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Strong Selection Significantly Increases Epistatic Interactions in the Long-Term Evolution of a Protein.

Gupta A, Adami C - PLoS Genet. (2016)

Bottom Line: While epistasis is thought to enhance evolvability via valley-crossing early-on in adaptation, it can hinder adaptation later when the landscape has turned rugged.However, we find no evidence that the HIV-1 protease has reached its potential for evolution after 9 years of adapting to a drug environment that itself is constantly changing.We suggest that the mechanism of encoding new information into pairwise interactions is central to protein evolution not just in HIV-1 protease, but for any protein adapting to a changing environment.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, United States of America.

ABSTRACT
Epistatic interactions between residues determine a protein's adaptability and shape its evolutionary trajectory. When a protein experiences a changed environment, it is under strong selection to find a peak in the new fitness landscape. It has been shown that strong selection increases epistatic interactions as well as the ruggedness of the fitness landscape, but little is known about how the epistatic interactions change under selection in the long-term evolution of a protein. Here we analyze the evolution of epistasis in the protease of the human immunodeficiency virus type 1 (HIV-1) using protease sequences collected for almost a decade from both treated and untreated patients, to understand how epistasis changes and how those changes impact the long-term evolvability of a protein. We use an information-theoretic proxy for epistasis that quantifies the co-variation between sites, and show that positive information is a necessary (but not sufficient) condition that detects epistasis in most cases. We analyze the "fossils" of the evolutionary trajectories of the protein contained in the sequence data, and show that epistasis continues to enrich under strong selection, but not for proteins whose environment is unchanged. The increase in epistasis compensates for the information loss due to sequence variability brought about by treatment, and facilitates adaptation in the increasingly rugged fitness landscape of treatment. While epistasis is thought to enhance evolvability via valley-crossing early-on in adaptation, it can hinder adaptation later when the landscape has turned rugged. However, we find no evidence that the HIV-1 protease has reached its potential for evolution after 9 years of adapting to a drug environment that itself is constantly changing. We suggest that the mechanism of encoding new information into pairwise interactions is central to protein evolution not just in HIV-1 protease, but for any protein adapting to a changing environment.

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Changes in protease entropy and physico-chemical properties.Changes in per-site entropies (top panel), residue isoelectric point (middle panel), and residue weights (bottom panel) due to treatment. The property difference at each site is obtained by subtracting property (entropy/pI/residue-weight) value of the untreated data from that of the treated data. Average values are obtained by sampling sequence data from all years (1998–2006, 10 subsamples/year of 300 sequences each). Error bars represent ±1 SE. Red dots represent positions known to be primary drug resistance loci, while black dots mark positions of compensatory or accessory mutations [52]. Resistance loci are shaded in red and accessory loci are shaded in black.
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pgen.1005960.g002: Changes in protease entropy and physico-chemical properties.Changes in per-site entropies (top panel), residue isoelectric point (middle panel), and residue weights (bottom panel) due to treatment. The property difference at each site is obtained by subtracting property (entropy/pI/residue-weight) value of the untreated data from that of the treated data. Average values are obtained by sampling sequence data from all years (1998–2006, 10 subsamples/year of 300 sequences each). Error bars represent ±1 SE. Red dots represent positions known to be primary drug resistance loci, while black dots mark positions of compensatory or accessory mutations [52]. Resistance loci are shaded in red and accessory loci are shaded in black.

Mentions: A closer look at the protease positions with increasing residue variability reveals that the protein loci that have undergone a marked increase in variation have been previously associated with drug resistance (Fig 2 top panel) [52]. Position 63 is the only site that becomes significantly less variable upon treatment. Many of the changes in entropy at each position correlate well with physico-chemical changes (such as changes in the iso-electric point pI or in the residue weight) at those positions (Spearman correlation coefficient between absolute values of entropy difference and pI difference: R = 0.738, p = 2.95 × 10−18; Spearman R between absolute values of entropy difference and residue weight difference: R = 0.819, p = 3.52 × 10−25) suggesting that these changes are adaptive and influence the function of the protein in its new environment (see S3 Text and Fig 2, middle and lower panels). Leucine at position 10 is substituted by the slightly heavier isoleucine, a compensatory mutation showing a slight increase in residue weight difference (Fig 2, bottom panel, L10I is a compensatory mutation as shown in [52, 53]); lysine is replaced by a more basic arginine residue at position 20, another compensatory mutation as arginine can form more electrostatic interactions compared to lysine and thus enhances protein stability [52, 54]; and aspartic acid is substituted by the uncharged asparagine at position 30, a strong resistance mutation [52, 55]. While the residue physico-chemical properties discussed here are not exhaustive, the significant positive correlation between changes in these properties and changes in residue variability suggest that the residue variation brought about by treatment is non-random.


Strong Selection Significantly Increases Epistatic Interactions in the Long-Term Evolution of a Protein.

Gupta A, Adami C - PLoS Genet. (2016)

Changes in protease entropy and physico-chemical properties.Changes in per-site entropies (top panel), residue isoelectric point (middle panel), and residue weights (bottom panel) due to treatment. The property difference at each site is obtained by subtracting property (entropy/pI/residue-weight) value of the untreated data from that of the treated data. Average values are obtained by sampling sequence data from all years (1998–2006, 10 subsamples/year of 300 sequences each). Error bars represent ±1 SE. Red dots represent positions known to be primary drug resistance loci, while black dots mark positions of compensatory or accessory mutations [52]. Resistance loci are shaded in red and accessory loci are shaded in black.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4814079&req=5

pgen.1005960.g002: Changes in protease entropy and physico-chemical properties.Changes in per-site entropies (top panel), residue isoelectric point (middle panel), and residue weights (bottom panel) due to treatment. The property difference at each site is obtained by subtracting property (entropy/pI/residue-weight) value of the untreated data from that of the treated data. Average values are obtained by sampling sequence data from all years (1998–2006, 10 subsamples/year of 300 sequences each). Error bars represent ±1 SE. Red dots represent positions known to be primary drug resistance loci, while black dots mark positions of compensatory or accessory mutations [52]. Resistance loci are shaded in red and accessory loci are shaded in black.
Mentions: A closer look at the protease positions with increasing residue variability reveals that the protein loci that have undergone a marked increase in variation have been previously associated with drug resistance (Fig 2 top panel) [52]. Position 63 is the only site that becomes significantly less variable upon treatment. Many of the changes in entropy at each position correlate well with physico-chemical changes (such as changes in the iso-electric point pI or in the residue weight) at those positions (Spearman correlation coefficient between absolute values of entropy difference and pI difference: R = 0.738, p = 2.95 × 10−18; Spearman R between absolute values of entropy difference and residue weight difference: R = 0.819, p = 3.52 × 10−25) suggesting that these changes are adaptive and influence the function of the protein in its new environment (see S3 Text and Fig 2, middle and lower panels). Leucine at position 10 is substituted by the slightly heavier isoleucine, a compensatory mutation showing a slight increase in residue weight difference (Fig 2, bottom panel, L10I is a compensatory mutation as shown in [52, 53]); lysine is replaced by a more basic arginine residue at position 20, another compensatory mutation as arginine can form more electrostatic interactions compared to lysine and thus enhances protein stability [52, 54]; and aspartic acid is substituted by the uncharged asparagine at position 30, a strong resistance mutation [52, 55]. While the residue physico-chemical properties discussed here are not exhaustive, the significant positive correlation between changes in these properties and changes in residue variability suggest that the residue variation brought about by treatment is non-random.

Bottom Line: While epistasis is thought to enhance evolvability via valley-crossing early-on in adaptation, it can hinder adaptation later when the landscape has turned rugged.However, we find no evidence that the HIV-1 protease has reached its potential for evolution after 9 years of adapting to a drug environment that itself is constantly changing.We suggest that the mechanism of encoding new information into pairwise interactions is central to protein evolution not just in HIV-1 protease, but for any protein adapting to a changing environment.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, United States of America.

ABSTRACT
Epistatic interactions between residues determine a protein's adaptability and shape its evolutionary trajectory. When a protein experiences a changed environment, it is under strong selection to find a peak in the new fitness landscape. It has been shown that strong selection increases epistatic interactions as well as the ruggedness of the fitness landscape, but little is known about how the epistatic interactions change under selection in the long-term evolution of a protein. Here we analyze the evolution of epistasis in the protease of the human immunodeficiency virus type 1 (HIV-1) using protease sequences collected for almost a decade from both treated and untreated patients, to understand how epistasis changes and how those changes impact the long-term evolvability of a protein. We use an information-theoretic proxy for epistasis that quantifies the co-variation between sites, and show that positive information is a necessary (but not sufficient) condition that detects epistasis in most cases. We analyze the "fossils" of the evolutionary trajectories of the protein contained in the sequence data, and show that epistasis continues to enrich under strong selection, but not for proteins whose environment is unchanged. The increase in epistasis compensates for the information loss due to sequence variability brought about by treatment, and facilitates adaptation in the increasingly rugged fitness landscape of treatment. While epistasis is thought to enhance evolvability via valley-crossing early-on in adaptation, it can hinder adaptation later when the landscape has turned rugged. However, we find no evidence that the HIV-1 protease has reached its potential for evolution after 9 years of adapting to a drug environment that itself is constantly changing. We suggest that the mechanism of encoding new information into pairwise interactions is central to protein evolution not just in HIV-1 protease, but for any protein adapting to a changing environment.

Show MeSH
Related in: MedlinePlus