Correction: Within-patient mutation frequencies reveal fitness costs of CpG dinucleotides and drastic amino acid changes in HIV

AbstractHIV has a high mutation rate, which contributes to its ability to evolve quickly. However, we know little about the fitness costs of individual HIV mutationsin vivo, their distribution and the different factors shaping the viral fitness landscape. We calculated the mean frequency of transition mutations at 870 sites of thepolgene in 160 patients, allowing us to determine the cost of these mutations. As expected, we found high costs for non-synonymous and nonsense mutations as compared to synonymous mutations. In addition, we found that non-synonymous mutations that lead to drastic amino acid changes are twice as costly as those that do not and mutations that create new CpG dinucleotides are also twice as costly as those that do not. We also found that G→A and C→T mutations are more costly than A→G mutations. We anticipate that our newin vivofrequency-based approach will provide insights into the fitness landscape and evolvability of not only HIV, but a variety of microbes.Author summaryHIV’s high mutation rate allows it to evolve quickly. However, most mutations probably reduce the virus’ ability to replicate – they are costly to the virus. Until now, the actual cost of mutations is not well understood. We used within-patient mutation frequencies to estimate the cost of 870 HIV mutationsin vivo. As expected, we found high costs for non-synonymous and nonsense mutations. In addition, we found surprisingly high costs for mutations that lead to drastic amino acid changes, mutations that create new CpG sites (possibly because they trigger the host’s immune system), and G→A and C→T mutations. Our results demonstrate the power of analyzing mutant frequencies fromin vivoviral populations to study costs of mutations. A better understanding of fitness costs will help to predict the evolution of HIV.

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Within-patient mutation frequencies reveal fitness costs of CpG dinucleotides and drastic amino acid changes in HIV

PLoS Genetics ◽

10.1371/journal.pgen.1007420 ◽

2018 ◽

Vol 14 (6) ◽

pp. e1007420 ◽

Cited By ~ 20

Author(s):

Kristof Theys ◽

Alison F. Feder ◽

Maoz Gelbart ◽

Marion Hartl ◽

Adi Stern ◽

...

Keyword(s):

Amino Acid ◽

Fitness Costs ◽

Cpg Dinucleotides ◽

Patient Mutation

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Fitness Costs Limit Viral Escape from Cytotoxic T Lymphocytes at a Structurally Constrained Epitope

Journal of Virology ◽

10.1128/jvi.78.24.13901-13910.2004 ◽

2004 ◽

Vol 78 (24) ◽

pp. 13901-13910 ◽

Cited By ~ 76

Author(s):

Fred W. Peyerl ◽

Heidi S. Bazick ◽

Michael H. Newberg ◽

Dan H. Barouch ◽

Joseph Sodroski ◽

...

Keyword(s):

Amino Acid ◽

T Lymphocytes ◽

Cytotoxic T Lymphocytes ◽

Point Mutations ◽

Viral Escape ◽

Amino Acid Substitutions ◽

Fitness Costs ◽

Gag Protein ◽

Ctl Epitope ◽

Immunodeficiency Virus

ABSTRACT The intense selection pressure exerted by virus-specific cytotoxic T lymphocytes (CTL) on replicating human immunodeficiency virus and simian immunodeficiency virus results in the accumulation of CTL epitope mutations. It has been assumed that fitness costs can limit the evolution of CTL epitope mutations. However, only a limited number of studies have carefully examined this possibility. To explore the fitness costs associated with viral escape from p11C, C-M-specific CTL, we constructed a panel of viruses encoding point mutations at each position of the entire p11C, C-M epitope. Amino acid substitutions at positions 3, 4, 5, 6, 7, and 9 of the epitope significantly impaired virus replication by altering virus production and Gag protein expression as well as by destabilizing mature cores. Amino acid substitutions at position 2 of the epitope were tolerated but required reversion or additional compensatory mutations to generate replication-competent viruses. Finally, while amino acid substitutions at positions 1 and 8 of the p11C, C-M epitope were functionally tolerated, these substitutions were recognized by p11C, C-M-specific CTL and therefore provided no selection advantage for the virus. Together, these data suggest that limited sequence variation is tolerated by the region of the capsid encoding the p11C, C-M epitope and therefore that only a very limited number of mutations can allow successful viral escape from the p11C, C-M-specific CTL response.

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Methods for Incorporating the Hypermutability of CpG Dinucleotides in Detecting Natural Selection Operating at the Amino Acid Sequence Level

Molecular Biology and Evolution ◽

10.1093/molbev/msp133 ◽

2009 ◽

Vol 26 (10) ◽

pp. 2275-2284 ◽

Cited By ~ 12

Author(s):

Y. Suzuki ◽

T. Gojobori ◽

S. Kumar

Keyword(s):

Natural Selection ◽

Amino Acid ◽

Amino Acid Sequence ◽

Amino Acid Sequence Level ◽

Cpg Dinucleotides

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Nutrient limitation magnifies fitness costs of antimalarial drug resistance mutations

10.1101/2021.08.02.454586 ◽

2021 ◽

Author(s):

Shalini K Nair ◽

Xue Li ◽

Grace Ann Arya ◽

Marina McDew-White ◽

Marco Ferrari ◽

...

Keyword(s):

Drug Resistance ◽

Amino Acid ◽

Resource Competition ◽

Culture Media ◽

Fold Increase ◽

Single Amino Acid ◽

Resistance Mutations ◽

Fitness Costs ◽

Drug Resistance Mutations ◽

The Impact

Drug resistance mutations tend to disrupt key physiological processes, and therefore carry a fitness cost. The size of these fitness costs is a central determinant of the rate of spread of these mutations in natural populations so are important to quantify. Head-to-head competition assays provide a standard approach to measuring differential fitness, and have been used extensively for malaria parasites. These assays typically use standardized culture media, containing RPMI 1640, which has a 1.4 to 5.5-fold (mean: 2.6-fold) higher concentration of amino acids than human blood. In this rich media we predict that fitness costs will be underestimated because resource competition is weak. We tested this prediction using an artemisinin sensitive parasite edited to contain kelch-C580Y or R561H mutations conferring resistance to artemisinin or synonymous control mutations. We examined the impact of these single amino acid mutations on fitness, using replicated head-to head competition experiments conducted in media containing (i) normal RPMI, (ii) modified RPMI with reduced amino acid concentration, (iii) RPMI containing only isoleucine, or (iv) 3-fold diluted RPMI. We found a significant 1.3 to 1.4-fold increase in fitness costs measured in modified and isoleucine-only media relative to normal media, while fitness costs were 2.5-fold higher in diluted media. We conclude that fitness costs are strongly affected by media composition and will be significantly underestimated in normal RPMI. Elevated fitness costs in nature will limit spread of ART-resistance but will also promote evolution of compensatory mutations that restore fitness, and can be exploited to maximize selection in laboratory experiments.

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The staining pattern of the tropomyosin sequence is displayed in a new paracrystal

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100142372 ◽

1986 ◽

Vol 44 ◽

pp. 150-151

Author(s):

M.K. Lamvik ◽

L.L. Klatt

Keyword(s):

Amino Acid ◽

Amino Acid Sequence ◽

Staining Pattern ◽

Banding Patterns ◽

Mass Thickness ◽

New Form

Tropomyosin paracrystals have been used extensively as test specimens and magnification standards due to their clear periodic banding patterns. The paracrystal type discovered by Ohtsuki1 has been of particular interest as a test of unstained specimens because of alternating bands that differ by 50% in mass thickness. While producing specimens of this type, we came across a new paracrystal form. Since this new form displays aligned tropomyosin molecules without the overlaps that are characteristic of the Ohtsuki-type paracrystal, it presents a staining pattern that corresponds to the amino acid sequence of the molecule.

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Electron probe x-ray microanalysis and electron microscopy of amino acid absorption and transport by the small intestine: inhibition by chemical poisons and correlation to the elemental composition of the epithelial cells

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100142311 ◽

1986 ◽

Vol 44 ◽

pp. 134-135

Author(s):

A. J. Tousimis

Keyword(s):

Small Intestine ◽

Amino Acid ◽

Epithelial Cells ◽

Elemental Composition ◽

Isotope Labeling ◽

Structural Components ◽

X Ray ◽

Human Small Intestine ◽

Transport Studies

The elemental composition of amino acids is similar to that of the major structural components of the epithelial cells of the small intestine and other tissues. Therefore, their subcellular localization and concentration measurements are not possible by x-ray microanalysis. Radioactive isotope labeling: I131-tyrosine, Se75-methionine and S35-methionine have been successfully employed in numerous absorption and transport studies. The latter two have been utilized both in vitro and vivo, with similar results in the hamster and human small intestine. Non-radioactive Selenomethionine, since its absorption/transport behavior is assumed to be the same as that of Se75- methionine and S75-methionine could serve as a compound tracer for this amino acid.

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Immunoelectron microscope detection of C-type natriuretic peptide in normal human atrial tissue

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100147776 ◽

1993 ◽

Vol 51 ◽

pp. 388-389

Author(s):

Chi-Ming Wei ◽

Margaret Hukee ◽

Christopher G.A. McGregor ◽

John C. Burnett

Keyword(s):

Amino Acid ◽

Natriuretic Peptide ◽

Vascular Tone ◽

Cardiac Tissue ◽

Ring Structure ◽

Terminal Amino Acid ◽

Amino Acid Peptide ◽

Normal Human ◽

Terminal Amino ◽

The Brain

C-type natriuretic peptide (CNP) is a newly identified peptide that is structurally related to atrial (ANP) and brain natriuretic peptide (BNP). CNP exists as a 22-amino acid peptide and like ANP and BNP has a 17-amino acid ring formed by a disulfide bond. Unlike these two previously identified cardiac peptides, CNP lacks the COOH-terminal amino acid extension from the ring structure. ANP, BNP and CNP decrease cardiac preload, but unlike ANP and BNP, CNP is not natriuretic. While ANP and BNP have been localized to the heart, recent investigations have failed to detect CNP mRNA in the myocardium although small concentrations of CNP are detectable in the porcine myocardium. While originally localized to the brain, recent investigations have localized CNP to endothelial cells consistent with a paracrine role for CNP in the control of vascular tone. While CNP has been detected in cardiac tissue by radioimmunoassay, no studies have demonstrated CNP localization in normal human heart by immunoelectron microscopy.

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