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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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Related in: MedlinePlus

The rate-shifting pattern at site 34 of Rev, displayed on the phylogenetic tree of all seven subtypes.Each leaf (HIV-1 sequence) is color-coded according to the amino-acid it encodes at this position. Each leaf is labeled by its accession number, subtype (A, B, C, D, F, G, or J), and the encoded residue. The different subtypes are marked at each subclade of the tree. This site is part of the RRE binding domain.
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pcbi-1000214-g003: The rate-shifting pattern at site 34 of Rev, displayed on the phylogenetic tree of all seven subtypes.Each leaf (HIV-1 sequence) is color-coded according to the amino-acid it encodes at this position. Each leaf is labeled by its accession number, subtype (A, B, C, D, F, G, or J), and the encoded residue. The different subtypes are marked at each subclade of the tree. This site is part of the RRE binding domain.

Mentions: Another interesting example of a rate shift at a functional position is site 34 of Rev, which is part of the Rev response element (RRE) binding domain (sites 33–46) [43]. This region in the Rev protein binds the intron-containing viral RNAs, and thus the ribonucleoprotein complex is exported from the nucleus to the cytoplasm. This process is crucial for expression of viral late phase genes that are necessary for viral particle formation [44]. Site 34 in Rev displays a high level of conservation, with threonine encoded at this position throughout the majority of the subtypes (Figure 3). Yet, in subtypes J and the African clade of subtype A, serine is prevalent. Since the two amino acids are quite similar in nature, one might argue that interchanging them has no functional consequence. If so, we would expect both amino-acids to prevail throughout all subtypes. However, it is evident that entire subtypes still “chose” to encode a specific amino-acid at that position. Thus, the shift between the two amino-acids displayed in the above-mentioned clades is likely to represent a genuine functional difference among the subtypes, and in fact may play a role in the binding properties of this region in Rev.


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)

The rate-shifting pattern at site 34 of Rev, displayed on the phylogenetic tree of all seven subtypes.Each leaf (HIV-1 sequence) is color-coded according to the amino-acid it encodes at this position. Each leaf is labeled by its accession number, subtype (A, B, C, D, F, G, or J), and the encoded residue. The different subtypes are marked at each subclade of the tree. This site is part of the RRE binding domain.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000214-g003: The rate-shifting pattern at site 34 of Rev, displayed on the phylogenetic tree of all seven subtypes.Each leaf (HIV-1 sequence) is color-coded according to the amino-acid it encodes at this position. Each leaf is labeled by its accession number, subtype (A, B, C, D, F, G, or J), and the encoded residue. The different subtypes are marked at each subclade of the tree. This site is part of the RRE binding domain.
Mentions: Another interesting example of a rate shift at a functional position is site 34 of Rev, which is part of the Rev response element (RRE) binding domain (sites 33–46) [43]. This region in the Rev protein binds the intron-containing viral RNAs, and thus the ribonucleoprotein complex is exported from the nucleus to the cytoplasm. This process is crucial for expression of viral late phase genes that are necessary for viral particle formation [44]. Site 34 in Rev displays a high level of conservation, with threonine encoded at this position throughout the majority of the subtypes (Figure 3). Yet, in subtypes J and the African clade of subtype A, serine is prevalent. Since the two amino acids are quite similar in nature, one might argue that interchanging them has no functional consequence. If so, we would expect both amino-acids to prevail throughout all subtypes. However, it is evident that entire subtypes still “chose” to encode a specific amino-acid at that position. Thus, the shift between the two amino-acids displayed in the above-mentioned clades is likely to represent a genuine functional difference among the subtypes, and in fact may play a role in the binding properties of this region in Rev.

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