Positive selection signals of hepatitis B virus and their association with disease stages and viral genotypes |
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| Institution: | 1. Laboratory of Disease Genomics and Individualized Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China;2. University of Chinese Academy of Sciences, Beijing 100049, China;3. College of Life Sciences Inner Mongolia University, Hohhot 010021, China;4. Science and Technology Department, People’s Government of Inner Mongolia Autonomous Region, Hohhot 010010, China;1. Departments of Respiratory Medicine, The First Affiliated Hospital of Third Military Medical University, Chongqing 400038, PR China;2. Center of Biotherapy, The First Affiliated Hospital of Third Military Medical University, Chongqing 400038, PR China;1. Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China;2. Department of Orthopaedics, 421 Hospital of PLA, Guangzhou 510318, China;3. Department of Orthopaedics, The First Affiliated Hospital to Guangzhou Medical University, Guangzhou 510120, China;4. Cancer Research Institute, Southern Medical University, Guangzhou 510515, China;5. Department of Orthopaedics, Subei People’s Hospital of Jiangsu Province (Clinical Medical College of Yangzhou University), Yangzhou, Jiangsu Province 225001, China;1. Department of Otorhinolaryngology, Affiliated Eye and ENT Hospital of Fudan University, Shanghai 200031, China;2. Research Center, Affiliated Eye and ENT Hospital of Fudan University, Shanghai 200031, China;3. Institute of Stem Cell and Regeneration Medicine, Institutions of Biomedical Science, Fudan University, Shanghai 200032, China;4. State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China;5. Key Laboratory of Hearing Science, Ministry of Health, Affiliated Eye and ENT Hospital of Fudan University, Shanghai 200031, China;1. Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, China;2. Department of Vascular Surgery, Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China;1. Department of Anesthesiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China;2. Brainnetome Center, Institute of Automation, Chinese Academy of Science, Beijing, China;3. Functional Imaging Center, Beijing Neurosurgical Institute, Beijing, China |
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| Abstract: | The hepatitis B virus (HBV) is a global health problem that causes different types of liver diseases. The high mutation rate of HBV, which results from a lack of proofreading activity of the viral polymerase, leads to the actively adaptive evolution of mutant strains under various selection pressures. This study focuses on the positive selection signals in the whole HBV genome and the association of these selection signals with the disease stages and/or viral genotypes. A total of 486 complete HBV genomes from HBV-infected individuals of different illness categories (i.e., acute, chronic, and severe hepatitis) were analyzed. To obtain a panoramic view of the selection signals, codon-based maximum likelihood analysis, three-dimensional (3D) mapping, and allele frequency comparison were conducted on genotypes B and C HBV from subjects with different stages of hepatitis. A total of 95 selected codons were resolved, and a significantly higher number of positive selection signatures were found in the chronic and severe hepatitis groups compared with the acute groups. Many of the selected codons were associated with either a unique disease stage or a specific genotype. The conservation analysis of the selection signals in the viral core protein (HBcAg) illustrated the occurrence of selected codons in the highly diversified regions. The allele-frequency-based analysis identified eight additional nucleotide substitutions, and the frequencies of these mutations were found to increase with disease progression. Moreover, we found that three substitutions, including A1762T, G1764A, and A2739C, were nearly fixed. The mapping of all of the selected codons and nucleotide substitutions to the functional domains of the viral proteins suggested that more than 60% of the mutations were subject to selection forces from host immune surveillance, antiviral therapy, and replication fitness. |
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| Keywords: | Hepatitis B virus Positive selection Mutation Disease stage Viral genotype Selection pressure |
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