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The hepatitis E virus (HEV) polyproline region (PPR) is an intrinsically unstructured region (IDR). This relaxed structure allows IDRs, which are implicated in the regulation of transcription and translation, to bind multiple ligands. Originally the nucleotide variability seen in the HEV PPR was assumed to be due to high rates of insertion and deletion. This study shows that the mutation rate is about the same in the PPR as in the rest of the nonstructural polyprotein. The difference between the PPR and the rest of the polyprotein is due to the higher tolerance of the PPR for substitutions at the first and second codon positions. With this higher promiscuity there is a shift in nucleotide occupation of these codons leading to translation of more cytosine residues: a shift that leads to more proline, alanine, serine, and threonine being encoded rather than histidine, phenylalanine, tryptophan, and tyrosine. This pattern of amino acid usage is typical of proline-rich IDRs. Increased usage of cytosine also leads to>22% of all amino acids in the PPR being prolines. Alignments of PPR sequences from HEV strains representing all genotypes indicate that all zoonotic isolates share an ancestor, and the carboxyl half of the PPR is more tolerant of mutations than the amino half. The evolution of HEV PPR, in contrast with that of the rest of the nonstructural polyprotein, is molded by pressures that lead toward increased proline usage with a corresponding decrease in the usage of aromatic amino acids, favoring formation of IDR structures. [ABSTRACT FROM AUTHOR]

Background: Hepatitis E virus (HEV) is an enterically transmitted hepatropic virus. It segregates as four genotypes. All genotypes infect humans while only genotypes 3 and 4 also infect several animal species. It has been suggested that hepatitis E is zoonotic, but no study has analyzed the evolutionary history of HEV. We present here an analysis of the evolutionary history of HEV. Methods and Findings: The times to the most recent common ancestors for all four genotypes of HEV were calculated using BEAST to conduct a Bayesian analysis of HEV. The population dynamics for genotypes 1, 3 and 4 were analyzed using skyline plots. Bayesian analysis showed that the most recent common ancestor for modern HEV existed between 536 and 1344 years ago. The progenitor of HEV appears to have given rise to anthropotropic and enzootic forms of HEV, which evolved into genotypes 1 and 2 and genotypes 3 and 4, respectively. Population dynamics suggest that genotypes 1, 3 and 4 experienced a population expansion during the 20th century. Genotype 1 has increased in infected population size <30- 35 years ago. Genotype 3 and 4 have experienced an increase in population size starting late in the 19th century until ca.1940-45, with genotype 3 having undergone additional rapid expansion until ca.1960. The effective population size for both genotype 3 and 4 rapidly declined to pre-expansion levels starting in ca.1990. Genotype 4 was further examined as Chinese and Japanese sequences, which exhibited different population dynamics, suggesting that this genotype experienced different evolutionary history in these two countries. Conclusions: HEV appears to have evolved through a series of steps, in which the ancestors of HEV may have adapted to a succession of animal hosts leading to humans. Analysis of the population dynamics of HEV suggests a substantial temporal variation in the rate of transmission among HEV genotypes in different geographic regions late in the 20th Century. [ABSTRACT FROM AUTHOR]

During 2001-2011, hepatitis E virus (HEV) was found in the blood of patients in Nanjing, China. All HEV-positive patients had virus genotype 4; subgenotype 4a was predominant. The effective population of HEV in Nanjing increased in ≈1980 and continued until ≈2003 when it plateaued. [ABSTRACT FROM AUTHOR]

During 2001-2011, hepatitis E virus (HEV) was found in the blood of patients in Nanjing, China. All HEV-positive patients had virus genotype 4; subgenotype 4a was predominant. The effective population of HEV in Nanjing increased in ≈1980 and continued until ≈ 2003 when it plateaued. [ABSTRACT FROM AUTHOR]