Analysis of changes occurring in Codon Positions due to mutations through the cellular automata transition rules

AbstractVariation in the nucleotides of a codon may cause variations in the evolutionary patterns of a DNA or amino acid sequence. To address the capability of each position of a codon to have non-synonymous mutations, the concept of degree of mutation has been introduced. The degree of mutation of a particular position of codon defines the number of non-synonymous mutations occurring for the substitution of nucleotides at each position of a codon, when other two positions of that codon remain unaltered. A Cellular Automaton (CA), is used as a tool to model the mutations of any one of the four DNA bases A, C, T and G at a time where the DNA bases correspond to the states of the CA cells. Point mutation (substitution type) of a codon which characterizes changes in the amino acids, have been associated with local transition rules of a CA. Though there can be transitions of a 4-state CA with 3-neighbourhood cells, here it has been possible to represent all possible point mutations of a codon in terms of combinations of 16 local transition functions of the CA. Further these rules are divided into 4 classes of equivalence. Also, according to the nature of mutations, the 16 local CA rules of substitutions are classified into 3 sets namely, ‘No Mutation’, ‘Transition’ and ‘Transversion’. The experiment has been carried out with three sets of single nucleotide variations(SNVs) of three different viruses but the symptoms of the diseases caused by them are to some extent similar to each other. They are SARS-CoV-1, SARS-CoV-2 and H1N1 Type A viruses. The aim is to understand the impact of nucleotide substitutions at different positions of a codon with respect to a particular disease phenotype.

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THE PROPORTION OF ALL POINT MUTATIONS WHICH ARE UNACCEPTABLE: AN ESTIMATE BASED ON HEMOGLOBIN AMINO ACID AND NUCLEOTIDE SEQUENCES

Canadian Journal of Genetics and Cytology ◽

10.1139/g78-013 ◽

1978 ◽

Vol 20 (1) ◽

pp. 111-137 ◽

Cited By ~ 5

Author(s):

Samuel H. Boyer ◽

Alan F. Scott ◽

Louis M. Kunkel ◽

Kirby D. Smith

Keyword(s):

Amino Acid ◽

Point Mutations ◽

Selective Constraint ◽

Nucleotide Sequences ◽

Nucleotide Substitutions ◽

Human Haemoglobin ◽

Interspecies Differences ◽

Synonymous Mutations ◽

Nucleotide Site ◽

Combined Use

Statistical analysis of the distribution of 156 kinds of human haemoglobin β (Hbβ) chain variants suggests that mutations are essentially random in their location. Thus differential fitness, not differential mutability, is the principal source of nonrandom distribution of interspecies differences in Hbβ amino acid sequence. Similar analyses of both the location and the kind of interspecies differences detected among primates support this viewpoint and lead us to estimate that at least 95% of all amino acid substitutions, i.e., nonsynonymous mutations, in Hbβ are functionally unacceptable in homozygous state. Through the combined use of this estimate and the number of nonsynonymous and synonymous substitutions per nucleotide site inferred from comparisons of entire human and rabbit HbβmRNA nucleotide sequences, we calculate (a) ~70% of synonymous Hbβ mutations are adaptively undesirable and (b) the mutation rate underlying all changes is ≤ 10−8 nucleotide substitutions per nucleotide site per year. Apart from such calculations, analyses of nucleotide patterns in HbβmRNA as well as in rat preproinsulin mRNA reinforce the notion that a large portion of synonymous mutations are functionally unacceptable and rendered so by selective constraint, at a pretranslational level, of the abundance of particular nucleotide doublets such as CpG.

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The Impact of Bioconjugation on the Interfacial Activity of a Protein Biosurfactant

10.26434/chemrxiv.7497053.v1 ◽

2018 ◽

Author(s):

Hossam H Tayeb ◽

Marina Stienecker ◽

Anton Middelberg ◽

Frank Sainsbury

Keyword(s):

Polyethylene Glycol ◽

Colloidal Stability ◽

Point Mutations ◽

Pharmaceutical Formulations ◽

Industrial Processes ◽

Parent Molecule ◽

Site Specific ◽

Interfacial Activity ◽

Surface Active ◽

The Impact

Biosurfactants, are surface active molecules that can be produced by renewable, industrially scalable biologic processes. DAMP4, a designer biosurfactant, enables the modification of interfaces via genetic or chemical fusion to functional moieties. However, bioconjugation of addressable amines introduces heterogeneity that limits the precision of functionalization as well as the resolution of interfacial characterization. Here we designed DAMP4 variants with cysteine point mutations to allow for site-specific bioconjugation. The DAMP4 variants were shown to retain the structural stability and interfacial activity characteristic of the parent molecule, while permitting efficient and specific conjugation of polyethylene glycol (PEG). PEGylation results in a considerable reduction on the interfacial activity of both single and double mutants. Comparison of conjugates with one or two conjugation sites shows that both the number of conjugates as well as the mass of conjugated material impacts the interfacial activity of DAMP4. As a result, the ability of DAMP4 variants with multiple PEG conjugates to impart colloidal stability on peptide-stabilized emulsions is reduced. We suggest that this is due to constraints on the structure of amphiphilic helices at the interface. Specific and efficient bioconjugation permits the exploration and investigation of the interfacial properties of designer protein biosurfactants with molecular precision. Our findings should therefore inform the design and modification of biosurfactants for their increasing use in industrial processes, and nutritional and pharmaceutical formulations.

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In Planta Mutagenesis Determines the Functional Regions of the Wheat Puroindoline Proteins

Genetics ◽

10.1534/genetics.109.106013 ◽

2009 ◽

Vol 183 (3) ◽

pp. 853-860 ◽

Cited By ~ 31

Author(s):

Leila Feiz ◽

Brian S. Beecher ◽

John M. Martin ◽

Michael J. Giroux

Keyword(s):

Functional Analysis ◽

Allelic Variation ◽

Screening Method ◽

Point Mutations ◽

Missense Mutations ◽

Grain Hardness ◽

In Planta ◽

Rich Region ◽

Critical Function ◽

The Impact

In planta analysis of protein function in a crop plant could lead to improvements in understanding protein structure/function relationships as well as selective agronomic or end product quality improvements. The requirements for successful in planta analysis are a high mutation rate, an efficient screening method, and a trait with high heritability. Two ideal targets for functional analysis are the Puroindoline a and Puroindoline b (Pina and Pinb, respectively) genes, which together compose the wheat (Triticum aestivum L.) Ha locus that controls grain texture and many wheat end-use properties. Puroindolines (PINs) together impart soft texture, and mutations in either PIN result in hard seed texture. Studies of the PINs' mode of action are limited by low allelic variation. To create new Pin alleles and identify critical function-determining regions, Pin point mutations were created in planta via EMS treatment of a soft wheat. Grain hardness of 46 unique PIN missense alleles was then measured using segregating F2:F3 populations. The impact of individual missense alleles upon PIN function, as measured by grain hardness, ranged from neutral (74%) to intermediate to function abolishing. The percentage of function-abolishing mutations among mutations occurring in both PINA and PINB was higher for PINB, indicating that PINB is more critical to overall Ha function. This is contrary to expectations in that PINB is not as well conserved as PINA. All function-abolishing mutations resulted from structure-disrupting mutations or from missense mutations occurring near the Tryptophan-rich region. This study demonstrates the feasibility of in planta functional analysis of wheat proteins and that the Tryptophan-rich region is the most important region of both PINA and PINB.

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Effects of Pathological Mutations on the Prion-Like Polymerisation of MyD88

10.1101/351726 ◽

2018 ◽

Author(s):

Ailís O’Carroll ◽

Brieuc Chauvin ◽

James Brown ◽

Ava Meagher ◽

Joanne Coyle ◽

...

Keyword(s):

Single Molecule ◽

Self Assembly ◽

Point Mutations ◽

Adaptor Protein ◽

Full Length ◽

Binary Response ◽

Death Domain ◽

Tir Domain ◽

The Impact

AbstractA novel concept has emerged whereby the higher-order self-assembly of proteins provides a simple and robust mechanism for signal amplification. This appears to be a universal signalling mechanism within the innate immune system, where the recognition of pathogens or danger-associated molecular patterns need to trigger a strong, binary response within cells. Previously, multiple structural studies have been limited to single domains, expressed and assembled at high protein concentrations. We therefore set out to develop new in vitro strategies to characterise the behaviour of full-length proteins at physiological levels. In this study we focus on the adaptor protein MyD88, which contains two domains with different self-assembly properties: a TIR domain that can polymerise similarly to the TIR domain of Mal, and a Death Domain that has been shown to oligomerise with helical symmetry in the Myddosome complex. To visualize the behaviour of full-length MyD88 without purification steps, we use single-molecule fluorescence coupled to eukaryotic cell-free protein expression. These experiments demonstrate that at low protein concentration, only full-length MyD88 forms prion-like polymers. We also demonstrate that the metastability of MyD88 polymerisation creates the perfect binary response required in innate signalling: the system is silenced at normal concentrations but upstream signalling creates a “seed” that triggers polymerisation and amplification of the response. These findings pushed us to re-interpret the role of polymerisation in MyD88-related diseases and we studied the impact of disease-associated point mutations L93P, R196C and L252P/L265P at the molecular level. We discovered that all mutations completely block the ability of MyD88 to polymerise. We also confirm that L252P, a gain-of-function mutation, allows the MyD88 mutant to form extremely stable oligomers, even when expressed at low nanomolar concentrations. Thus, our results are consistent with and greatly add to the findings on the Myddosomes digital ‘all-or-none’ responses and the behaviour of the oncogenic mutation of MyD88.

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The Impact of Acquired Genetic Abnormalities on the Clinical Translation of Human Pluripotent Stem Cells

Cells ◽

10.3390/cells10113246 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3246

Author(s):

Alexander Keller ◽

Claudia Spits

Keyword(s):

Stem Cells ◽

Pluripotent Stem Cells ◽

Chromosomal Abnormalities ◽

Current Knowledge ◽

Point Mutations ◽

Human Pluripotent Stem Cells ◽

Clinical Translation ◽

Copy Number Changes ◽

Clinical Potential ◽

The Impact

Human pluripotent stem cells (hPSC) are known to acquire chromosomal abnormalities, which range from point mutations to large copy number changes, including full chromosome aneuploidy. These aberrations have a wide-ranging influence on the state of cells, in both the undifferentiated and differentiated state. Currently, very little is known on how these abnormalities will impact the clinical translation of hPSC, and particularly their potential to prime cells for oncogenic transformation. A further complication is that many of these abnormalities exist in a mosaic state in culture, which complicates their detection with conventional karyotyping methods. In this review we discuss current knowledge on how these aberrations influence the cell state and how this may impact the future of research and the cells’ clinical potential.

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Molecular characterization of glucose-6-phosphate dehydrogenase (G6PD) deficiency in patients of Chinese descent and identification of new base substitutions in the human G6PD gene

Blood ◽

10.1182/blood.v81.8.2150.2150 ◽

1993 ◽

Vol 81 (8) ◽

pp. 2150-2154 ◽

Cited By ~ 40

Author(s):

DT Chiu ◽

L Zuo ◽

L Chao ◽

E Chen ◽

E Louie ◽

...

Keyword(s):

G6pd Deficiency ◽

Point Mutations ◽

Nucleotide Substitutions ◽

New Findings ◽

G6pd Gene ◽

High Prevalence ◽

Chinese Descent ◽

Glucose 6 Phosphate Dehydrogenase ◽

Sequencing Procedure

Abstract The underlying DNA changes associated with glucose-6-phosphate dehydrogenase (G6PD)-deficient Asians have not been extensively investigated. To fill this gap, we sequenced the G6PD gene of 43 G6PD- deficient Chinese whose G6PD was well characterized biochemically. DNA samples were obtained from peripheral blood of these individuals for sequencing using a direct polymerase chain reaction (PCR) sequencing procedure. From these 43 samples, we have identified five different types of nucleotide substitutions in the G6PD gene: at cDNA 1388 from G to A (Arg to His); at cDNA 1376 from G to T (Arg to Leu); at cDNA 1024 from C to T (Leu to Phe); at cDNA 392 from G to T (Gly to Val); at cDNA 95 from A to G (His to Arg). These five nucleotide substitutions account for over 83% of our 43 G6PD-deficient samples and these substitutions have not been reported in non-Asians. The substitutions found at cDNA 392 and cDNA 1024 are new findings. The substitutions at cDNA 1376 and 1388 account for over 50% of the 43 samples examined indicating a high prevalence of these two alleles among G6PD-deficient Chinese. Our findings add support to the notion that diverse point mutations may account largely for much of the phenotypic heterogeneity of G6PD deficiency.

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Quantifying Influences on Intragenomic Mutation Rate

G3 Genes|Genome|Genetics ◽

10.1534/g3.120.401335 ◽

2020 ◽

Vol 10 (8) ◽

pp. 2641-2652

Author(s):

Helmut Simon ◽

Gavin Huttley

Keyword(s):

Point Mutations ◽

Population Based ◽

Genomic Diversity ◽

Ensembl Database ◽

Sequence Context ◽

The Public ◽

Recombination Hotspots ◽

Strand Asymmetry ◽

The Impact ◽

Central Base

We report work to quantify the impact on the probability of human genome polymorphism both of recombination and of sequence context at different scales. We use population-based analyses of data on human genetic variants obtained from the public Ensembl database. For recombination, we calculate the variance due to recombination and the probability that a recombination event causes a mutation. We employ novel statistical procedures to take account of the spatial auto-correlation of recombination and mutation rates along the genome. Our results support the view that genomic diversity in recombination hotspots arises largely from a direct effect of recombination on mutation rather than predominantly from the effect of selective sweeps. We also use the statistic of variance due to context to compare the effect on the probability of polymorphism of contexts of various sizes. We find that when the 12 point mutations are considered separately, variance due to context increases significantly as we move from 3-mer to 5-mer and from 5-mer to 7-mer contexts. However, when all mutations are considered in aggregate, these differences are outweighed by the effect of interaction between the central base and its immediate neighbors. This interaction is itself dominated by the transition mutations, including, but not limited to, the CpG effect. We also demonstrate strand-asymmetry of contextual influence in intronic regions, which is hypothesized to be a result of transcription coupled DNA repair. We consider the extent to which the measures we have used can be used to meaningfully compare the relative magnitudes of the impact of recombination and context on mutation.

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Understanding the Pyrimethamine Drug Resistance Mechanism via Combined Molecular Dynamics and Dynamic Residue Network Analysis

Molecules ◽

10.3390/molecules25040904 ◽

2020 ◽

Vol 25 (4) ◽

pp. 904 ◽

Cited By ~ 1

Author(s):

Arnold Amusengeri ◽

Rolland Bantar Tata ◽

Özlem Tastan Bishop

Keyword(s):

Molecular Dynamics ◽

Drug Resistance ◽

Network Analysis ◽

Binding Free Energy ◽

Resistance Mechanism ◽

Point Mutations ◽

Md Simulations ◽

Conformational Plasticity ◽

New Perspective ◽

The Impact

In this era of precision medicine, insights into the resistance mechanism of drugs are integral for the development of potent therapeutics. Here, we sought to understand the contribution of four point mutations (N51I, C59R, S108N, and I164L) within the active site of the malaria parasite enzyme dihydrofolate reductase (DHFR) towards the resistance of the antimalarial drug pyrimethamine. Homology modeling was used to obtain full-length models of wild type (WT) and mutant DHFR. Molecular docking was employed to dock pyrimethamine onto the generated structures. Subsequent all-atom molecular dynamics (MD) simulations and binding free-energy computations highlighted that pyrimethamine’s stability and affinity inversely relates to the number of mutations within its binding site and, hence, resistance severity. Generally, mutations led to reduced binding affinity to pyrimethamine and increased conformational plasticity of DHFR. Next, dynamic residue network analysis (DRN) was applied to determine the impact of mutations and pyrimethamine binding on communication dispositions of DHFR residues. DRN revealed residues with distinctive communication profiles, distinguishing WT from drug-resistant mutants as well as pyrimethamine-bound from pyrimethamine-free models. Our results provide a new perspective on the understanding of mutation-induced drug resistance.

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