Evolution of the hepatitis E virus hypervariable region.

Area of Science:

• Virology
• Molecular Biology
• Evolutionary Biology

Background:

• The function of the hypervariable region (HVR) in the hepatitis E virus (HEV) genome is currently unexplained.
• Previous research has proposed various roles for the HVR, including a proline-rich spacer, a non-functional region, a hypermutable area, or a sequence influenced by host factors or positive selection.

Purpose of the Study:

• To investigate the evolutionary processes within the HEV HVR to differentiate between proposed functional explanations.
• To analyze the diversity and evolutionary dynamics of the HVR in HEV.

Main Methods:

• Measuring HVR sequence diversity within acutely infected individuals and epidemiologically linked samples.
• Analyzing published HEV sequences to assess evolutionary patterns, including substitutions, deletions, and duplications.
• Evaluating the overabundance of proline and serine residues and the frequency of PxxP motifs in HVR sequences.

Main Results:

• HVR sequences exhibited relative homogeneity within acutely infected individuals and linked samples.
• No evidence of positive selection for amino acid substitution was found in the HVR.
• Observed HVR diversity across genotypes is attributable to accumulated substitutions, with minor contributions from deletions or duplications.
• A consistent overabundance of proline and serine residues was noted, independent of local genomic bias.
• SH3-binding PxxP motifs were not found to be more frequent than expected based on proline content.

Conclusions:

• The HEV HVR's diversity is primarily driven by sequence substitutions, deletions, and duplications, not positive selection.
• The consistent amino acid composition, particularly proline and serine enrichment, suggests a structural role for the HVR.
• The HVR's function appears to depend on its length and overall amino acid composition rather than a specific sequence.