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Constant relative rate of protein evolution and detection of functional diversification among bacterial, archaeal and eukaryotic proteins.

Jordan IK, Kondrashov FA, Rogozin IB, Tatusov RL, Wolf YI, Koonin EV - Genome Biol. (2001)

Bottom Line: Amino-acid sequence evolution rates are significantly correlated on different branches of phylogenetic trees representing the great majority of analyzed orthologous protein sets from all three domains of life.Deviations from this rate constancy are probably due to changes in selective constraints associated with diversification between orthologs.However, the resolution afforded by the test designed specifically for genomic-scale datasets allowed us to identify numerous cases of possible functional diversification between orthologous proteins.

View Article: PubMed Central - HTML - PubMed

Affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD20894, USA. Jordan@ncbi.nlm.nih.gov

ABSTRACT

Background: Detection of changes in a protein's evolutionary rate may reveal cases of change in that protein's function. We developed and implemented a simple relative rates test in an attempt to assess the rate constancy of protein evolution and to detect cases of functional diversification between orthologous proteins. The test was performed on clusters of orthologous protein sequences from complete bacterial genomes (Chlamydia trachomatis, C. muridarum and Chlamydophila pneumoniae), complete archaeal genomes (Pyrococcus horikoshii, P. abyssi and P. furiosus) and partially sequenced mammalian genomes (human, mouse and rat).

Results: Amino-acid sequence evolution rates are significantly correlated on different branches of phylogenetic trees representing the great majority of analyzed orthologous protein sets from all three domains of life. However, approximately 1% of the proteins from each group of species deviates from this pattern and instead shows variation that is consistent with an acceleration of the rate of amino-acid substitution, which may be due to functional diversification. Most of the putative functionally diversified proteins from all three species groups are predicted to function at the periphery of the cells and mediate their interaction with the environment.

Conclusions: Relative rates of protein evolution are remarkably constant for the three species groups analyzed here. Deviations from this rate constancy are probably due to changes in selective constraints associated with diversification between orthologs. Functional diversification between orthologs is thought to be a relatively rare event. However, the resolution afforded by the test designed specifically for genomic-scale datasets allowed us to identify numerous cases of possible functional diversification between orthologous proteins.

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Non-synonymous (Ka) versus synonymous (Ks) substitution rates for the human-mouse-rat orthologous protein sets. (a) Average Ks and Ka for the human-mouse and human-rat pairwise comparisons. (b) Ks and Ka for the mouse-rat pairwise comparisons. Thick diagonal line, Ks = Ka; thin horizontal line, average Ka. All values are shown with circles and the values corresponding to the functionally diversified proteins are indicated by larger squares.
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Figure 4: Non-synonymous (Ka) versus synonymous (Ks) substitution rates for the human-mouse-rat orthologous protein sets. (a) Average Ks and Ka for the human-mouse and human-rat pairwise comparisons. (b) Ks and Ka for the mouse-rat pairwise comparisons. Thick diagonal line, Ks = Ka; thin horizontal line, average Ka. All values are shown with circles and the values corresponding to the functionally diversified proteins are indicated by larger squares.

Mentions: A number of cases of positive selection at the molecular level have been supported by comparison of the rates of synonymous (Ks) and non-synonymous (Ka) substitution [3]. Ka > Ks is considered unequivocal evidence of positive selection [2]. With this in mind, comparisons of Ks and Ka were carried out for the orthologous protein sets that showed a pattern of variation consistent with functional diversification in the whole-genome test (Figure 3). For the bacterial and archaeal species groups, the vast majority of these comparisons were inconclusive because the evolutionary distance between phylogenetic partitions resulted in a saturation of Ks. The more closely related human-mouse-rat group did not show saturation of Ks. Comparisons of Ks and Ka for functionally diversified mammalian protein sets did not reveal any cases with Ka > Ks. This is probably due to the fact that, if directional selection led to the acceleration of the amino-acid substitution rate in these proteins, it acted in an episodic manner [6,7] and on a minority of residues against a constant background of purifying selection [8,9]. This is consistent with previous work suggesting that adaptive changes are difficult to find using the strict Ka > Kscriterion and that even documented cases of positive selection can be missed using this technique alone [6,10,11,12,13]. The average Ka is, however, significantly higher for the putative functionally diversified proteins than for the total dataset (Table 1, Figure 4). The mammalian proteins with an increased rate of amino-acid substitution between the human and rodent lineages also show a level of Ks significantly higher than that of the total dataset (Table 1). This can be explained by the fact that, consistent with previous reports [10,14,15,16,17], we observe a positive correlation between Ks and Ka (r = 0.556, P < 10-10). This correlation could reflect a mechanistic bias in mutation [10,18,19] or synonymous sites may be subject to some degree of selection [20,21,22,23] (or both). However, the Ka/Ks ratio is also significantly higher for the sets of putative functionally diversified proteins (Table 1), indicating a relative acceleration of amino-acid substitution, which could be due to a relaxation of functional constraints and/or directional selection.


Constant relative rate of protein evolution and detection of functional diversification among bacterial, archaeal and eukaryotic proteins.

Jordan IK, Kondrashov FA, Rogozin IB, Tatusov RL, Wolf YI, Koonin EV - Genome Biol. (2001)

Non-synonymous (Ka) versus synonymous (Ks) substitution rates for the human-mouse-rat orthologous protein sets. (a) Average Ks and Ka for the human-mouse and human-rat pairwise comparisons. (b) Ks and Ka for the mouse-rat pairwise comparisons. Thick diagonal line, Ks = Ka; thin horizontal line, average Ka. All values are shown with circles and the values corresponding to the functionally diversified proteins are indicated by larger squares.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC64838&req=5

Figure 4: Non-synonymous (Ka) versus synonymous (Ks) substitution rates for the human-mouse-rat orthologous protein sets. (a) Average Ks and Ka for the human-mouse and human-rat pairwise comparisons. (b) Ks and Ka for the mouse-rat pairwise comparisons. Thick diagonal line, Ks = Ka; thin horizontal line, average Ka. All values are shown with circles and the values corresponding to the functionally diversified proteins are indicated by larger squares.
Mentions: A number of cases of positive selection at the molecular level have been supported by comparison of the rates of synonymous (Ks) and non-synonymous (Ka) substitution [3]. Ka > Ks is considered unequivocal evidence of positive selection [2]. With this in mind, comparisons of Ks and Ka were carried out for the orthologous protein sets that showed a pattern of variation consistent with functional diversification in the whole-genome test (Figure 3). For the bacterial and archaeal species groups, the vast majority of these comparisons were inconclusive because the evolutionary distance between phylogenetic partitions resulted in a saturation of Ks. The more closely related human-mouse-rat group did not show saturation of Ks. Comparisons of Ks and Ka for functionally diversified mammalian protein sets did not reveal any cases with Ka > Ks. This is probably due to the fact that, if directional selection led to the acceleration of the amino-acid substitution rate in these proteins, it acted in an episodic manner [6,7] and on a minority of residues against a constant background of purifying selection [8,9]. This is consistent with previous work suggesting that adaptive changes are difficult to find using the strict Ka > Kscriterion and that even documented cases of positive selection can be missed using this technique alone [6,10,11,12,13]. The average Ka is, however, significantly higher for the putative functionally diversified proteins than for the total dataset (Table 1, Figure 4). The mammalian proteins with an increased rate of amino-acid substitution between the human and rodent lineages also show a level of Ks significantly higher than that of the total dataset (Table 1). This can be explained by the fact that, consistent with previous reports [10,14,15,16,17], we observe a positive correlation between Ks and Ka (r = 0.556, P < 10-10). This correlation could reflect a mechanistic bias in mutation [10,18,19] or synonymous sites may be subject to some degree of selection [20,21,22,23] (or both). However, the Ka/Ks ratio is also significantly higher for the sets of putative functionally diversified proteins (Table 1), indicating a relative acceleration of amino-acid substitution, which could be due to a relaxation of functional constraints and/or directional selection.

Bottom Line: Amino-acid sequence evolution rates are significantly correlated on different branches of phylogenetic trees representing the great majority of analyzed orthologous protein sets from all three domains of life.Deviations from this rate constancy are probably due to changes in selective constraints associated with diversification between orthologs.However, the resolution afforded by the test designed specifically for genomic-scale datasets allowed us to identify numerous cases of possible functional diversification between orthologous proteins.

View Article: PubMed Central - HTML - PubMed

Affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD20894, USA. Jordan@ncbi.nlm.nih.gov

ABSTRACT

Background: Detection of changes in a protein's evolutionary rate may reveal cases of change in that protein's function. We developed and implemented a simple relative rates test in an attempt to assess the rate constancy of protein evolution and to detect cases of functional diversification between orthologous proteins. The test was performed on clusters of orthologous protein sequences from complete bacterial genomes (Chlamydia trachomatis, C. muridarum and Chlamydophila pneumoniae), complete archaeal genomes (Pyrococcus horikoshii, P. abyssi and P. furiosus) and partially sequenced mammalian genomes (human, mouse and rat).

Results: Amino-acid sequence evolution rates are significantly correlated on different branches of phylogenetic trees representing the great majority of analyzed orthologous protein sets from all three domains of life. However, approximately 1% of the proteins from each group of species deviates from this pattern and instead shows variation that is consistent with an acceleration of the rate of amino-acid substitution, which may be due to functional diversification. Most of the putative functionally diversified proteins from all three species groups are predicted to function at the periphery of the cells and mediate their interaction with the environment.

Conclusions: Relative rates of protein evolution are remarkably constant for the three species groups analyzed here. Deviations from this rate constancy are probably due to changes in selective constraints associated with diversification between orthologs. Functional diversification between orthologs is thought to be a relatively rare event. However, the resolution afforded by the test designed specifically for genomic-scale datasets allowed us to identify numerous cases of possible functional diversification between orthologous proteins.

Show MeSH
Related in: MedlinePlus