Understanding the origin and nature of hepatitis C virus (HCV) genetic diversity is critical for improving treatment and vaccine design, and such diversity is the sole source of information about the virus' epidemic history prior to its identification 20 years ago. In this paper, we study the molecular epidemiology of HCV genotype 2 in its region of endemic origin, west and central Africa. Our analysis includes 56 new and highly diverse HCV isolates sampled from infected individuals in Guinea-Bissau. By combining phylogenetic, geographical and epidemiological information, we find a previously unappreciated geographical structure in the diversity of HCV genotype 2, pointing to a history of eastwards spatial spread from the west African coast to Cameroon that took place over several centuries. Molecular clock analysis dates the common ancestor of HCV in Guinea-Bissau to 1470 (1414–1582). The phylogenetic position of isolates from Madagascar and Martinique suggests a role for the historical slave trade in the global dissemination of HCV and of the epidemic subtypes 2a and 2c. Coalescent-based estimates of epidemic growth indicate a rapid 20th-century spread of HCV genotype 2 in Cameroon that is absent in Guinea-Bissau. We discuss this contrast in the context of possible parenteral HCV exposure during public-health campaigns undertaken during the colonial era.


Article metrics loading...

Loading full text...

Full text loading...



  1. Agwale, S. M., Tanimoto, L., Womack, C., Odama, L., Leung, K., Duey, D., Negedu-Momoh, R., Audu, I., Mohammed, S. B. & other authors(2004). Prevalence of HCV coinfection in HIV-infected individuals in Nigeria and characterization of HCV genotypes. J Clin Virol 31 (Supp. 1), S3–S6.[CrossRef] [Google Scholar]
  2. Bryant, J. E., Holmes, E. C. & Barrett, A. D.(2007). Out of Africa: a molecular perspective on the introduction of yellow fever virus into the Americas. PLoS Pathog 3, e75[CrossRef] [Google Scholar]
  3. Candotti, D., Temple, J., Sarkodie, F. & Allain, J.(2003). Frequent recovery and broad genotype 2 diversity characterize hepatitis C virus infection in Ghana, west Africa. J Virol 77, 7914–7923.[CrossRef] [Google Scholar]
  4. CDC(1998). Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR Morb Mortal Wkly Rep 47(RR-19), 1–39. [Google Scholar]
  5. Chemello, L., Alberti, A., Rose, K. & Simmonds, P.(1994). Hepatitis C serotype and response to interferon therapy. N Engl J Med 330, 143 [Google Scholar]
  6. Clayton, A.(1988).France, Soldiers and Africa. London: Brassey's Defence Publishers.
  7. Deroo, E. & Champeaux, A.(2006).La Force Noire. Gloire et Infortunes d'une Légende Coloniale. Paris: Tallandier (in French).
  8. Drummond, A. J. & Rambaut, A.(2007).beast: Bayesian evolutionary analysis by sampling trees. BMC Evol Biol 7, 214[CrossRef] [Google Scholar]
  9. Drummond, A. J., Rambaut, A., Shapiro, B. & Pybus, O. G.(2005). Bayesian coalescent inference of past population dynamics from molecular sequences. Mol Biol Evol 22, 1185–1192.[CrossRef] [Google Scholar]
  10. Echenberg, M.(1991).Colonial Conscripts: The Tirailleurs Sénégalais in French West Africa, 1857–1960. Portsmouth, NH: Heinemann Educational Books.
  11. Eltis, D., Behrendt, S. D., Richardson, D. & Klein, H. S. (editors)(1999).The Trans-Atlantic Slave Trade – A Database on CD-ROM. New York: Cambridge University Press.
  12. Ferreira, F. S.(1961a). História da doença do sono na Guiné portuguesa: IV – período de 1927 a 1932. Boletim Cultural da Guiné Portuguesa 16, 139–157 (in Portuguese). [Google Scholar]
  13. Ferreira, F. S.(1961b). História da doença do sono na Guiné Portuguesa: V – período de 1933 a 1946. Boletim Cultural da Guiné Portuguesa 16, 313–347 (in Portuguese). [Google Scholar]
  14. Ferreira, F. S.(1961c). História da doença do sono na Guiné Portuguesa: VII – período de 1947 a 1956. Boletim Cultural da Guiné Portuguesa 16, 569–606 (in Portuguese). [Google Scholar]
  15. Frank, C., Mohamed, M. K., Strickland, G. T., Lavanchy, D., Arthur, R. R., Magder, L. S., El Khoby, T., Abdel-Wahab, Y., Aly Ohn, E. S. & other authors(2000). The role of parenteral antischistosomal therapy in the spread of hepatitis C virus in Egypt. Lancet 355, 887–891.[CrossRef] [Google Scholar]
  16. Gouvernement Français(1921–1938).Rapport Annuel adressé par le Gouvernement Français au Conseil de la Société des Nations conformément à l'article 22 du pacte sur l'Administration sous mandat du Territoire du Cameroun pour l'année: 1921–1938. Geneva, Switzerland: Office des Nations Unies à Genève (in French).
  17. Gouvernement Français(1947–1957).Rapport Annuel du Gouvernement Français aux Nations-Unies sur l'Administration du Cameroun placé sous la tutelle de la France. Geneva, Switzerland: Office des Nations Unies à Genève (in French).
  18. Hasegawa, M., Kishino, H. & Yano, T.(1985). Dating of the human-ape splitting by a molecular clock of mitochondrial DNA. J Mol Evol 22, 160–174.[CrossRef] [Google Scholar]
  19. Jamot, E.(1932). La lutte contre la maladie du sommeil au Cameroun. Ann Inst Pasteur (Paris) 48, 481–539 (in French). [Google Scholar]
  20. Jeannel, D., Fretz, C., Traore, Y., Kohdjo, N., Bigot, A., Pê Gamy, E., Jourdan, G., Kourouma, K., Maertens, G. & other authors(1998). Evidence for high genetic diversity and long-term endemicity of hepatitis C virus genotypes 1 and 2 in West Africa. J Med Virol 55, 92–97.[CrossRef] [Google Scholar]
  21. Kimura, Y., Hayashida, K., Ishibashi, H., Niho, Y. & Yanagi, Y.(2000). Antibody-free virion titer greatly differs between hepatitis C virus genotypes. J Med Virol 61, 37–43.[CrossRef] [Google Scholar]
  22. Kuiken, C., Yusim, K., Boykin, L. & Richardson, R.(2005). The Los Alamos HCV sequence database. Bioinformatics 21, 379–384.[CrossRef] [Google Scholar]
  23. Mellor, J., Holmes, E. C., Jarvis, L. M., Yap, P. L. & Simmonds, P.(1995). Investigation of the pattern of hepatitis C virus sequence diversity in different geographical regions: implications for virus classification. J Gen Virol 76, 2493–2507.[CrossRef] [Google Scholar]
  24. Mizokami, M., Tanaka, Y. & Miyakawa, Y.(2006). Spread times of hepatitis C virus estimated by the molecular clock differ among Japan, the United States and Egypt in reflection of their distinct socioeconomic backgrounds. Intervirology 49, 28–36.[CrossRef] [Google Scholar]
  25. Ndjomou, J., Kupfer, B., Kochan, B., Zekeng, L., Kaptue, L. & Matz, B.(2002). Hepatitis C virus infection and genotypes among human immunodeficiency virus high-risk groups in Cameroon. J Med Virol 66, 179–186.[CrossRef] [Google Scholar]
  26. Ndjomou, J., Pybus, O. G. & Matz, B.(2003). Phylogenetic analysis of hepatitis C virus isolates indicates a unique pattern of endemic infection in Cameroon. J Gen Virol 84, 2333–2341.[CrossRef] [Google Scholar]
  27. Nerrienet, E., Pouillot, R., Lachenal, G., Njouom, R., Mfoupouendoun, J., Bilong, C. & other authors(2005). Hepatitis C virus infection in Cameroon: a cohort-effect. J Med Virol 76, 208–214.[CrossRef] [Google Scholar]
  28. Njouom, R., Nerrienet, E., Dubois, M., Lachenal, G., Rousset, D., Vessière, A., Ayouba, A., Pasquier, C. & Pouillot, R.(2007). The hepatitis C virus epidemic in Cameroon: genetic evidence for rapid transmission between 1920 and 1960. Infect Genet Evol 7, 361–367.[CrossRef] [Google Scholar]
  29. Nkengasong, J. N., Nyambi, P., Claeys, H., De Beenhouwer, H., Collart, J.-P., Ayuk, J. & Ndumbe, P.(1995). Predominantly hepatitis C virus genotypes 1 and 2 are found in Cameroon. J Infect Dis 171, 1380–1381. [Google Scholar]
  30. Parker, J., Rambaut, A. & Pybus, O. G.(2008). Correlating viral phenotypes with phylogeny: accounting for phylogenetic uncertainty. Infect Genet Evol 8, 239–246.[CrossRef] [Google Scholar]
  31. Pasquier, C., Njouom, R., Ayouba, A., Dubois, M., Sartre, M. T., Vessière, A., Timba, I., Thonnon, J., Izopet, J. & Nerrienet, E.(2005). Distribution and heterogeneity of hepatitis C genotypes in hepatitis patients in Cameroon. J Med Virol 77, 390–398.[CrossRef] [Google Scholar]
  32. Pépin, J. & Labbé, A. C.(2008). Noble goals, unforeseen consequences: control of tropical diseases in colonial central Africa and the iatrogenic transmission of blood-borne viruses. Trop Med Int Health 13, 744–753.[CrossRef] [Google Scholar]
  33. Perz, J. F., Farrington, L. A., Pecoraro, C., Hutin, Y. J. F., Armstrong, G. L. & Bell, B. P.(2004). Estimated global prevalence of hepatitis C virus infection. Presented at the 42nd Annual Meeting of the Infectious Diseases Society of America, 30 September–3 October 2004, Boston, MA, USA. Arlington, VA: Infectious Diseases Society of America.
  34. Pinto, A. R.(1955). Relatório sobre a actividade da missão permanente de estudo e combate da doença do sono e outros endemas na Guiné Portuguesa: referente ao ano de 1955. An Inst Med Trop (Lisb) 13, 275–332 (in Portuguese). [Google Scholar]
  35. Plamondon, M., Labbé, A. C., Frost, E., Deslandes, S., Alves, A. C., Bastien, N. & Pépin, J.(2007). Hepatitis C virus infection in Guinea-Bissau: a sexually transmitted genotype 2 with parenteral amplification? PLoS One 2, e372[CrossRef] [Google Scholar]
  36. Pouillot, R., Lachenal, G., Pybus, O. G., Rousset, D. & Njouom, R.(2008). Variable epidemic histories of hepatitis C virus genotype 2 infection in West Africa and Cameroon. Infect Genet Evol 8, 676–681.[CrossRef] [Google Scholar]
  37. Pybus, O. G., Charleston, M. A., Gupta, S., Rambaut, A., Holmes, E. C. & Harvey, P. H.(2001). The epidemic behavior of the hepatitis C virus. Science 292, 2323–2325.[CrossRef] [Google Scholar]
  38. Pybus, O. G., Drummond, A. J., Nakano, T., Robertson, B. H. & Rambaut, A.(2003). The epidemiology and iatrogenic transmission of hepatitis C virus in Egypt: a Bayesian coalescent approach. Mol Biol Evol 20, 381–387.[CrossRef] [Google Scholar]
  39. Pybus, O. G., Cochrane, A., Holmes, E. C. & Simmonds, P.(2005). The hepatitis C virus epidemic among injecting drug users. Infect Genet Evol 5, 131–139.[CrossRef] [Google Scholar]
  40. Pybus, O. G., Markov, P. V., Wu, A. & Tatem, A.(2007). Investigating the endemic transmission of the hepatitis C virus. Int J Parasitol 37, 839–849.[CrossRef] [Google Scholar]
  41. Pybus, O. G., Barnes, E., Taggart, R., Lemey, P., Markov, P. V., Rasachak, B., Syhavong, B., Phetsouvanah, R., Sheridan, I. & other authors(2009). Genetic history of the hepatitis C virus in East Asia. J Virol 83, 1071–1082.[CrossRef] [Google Scholar]
  42. Rambaut, A. & Drummond, A. J.(2007). Tracer v. 1.4. http://beast.bio.ed.ac.uk/Tracer
  43. Ray, S. C., Arthur, R. R., Carella, A., Bukh, J. & Thomas, D. L.(2000). Genetic epidemiology of hepatitis C virus throughout Egypt. J Infect Dis 182, 698–707.[CrossRef] [Google Scholar]
  44. Ruggieri, A., Argentini, C., Kouruma, F., Chionne, P., D'Ugo, E., Spada, E., Dettori, S., Sabbatani, S. & Rapicetta, M.(1996). Heterogeneity of hepatitis C virus genotype 2 variants in West Central Africa (Guinea Conakry). J Gen Virol 77, 2073–2076.[CrossRef] [Google Scholar]
  45. Seeff, L. B.(2000). Hepatitis C. In Natural History of Hepatitis C. Edited by T. J. Liang & J. H. Hoofnagle. San Diego, CA: Academic Press.
  46. Simmonds, P.(2001). The origin and evolution of hepatitis viruses in humans. J Gen Virol 82, 693–712. [Google Scholar]
  47. Simmonds, P.(2004). Genetic diversity and evolution of hepatitis C virus – 15 years on. J Gen Virol 85, 3173–3188.[CrossRef] [Google Scholar]
  48. Simmonds, P., Holmes, E. C., Cha, T. A., Chan, S. W., McOmish, F., Irvine, B., Beall, E., Yap, P. L., Kolberg, J. & Urdea, M. S.(1993). Classification of hepatitis C virus into six major genotypes and a series of subtypes by phylogenetic analysis of the NS-5 region. J Gen Virol 74, 2391–2399.[CrossRef] [Google Scholar]
  49. Simmonds, P., Bukh, J., Combet, C., Deleage, G., Enomoto, N., Feinstone, S., Halfon, P., Inchauspé, G., Kuiken, C. & other authors(2005). Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes. Hepatology 42, 962–973.[CrossRef] [Google Scholar]
  50. Slatkin, M. & Maddison, W. P.(1989). A cladistic measure of gene flow inferred from the phylogenies of alleles. Genetics 123, 603–613. [Google Scholar]
  51. Smith, D. B., Pathirana, S., Davidson, F., Lawlor, E., Power, J., Yap, P. L. & Simmonds, P.(1997). The origin of hepatitis C virus genotypes. J Gen Virol 78, 321–328. [Google Scholar]
  52. Wang, T. H., Donaldson, Y. K., Brettle, R. P., Bell, J. E. & Simmonds, P.(2001). Identification of shared populations of human immunodeficiency Virus Type 1 infecting microglia and tissue macrophages outside the central nervous system. J Virol 75, 11686–11699.[CrossRef] [Google Scholar]
  53. Wansbrough-Jones, M. H., Frimpong, E., Cant, B., Harris, K., Evans, M. & Teo, C.(1998). Prevalence and genotype of hepatitis C virus infection in pregnant women and blood donors in Ghana. Trans R Soc Trop Med Hyg 92, 496–499.[CrossRef] [Google Scholar]
  54. WHO(1999). Hepatitis C – global prevalence (update). Wkly Epidemiol Rec 49, 10 [Google Scholar]
  55. Worobey, M., Gemmel, M., Teuwen, D. E., Haselkorn, T., Kunstman, K., Bunce, M., Muyembe, J. J., Kabongo, J. M., Kalengayi, R. M. & other authors(2008). Direct evidence of extensive diversity of HIV-1 in Kinshasa by 1960. Nature 455, 661–664.[CrossRef] [Google Scholar]
  56. Yoshioka, K., Kakumu, S., Wakita, T., Ishikawa, T., Itoh, Y., Takayanagi, M., Higashi, Y., Shibata, M. & Morishima, T.(1992). Detection of hepatitis C virus by polymerase chain reaction and response to interferon-alpha therapy: relationship to genotypes of hepatitis C virus. Hepatology 16, 293–299.[CrossRef] [Google Scholar]
  57. Zein, N. N.(2000). Clinical significance of hepatitis C virus genotypes. Clin Microbiol Rev 13, 223–235.[CrossRef] [Google Scholar]
  58. Zwickl, D. J.(2006).Genetic algorithm approaches for the phylogenetic analysis of large biological sequence datasets under the maximum likelihood criterion. PhD dissertation, The University of Texas at Austin, TX, USA.

Data & Media loading...


vol. , part 9, pp. 2086 –2096

Molecular clock phylogenies estimated from the NS5B region alone and from a concatenated alignment.

GenBank accession numbers and their corresponding taxon labels for all sequences used in our study.

GenBank accession numbers of newly generated sequences.

[ Single PDF file] (352 KB)


Most cited this month Most Cited RSS feed

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