title: Investigation of the pattern of diversity of hepatitis C virus in relation to times of transmission.
abstract: The rate of sequence change of HCV in vivo was used to date the spread of HCV genotype 1b in European, USA and Japanese populations. Silent substitution rates of 0.0011 and 0.0017 substitutions per site per year were observed in the NS5 and E1 regions by sequence comparisons from a cohort of individuals infected from a common source of infection 17 years previously. Mean silent substitution frequencies of 0.169 and 0.224 in NS5 and E1, respectively, were observed amongst type 1b variants infecting epidemiologically unrelated individuals from several countries. This predicted a time of divergence from a common ancestor of 64-69 years. The absence of country-specific groupings by phylogenetic analysis of these sequences suggested that the spread of this genotype occurred on a worldwide basis at a similar time. Dates for the spread of other genotypes varied from around 80 years (type 2a) to 54 years (type 3a), suggesting that different variants spread into communities at different times this century. By extrapolating the silent substitution rate, the time of divergence of type 1a from 1b can be estimated at 200-300 years, but even this is likely to be an underestimate of the true time due to inequalities on the transition and transversion ratios, and the greater frequency of G <--> A transitions, compared with C <--> U, which are not considered in the current analysis. Thus, the diversity of the globally distributed genotypes such as type 1b and 3a suggests a relatively recent origin for HCV in Western countries and Japan, and contrast with the much greater diversity of specific genotypes in Central Africa (type 4) and South East Asia (type 6). These data may assist in understanding the global epidemiology of HCV and the mechanisms by which it has spread.
authors.affiliation: Department of Medical Microbiology, University of Edinburgh, UK.
authors.forename: P
authors.initials: P
authors.lastname: Simmonds
authors.forename: D B
authors.initials: DB
authors.lastname: Smith
mesh_terms: D014644:Genetic Variation; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000235:genetics*; D006526:Hepatitis C / Q000635:transmission / Q000821:virology*; D006801:Humans; D010802:Phylogeny; D012367:RNA, Viral / Q000032:analysis; D013997:Time Factors; D014759:Viral Envelope Proteins / Q000235:genetics*; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D012367:RNA, Viral; D014759:Viral Envelope Proteins; D017361:Viral Nonstructural Proteins; C087035:E1 protein, Hepatitis C virus; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase