A nonsynonymous substitution is a nucleotide mutation that alters the amino acid sequence of a protein. Nonsynonymous substitutions differ from synonymous substitutions, which do not alter amino acid sequences and are (sometimes) silent mutations. As nonsynonymous substitutions result in a biological change in the organism, they are subject to natural selection. Nonsynonymous substitutions at a certain loci can be compared to the synonymous substitutions at that loci to obtain the Ka/Ks ratio.
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The two alternative hypotheses are a relative absence of nonsynonymous substitutions (dN < dS; ω < 1), suggesting the effect on fitness ('fitness effect', or 'selection pressure') of such mutations is negative (purifying selection has operated over time; or a relative excess of nonsynonymous substitutions (dN > dS; ω > 1), indicating positive effect on fitness, i.e. diversifying selection (Yang and Bielawski 2000). The McDonald-Kreitman (MK) test quantifies the amount of adaptive evolution occurring by estimating the proportion of nonsynonymous substitutions which are adaptive, referred to as α (McDonald and Kreitman 1991, Eyre-Walker 2006).
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The "nearly neutral" theory proposes that molecular evolution acting on nonsynonymous substitutions is driven by mutation, genetic drift, and very weak natural selection, and that it is extremely sensitive to population size. In order to determine whether natural selection is taking place at a certain loci, the McDonald–Kreitman test can be performed. The test consists of comparing ratios of synonymous and nonsynonymous genes between closely related species to the ratio of synonymous to nonsynonymous polymorphisms within species. If the ratios are the same, then Neutral theory of molecular evolution is true for that loci, and evolution is proceeding primarily through genetic drift.
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This ratio is used to measure the evolutionary rate of gene sequences. If a gene has lower levels of nonsynonymous than synonymous nucleotide substitution, then it can be inferred to be functional because a Ka/Ks ratio < 1 is a hallmark of sequences that are being constrained to code for proteins. Nonsynonymous substitutions are also referred to as replacement mutations.
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If there are more nonsynonymous substitutions between species than within a species, positive natural selection is occurring on beneficial alleles and natural selection is taking place. Nonsynonymous substitutions have been found to be more common in loci involving pathogen resistance, reproductive loci involving sperm competition or egg-sperm interactions, and genes that have replicated and gained new functions, indicating that positive selection is taking place.
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There are several common types of nonsynonymous substitutions. Missense mutations are nonsynonymous substitutions that arise from point mutations, mutations in a single nucleotide that result in the substitution of a different amino acid, resulting in a change to the protein encoded. Nonsense mutations are nonsynonymous substitutions that arise when a mutation in the DNA sequence causes a protein to terminate prematurely by changing the original amino acid to a stop codon. Another type of mutation that deals with stop codons is known as a nonstop mutation or readthrough mutation, which occurs when a stop codon is exchanged for an amino acid codon, causing the protein to be longer than specified.
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Studies have shown that diversity among nonsynonymous substitutions is significantly lower than among synonymous substitutions. This is due to the fact that nonsynonymous substitutions are subject to much higher selective pressures than synonymous mutations. Motoo Kimura (1968) determined that calculated mutation rates were impossibly high, unless most of the mutations that occurred were either neutral or "nearly neutral". He determined that if this were true, genetic drift would be a more powerful factor in molecular evolution than natural selection.
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In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution.
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The mutation rate for synonymous and nonsynonymous mutation rates among the herpesviruses have been estimated at 1 × 10−7 and 2.7 × 10−8 mutations/site/year, respectively, based on the highly conserved gB gene.
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Approximate methods involve three basic steps: (1) counting the number of synonymous and nonsynonymous sites in the two sequences, or estimating this number by multiplying the sequence length by the proportion of each class of substitution; (2) counting the number of synonymous and nonsynonymous substitutions; and (3) correcting for multiple substitutions. These steps, particularly the latter, require simplistic assumptions to be made if they are to be achieved computationally; for reasons discussed later, it is impossible to exactly determine the number of multiple substitutions.
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The methods used to identify adaptive evolution are generally devised to test the null hypothesis of neutral evolution, which, if rejected, provides evidence of adaptive evolution. These tests can be broadly divided into two categories. Firstly, there are methods that use a comparative approach to search for evidence of function altering mutations. The dN/dS rates-ratio test estimates ω, the rates at which nonsynonymous ('dN') and synonymous ('dS') nucleotide substitutions occur ('synonymous' nucleotide substitutions do not lead to a change in the coding amino acid, while 'nonsynonymous' ones do). In this model, neutral evolution is considered the null hypothesis, in which dN and dS approximately balance so that ω ≈ 1.
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Amino acid replacement is a change from one amino acid to a different amino acid in a protein due to point mutation in the corresponding DNA sequence. It is caused by nonsynonymous missense mutation which changes the codon sequence to code other amino acid instead of the original.
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Missense mutation is a type of nonsynonymous substitution in a DNA sequence. Two other types of nonsynonymous substitution are the nonsense mutations — in which a codon is changed to a premature stop codon that results in truncation of the resulting protein —, and the nonstop mutations — in which a stop codon erasement results in a longer, nonfunctional protein. Missense mutations can render the resulting protein nonfunctional, and such mutations are responsible for human diseases such as Epidermolysis bullosa, sickle-cell disease, and SOD1 mediated ALS. In the most common variant of sickle-cell disease, the 20th nucleotide of the gene for the beta chain of hemoglobin is altered from the codon GAG to GTG.
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Nonsynonymous substitutions in the OR10G4 gene have a significant effect on the perception of the "smoky" odorant guaiacol. Individuals with mutations that reduce the affinity of the OR10G4 receptor for guaiacol have a reduced sensitivity to it, and the same people who report guaiacol as weaker tend to rate it as more pleasant.
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The ratio of nonsynonymous to synonymous substitutions (dN/dS) is greater than one for every KIR and every KIR domain, indicating that positive selection is occurring. Further, the 5` exons, which encode the leader peptide and the Ig-like domains, have a larger proportion of nonsynonymous substitutions than do the 3` exons, which encode the stem, transmembrane region, and the cytoplasmic tail. This indicates that stronger selection is occurring on the 5` exons, which encodes the extracellular part of the KIR that binds to the MHC. There is, therefore, evidence of strong selection on the KIR ligand binding sites, which is consistent with the high specificity of the KIR ligand binding site, as well as the rapid evolution of class I MHC molecules and viruses.
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Prostate stem cell antigen is a protein that in humans is encoded by the PSCA gene. This gene encodes a glycosylphosphatidylinositol-anchored cell membrane glycoprotein. In addition to being highly expressed in the prostate it is also expressed in the bladder, placenta, colon, kidney, and stomach. This gene has a nonsynonymous nucleotide polymorphism at its start codon.
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Evolution of proteins is slower than DNA since only nonsynonymous mutations in DNA can result in amino acid replacements. Most mutations are neutral to maintain protein function and structure. Therefore, the more similar amino acids are, the more probable that they will be replaced. Conservative replacements are more common than radical replacements, since they can result in less important phenotypic changes.
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All but two KIR genes (KIR2DP1 and KIR3DL3) have multiple alleles, with KIR3DL2 and KIR3DL1 having the most variations (12 and 11, respectively). In total, as of 2012 there were 614 known KIR nucleotide sequences encoding 321 distinct KIR proteins. Further, inhibitory receptors are more polymorphic than activating receptors. The great majority (69%) of substitutions in the KIR DNA sequence are nonsynonymous, and 31% are synonymous.
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In order to determine this, lineages are tested for the functional changes that accrue over time. This is often measured as a ratio of nonsynonymous substitutions to synonymous substitutions or the dN/dS ratio (sometimes, further abbreviated to ω). When the dN/dS ratio is greater than 1, this indicates positive selection. A dN/dS ratio equal to 1 is evidence of no selective pressures.
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Weak selection is therefore also especially sensitive to the effects of population size. In smaller populations, a weakly selected mutation could proliferate due to stochastic processes such as genetic drift even more easily. Empirically, nonsynonymous substitutions have been reported to proliferate through weak selection in Drosophila melanogaster and Arabidopsis. These non-neutral mutations are thought to have special significance evolutionarily when they affect gene regulatory elements.
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Immunostimulatory antibodies increase the activity of T lymphocytes through several mechanisms, including the blockade of inhibitory molecules that are present at the surface of T lymphocytes. These antibodies are often named "checkpoint inhibitors". Using them in cancer patients can lead to important and durable tumor regressions, and to improved survival of the patients. Clinical benefit from these treatments is positively correlated with the number of nonsynonymous mutations present in the tumors.
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DNA excision pathways work in tandem to repair DNA damage. Unrepaired damage or malfunctioning proteins associated with excision repair could lead to unregulated cell growth and cancer. Though historical studies have shown inconsistent results, genetic variation or mutation to nucleotide excision repair genes can impact cancer risk by affecting repair efficacy. Single-nucleotide polymorphisms (SNPs) and nonsynonymous coding SNPs (nsSNPs) are present at very low levels (>1%) in the human population.
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Nei's group invented a simple statistical method for detecting positive Darwinian selection by comparing the numbers of synonymous nucleotide substitutions and nonsynonymous nucleotide substitutions. Applying this method, they showed that the exceptionally high degree of sequence polymorphism at MHC loci is caused by overdominant selection. Although various statistical methods for this test have been developed later, their original methods are still widely used.Nei, M. (2013) Mutation-Driven Evolution.
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The score is the normalized probability that the amino acid change is tolerated so scores near 0 are more likely to be deleterious. The qualitative prediction is derived from this score such that substitutions with a score < 0.05 are called 'deleterious' and all others are called 'tolerated'. SIFT can be applied to naturally occurring nonsynonymous polymorphisms and laboratory-induced missense mutations, that will lead to build relationships in phenotype characteristics, proteomics and genomics.
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The women that have the single- nucleotide polymorphism (SNP) are about 1.4 times more likely to get ill, according to the study. Allelic variations of RELN have also been correlated with working memory, memory and executive functioning in nuclear families where one of the members suffers from schizophrenia. The association with working memory was later replicated. In one small study, nonsynonymous polymorphism Val997Leu of the gene was associated with left and right ventricular enlargement in patients.
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98(1): p. 182-187. Sequencing of five late genes from 18 isolates of P2-like phages demonstrated that homologous recombination is extensive and occurs randomly at multiple breakpoints. The genetic variations in the late genes of the 18 close relatives are small, as the greatest difference in any gene was only 3.7%. For there was much more variation in synonymous rather than nonsynonymous third-codon positions, these late genes are likely to be subject to rather strong stabilizing selection.
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The substrate specificity of the tRNA to the rare codon can affect the timing of translation, and in turn the co-translational folding of the protein. This is reflected in the codon usage bias that is observed in many species. A nonsynonymous substitution results in a change in amino acid that may be arbitrarily further classified as conservative (a change to an amino acid with similar physiochemical properties), semi-conservative (e.g. negatively to positively charged amino acid), or radical (vastly different amino acid).
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The common 1858T (rs2476601) Arg620Trp nonsynonymous single nucleotide polymorphism located in the PTPN22 gene has been associated with autoimmune disorders, including an increased risk of Type 1 Diabetes, rheumatoid arthritis, lupus, Vitiligo and Graves' disease, but a decreased risk of Crohn's disease. A recent study suggests that the mutation does not, on a population basis, reduce life span. The mutation may be conserved in human evolution because it may provide a hyper-immune response to infectious disease. Mutations in PTPN22 are over-represented in breast cancer.
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However, the results could not be replicated in a more recent paper published in 2014 where "Auguste D's DNA revealed no indication of a nonsynonymous hetero- or homozygous mutation in the exons of APP, PSEN1, and PSEN2 genes comprising the already known familial AD mutations." Alzheimer concluded that she had no sense of time or place. She could barely remember details of her life and frequently gave answers that had nothing to do with the question and were incoherent. Her moods changed rapidly between anxiety, mistrust, withdrawal and 'whininess'.
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A nonsynonymous mutation that occurs at the genomic or transcriptional levels is one that results in an alteration to the amino acid sequence in the protein product. A protein's primary structure refers to its amino acid sequence. A substitution of one amino acid for another can impair protein function and tertiary structure, however its effects may be minimal or tolerated depending on how closely the properties of the amino acids involved in the swap correlate. The premature insertion of a stop codon, a nonsense mutation, can alter the primary structure of a protein.
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A nonsynonymous mutation in CDHR3 at rs6967330 (C529Y) was at first found to be associated with severe asthma exacerbations in early childhood, with genome- wide significance. Functional experiments further indicated that this gene polymorphism leads to increased surface expression of the CDHR3 protein. A subsequent study found that CDHR3 is a probable receptor for rhinovirus type C, a common form of rhinovirus. Recent studies furthermore found that CDHR3 gene variation is not associated with childhood bronchiolitis from respiratory syncytial virus (RSV) infection, which resemble early asthma exacerbations as a phenotype.
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Initially, Moran and Baumman used 16S ribosomal RNA sequencing to demonstrate that Buchnera aphidicola bacteria and their aphid hosts co-evolve, or evolve together, due to their long-term symbiotic relationship. Subsequently, they demonstrated this coevolution of symbionts in mealybugs. As new technologies emerged and improved, Moran transitioned to examining the genomic evolution of symbiotic bacteria. By comparing Buchnera, an obligately host-associated bacteria, with closely related free-living bacteria, she demonstrated that Buchnera tends to accumulate nonsynonymous, silent mutations, more rapidly, increasing the AT-content of the genome with an accelerated rate of evolution.
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The number of guanine/cytosine base pairs were utilized in pseudogenes that mimicked nonsynonymous and synonymous mutations that began at what would be expected in a truly neutrally evolving genome for both rodents and primates. Their findings showed that in rodents, the pseudogenes were evolving as one would expect under neutral conditions whereas in primates purifying selection was having an effect on as many as 20% of the pseudogenes tested. By these estimates in primates, 20-40% of their genes could be under selective constraint in the neutral model.
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Many organophosphorus insecticides target the enzyme acetylcholinesterase (AChE); mutations in the acetylcholinesterase gene of B. dorsalis have been found to be associated to resistance to such insecticides. Researchers have identified three point mutations in B. dorsalis' gene encoding AChE that generate nonsynonymous changes in the produced amino acid sequence. Two of the point mutations are identical in site to mutations identified in other Bactrocera species, but one of the mutations is specific to B. dorsalis. Widespread use of such insecticides could result in rapid resistance acquisition in populations of B. dorsalis.
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In a study, it was found that in all species in the order Carnivora except the panda, the open reading frame was maintained. In panda, the nonsynonymous to synonymous substitutions ratio was found to be much higher than other species in order Carnivora. This data correlates with fossil records date of the panda to show where panda switched from carnivore to herbivore diet. Therefore, the loss of function of umami in panda is hypothesized to be caused by dietary change where the panda became less dependence on meat.
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Two proteins have been found to play a major role in toothed whale echolocation. Prestin, a motor protein of the outer hair cells of the inner ear of the mammalian cochlea, has an association between the number of nonsynonymous substitutions and hearing sensitivity. It has undergone two clear episodes of accelerated protein evolution in cetaceans: on the ancestral branch of odontocetes and on the branch leading to delphinioidae. The first episode of acceleration is connected to odontocete divergence, when echolocation first developed, and the second occurs with the increase in echolocation frequency seen in the family Delphinioidae.
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Research on accurately modeling rates of mutation has been conducted for many years. A recent paper by Ziheng Yang and Rasmus Nielsen compared various methods and developed a new modeling method. They found that the new method was preferable for its smaller biases, which make it useful for large scale screening, but that the maximum-likelihood model was preferable in most scenarios because of its simplicity, and its flexibility in comparing multiple sequences while taking into account phylogeny. Further research by Yang and Nielsen found that nonsynonymous to synonymous substitution ratios varied across loci in differing evolutionary lineages.
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A missense mRNA arises from a missense mutation, in the event of which a DNA nucleotide base pair in the coding region of a gene is changed such that it results in the substitution of one amino acid for another. The point mutation is nonsynonymous because it alters the RNA codon in the mRNA transcript such that translation results in amino acid change. An amino acid change may not result in appreciable changes in protein structure depending on whether the amino acid change is conservative or non-conservative. This owes to the similar physicochemical properties exhibited by some amino acids.
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A nonsynonymous amino acid change affecting conserved cysteine of the CaB-EGF- like domain encoded by exon 13 of the FBN1 gene can cause MFS to develop. Higher frequency and severity of MFS occurs when there are incorrect substitutions at the C1-C2 or C3-C4 disulphide bonds, therefore, correct cysteine localisation and disulphide bonding at these loci are critical to structural integrity. Mutations in the FBN1 gene resulting in incorrect bonding at the C5-C6 disulphide bond generally results in MFS of lesser severity. Concentrated mutations of the CaB-EGF domain along the FBN1 polypeptide affects MFS severity phenotype.
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In the case of TRGs, one common signature of selection is the ratio of nonsynonymous to synonymous substitutions (dN/dS ratio), calculated from different species from the same taxon. The neutral expectation for this ratio is 1; most protein-coding genes have a ratio below 1, indicating selective constraint, although a gene under strong directional selection may have a ratio above 1. A ratio below 1 is thus taken as evidence for selection against loss of function. Similarly, in the case of species-specific genes, polymorphism data may be used to calculate a pN/pS ratio from different strains or populations of the focal species.
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Natural separation into regional subspecies is prevented by gyrfalcons' habit of flying long distances whilst exchanging alleles between subpopulations; thus, the allele distributions for the color polymorphism form clines and in darker birdsThe allele combination producing the white morph seems to be recessive. of unknown origin, theoretically any allele combination might be present. For instance, a mating of a pair of captive gyrfalcons is documented to have produced a clutch of four young: one white, one silver, one brown, and one black. Molecular work suggests plumage color is associated with the melanocortin 1 receptor gene (MC1R), where a nonsynonymous point substitution was perfectly associated with the white/melanic polymorphism.
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At the base of this heterozygosity lies the occurrence of numeric and structural chromosomal rearrangements and changes as means of generating genetic diversity by chromosome length polymorphisms (contraction/expansion of repeats), reciprocal translocations, chromosome deletions, Nonsynonymous single-nucleotide polymorphisms and trisomy of individual chromosomes. These karyotypic alterations lead to changes in the phenotype, which is an adaptation strategy of this fungus. These mechanisms are further being explored with the availability of the complete analysis of the C. albicans genome. An unusual feature of the genus Candida is that in many of its species (including C. albicans and C. tropicalis, but not, for instance, C. glabrata) the CUG codon, which normally specifies leucine, specifies serine in these species.
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Neutral mutation and the neutral theory of molecular evolution are not separate from natural selection but add to Darwin's original thoughts. Mutations can give an advantage, create a disadvantage, or make no measurable difference to an organism's survival. A number of observations associated with neutral mutation were predicted in neutral theory including: amino acids with similar biochemical properties should be substituted more often than biochemically different amino acids; synonymous base substitutions should be observed more often than nonsynonymous substitutions; introns should evolve at the same rate as synonymous mutations in coding exons; and pseudogenes should also evolve at a similar rate. These predictions have been confirmed with the introduction of additional genetic data since the theory’s introduction.
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In genetics, the Ka/Ks ratio, also known as ω or dN/dS ratio, is used to estimate the balance between neutral mutations, purifying selection and beneficial mutations acting on a set of homologous protein-coding genes. It is calculated as the ratio of the number of nonsynonymous substitutions per non- synonymous site (Ka), in a given period of time, to the number of synonymous substitutions per synonymous site (Ks), in the same period. The latter are assumed to be neutral, so that the ratio indicates the net balance between deleterious and beneficial mutations. Values of Ka/Ks significantly above 1 are unlikely to occur without at least some of the mutations being advantageous.
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In order to detect selection between lineages, then the selection, averaged over all sites in the sequence, must produce a Ka/Ks greater than one—quite a feat if regions of the gene are strongly conserved. In order to detect selection at specific sites, then the Ka/Ks ratio must be greater than one when averaged over all included lineages at that site—implying that the site must be under selective pressure in all sampled lineages. This limitation can be moderated by allowing the Ka/Ks rate to take multiple values across sites and across lineages; the inclusion of more lineages also increases the power of a sites-based approach. Further, the method lacks the capability to distinguish between positive and negative nonsynonymous substitutions.
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Non-synonymous is the variant in exons that change the amino acid sequence encoded by the gene, including single base changes and non frameshift indels. It has been extremely investigated the function of non-synonymous variants on protein and many algorithms have been developed to predict the deleteriousness and pathogenesis of single nucleotide variants (SNVs). Classical bioinformatics tools, such as SIFT, Polyphen and MutationTaster, successfully predict the functional consequence of non- synonymous substitution.J. Wu, R. Jiang, "Prediction of Deleterious Nonsynonymous Single-Nucleotide Polymorphism for Human Diseases", The Scientific World Journal, 2013, 10 pages PopViz webserver provides a gene- centric approach to visualize the mutation damage prediction scores (CADD, SIFT, PolyPhen-2) or the population genetics (minor allele frequency) versus the amino acid positions of all coding variants of a certain human gene.
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