Although hepatitis C virus (HCV) is a major cause of viral hepatitis and hepatocellular carcinoma, many aspects of its evolution remain poorly understood. Relevant to its evolution and the development of antiviral drug resistance is the role of recombination in HCV, which has not been resolved using phylogenetic tests. In line with previous studies, we found no strong support for a role of recombination in the dominant subtypes 1A and 1B using phylogenetic approaches. In contrast, signatures of gene conversion were abundant if a population recombination model, which takes into account diversity within and between groups, was used (9676 gene conversion signatures between the genomes of subtypes 1A and 1B and 170 between the NS5A regions of subtypes 1A and 1B and the minor subtypes 1c–1g). The gene conversion signatures coincided with a striking lack of diagnostically informative sites between subtypes and a large number of shared mutations between complete subtype 1A and 1B genomes (0.76 and 62.2 % of nucleotide sites, respectively). Maximum-likelihood trees revealed significant topological incongruence among conserved PFAM domains and genome regions targeted by diagnostic assays, which underpins a major role for recombination. The same results were obtained with smaller numbers of genomes and with only synonymous sites. Topological concordance increased only marginally if larger genome regions were compared. The level of recombination in HCV subtype 1, which is probably significantly higher than can currently be measured, also illustrates the complexity of designing diagnostic assays based on the unusual patterns of genomic diversity of HCV.


Article metrics loading...

Loading full text...

Full text loading...



  1. Alcantara, L. C., Cassol, S., Libin, P., Deforche, K., Pybus, O. G., Van Ranst, M., Galvão-Castro, B., Vandamme, A. M. & de Oliveira, T.(2009). A standardized framework for accurate, high-throughput genotyping of recombinant and non-recombinant viral sequences. Nucleic Acids Res 37, W634–W642.[CrossRef] [Google Scholar]
  2. Awadalla, P.(2003). The evolutionary genomics of pathogen recombination. Nat Rev Genet 4, 50–60.[CrossRef] [Google Scholar]
  3. Betrán, E., Rozas, J., Navarro, A. & Barbadilla, A.(1997). The estimation of the number and the length distribution of gene conversion tracts from population DNA sequence data. Genetics 146, 89–99. [Google Scholar]
  4. Bouchardeau, F., Cantaloube, J. F., Chevaliez, S., Portal, C. & Razer, A.(2007). Improvement of hepatitis C virus (HCV) genotype determination with the new version of the INNO-LiPA HCV assay. J Clin Microbiol 45, 1140–1145.[CrossRef] [Google Scholar]
  5. Bracho, M. A., Saludes, V., Martro, E., Bargallo, A. Q., Gonzalez-Candelas, F. & Ausina, V.(2008). Complete genome of European hepatitis C virus subtype 1g isolate: phylogenetic and genetic analyses. Virol J 5, 72.[CrossRef] [Google Scholar]
  6. Chevaliez, S., Bouvier-Alias, S., Brillet, R. & Pawlotsky, J. M.(2009). Hepatitis C virus (HCV) genotype 1 subtype identification in new HCV drug development and future clinical practice. PLoS ONE 4, e8209.[CrossRef] [Google Scholar]
  7. Cristina, J. & Colina, R.(2006). Evidence of structural genomic region recombination in hepatitis C virus. Virol J 3, 53.[CrossRef] [Google Scholar]
  8. de Carvalho-Mello, I. M. V. G., Medeiros Filho, J. E., Gomes-Gouvêa, M. S., Malta, F. de M., de Queiróz, A. T. L., Pinho, J. R. R. & Carrilho, F. J.(2010). Molecular evidence of horizontal transmission of hepatitis C virus within couples. J Gen Virol 91, 691–696.[CrossRef] [Google Scholar]
  9. Djebbi, A., Mejri, S., Tiers, V. & Triki, H.(2004). Phylogenetic analysis of hepatitis C virus isolates from Tunisian patients. Eur J Epidemiol 19, 555–562. [Google Scholar]
  10. Erhardt, A., Deterding, K., Benhamou, Y., Reiser, M., Forns, X., Pol, S., Calleja, J. L., Ross, S., Spangenberg, H. C. & other authors(2009). Safety, pharmacokinetics and antiviral effect of BILB 1941, a novel hepatitis C virus RNA polymerase inhibitor, after 5 days oral treatment. Antivir Ther 14, 23–32. [Google Scholar]
  11. Heath, L., van der Walt, E., Varsani, A. & Martin, D. P.(2006). Recombination patterns in aphthoviruses mirror those found in other picornaviruses. J Virol 80, 11827–11832.[CrossRef] [Google Scholar]
  12. Holmes, E. C., Worobey, M. & Rambaut, A.(1999). Phylogenetic evidence for recombination in dengue virus. Mol Biol Evol 16, 405–409.[CrossRef] [Google Scholar]
  13. Librado, P. & Rozas, J.(2009). DnaSP v5: a software for comprehensive analysis of DNA polymorphism data. Bioinformatics 25, 1451–1452.[CrossRef] [Google Scholar]
  14. Magiorkinis, G., Magiorkinis, E., Paraskevis, D., Ho, S. Y. W., Shapiro, B., Pybus, O. G., Allain, J. P. & Hetzakis, A.(2009). The global spread of hepatitis C virus 1a and 1b: a phylodynamic and phylogeographic analysis. PLoS Med 6, e1000198.[CrossRef] [Google Scholar]
  15. Martin, D. P., Williamson, C. & Posada, D.(2005). RDP2: recombination detection and analysis from sequence alignments. Bioinformatics 21, 260–262.[CrossRef] [Google Scholar]
  16. McCown, M. F., Rajyaguru, S., Kular, S., Cammack, N. & Najera, I.(2009). GT-1a or GT-1b subtype-specific resistance profiles for hepatitis C virus inhibitors telaprevir and HCV-796. Antimicrob Agents Chemother 53, 2129–2132.[CrossRef] [Google Scholar]
  17. Moreno, M. P., Casane, D., López, L. & Cristina, J.(2006). Evidence of recombination in quasispecies populations of a hepatitis C virus patient undergoing anti-viral therapy. Virol J 3, 87.[CrossRef] [Google Scholar]
  18. Nakatani, S. M., Santos, C. A., Riediger, I. N., Krieger, M. A., Duarte, C. A., Lacerda, M. A., Biondo, A. W., Carilho, F. J. & Ono-Nita, S. K.(2010). Development of hepatitis C virus genotyping by real-time PCR based on the NS5B region. PLoS ONE 5, e10150.[CrossRef] [Google Scholar]
  19. Penny, D. & Hendy, M. D.(1985). The use of tree comparison metrics. Syst Zool 34, 75–82.[CrossRef] [Google Scholar]
  20. Sentandreu, V., Jiminez-Hernandez, N., Torre-Puente, M., Bracho, M. A., Valero, A., Gosalbes, M. G., Ortega, E., Moya, A. & Gonzalez-Candelas, F.(2008). Evidence of recombination in intrapatient populations of hepatitis C virus. PLoS ONE 3, e3239.[CrossRef] [Google Scholar]
  21. Shimodaira, H. & Hasegawa, M.(1999). Multiple comparisons of log-likelihoods with applications to phylogenetic inference. Mol Biol Evol 16, 1114–1116.[CrossRef] [Google Scholar]
  22. Simmonds, P.(2004). Genetic diversity and evolution of hepatitis C virus – 15 years on. J Gen Virol 85, 3173–3188.[CrossRef] [Google Scholar]
  23. Simmonds, P., Bukh, J., Combet, C., Deléage, G., Enomoto, N., Feinstone, S., Halfon, P., Inchauspé, G., Kuiken, C. & other authors(2005). Consensus classification for a unified system of nomenclature of hepatitis C virus genotypes. Hepatology 42, 962–973.[CrossRef] [Google Scholar]
  24. Stamatakis, A.(2006). RAxML-VI-HPC: maximum likelihood-based phylogenetic analyses with thousands of taxa and mixed models. Bioinformatics 22, 2688–2690.[CrossRef] [Google Scholar]
  25. Stamatakis, A., Hoover, P. & Rougemont, J.(2008). A rapid bootstrap algorithm for the RAxML web servers. Syst Biol 57, 758–771.[CrossRef] [Google Scholar]
  26. Strimmer, K. & Rambaut, A.(2002). Inferring confidence sets of possibly mis-specified gene trees. Proc Biol Sci 269, 137–142.[CrossRef] [Google Scholar]
  27. Swofford, D. L.(2003).paup*. Phylogenetic analysis using parsimony (*and other methods), version 4. Sunderland, MA: Sinauer Associates.
  28. Tamura, K., Dudley, J., Nei, M. & Kumar, S.(2007).mega4: molecular evolutionary genetics analysis (mega) software version 4.0. Mol Biol Evol 24, 1596–1599.[CrossRef] [Google Scholar]
  29. Thompson, J. D., Gibson, T. J., Plewniak, F., Jeanmougin, F. & Higgins, D. G.(1997). The clustal_x windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res 25, 4876–4882.[CrossRef] [Google Scholar]
  30. Viazov, S., Kuzin, S., Paladi, N., Tchernoversky, M., Isaeva, E., Mazhul, L., Vasychova, F., Widell, A. & Roggendorf, M.(1997). Hepatitis C virus genotypes in different regions of the former Soviet Union (Russia, Belarus, Moldova, and Uzbekistan). J Med Virol 53, 36–40.[CrossRef] [Google Scholar]
  31. Villano, S. A., Vlahov, D., Nelson, K. E., Cohn, S. & Thomas, D. L.(1999). Persistence of viremia and the importance of long-term follow-up after acute hepatitis C infection. Hepatology 29, 908–914.[CrossRef] [Google Scholar]
  32. Worobey, M. & Holmes, E. C.(1999). Evolutionary aspects of recombination in RNA viruses. J Gen Virol 80, 2535–2543. [Google Scholar]

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error