Evolutionary selection associated with the multi-function of overlapping genes in the hepatitis B virus |
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| Authors: | Dake Zhang Jian Chen Libin Deng Qing Mao Jiang Zheng Jun Wu Changqing Zeng Yan Li |
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| Affiliation: | 1. Southwest Hospital, Third Military Medical University, Chongqing 400038, China;2. Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 101300, China;3. Faculty of Basic Medical Science, Nanchang University, Nanchang, 330046, China;1. Department of Epidemiology and Statistics, School of Public Health, Jiangsu Key Laboratory and Translational Medicine for Geriatric Disease, Medical College of Soochow University, Suzhou, Jiangsu, China;2. Suzhou Industrial Park Centers for Disease Control and Prevention, Suzhou 215123, China;1. “L. Spallanzani” National Institute for Infectious Diseases, Rome, Italy;2. Research & Development, Bristol-Myers Squibb, Wallingford, CT, United States;3. Research & Development, Bristol-Myers Squibb, Princeton, NJ, United States;3. Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada;4. Department of Cell Biology and Physiology;5. Center for Investigation of Membrane Excitability Diseases (CIMED), Washington University School of Medicine, St. Louis, Missouri 63110;6. Department of Laboratory Medicine, University of California, San Francisco, Palo Alto, California 94306;1. Department of Biomedical and Clinical Sciences L Sacco, University of Milan, Via GB Grassi 74, 20157, Milan, Italy;1. Department of Biological Sciences, Louisiana State University, Baton Rouge, LA, USA;2. Human Genome Sequencing Center, Department of Molecular and Human Genetics, and Cell and Molecular Biology Program, Baylor College of Medicine, Houston, TX, USA;1. Islamic Azad University, Shahrekord Branch, Shahrekord, Iran;2. Department of Microbiology, Faculty of Basic Sciences, Islamic Azad University, Shahrekord Branch, Shahrekord, Iran;3. Department of Microbiology, Faculty of Veterinary Medicine, Islamic Azad University, Shahrekord Branch, Shahrekord, Iran |
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| Abstract: | It is a challenge to understand the discrete roles of each point mutation in viral evolution, but overlapping genes provide an excellent entrance for the investigation of this complicated process. We obtained 132 sequences from the largest overlapping region in the HBV genome. Based on the genetic divergence between genotypes B and C, we distinguished a set of related footprint mutations that are believed to be responsible for historical selection events. Examining the mutations in the functional domains, we found that the virus has adopted a coherent strategy in its evolutionary process that can be summarized as follows: (1) the distribution of mutations was non-random throughout the overlapping region, and more mutations were preserved in the sequence when one of the genes was under relaxed selection; (2) the viral domains were subject to different selective pressures; for instance, the PreS1 domain underwent a strict selection, whereas the overlapped Spacer domain was relatively relaxed with obvious tolerance of non-synonymous mutations with a high dN/dS ratio; (3) different selective pressures on two codon sites ultimately determined that every mutation persevered at a proper position. Taken together, the functional constraints of protein domains are believed to be primarily responsible for the different selection patterns exhibited by the distribution of mutations and amino acid changes in the region where overlapping genes reside. |
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