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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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Identification of two sequence groups (G1 and G2) tightly clustered in the VP1 unique region.A. A Phyml maximum likelihood (ML) tree for R1 region was generated for a dataset of 29 sequences (see selection in Table S1). AAV4 was used as the outgroup and the bootstrap scores greater than 80 % are shown. Tightly clustered sequence groups, G1 of 15 sequences and G2 of 10 sequences, were identified and indicated. A similar tree was obtained using neighbour-joining method and its bootstrap scores that support G1 and G2 clustering are shown in parentheses. B. An ML tree for the full-length cap was obtained and shown in the same way as the R1 tree (Panel A). C. Average group LOHA profiles based on the nucleotide alignment are shown. Percent mismatch scores across a sliding window of 101 Nt positions for all possible pairs between all 29 sequences (Control), 15 G1 sequences (G1) and 10 G2 sequences (G2) were averaged and plotted against the nucleotide positions. D. Similar average LOHA profiles with 33 a.a. window size were obtained based on the amino acid sequence alignment.
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pone-0001634-g003: Identification of two sequence groups (G1 and G2) tightly clustered in the VP1 unique region.A. A Phyml maximum likelihood (ML) tree for R1 region was generated for a dataset of 29 sequences (see selection in Table S1). AAV4 was used as the outgroup and the bootstrap scores greater than 80 % are shown. Tightly clustered sequence groups, G1 of 15 sequences and G2 of 10 sequences, were identified and indicated. A similar tree was obtained using neighbour-joining method and its bootstrap scores that support G1 and G2 clustering are shown in parentheses. B. An ML tree for the full-length cap was obtained and shown in the same way as the R1 tree (Panel A). C. Average group LOHA profiles based on the nucleotide alignment are shown. Percent mismatch scores across a sliding window of 101 Nt positions for all possible pairs between all 29 sequences (Control), 15 G1 sequences (G1) and 10 G2 sequences (G2) were averaged and plotted against the nucleotide positions. D. Similar average LOHA profiles with 33 a.a. window size were obtained based on the amino acid sequence alignment.

Mentions: 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).


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

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

Identification of two sequence groups (G1 and G2) tightly clustered in the VP1 unique region.A. A Phyml maximum likelihood (ML) tree for R1 region was generated for a dataset of 29 sequences (see selection in Table S1). AAV4 was used as the outgroup and the bootstrap scores greater than 80 % are shown. Tightly clustered sequence groups, G1 of 15 sequences and G2 of 10 sequences, were identified and indicated. A similar tree was obtained using neighbour-joining method and its bootstrap scores that support G1 and G2 clustering are shown in parentheses. B. An ML tree for the full-length cap was obtained and shown in the same way as the R1 tree (Panel A). C. Average group LOHA profiles based on the nucleotide alignment are shown. Percent mismatch scores across a sliding window of 101 Nt positions for all possible pairs between all 29 sequences (Control), 15 G1 sequences (G1) and 10 G2 sequences (G2) were averaged and plotted against the nucleotide positions. D. Similar average LOHA profiles with 33 a.a. window size were obtained based on the amino acid sequence alignment.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2238796&req=5

pone-0001634-g003: Identification of two sequence groups (G1 and G2) tightly clustered in the VP1 unique region.A. A Phyml maximum likelihood (ML) tree for R1 region was generated for a dataset of 29 sequences (see selection in Table S1). AAV4 was used as the outgroup and the bootstrap scores greater than 80 % are shown. Tightly clustered sequence groups, G1 of 15 sequences and G2 of 10 sequences, were identified and indicated. A similar tree was obtained using neighbour-joining method and its bootstrap scores that support G1 and G2 clustering are shown in parentheses. B. An ML tree for the full-length cap was obtained and shown in the same way as the R1 tree (Panel A). C. Average group LOHA profiles based on the nucleotide alignment are shown. Percent mismatch scores across a sliding window of 101 Nt positions for all possible pairs between all 29 sequences (Control), 15 G1 sequences (G1) and 10 G2 sequences (G2) were averaged and plotted against the nucleotide positions. D. Similar average LOHA profiles with 33 a.a. window size were obtained based on the amino acid sequence alignment.
Mentions: 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).

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