Genotype-Specific Evolution of Hepatitis E Virus

Abstract

Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis globally. HEV comprises four genotypes with different geographic distributions and host ranges. We utilize this natural case-control study for investigating the evolution of zoonotic viruses compared to single-host viruses, using 244 near-full-length HEV genomes. Genome-wide estimates of the ratio of nonsynonymous to synonymous evolutionary changes (dN/dS ratio) located a region of overlapping reading frames, which is subject to positive selection in genotypes 3 and 4. The open reading frames (ORFs) involved have functions related to host-pathogen interaction, so genotype-specific evolution of these regions may reflect their fitness. Bayesian inference of evolutionary rates shows that genotypes 3 and 4 have significantly higher rates than genotype 1 across all ORFs. Reconstruction of the phylogenies of zoonotic genotypes demonstrates significant intermingling of isolates between hosts. We speculate that the genotype-specific differences may result from cyclical adaptation to different hosts in genotypes 3 and 4.IMPORTANCE Hepatitis E virus (HEV) is increasingly recognized as a pathogen that affects both the developing and the developed world. While most often clinically mild, HEV can be severe or fatal in certain demographics, such as expectant mothers. Like many other viral pathogens, HEV has been classified into several distinct genotypes. We show that most of the HEV genome is evolutionarily constrained. One locus of positive selection is unusual in that it encodes two distinct protein products. We are the first to detect positive selection in this overlap region. Genotype 1, which infects humans only, appears to be evolving differently from genotypes 3 and 4, which infect multiple species, possibly because genotypes 3 and 4 are unable to achieve the same fitness due to repeated host jumps. KEYWORDS evolution, evolutionary biology, genotypic identification, hepatitis E virus, positive selection H epatitis E virus (HEV) is a nonenveloped single-stranded positive-sense RNA virus that infects approximately 20 million people globally each year (1). It causes large propagated epidemics of acute hepatitis in Asia and Africa, as well as low-level, sporadic, food-associated infections in the developed world (2, 3). Its pathogenicity ranges from acute liver failure and mortality rates as high as 20% in some subpopulations (for example, in pregnant women) to apparently asymptomatic infections in others (4). Acquired via the fecal-oral route, HEV is associated with poor hygiene and living conditions. It can also be acquired by eating contaminated food, including infected artiodactyls (swine, deer, and boar) and shellfish (4-6).Mammalian HEV exists in four internationally recognized genotypes (7). Genotyping is based on nucleotide divergence in the capsid open reading frame (ORF) (8) and on whole-genome phylogenetic analysis (9). Genotypes differ at the epidemiological (distribution, hosts) and virological (pathogenicity, translation mecha...

Patterns of mutation within an emerging endemic lineage of HEV‐3a

“…Across NUH patient sequences, two protein regions were highly conserved, similar to a previous analysis of global HEV‐3 genotypes . The first region in ORF1 between aa residues 250‐450 covers the entire Y domain (aa241‐442), a sequence highly similar to the Rubella virus, and critical to HEV infectivity .…”

“…Across NUH patient sequences, two protein regions were highly conserved, similar to a previous analysis of global HEV-3 genotypes. 40 The first region in ORF1 between aa residues 250-450 covers the entire Y domain (aa241-442), a sequence highly similar to the Rubella virus, 3 and critical to HEV infectivity. 41 The second conserved region in ORF2 between aa residues 120-400 cover the entire S domain (aa130-319) and half of the M domain (aa320-456).…”

Asymmetric evolution in viral overlapping genes is a source of selective protein adaptation

“…I thus chose an approach focused, at first instance, on the evaluation of the amino acid diversity of homologous overlapping proteins, which is the final result of the complex pattern of the interdependent nucleotide substitutions that occur in dual-coding regions. Unlike previous studies, limited to a few virus species (Sabath et al, 2012;Zaaijer et al, 2007;Liang et al, 2010;Shukla and Hilgenfeld, 2015;Brayne et al, 2017), I examined a large dataset of 75 overlaps from 59 virus species.…”

Hepatitis E virus infection of slaughtered healthy pigs in Brazil

“…Recombination between strains infecting different host species can have serious implications for HEV evolution and inter‐species transmission. It has been suggested that the overall distribution of different HEV genotypes is due to the fact that different clades of the virus interact with different hosts, which could impose differential selective pressures on the pathogen as a part of host–pathogen interactions (Brayne, Dearlove, Lester, Kosakovsky Pond, & Frost, ). Moreover, the analysis of mutations in the viral genome suggests that HEV is under substantial evolutionary pressure to develop mutations enabling evasion of the host immune response and resistance to antiviral treatment (Ikram et al., ).…”