Estimation of the mutation rate of hepatitis E virus based on a set of closely related 7.5-year-apart isolates from Sapporo, Japan

Abstract Since hepatitis E virus (HEV) does not persist in infected hosts or in cultured cell lines, it has been difficult to know its spontaneous mutation rate. Recently, we identified an HEV isolate in stored serum from a patient having developed hepatitis E in 1995 (JSM-Sap95), nucleotide sequence of which showed a strong resemblance to those obtained from three patients who contracted hepatitis E in 2000 and 2002 (JKK-Sap00, JYW-Sap02, and JTS-Sap02). The remarkable nucleotide similarity together with the fact that all these patients were residents of the same city, Sapporo, prompted us to hypothesize that JKK-Sap00, JYW-Sap02 and JTS-Sap02 are descendants of JSM-Sap95. Then, the mutation rate of HEV was calculated to be 1.72, 1.41, or 1.40×10 −3 base substitutions per site per year, from JSM-Sap95 to JKK-Sap00, JYW-Sap02 or JTS-Sap02, respectively. Interestingly, these values were very similar to those (1.44×10 −3 to 1.92×10 −3 ) reported for hepatitis C virus. Because it remains possible that JSM-Sap95 is not the direct ancestor of the other three isolates but was merely a relative of the true ancestor, HEV mutation rate may be a little lower than 1.40×10 −3 base substitutions per site per year.