Virol 75:9623–9632 Pathak VK, Temin HM (1990) Broad spectrum of in vivo forward mutations, hypermutations, and mutational hotspots in a retroviral shuttle vector after a single replication cycle: substitutions, frameshifts, and hypermutations. Proc Natl Acad Sci USA 87:6019–6023 Dougherty JP, Temin HM (1988) Determination of the rate of base-pair substitution and insertion mutations in retrovirus replication. J Virol 62:2817–2822 Varela-Echavarría A, Garvey N, Preston BD, Dougherty JP (1992) Comparison of Moloney murine leukemia virus mutation rate with the fidelity of its reverse transcriptase in vitro. J Biol Chem 267:24681–24688 Monk RJ, Malik FG, Stokesberry D, Evans LH (1992) Direct determination of the point mutation rate of a murine retrovirus. J Virol 66:3683–3689 Parthasarathi S, Varela-Echavarría A, Ron Y, Preston BD, Dougherty JP (1995) Genetic rearrangements occurring during a single cycle of murine leukemia virus vector replication: characterization and implications. J Virol 69:7991–8000 Drake JW, Charlesworth B, Charlesworth D, Crow JF (1998) Rates of spontaneous mutation. Genetics 148:1667–1686 Mansky LM, Temin HM (1994) Lower mutation rate of bovine leukemia virus relative to that of spleen necrosis virus. J Virol 68:494–499 Mansky LM (2000) In vivo analysis of human T-cell leukemia virus type 1 reverse transcription accuracy. J Virol 74:9525–9531 Mansky LM, Temin HM (1995) Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J Virol 69:5087–5094 Mansky LM, Bernard LC (2000) 3′-Azido-3′-deoxythymidine (AZT) and AZT-resistant reverse transcriptase can increase the in vivo mutation rate of human immunodeficiency virus type 1. J Virol 74:9532–9539 Gao F, Chen Y, Levy DN, Conway JA, Kepler TB, Hui H (2004) Unselected mutations in the human immunodeficiency virus type 1 genome are mostly nonsynonymous and often deleterious. J Virol 78:2426–2433 Huang KJ, Wooley DP (2005) A new cell-based assay for measuring the forward mutation rate of HIV-1. J Virol Methods 124:95–104 Abram ME, Ferris AL, Shao W, Alvord WG, Hughes SH (2010) Nature, position, and frequency of mutations made in a single cycle of HIV-1 replication. J Virol 84:9864–9878 Gartner K, Wiktorowicz T, Park J, Mergia A, Rethwilm A, Scheller C (2009) Accuracy estimation of foamy virus genome copying. Retrovirology 6:32 Leider JM, Palese P, Smith FI (1988) Determination of the mutation rate of a retrovirus. J Virol 62:3084–3091 Raney JL, Delongchamp RR, Valentine CR (2004) Spontaneous mutant frequency and mutation spectrum for gene A of ϕX174 grown in E. coli. Environ Mol Mutagen 44:119–127 Drake JW (1991) A constant rate of spontaneous mutation in DNA-based microbes. Proc Natl Acad Sci USA 88:7160–7164 Dove WF (1968) The genetic of the lambdoid phages. Annu Rev Genet 2:305–340 Lu Q, Hwang YT, Hwang CB (2002) Mutation spectra of herpes simplex virus type 1 thymidine kinase mutants. J Virol 76:5822–5828 Drake JW, Hwang CB (2005) On the mutation rate of herpes simplex virus type 1. Genetics 170:969–970 Luria SE (1951) The frequency distribution of spontaneous bacteriophage mutants as evidence for the exponential rate of phage reproduction. Cold Spring Harb Symp Quant Biol 16:463–470