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Recombination and population mosaic of a multifunctional viral gene, adeno-associated virus cap.

Takeuchi Y, Myers R, Danos O - PLoS ONE (2008)

Bottom Line: Homologous recombination is a dominant force in evolution and results in genetic mosaics.Recombination events in this region preserve protein blocks of distinctive functions and contribute to convergence in VP1u and divergence of the rest of cap.Additionally the possible biological significance of two dominant VP1u forms is inferred.

View Article: PubMed Central - PubMed

Affiliation: Medical Reserach Council (MRC)/UCL Centre for Medical Molecular Virology, Division of Infection and Immunology, University College London, London, United Kingdom. y.takeuchi@ucl.ac.uk

ABSTRACT
Homologous recombination is a dominant force in evolution and results in genetic mosaics. To detect evidence of recombination events and assess the biological significance of genetic mosaics, genome sequences for various viral populations of reasonably large size are now available in the GenBank. We studied a multi-functional viral gene, the adeno-associated virus (AAV) cap gene, which codes for three capsid proteins, VP1, VP2 and VP3. VP1-3 share a common C-terminal domain corresponding to VP3, which forms the viral core structure, while the VP1 unique N-terminal part contains an enzymatic domain with phospholipase A2 activity. Our recombinant detection program (RecI) revealed five novel recombination events, four of which have their cross-over points in the N-terminal, VP1 and VP2 unique region. Comparison of phylogenetic trees for different cap gene regions confirmed discordant phylogenies for the recombinant sequences. Furthermore, differences in the phylogenetic tree structures for the VP1 unique (VP1u) region and the rest of cap highlighted the mosaic nature of cap gene in the AAV population: two dominant forms of VP1u sequences were identified and these forms are linked to diverse sequences in the rest of cap gene. This observation together with the finding of frequent recombination in the VP1 and 2 unique regions suggests that this region is a recombination hot spot. Recombination events in this region preserve protein blocks of distinctive functions and contribute to convergence in VP1u and divergence of the rest of cap. Additionally the possible biological significance of two dominant VP1u forms is inferred.

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Profiles and cross-over points of novel recombination in the AAV cap gene.A. Schematic drawing of the cap gene products (VP1-3) with five recombination cross-over points inferred by LOHA analyses below (triangles colour-coordinated with Panels B-F) is shown. Viral phospholipase A and antigenic GH loop domains are indicated. B–F. Recombination profiles for representative combinations of 3 sequences (recombinant/parent 1×parent 2) were visualised by the LOHA analysis. Percent mismatch across a sliding window of 41 Nt positions between recombinant/parent pairs were plotted against the nucleotide positions along the multiple alignment with a step interval of 1 position. The x-axis also indicates three regions (R1-3) separately analysed in the following studies (see Fig 2 and 3).
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pone-0001634-g001: Profiles and cross-over points of novel recombination in the AAV cap gene.A. Schematic drawing of the cap gene products (VP1-3) with five recombination cross-over points inferred by LOHA analyses below (triangles colour-coordinated with Panels B-F) is shown. Viral phospholipase A and antigenic GH loop domains are indicated. B–F. Recombination profiles for representative combinations of 3 sequences (recombinant/parent 1×parent 2) were visualised by the LOHA analysis. Percent mismatch across a sliding window of 41 Nt positions between recombinant/parent pairs were plotted against the nucleotide positions along the multiple alignment with a step interval of 1 position. The x-axis also indicates three regions (R1-3) separately analysed in the following studies (see Fig 2 and 3).

Mentions: Parvoviruses are eukaryotic viruses that infect a wide variety of hosts from insects to human and non-human primates. They are composed of a small icosahedral capsid, 22 to 24 nm in diameter into which is packaged a single stranded DNA genome of less than 5.6 kilobases with terminal palindromic sequences. In recent years, studies of the carnivore parvovirus subgroup have allowed the observation of cross species transmission between cat and dog populations. This host range shift was due to a high mutation rate in the capsid protein gene that enabled rapid adaptation to a new cell surface receptor [1], [2]. Host range variation has also been studied among Adeno-Associated Viruses (AAV), which are helper-dependent Parvoviruses (dependoviruses) with great potential as gene transfer vectors [3]. The capsid of AAV is formed by three proteins, VP1, VP2 and VP3 which are encoded by the same cap gene and differ in their N-terminal domain (Fig 1A). The common C-terminal domain corresponds to VP3 and folds into capsomer units that display a typical beta-barrel structure [4] with solvent exposed loops of variable amino-acids sequences. These variable regions of VP3 form the structural elements that recognize cell surface receptors. About one tenth of the capsomers are VP1 or VP2 and display additional N-terminal domains.


Recombination and population mosaic of a multifunctional viral gene, adeno-associated virus cap.

Takeuchi Y, Myers R, Danos O - PLoS ONE (2008)

Profiles and cross-over points of novel recombination in the AAV cap gene.A. Schematic drawing of the cap gene products (VP1-3) with five recombination cross-over points inferred by LOHA analyses below (triangles colour-coordinated with Panels B-F) is shown. Viral phospholipase A and antigenic GH loop domains are indicated. B–F. Recombination profiles for representative combinations of 3 sequences (recombinant/parent 1×parent 2) were visualised by the LOHA analysis. Percent mismatch across a sliding window of 41 Nt positions between recombinant/parent pairs were plotted against the nucleotide positions along the multiple alignment with a step interval of 1 position. The x-axis also indicates three regions (R1-3) separately analysed in the following studies (see Fig 2 and 3).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2238796&req=5

pone-0001634-g001: Profiles and cross-over points of novel recombination in the AAV cap gene.A. Schematic drawing of the cap gene products (VP1-3) with five recombination cross-over points inferred by LOHA analyses below (triangles colour-coordinated with Panels B-F) is shown. Viral phospholipase A and antigenic GH loop domains are indicated. B–F. Recombination profiles for representative combinations of 3 sequences (recombinant/parent 1×parent 2) were visualised by the LOHA analysis. Percent mismatch across a sliding window of 41 Nt positions between recombinant/parent pairs were plotted against the nucleotide positions along the multiple alignment with a step interval of 1 position. The x-axis also indicates three regions (R1-3) separately analysed in the following studies (see Fig 2 and 3).
Mentions: Parvoviruses are eukaryotic viruses that infect a wide variety of hosts from insects to human and non-human primates. They are composed of a small icosahedral capsid, 22 to 24 nm in diameter into which is packaged a single stranded DNA genome of less than 5.6 kilobases with terminal palindromic sequences. In recent years, studies of the carnivore parvovirus subgroup have allowed the observation of cross species transmission between cat and dog populations. This host range shift was due to a high mutation rate in the capsid protein gene that enabled rapid adaptation to a new cell surface receptor [1], [2]. Host range variation has also been studied among Adeno-Associated Viruses (AAV), which are helper-dependent Parvoviruses (dependoviruses) with great potential as gene transfer vectors [3]. The capsid of AAV is formed by three proteins, VP1, VP2 and VP3 which are encoded by the same cap gene and differ in their N-terminal domain (Fig 1A). The common C-terminal domain corresponds to VP3 and folds into capsomer units that display a typical beta-barrel structure [4] with solvent exposed loops of variable amino-acids sequences. These variable regions of VP3 form the structural elements that recognize cell surface receptors. About one tenth of the capsomers are VP1 or VP2 and display additional N-terminal domains.

Bottom Line: Homologous recombination is a dominant force in evolution and results in genetic mosaics.Recombination events in this region preserve protein blocks of distinctive functions and contribute to convergence in VP1u and divergence of the rest of cap.Additionally the possible biological significance of two dominant VP1u forms is inferred.

View Article: PubMed Central - PubMed

Affiliation: Medical Reserach Council (MRC)/UCL Centre for Medical Molecular Virology, Division of Infection and Immunology, University College London, London, United Kingdom. y.takeuchi@ucl.ac.uk

ABSTRACT
Homologous recombination is a dominant force in evolution and results in genetic mosaics. To detect evidence of recombination events and assess the biological significance of genetic mosaics, genome sequences for various viral populations of reasonably large size are now available in the GenBank. We studied a multi-functional viral gene, the adeno-associated virus (AAV) cap gene, which codes for three capsid proteins, VP1, VP2 and VP3. VP1-3 share a common C-terminal domain corresponding to VP3, which forms the viral core structure, while the VP1 unique N-terminal part contains an enzymatic domain with phospholipase A2 activity. Our recombinant detection program (RecI) revealed five novel recombination events, four of which have their cross-over points in the N-terminal, VP1 and VP2 unique region. Comparison of phylogenetic trees for different cap gene regions confirmed discordant phylogenies for the recombinant sequences. Furthermore, differences in the phylogenetic tree structures for the VP1 unique (VP1u) region and the rest of cap highlighted the mosaic nature of cap gene in the AAV population: two dominant forms of VP1u sequences were identified and these forms are linked to diverse sequences in the rest of cap gene. This observation together with the finding of frequent recombination in the VP1 and 2 unique regions suggests that this region is a recombination hot spot. Recombination events in this region preserve protein blocks of distinctive functions and contribute to convergence in VP1u and divergence of the rest of cap. Additionally the possible biological significance of two dominant VP1u forms is inferred.

Show MeSH
Related in: MedlinePlus