Abstract
BackgroundThe human rhinoviruses (HRV) are one of the most common and diverse respiratory pathogens of humans. Over 100 distinct HRV serotypes are known, yet only 6 genomes are available. Due to the paucity of HRV genome sequence, little is known about the genetic diversity within HRV or the forces driving this diversity. Previous comparative genome sequence analyses indicate that recombination drives diversification in multiple genera of the picornavirus family, yet it remains unclear if this holds for HRV.ResultsTo resolve this and gain insight into the forces driving diversification in HRV, we generated a representative set of 34 fully sequenced HRVs. Analysis of these genomes shows consistent phylogenies across the genome, conserved non-coding elements, and only limited recombination. However, spikes of genetic diversity at both the nucleotide and amino acid level are detectable within every locus of the genome. Despite this, the HRV genome as a whole is under purifying selective pressure, with islands of diversifying pressure in the VP1, VP2, and VP3 structural genes and two non-structural genes, the 3C protease and 3D polymerase. Mapping diversifying residues in these factors onto available 3-dimensional structures revealed the diversifying capsid residues partition to the external surface of the viral particle in statistically significant proximity to antigenic sites. Diversifying pressure in the pleconaril binding site is confined to a single residue known to confer drug resistance (VP1 191). In contrast, diversifying pressure in the non-structural genes is less clear, mapping both nearby and beyond characterized functional domains of these factors.ConclusionThis work provides a foundation for understanding HRV genetic diversity and insight into the underlying biology driving evolution in HRV. It expands our knowledge of the genome sequence space that HRV reference serotypes occupy and how the pattern of genetic diversity across HRV genomes differs from other picornaviruses. It also reveals evidence of diversifying selective pressure in both structural genes known to interact with the host immune system and in domains of unassigned function in the non-structural 3C and 3D genes, raising the possibility that diversification of undiscovered functions in these essential factors may influence HRV fitness and evolution.
Highlights
The human rhinoviruses (HRV) are one of the most common and diverse respiratory pathogens of humans
Generation of a representative set of HRV genome sequences for analysis In order to obtain an accurate picture of the genetic diversity and selective pressure across the HRV genome, our first task was to expand the set of 6 fully sequenced HRV serotypes to a larger set of HRV genomes that more fully captured the genetic diversity of the known set of 102 serotypes
We identified 28 additional serotypes from across the HRV gene capsid phylogenies (Additional File 1, Figure S1) that yielded selective pressure results for the VP1 gene that were well-correlated with the results obtained from the full set of 102 HRV serotype VP1 gene sequences (Materials and Methods, Additional file 1, Figure S2)
Summary
The human rhinoviruses (HRV) are one of the most common and diverse respiratory pathogens of humans. Over 100 distinct HRV serotypes are known, yet only 6 genomes are available. Previous comparative genome sequence analyses indicate that recombination drives diversification in multiple genera of the picornavirus family, yet it remains unclear if this holds for HRV. Human rhinoviruses (HRV) are the major cause of the common cold, accounting for as much as 80% of upper respiratory infections in the fall cold season (reviewed in [1]). Despite typically presenting as a mild, self-limited upper respiratory infection, HRVs exact a significant health and economic burden on society in general. Recent evidence suggests that HRV infections may not always be mild or restricted to the upper respiratory tract. HRV infections can cause acute bronchitis in healthy children and adults (especially the elderly), precipitate exacerbations in patients with asthma, chronic obstructive pulmonary disease, and cystic fibrosis, and can lead to fatal pneumonia in immunocompromised patients (reviewed in [9,10,11,12])
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