The Molecular Evolution of Influenza Viruses
Open Access
- Author:
- Chen, Rubing
- Graduate Program:
- Biology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 22, 2009
- Committee Members:
- Benjamin Edward Holmes, Dissertation Advisor/Co-Advisor
Bryan T Grenfell, Committee Chair/Co-Chair
Edward C Holmes, Committee Member
Kateryna Dmytrivna Makova, Committee Member
Anthony Paul Schmitt, Committee Member - Keywords:
- Molecular Evolution
Avian influenza virus
Phylogenetics
Reassortment
Transmission - Abstract:
- Despite intermittent historical pandemics caused by the cross-species transmission of avian influenza viruses (AIV), our knowledge of how influenza viruses evolve, transmit and persist in the wild bird population is obscure. In particular, since RNA viruses normally have very rapid evolutionary rates due to the error prone character of RNA depended RNA polymerase coupled with large population sizes, the often stated idea that AIVs exhibit “evolutionary stasis” is highly questionable. In addition, the impact made by natural selection and reassortment on the evolution of AIVs is obscure. Finally, although bird migration is believed to play an important role in the transmission and spread of avian influenza viruses in natural situations, our current understanding of how AIVs transmit among birds along their migration flyways, or how genetic diversity accumulates through space and time, as well as the interactions among viral strains with different subtype or genome constellations, is inadequate. Thanks to greatly increasing numbers of AIV genome sequences and newly developed methods of bioinformatic analyses, these questions are now explored in detail, for the first time, in different chapters of the thesis. First, I observed rapid rates of nucleotide substitution – ranging from 1.8 – 8.4×10-3 nucleotide substitutions per site, per year – among different avian species (including both wild aquatic birds and poultry), gene segments and serotypes of a broad range of AIVs. These rates are similar to those seen in most other RNA viruses. Second, extensive phylogenetic analyses of genome sequences revealed 1) frequent reassortment events among a diverse range of AIVs, 2) geographic segregation between Eurasian/Australian and North American strains (although with some limited gene flow among these regions), and 3) contrasting phylogenetic patterns between segments encoding surface glycoprotein or nonstructural proteins (HA/NA/NS), and those encoding the internal proteins (PB2/PB1/PA/NP/M). Specifically, the HA/NA/NS are characterized by distinct clades/subtypes and extensive genetic diversity, whereas the PB2/PB1/PA/NP/M segments comprise a single gene pool with much shallower genetic diversity. By estimating the time to the Most Recent Common Ancestor (MRCA) of each segment, we found that the current genetic diversity of the internal gene segments has a surprisingly recent origin, only ~100 (95% HPD: 74 – 170) years ago, and hence similar to the individual subtypes of HA, NA and NS. In marked contrast, the total MRCAs for HA, NA and NS are much older, dating back from ~500 (NS) to more than 1000 (HA and NA) years ago. As a result of these distinct evolutionary processes I suggest that the population genetic structure of the internal segments is the result of a complex process of serial hitch-hiking among competing viral strains characterized by differing antigenicity, coupled with rapid gene flow on both the continental and global scales. In a complementary study I examined the transmission pattern of AIVs in North America using a parsimony mapping approach. This revealed that the evolution of AIV is significantly shaped by geographic location and time of sampling, but not by host avian species, indicative of frequent cross-species transmission. Finally, as a counterpoint to my work on influenza A virus, I also considered the evolutionary patterns and dynamics of human influenza B virus. This revealed a complex process of divergence and competitive evolution between antigenically different strains, as well as a likely interaction between influenza A and B viruses.