| Autor: |
Tisthammer KH; Department of Biology, San Francisco State University, San Francisco, CA 94132, USA., Dong W; BC Centre for Excellence in HIV/AIDS, Vancouver, BC V6Z 1Y6, Canada., Joy JB; BC Centre for Excellence in HIV/AIDS, Vancouver, BC V6Z 1Y6, Canada.; Division of Infectious Diseases, Department of Medicine, University of British Columbia, Vancouver, BC V5Z 3J5, Canada.; Bioinformatics Programme, University of British Columbia, Vancouver, BC V6T 1Z4, Canada., Pennings PS; Department of Biology, San Francisco State University, San Francisco, CA 94132, USA. |
| Abstrakt: |
Understanding within-host evolution is critical for predicting viral evolutionary outcomes, yet such studies are currently lacking due to difficulty involving human subjects. Hepatitis C virus (HCV) is an RNA virus with high mutation rates. Its complex evolutionary dynamics and extensive genetic diversity are demonstrated in over 67 known subtypes. In this study, we analyzed within-host mutation frequency patterns of three HCV subtypes, using a large number of samples obtained from treatment-naïve participants by next-generation sequencing. We report that overall mutation frequency patterns are similar among subtypes, yet subtype 3a consistently had lower mutation frequencies and nucleotide diversity, while subtype 1a had the highest. We found that about 50% of genomic sites are highly conserved across subtypes, which are likely under strong purifying selection. We also compared within-host and between-host selective pressures, which revealed that Hyper Variable Region 1 within hosts was under positive selection, but was under slightly negative selection between hosts, which indicates that many mutations created within hosts are removed during the transmission bottleneck. Examining the natural prevalence of known resistance-associated variants showed their consistent existence in the treatment-naïve participants. These results provide insights into the differences and similarities among HCV subtypes that may be used to develop and improve HCV therapies. |
