scholarly journals Rampant C->U hypermutation in the genomes of SARS-CoV-2 and other coronaviruses – causes and consequences for their short and long evolutionary trajectories

2020 ◽  
Author(s):  
P. Simmonds
Keyword(s):  
Amino Acid ◽  
Molecular Epidemiology ◽  
Directional Asymmetry ◽  
Flanking Sequence ◽  
Long Term Effects ◽  
Sequence Change ◽  
Mutational Hotspots ◽  
Evolutionary Trajectories ◽  
Human Coronaviruses

AbstractThe pandemic of SARS coronavirus 2 (SARS-CoV-2) has motivated an intensive analysis of its molecular epidemiology following its worldwide spread. To understand the early evolutionary events following its emergence, a dataset of 985 complete SARS-CoV-2 sequences was assembled. Variants showed a mean 5.5-9.5 nucleotide differences from each other, commensurate with a mid-range coronavirus substitution rate of 3×10−4 substitutions/site/year. Almost half of sequence changes were C->U transitions with an 8-fold base frequency normalised directional asymmetry between C->U and U->C substitutions. Elevated ratios were observed in other recently emerged coronaviruses (SARS-CoV and MERS-CoV) and to a decreasing degree in other human coronaviruses (HCoV-NL63, -OC43, -229E and -HKU1) proportionate to their increasing divergence. C->U transitions underpinned almost half of the amino acid differences between SARS-CoV-2 variants, and occurred preferentially in both 5’U/A and 3’U/A flanking sequence contexts comparable to favoured motifs of human APOBEC3 proteins. Marked base asymmetries observed in non-pandemic human coronaviruses (U>>A>G>>C) and low G+C contents may represent long term effects of prolonged C->U hypermutation in their hosts.ImportanceThe evidence that much of sequence change in SARS-CoV-2 and other coronaviruses may be driven by a host APOBEC-like editing process has profound implications for understanding their short and long term evolution. Repeated cycles of mutation and reversion in favoured mutational hotspots and the widespread occurrence of amino acid changes with no adaptive value for the virus represents a quite different paradigm of virus sequence change from neutral and Darwinian evolutionary frameworks that are typically used in molecular epidemiology investigations.

scholarly journals Rampant C→U Hypermutation in the Genomes of SARS-CoV-2 and Other Coronaviruses: Causes and Consequences for Their Short- and Long-Term Evolutionary Trajectories

mSphere ◽  
2020 ◽  
Vol 5 (3) ◽  
Author(s):  
P. Simmonds
Keyword(s):  
Amino Acid ◽  
Severe Acute Respiratory Syndrome ◽  
Molecular Epidemiology ◽  
Substitution Rate ◽  
Directional Asymmetry ◽  
Sequence Change ◽  
Short And Long Term ◽  
Standard Models ◽  
Human Coronaviruses

ABSTRACT The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has motivated an intensive analysis of its molecular epidemiology following its worldwide spread. To understand the early evolutionary events following its emergence, a data set of 985 complete SARS-CoV-2 sequences was assembled. Variants showed a mean of 5.5 to 9.5 nucleotide differences from each other, consistent with a midrange coronavirus substitution rate of 3 × 10−4 substitutions/site/year. Almost one-half of sequence changes were C→U transitions, with an 8-fold base frequency normalized directional asymmetry between C→U and U→C substitutions. Elevated ratios were observed in other recently emerged coronaviruses (SARS-CoV, Middle East respiratory syndrome [MERS]-CoV), and decreasing ratios were observed in other human coronaviruses (HCoV-NL63, -OC43, -229E, and -HKU1) proportionate to their increasing divergence. C→U transitions underpinned almost one-half of the amino acid differences between SARS-CoV-2 variants and occurred preferentially in both 5′ U/A and 3′ U/A flanking sequence contexts comparable to favored motifs of human APOBEC3 proteins. Marked base asymmetries observed in nonpandemic human coronaviruses (U ≫ A > G ≫ C) and low G+C contents may represent long-term effects of prolonged C→U hypermutation in their hosts. The evidence that much of sequence change in SARS-CoV-2 and other coronaviruses may be driven by a host APOBEC-like editing process has profound implications for understanding their short- and long-term evolution. Repeated cycles of mutation and reversion in favored mutational hot spots and the widespread occurrence of amino acid changes with no adaptive value for the virus represent a quite different paradigm of virus sequence change from neutral and Darwinian evolutionary frameworks and are not incorporated by standard models used in molecular epidemiology investigations. IMPORTANCE The wealth of accurately curated sequence data for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), its long genome, and its low substitution rate provides a relatively blank canvas with which to investigate effects of mutational and editing processes imposed by the host cell. The finding that a large proportion of sequence change in SARS-CoV-2 in the initial months of the pandemic comprised C→U mutations in a host APOBEC-like context provides evidence for a potent host-driven antiviral editing mechanism against coronaviruses more often associated with antiretroviral defense. In evolutionary terms, the contribution of biased, convergent, and context-dependent mutations to sequence change in SARS-CoV-2 is substantial, and these processes are not incorporated by standard models used in molecular epidemiology investigations.

scholarly journals Amino acid concentrations in the hamster central auditory system and long-term effects of intense tone exposure

2012 ◽  
Vol 90 (11) ◽  
pp. 2214-2224 ◽  
Author(s):  
Donald A. Godfrey ◽  
James A. Kaltenbach ◽  
Kejian Chen ◽  
Omer Ilyas ◽  
Xiaochen Liu ◽  
...  
Keyword(s):  
Amino Acid ◽  
Auditory System ◽  
Central Auditory System ◽  
Long Term Effects ◽  
Amino Acid Concentrations

Modification of An Amino Acid Solution for Peritoneal Dialysis to Reduce Risk of Acidemia

1997 ◽  
Vol 17 (1) ◽  
pp. 66-71 ◽  
Author(s):  
Michael Jones ◽  
Roberto Kalil ◽  
Peter Blake ◽  
Leo Martis ◽  
Dimitrios G. Oreopoulos
Keyword(s):  
Amino Acids ◽  
Body Weight ◽  
Peritoneal Dialysis ◽  
Amino Acid ◽  
Acid Solution ◽  
Long Term Effects ◽  
Amino Acid Solution ◽  
Nutritional Benefits ◽  
Modified Formula

Objective Some patients develop a mild acidemia during treatment with amino acid-based peritoneal dialysis solutions due to hydrogen ion produced by metabolism of lysine, arginine, and methionine. In this study we modified the formulation of such a solution by reducing these amino acids and adding anionic amino acids so as to provide minimal net acid production. Design A modified formula (MF) was compared to a conventional formula (CF) of the solution in a randomized crossover study in 12 stable continuous ambulatory peritoneal dialysis patients. Patients were given each solution for 14 days without a wash-out period. Each patient replaced one or two dextrose dialysis exchanges with amino acid solution, depending upon oral protein intake and body weight. Total intake (oral protein plus amino acids absorbed) was equivalent to 1.1 -1.3 g protein/kg body weight/day.Plasma bicarbonate and urea were assessed at the beginning and end of each 14-day period. Results In the group as a whole, without regard to the order in which the solutions were given, patients had a decrease in serum bicarbonate with CF and an increase in bicarbonate when they received MF. Similar trends were observed regardless of the order in which the solutions were administered. Serum urea did not differ between the two solutions. Conclusion The results suggest that patients are less prone to develop acidemia when receiving MF as opposed to CF. Further studies will be necessary to determine the long-term effects and the relative nutritional benefits of the two solutions.

Long-term effects of excitatory amino acid antagonist NBQX and MK-801 on the developing brain

1996 ◽  
Vol 99 (2) ◽  
pp. P12
Author(s):  
P. Tandon ◽  
Z. Liu ◽  
C.E. Stafstrom ◽  
M. Sarkisian ◽  
S.J. Werner ◽  
...  
Keyword(s):  
Amino Acid ◽  
Excitatory Amino Acid ◽  
Developing Brain ◽  
Long Term Effects ◽  
Mk 801 ◽  
Acid Antagonist

Long-term effects of lysine concentration on growth performance, intestinal microbiome, and metabolic profiles in a pig model

2018 ◽  
Vol 9 (8) ◽  
pp. 4153-4163 ◽  
Author(s):  
Jie Yin ◽  
Yuying Li ◽  
Hui Han ◽  
Zhaojin Liu ◽  
Xiangfang Zeng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Amino Acid ◽  
Growth Performance ◽  
Pig Model ◽  
Intestinal Microbiome ◽  
Metabolic Profiles ◽  
Long Term Effects ◽  
Lysine Concentration ◽  
Limiting Amino Acid

Lysine is a common limiting amino acid in human and animal diets and plays an important role in cell proliferation and metabolism.

Short- and long-term effects of perinatal asphyxia on monoamine, amino acid and glycolysis product levels measured in the basal ganglia of the rat

1997 ◽  
Vol 104 (1-2) ◽  
pp. 19-30 ◽  
Author(s):  
Yong Chen ◽  
Ephrem Engidawork ◽  
Fabian Loidl ◽  
Elisabetta Dell'Anna ◽  
Michel Goiny ◽  
...  
Keyword(s):  
Amino Acid ◽  
Basal Ganglia ◽  
Perinatal Asphyxia ◽  
Long Term Effects ◽  
Short And Long Term

LONG-TERM EFFECTS OF LEUCINE AND ARGININE ON B-CELL FUNCTION OF CULTIVATED PANCREATIC RAT ISLETS

1981 ◽  
Vol 91 (2) ◽  
pp. 255-262 ◽  
Author(s):  
G. SCHÄFER ◽  
H. SCHATZ
Keyword(s):  
Amino Acid ◽  
B Cell ◽  
Cell Function ◽  
Insulin Biosynthesis ◽  
Long Term Effects ◽  
Hormone Synthesis ◽  
Rat Islets ◽  
B Cell Function ◽  
Releasing Effect

Leucine and arginine are well-known stimulators of insulin release, but they exert different actions on insulin biosynthesis in short-term incubations of isolated islets. In order to study their long-term effects on the B-cell, isolated rat islets were cultivated for 40 h in medium containing 0·5 or 3 mg glucose/ml supplemented with l-leucine (10 mmol/l) or l-arginine (10 mmol/l). After the culture the islets were incubated for 3 h with 2 mg glucose/ml without addition of the respective amino acid. Insulin biosynthesis was estimated from incorporation of [3H]phenylalanine or [3H]leucine into the (pro)insulin fraction of the islet proteins during this incubation. At the low concentration of glucose, the leucine-cultivated islets released much more insulin than the control islets during culture as well as during subsequent incubation. At both glucose concentrations cultivation together with this amino acid resulted in an enhanced insulin biosynthesis. The insulin-releasing effect of arginine with 0·5 mg glucose/ml was not as marked as that observed with an equimolar concentration of leucine. Islets cultivated with arginine showed no response to glucose during the incubation after culture. Hormone synthesis was found to be inhibited. Shortening of culture time to 20 h, followed by an additional 4 h of cultivation without arginine did not result in an improvement of B-cell function after culture. It is concluded that leucine, in contrast with arginine, supports B-cell function, especially insulin biosynthesis, during long-term culture of islets. Stimulation of release of insulin with a concomitant inhibition of insulin biosynthesis caused by arginine during culture did not lead to a compensatory increase in hormone synthesis after culture.

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