title: New insights into the evolutionary rate of hepatitis B virus at different biological scales.
abstract: The evolutionary rates of hepatitis B virus (HBV) estimated using contemporary sequences are 10(2) to 10(4) times higher than those derived from archaeological and genetic evidence. This discrepancy makes the origin of HBV and the time scale of its spread, both of which are critical for studying the burden of HBV pathogenicity, largely unresolved. To evaluate whether the dual demands (i.e., adaptation within hosts and colonization between hosts) of the viral life cycle affect this conundrum, the HBV quasispecies dynamics within and among hosts from a family consisting of a grandmother, her 5 children, and her 2 granddaughters, all of whom presumably acquired chronic HBV through mother-to-infant transmission, were examined by PCR cloning and next-generation sequencing methods. We found that the evolutionary rate of HBV between hosts was considerably lower than that within hosts. Moreover, the between-host substitution rates of HBV decreased as transmission numbers between individuals increased. Both observations were due primarily to changes at nonsynonymous rather than synonymous sites. There were significantly more multiple substitutions than expected for random mutation processes, and 97% of substitutions were changed from common to rare amino acid residues in the database. Continual switching between colonization and adaptation resulted in a rapid accumulation of mutations at a limited number of positions, which quickly became saturated, whereas substitutions at the remaining regions occurred at a much lower rate. Our study may help to explain the time-dependent HBV substitution rates reported in the literature and provide new insights into the origin of the virus.
  
  
  OBJECTIVE
  It is known that the estimated hepatitis B virus (HBV) substitution rate is time dependent, but the reason behind this observation is still elusive. We hypothesize that owing to the small genome size of HBV, transmission between hosts and adaptation within hosts must exhibit high levels of fitness trade-offs for the virus. By studying the HBV quasispecies dynamics for a chain of sequentially infected transmissions within a family, we found the HBV substitution rate between patients to be negatively correlated with the number of transmissions. Continual switching between hosts resulted in a rapid accumulation of mutations at a limited number of genomic sites, which quickly became saturated in the short term. Nevertheless, substitutions at the remaining regions occurred at a much lower rate. Therefore, the HBV substitution rate decreased as the divergence time increased.
authors.affiliation: Department of Life Science, National Taiwan University, Taipei, Taiwan.
authors.forename: You-Yu
authors.initials: YY
authors.lastname: Lin
authors.affiliation: Department of Microbiology, National Taiwan University, Taipei, Taiwan.
authors.forename: Chieh
authors.initials: C
authors.lastname: Liu
authors.affiliation: Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Wei-Hung
authors.initials: WH
authors.lastname: Chien
authors.affiliation: Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Li-Ling
authors.initials: LL
authors.lastname: Wu
authors.affiliation: Laboratory of Disease Genomics and Individualized Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Tao
authors.affiliation: Laboratory of Disease Genomics and Individualized Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Dafei
authors.initials: D
authors.lastname: Wu
authors.affiliation: Laboratory of Disease Genomics and Individualized Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Forestry and Nature Conservation, Chinese Culture University, Taipei, Taiwan.
authors.forename: Chia-Hung
authors.initials: CH
authors.lastname: Hsieh
authors.affiliation: Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan Institute of Ecology and Evolution, National Taiwan University, Taipei, Taiwan Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan hurngyi@ntu.edu.tw kaojh@ntu.edu.tw.
authors.forename: Hurng-Yi
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan hurngyi@ntu.edu.tw kaojh@ntu.edu.tw.
authors.forename: Jia-Horng
authors.initials: JH
authors.lastname: Kao
authors.affiliation: Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Ding-Shinn
authors.initials: DS
authors.lastname: Chen
mesh_terms: D000220:Adaptation, Biological; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D004279:DNA, Viral / Q000235:genetics; D019143:Evolution, Molecular; D005192:Family Health; D005260:Female; D014644:Genetic Variation; D006515:Hepatitis B virus / Q000145:classification / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000635:transmission* / Q000821:virology*; D006801:Humans; D018445:Infectious Disease Transmission, Vertical; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: D004279:DNA, Viral