. Earlier, Amedee Maratier Institute for the Study of Blindness and Visual Disorders; I-CORE Program of the Planning and Budgeting Committee The Israel Science Foundation [41/11]; The Israeli Ministry of Defense, Office of Assistant Minister of Defense for Chemical, Biological, Radiological and Nuclear (CBRN) Defense; Foundation Fighting Blindness; Saban Family Foundation, Melanoma Research Alliance ICRF Acceleration Grant; Israel Cancer Association (ICA); Donation from the Kateznik K. Association Holocaust; Margot Stoltz Foundation through the Faculty of Medicine grants of Tel-Aviv University; The Varda and Boaz Dotan Research Center in Hemato-Oncology, Idea Grant. M. Vignuzzi and H. Blanc are supported in part by the ERC Starting [242719]. A.B. was supported by the ANR-09-JCJC-0118. O. Isakov and D. Golan are supported in part by the Colton Family Foundation. Conflict of Interest: none declared

A. Acevedo, Mutational and fitness landscapes of an RNA virus revealed through population sequencing, Nature, vol.20, issue.7485, 2013.
DOI : 10.1038/nature12861

P. Ahlquist, RNA-Dependent RNA Polymerases, Viruses, and RNA Silencing, Science, vol.296, issue.5571, pp.1270-1273, 2002.
DOI : 10.1126/science.1069132

J. Archer, Analysis of high-depth sequence data for studying viral diversity: a comparison of next generation sequencing platforms using Segminator II., BMC Bioinformatics, vol.13, issue.1, p.47, 2012.
DOI : 10.1186/1471-2105-13-47

J. Archer, Use of Four Next-Generation Sequencing Platforms to Determine HIV-1 Coreceptor Tropism, PLoS ONE, vol.28, issue.11, p.49602, 2012.
DOI : 10.1371/journal.pone.0049602.t002

A. Bankevich, SPAdes: A New Genome Assembly Algorithm and Its Applications to Single-Cell Sequencing, Journal of Computational Biology, vol.19, issue.5, pp.455-477, 2012.
DOI : 10.1089/cmb.2012.0021

L. Barzon, Applications of Next-Generation Sequencing Technologies to Diagnostic Virology, International Journal of Molecular Sciences, vol.12, issue.12, pp.7861-7884, 2011.
DOI : 10.3390/ijms12117861

N. Beerenwinkel and O. Zagordi, Ultra-deep sequencing for the analysis of viral populations, Current Opinion in Virology, vol.1, issue.5, pp.413-418, 2011.
DOI : 10.1016/j.coviro.2011.07.008

J. J. Bull, Theory of Lethal Mutagenesis for Viruses, Journal of Virology, vol.81, issue.6, pp.2930-2939, 2007.
DOI : 10.1128/JVI.01624-06

R. A. Bull, Sequential Bottlenecks Drive Viral Evolution in Early Acute Hepatitis C Virus Infection, PLoS Pathogens, vol.7, issue.9, p.1002243, 2011.
DOI : 10.1371/journal.ppat.1002243.s012

M. R. Capobianchi, Next-generation sequencing technology in clinical virology, Clinical Microbiology and Infection, vol.19, issue.1, pp.15-22, 2013.
DOI : 10.1111/1469-0691.12056

S. D. Carson, Variations of Coxsackievirus B3 Capsid Primary Structure, Ligands, and Stability Are Selected for in a Coxsackievirus and Adenovirus Receptor-Limited Environment, Journal of Virology, vol.85, issue.7, pp.3306-3314, 2011.
DOI : 10.1128/JVI.01827-10

S. D. Carson, Purification of the Putative Coxsackievirus B Receptor from HeLa Cells, Biochemical and Biophysical Research Communications, vol.233, issue.2, pp.325-328, 1997.
DOI : 10.1006/bbrc.1997.6449

L. L. Coffey, Arbovirus high fidelity variant loses fitness in mosquitoes and mice, Proc. Natl Acad. Sci. USA, pp.16038-16043, 2011.
DOI : 10.1073/pnas.1111650108

URL : https://hal.archives-ouvertes.fr/pasteur-00620624

L. L. Coffey, Arbovirus evolution in vivo is constrained by host alternation, Proc. Natl Acad. Sci. USA, pp.6970-6975, 2008.
DOI : 10.1073/pnas.0712130105

L. L. Coffey and M. Vignuzzi, Host Alternation of Chikungunya Virus Increases Fitness while Restricting Population Diversity and Adaptability to Novel Selective Pressures, Journal of Virology, vol.85, issue.2, pp.1025-1035, 2011.
DOI : 10.1128/JVI.01918-10

URL : https://hal.archives-ouvertes.fr/pasteur-00546712

S. Crotty and R. Andino, Implications of high RNA virus mutation rates: lethal mutagenesis and the antiviral drug ribavirin, Microbes and Infection, vol.4, issue.13, pp.1301-1307, 2002.
DOI : 10.1016/S1286-4579(02)00008-4

S. Crotty, RNA virus error catastrophe: Direct molecular test by using ribavirin, Proc. Natl Acad. Sci. USA, 98, pp.6895-6900, 2001.
DOI : 10.1073/pnas.111085598

S. Crotty, The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen, Nat. Med, vol.6, pp.1375-1379, 2000.

E. Delwart, A Roadmap to the Human Virome, PLoS Pathogens, vol.106, issue.5, p.1003146, 2013.
DOI : 10.1371/journal.ppat.1003146.g001

X. Didelot, Transforming clinical microbiology with bacterial genome sequencing, Nature Reviews Genetics, vol.156, issue.9, pp.601-612, 2012.
DOI : 10.1093/bioinformatics/btp097

G. Dusheiko, Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study, Journal of Hepatology, vol.25, issue.5, pp.591-598, 1996.
DOI : 10.1016/S0168-8278(96)80225-X

N. Eriksson, Viral Population Estimation Using Pyrosequencing, PLoS Computational Biology, vol.25, issue.5, 2008.
DOI : 10.1371/journal.pcbi.1000074.s004

A. Escobar-gutiérrez, Identification of Hepatitis C Virus Transmission Using a Next-Generation Sequencing Approach, Journal of Clinical Microbiology, vol.50, issue.4, pp.1461-1463, 2012.
DOI : 10.1128/JCM.00005-12

P. Flaherty, Ultrasensitive detection of rare mutations using next-generation targeted resequencing, Nucleic Acids Research, vol.40, issue.1, p.2, 2012.
DOI : 10.1093/nar/gkr861

V. Foulongne, Human Skin Microbiota: High Diversity of DNA Viruses Identified on the Human Skin by High Throughput Sequencing, PLoS ONE, vol.7, issue.5, p.38499, 2012.
DOI : 10.1371/journal.pone.0038499.s001

E. Ghedin, Presence of Oseltamivir-Resistant Pandemic A/H1N1 Minor Variants Before Drug Therapy With Subsequent Selection and Transmission, Journal of Infectious Diseases, vol.206, issue.10, pp.1504-1511, 2012.
DOI : 10.1093/infdis/jis571

N. F. Gnä-dig, Coxsackievirus B3 mutator strains are attenuated in vivo, Proc. Natl Acad. Sci. USA, pp.2294-2303, 2012.

J. D. Graci and C. E. Cameron, Therapeutically targeting RNA viruses via lethal mutagenesis, Future Virology, vol.3, issue.6, pp.553-566, 2008.
DOI : 10.2217/17460794.3.6.553

Y. H. Grad, Within-Host Whole-Genome Deep Sequencing and Diversity Analysis of Human Respiratory Syncytial Virus Infection Reveals Dynamics of Genomic Diversity in the Absence and Presence of Immune Pressure, Journal of Virology, vol.88, issue.13, pp.7286-7293, 2014.
DOI : 10.1128/JVI.00038-14

R. L. Graham, A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease, Nature Medicine, vol.110, issue.12, pp.1820-1826, 2012.
DOI : 10.1073/pnas.0808116105

A. Grande-pérez, Molecular indetermination in the transition to error catastrophe: Systematic elimination of lymphocytic choriomeningitis virus through mutagenesis does not correlate linearly with large increases in mutant spectrum complexity, Proc. Natl Acad. Sci. USA, pp.12938-12943, 2002.
DOI : 10.1073/pnas.182426999

Y. Guo, The effect of strand bias in Illumina short-read sequencing data, BMC Genomics, vol.13, issue.1, p.666, 2012.
DOI : 10.1101/gr.129684.111

B. L. Hurwitz and M. B. Sullivan, The Pacific Ocean Virome (POV): A Marine Viral Metagenomic Dataset and Associated Protein Clusters for Quantitative Viral Ecology, PLoS ONE, vol.3, issue.2, p.57355, 2013.
DOI : 10.1371/journal.pone.0057355.s003

C. B. Jabara, Accurate sampling and deep sequencing of the HIV-1 protease gene using a Primer ID, Proc. Natl Acad. Sci. USA, pp.20166-20171, 2011.
DOI : 10.1073/pnas.1110064108

I. Kinde, Detection and quantification of rare mutations with massively parallel sequencing, Proc. Natl Acad. Sci. USA, pp.9530-9535, 2011.
DOI : 10.1073/pnas.1105422108

A. L. Kistler, Genome-wide diversity and selective pressure in the human rhinovirus, Virology Journal, vol.4, issue.1, p.40, 2007.
DOI : 10.1186/1743-422X-4-40

A. S. Lauring and R. Andino, Quasispecies Theory and the Behavior of RNA Viruses, PLoS Pathogens, vol.7, issue.7, p.1001005, 2010.
DOI : 10.1371/journal.ppat.1001005.g004

L. I. Levi, Fidelity Variants of RNA Dependent RNA Polymerases Uncover an Indirect, Mutagenic Activity of Amiloride Compounds, PLoS Pathogens, vol.104, issue.Pt 1, p.1001163, 2010.
DOI : 10.1371/journal.ppat.1001163.s004

URL : https://hal.archives-ouvertes.fr/pasteur-00530598

H. Li and R. Durbin, Fast and accurate short read alignment with Burrows-Wheeler transform, Bioinformatics, vol.25, issue.14, pp.1754-1760, 2009.
DOI : 10.1093/bioinformatics/btp324

H. Li, The Sequence Alignment/Map format and SAMtools, Bioinformatics, vol.25, issue.16, pp.2078-2079, 2009.
DOI : 10.1093/bioinformatics/btp352

T. M. Love, Mathematical Modeling of Ultradeep Sequencing Data Reveals that Acute CD8+ T-Lymphocyte Responses Exert Strong Selective Pressure in Simian Immunodeficiency Virus-Infected Macaques but Still Fail To Clear Founder Epitope Sequences, Journal of Virology, vol.84, issue.11, pp.5802-5814, 2010.
DOI : 10.1128/JVI.00117-10

A. R. Macalalad, Highly Sensitive and Specific Detection of Rare Variants in Mixed Viral Populations from Massively Parallel Sequence Data, PLoS Computational Biology, vol.407, issue.3, p.1002417, 2012.
DOI : 10.1371/journal.pcbi.1002417.s002

S. Mangul, Accurate viral population assembly from ultra-deep sequencing data, Bioinformatics, vol.30, issue.12, pp.329-337, 2014.
DOI : 10.1093/bioinformatics/btu295

F. Martínez, Ultradeep Sequencing Analysis of Population Dynamics of Virus Escape Mutants in RNAi-Mediated Resistant Plants, Molecular Biology and Evolution, vol.29, issue.11, pp.3297-3307, 2012.
DOI : 10.1093/molbev/mss135

K. Mcelroy, Accurate single nucleotide variant detection in viral populations by combining probabilistic clustering with a statistical test of strand bias, BMC Genomics, vol.14, issue.1, p.501, 2013.
DOI : 10.1093/bioinformatics/btp698

I. Ná-jera, Pol gene quasispecies of human immunodeficiency virus: mutations associated with drug resistance in virus from patients undergoing no drug therapy, J. Virol, vol.69, pp.23-31, 1995.

A. D. Radford, Application of next-generation sequencing technologies in virology, Journal of General Virology, vol.93, issue.Pt_9, pp.1853-1868, 2012.
DOI : 10.1099/vir.0.043182-0

S. Roux, Assessing the Diversity and Specificity of Two Freshwater Viral Communities through Metagenomics, PLoS ONE, vol.23, issue.1, p.33641, 2012.
DOI : 10.1371/journal.pone.0033641.s009

URL : https://hal.archives-ouvertes.fr/hal-00819334

R. Sanjuá-n, Viral Mutation Rates, Journal of Virology, vol.84, issue.19, pp.9733-9748, 2010.
DOI : 10.1128/JVI.00694-10

M. Sanz-ramos, Hidden Virulence Determinants in a Viral Quasispecies In Vivo, Journal of Virology, vol.82, issue.21, pp.10465-10476, 2008.
DOI : 10.1128/JVI.00825-08

M. W. Schmitt, Detection of ultra-rare mutations by next-generation sequencing, Proc. Natl Acad. Sci. USA, pp.14508-14513, 2012.
DOI : 10.1073/pnas.1208715109

M. Selleri, Detection of haemagglutinin D222 polymorphisms in influenza A(H1N1)pdm09-infected patients by ultra-deep pyrosequencing Genetics research: jumping into the deep end of the pool, Clin. Microbiol. Infect., Shomron,N. Genet. Res. (Camb), vol.95, pp.1-3, 2012.

J. T. Simpson, ABySS: A parallel assembler for short read sequence data, Genome Research, vol.19, issue.6, pp.1117-1123, 2009.
DOI : 10.1101/gr.089532.108

P. D. Sniegowski, Evolution of high mutation rates in experimental populations of E. coli, Nature, vol.387, issue.6634, pp.703-705, 1997.
DOI : 10.1038/42701

D. A. Steinhauer and J. J. Holland, Rapid Evolution of RNA Viruses, Annual Review of Microbiology, vol.41, issue.1, pp.409-431, 1987.
DOI : 10.1146/annurev.mi.41.100187.002205

A. Tö-pfer, Sequencing approach to analyze the role of quasispecies for classical swine fever, Virology, vol.438, issue.1, pp.14-19, 2013.
DOI : 10.1016/j.virol.2012.11.020

M. Vignuzzi, Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population, Nature, vol.77, issue.7074, pp.439-344, 2005.
DOI : 10.1038/nature04388

S. J. Watson, Viral population analysis and minority-variant detection using short read next-generation sequencing, Philosophical Transactions of the Royal Society B: Biological Sciences, vol.20, issue.9, 2013.
DOI : 10.1101/gr.107524.110

S. M. Willerth, Development of a Low Bias Method for Characterizing Viral Populations Using Next Generation Sequencing Technology, PLoS ONE, vol.19, issue.10, p.13564, 2010.
DOI : 10.1371/journal.pone.0013564.s004

A. Wilm, LoFreq: a sequence-quality aware, ultra-sensitive variant caller for uncovering cell-population heterogeneity from high-throughput sequencing datasets, Nucleic Acids Research, vol.40, issue.22, pp.11189-11201, 2012.
DOI : 10.1093/nar/gks918

H. Woo and J. And-reifman, A quantitative quasispecies theory-based model of virus escape mutation under immune selection, Proc. Natl Acad. Sci. USA, pp.12980-12985, 2012.
DOI : 10.1073/pnas.1117201109

C. F. Wright, Beyond the Consensus: Dissecting Within-Host Viral Population Diversity of Foot-and-Mouth Disease Virus by Using Next-Generation Genome Sequencing, Journal of Virology, vol.85, issue.5, pp.2266-2275, 2011.
DOI : 10.1128/JVI.01396-10

N. C. Wu, High-throughput profiling of influenza A virus hemagglutinin gene at single-nucleotide resolution, Scientific Reports, vol.81, p.4942, 2014.
DOI : 10.1038/srep04942

X. Yang, V-Phaser 2: variant inference for viral populations, BMC Genomics, vol.14, issue.1, p.674, 2013.
DOI : 10.1016/j.coviro.2011.07.008

L. Yin, High-resolution deep sequencing reveals biodiversity, population structure, and persistence of HIV-1 quasispecies within host ecosystems, Retrovirology, vol.9, issue.1, p.108, 2012.
DOI : 10.1016/j.ympev.2010.01.019

O. Zagordi, ShoRAH: estimating the genetic diversity of a mixed sample from next-generation sequencing data, BMC Bioinformatics, vol.12, issue.1, p.119, 2011.
DOI : 10.1186/1471-2105-12-5

D. R. Zerbino and E. Birney, Velvet: Algorithms for de novo short read assembly using de Bruijn graphs, Genome Research, vol.18, issue.5, pp.821-829, 2008.
DOI : 10.1101/gr.074492.107