title: Identification of Indian sub-continent as hotspot for HCV genotype 3a origin by Bayesian evolutionary reconstruction.
abstract: BACKGROUND
  Recent emphasis in Hepatitis C virus (HCV) evolutionary biology has focused on analysis using Core, E1/E2 and/or NS5b regions, with limited appreciation of full length genome. While HCV genotypes have been described as endemic in the Indian subcontinent, there has been no confirmation at the molecular evolutionary level of these genotypes. We have attempted here to determine the status of Indian HCV genotype 3a sequences in relation to similar genotypes from other parts of the world.
  
  
  METHODS
  Cloning, sequencing and molecular characterization was performed on 9 Indian sequences and comparative analyses were performed with 46 sequences from other countries. Evolutionary-rate and molecular-clock hypothesis testing was addressed by Bayesian MCMC.
  
  
  RESULTS
  Genetic analysis of full length genome revealed two hypervariable regions (HVR) in E2 region - HVR496 and HVR576, with a variable 5-8 amino-acid insertion sequence and a putative N-glycosylation site. Phylogenetic analysis revealed a divergence resulting in 2 distinct clades: clade-1 represented by HCV 3a subtype and clade-2 represented by other 3 subtype genomes. Clade-2 shows earlier divergence than clade-1. Analysis revealed that genotype 3a genomes from India roots out first (∼99 years ago) in clade1. Bayesian skyline plot analysis revealed an increase in effective number of infections from 1940s to 1990s, followed by a gradual decrease after 2000.
  
  
  CONCLUSIONS
  Genotype 3a sequences appear to have originated in India and later dispersed to United Kingdom around mid 1940s, most likely around the time of Indian independence and World War II.
authors.affiliation: Department of Research, Institute of Liver & Biliary Sciences (ILBS), Vasant Kunj, New Delhi 110070, India; Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India.
authors.forename: Manish Chandra
authors.initials: MC
authors.lastname: Choudhary
authors.affiliation: Department of Research, Institute of Liver & Biliary Sciences (ILBS), Vasant Kunj, New Delhi 110070, India.
authors.forename: Vidhya
authors.initials: V
authors.lastname: Natarajan
authors.affiliation: Department of Virology, Institute of Liver & Biliary Sciences (ILBS), Vasant Kunj, New Delhi 110070, India.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Pandey
authors.affiliation: Department of Virology, Institute of Liver & Biliary Sciences (ILBS), Vasant Kunj, New Delhi 110070, India.
authors.forename: Ekta
authors.initials: E
authors.lastname: Gupta
authors.affiliation: Department of Research, Institute of Liver & Biliary Sciences (ILBS), Vasant Kunj, New Delhi 110070, India.
authors.forename: Shvetank
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Molecular Diagnostics, RAS Lifesciences Pvt. Ltd., Nacharam, Hyderabad, Andhra Pradesh 500076, India.
authors.forename: Rachana
authors.initials: R
authors.lastname: Tripathi
authors.affiliation: Molecular Diagnostics, RAS Lifesciences Pvt. Ltd., Nacharam, Hyderabad, Andhra Pradesh 500076, India.
authors.forename: M Shesheer
authors.initials: MS
authors.lastname: Kumar
authors.affiliation: Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India.
authors.forename: Syed N
authors.initials: SN
authors.lastname: Kazim
authors.affiliation: Department of Research, Institute of Liver & Biliary Sciences (ILBS), Vasant Kunj, New Delhi 110070, India. Electronic address: shivsarin@gmail.com.
authors.forename: Shiv K
authors.initials: SK
authors.lastname: Sarin
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001499:Bayes Theorem; D066264:Datasets as Topic; D019143:Evolution, Molecular; D005260:Female; D014644:Genetic Variation; D016679:Genome, Viral; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000235:genetics*; D006526:Hepatitis C / Q000453:epidemiology / Q000821:virology*; D006801:Humans; D007194:India / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010802:Phylogeny; D012367:RNA, Viral; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
chemical_list: D012367:RNA, Viral
keywords: Bayesian skyline; Genotype 3a; HCV; Hepatitis C; India; Molecular evolution