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Evolutionary modeling of rate shifts reveals specificity determinants in HIV-1 subtypes.

Penn O, Stern A, Rubinstein ND, Dutheil J, Bacharach E, Galtier N, Pupko T - PLoS Comput. Biol. (2008)

Bottom Line: Most of these rate shifts have occurred during the divergence of the major subtypes, establishing that subtype divergence occurred together with functional diversification.When focusing on the rate-shifting sites detected, we find that many are associated with known function relating to viral life cycle and drug resistance.Finally, we discuss mechanisms of covariation of rate-shifting sites.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Research and Immunology, George S Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.

ABSTRACT
A hallmark of the human immunodeficiency virus 1 (HIV-1) is its rapid rate of evolution within and among its various subtypes. Two complementary hypotheses are suggested to explain the sequence variability among HIV-1 subtypes. The first suggests that the functional constraints at each site remain the same across all subtypes, and the differences among subtypes are a direct reflection of random substitutions, which have occurred during the time elapsed since their divergence. The alternative hypothesis suggests that the functional constraints themselves have evolved, and thus sequence differences among subtypes in some sites reflect shifts in function. To determine the contribution of each of these two alternatives to HIV-1 subtype evolution, we have developed a novel Bayesian method for testing and detecting site-specific rate shifts. The RAte Shift EstimatoR (RASER) method determines whether or not site-specific functional shifts characterize the evolution of a protein and, if so, points to the specific sites and lineages in which these shifts have most likely occurred. Applying RASER to a dataset composed of large samples of HIV-1 sequences from different group M subtypes, we reveal rampant evolutionary shifts throughout the HIV-1 proteome. Most of these rate shifts have occurred during the divergence of the major subtypes, establishing that subtype divergence occurred together with functional diversification. We report further evidence for the emergence of a new sub-subtype, characterized by abundant rate-shifting sites. When focusing on the rate-shifting sites detected, we find that many are associated with known function relating to viral life cycle and drug resistance. Finally, we discuss mechanisms of covariation of rate-shifting sites.

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Phylogenetic tree of all nine concatenated datasets of the ORFs.The different subtypes are marked at each subclade of the tree. Branches in red are the top scoring lineages for which rate shifts were found. Arrows mark the two distinct clades of subtype A (see text for details).
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pcbi-1000214-g001: Phylogenetic tree of all nine concatenated datasets of the ORFs.The different subtypes are marked at each subclade of the tree. Branches in red are the top scoring lineages for which rate shifts were found. Arrows mark the two distinct clades of subtype A (see text for details).

Mentions: We next asked whether this pattern of rate shifts throughout all the nine ORFs can be ascribed to the temporal pattern across the phylogeny, which also represents the divergence into the different subtypes. We thus developed a method based on a Bayesian approach to map significant rate-shifting sites to specific lineages. The method also reports whether a rate shift corresponds to an acceleration or deceleration of the rate at the inferred lineage. Figure 1 shows the top ten lineages for which the most rate-shifting sites were found. The majority of these lineages are ones that separate between different subtypes. Together with the above described results, this result conclusively points to the fact that the sequence-based differences among the subtypes cannot be attributed to random stochastic changes alone, but are, at least in part, a consequence of functional requirements that arose following the emergence of the subtypes. Accordingly, each subtype is characterized by specific specificity determinant sites which display a unique pattern as compared to other subtypes. Table S2 summarizes all the rate-shifting sites for each subtype, according to accelerations and decelerations.


Evolutionary modeling of rate shifts reveals specificity determinants in HIV-1 subtypes.

Penn O, Stern A, Rubinstein ND, Dutheil J, Bacharach E, Galtier N, Pupko T - PLoS Comput. Biol. (2008)

Phylogenetic tree of all nine concatenated datasets of the ORFs.The different subtypes are marked at each subclade of the tree. Branches in red are the top scoring lineages for which rate shifts were found. Arrows mark the two distinct clades of subtype A (see text for details).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2566816&req=5

pcbi-1000214-g001: Phylogenetic tree of all nine concatenated datasets of the ORFs.The different subtypes are marked at each subclade of the tree. Branches in red are the top scoring lineages for which rate shifts were found. Arrows mark the two distinct clades of subtype A (see text for details).
Mentions: We next asked whether this pattern of rate shifts throughout all the nine ORFs can be ascribed to the temporal pattern across the phylogeny, which also represents the divergence into the different subtypes. We thus developed a method based on a Bayesian approach to map significant rate-shifting sites to specific lineages. The method also reports whether a rate shift corresponds to an acceleration or deceleration of the rate at the inferred lineage. Figure 1 shows the top ten lineages for which the most rate-shifting sites were found. The majority of these lineages are ones that separate between different subtypes. Together with the above described results, this result conclusively points to the fact that the sequence-based differences among the subtypes cannot be attributed to random stochastic changes alone, but are, at least in part, a consequence of functional requirements that arose following the emergence of the subtypes. Accordingly, each subtype is characterized by specific specificity determinant sites which display a unique pattern as compared to other subtypes. Table S2 summarizes all the rate-shifting sites for each subtype, according to accelerations and decelerations.

Bottom Line: Most of these rate shifts have occurred during the divergence of the major subtypes, establishing that subtype divergence occurred together with functional diversification.When focusing on the rate-shifting sites detected, we find that many are associated with known function relating to viral life cycle and drug resistance.Finally, we discuss mechanisms of covariation of rate-shifting sites.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Research and Immunology, George S Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.

ABSTRACT
A hallmark of the human immunodeficiency virus 1 (HIV-1) is its rapid rate of evolution within and among its various subtypes. Two complementary hypotheses are suggested to explain the sequence variability among HIV-1 subtypes. The first suggests that the functional constraints at each site remain the same across all subtypes, and the differences among subtypes are a direct reflection of random substitutions, which have occurred during the time elapsed since their divergence. The alternative hypothesis suggests that the functional constraints themselves have evolved, and thus sequence differences among subtypes in some sites reflect shifts in function. To determine the contribution of each of these two alternatives to HIV-1 subtype evolution, we have developed a novel Bayesian method for testing and detecting site-specific rate shifts. The RAte Shift EstimatoR (RASER) method determines whether or not site-specific functional shifts characterize the evolution of a protein and, if so, points to the specific sites and lineages in which these shifts have most likely occurred. Applying RASER to a dataset composed of large samples of HIV-1 sequences from different group M subtypes, we reveal rampant evolutionary shifts throughout the HIV-1 proteome. Most of these rate shifts have occurred during the divergence of the major subtypes, establishing that subtype divergence occurred together with functional diversification. We report further evidence for the emergence of a new sub-subtype, characterized by abundant rate-shifting sites. When focusing on the rate-shifting sites detected, we find that many are associated with known function relating to viral life cycle and drug resistance. Finally, we discuss mechanisms of covariation of rate-shifting sites.

Show MeSH
Related in: MedlinePlus