Nonsynonymous substitution

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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.

Contents

Nonsynonymous substitutions at a certain locus can be compared to the synonymous substitutions at the same locus to obtain the Ka/Ks ratio. This ratio is used to measure the evolutionary rate of gene sequences. [1] 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.

[2] Nonsynonymous substitutions are also referred to as replacement mutations.

Types

There are several common types of nonsynonymous substitutions. [3]

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. [3]

Natural selection and the nearly neutral theory

Studies have shown that diversity among nonsynonymous substitutions is significantly lower than among synonymous substitutions. [4] This is due to the fact that nonsynonymous substitutions are subject to much higher selective pressures than synonymous mutations. [5] Motoo Kimura (1968) determined that calculated mutation rates were impossibly high, unless most of the mutations that occurred were either neutral or "nearly neutral". [3] He determined that if this were true, genetic drift would be a more powerful factor in molecular evolution than natural selection. [6] 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. [7] In order to determine whether natural selection is taking place at a certain loci, the McDonald–Kreitman test can be performed. [8] 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. 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. [3] 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. [3]

Research

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. [9]

Further research by Yang and Nielsen found that nonsynonymous to synonymous substitution ratios varied across loci in differing evolutionary lineages. During their study of nuclear loci of primates, even-toed ungulates, and rodents, they found that the ratio varied significantly at 22 of the 48 loci studied. This result provides strong evidence against a strictly neutral theory of molecular evolution, which states that mutations are mostly neutral or deleterious, and provides support for theories that include advantageous mutations. [10]

See also

Related Research Articles

Mutation Alteration in the nucleotide sequence of a genome

In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosis, or meiosis or other types of damage to DNA, which then may undergo error-prone repair, cause an error during other forms of repair, or cause an error during replication. Mutations may also result from insertion or deletion of segments of DNA due to mobile genetic elements.

Molecular evolution Process of change in the sequence composition of cellular molecules across generations

Molecular evolution is the process of change in the sequence composition of cellular molecules such as DNA, RNA, and proteins across generations. The field of molecular evolution uses principles of evolutionary biology and population genetics to explain patterns in these changes. Major topics in molecular evolution concern the rates and impacts of single nucleotide changes, neutral evolution vs. natural selection, origins of new genes, the genetic nature of complex traits, the genetic basis of speciation, evolution of development, and ways that evolutionary forces influence genomic and phenotypic changes.

The neutral theory of molecular evolution holds that most evolutionary changes occur at the molecular level, and most of the variation within and between species are due to random genetic drift of mutant alleles that are selectively neutral. The theory applies only for evolution at the molecular level, and is compatible with phenotypic evolution being shaped by natural selection as postulated by Charles Darwin. The neutral theory allows for the possibility that most mutations are deleterious, but holds that because these are rapidly removed by natural selection, they do not make significant contributions to variation within and between species at the molecular level. A neutral mutation is one that does not affect an organism's ability to survive and reproduce. The neutral theory assumes that most mutations that are not deleterious are neutral rather than beneficial. Because only a fraction of gametes are sampled in each generation of a species, the neutral theory suggests that a mutant allele can arise within a population and reach fixation by chance, rather than by selective advantage.

Single-nucleotide polymorphism Single nucleotide position in genomic DNA at which different sequence alternatives exist

In genetics, a single-nucleotide polymorphism is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently large fraction of the population, many publications do not apply such a frequency threshold.

Silent mutation

Silent mutations are mutations in DNA that do not have an observable effect on the organism's phenotype. They are a specific type of neutral mutation. The phrase silent mutation is often used interchangeably with the phrase synonymous mutation; however, synonymous mutations are not always silent, nor vice versa. Synonymous mutations can affect transcription, splicing, mRNA transport, and translation, any of which could alter phenotype, rendering the synonymous mutation non-silent. 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. Mutations that cause the altered codon to produce an amino acid with similar functionality are often classified as silent; if the properties of the amino acid are conserved, this mutation does not usually significantly affect protein function.

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.

Substitution model Description of the process by which states in sequences change into each other and back

In biology, a substitution model, also called models of DNA sequence evolution, are Markov models that describe changes over evolutionary time. These models describe evolutionary changes in macromolecules represented as sequence of symbols. Substitution models are used to calculate the likelihood of phylogenetic trees using multiple sequence alignment data. Thus, substitution models are central to maximum likelihood estimation of phylogeny as well as Bayesian inference in phylogeny. Estimates of evolutionary distances are typically calculated using substitution models. Substitution models are also central to phylogenetic invariants since they can be used to predict the frequencies of site pattern frequencies given a tree topology. Substitution models are necessary to simulate sequence data for a group of organisms related by a specific tree.

A synonymous substitution is the evolutionary substitution of one base for another in an exon of a gene coding for a protein, such that the produced amino acid sequence is not modified. This is possible because the genetic code is "degenerate", meaning that some amino acids are coded for by more than one three-base-pair codon; since some of the codons for a given amino acid differ by just one base pair from others coding for the same amino acid, a mutation that replaces the "normal" base by one of the alternatives will result in incorporation of the same amino acid into the growing polypeptide chain when the gene is translated. Synonymous substitutions and mutations affecting noncoding DNA are often considered silent mutations; however, it is not always the case that the mutation is silent.

Conserved sequence Similar DNA, RNA or protein sequences within genomes or among species

In evolutionary biology, conserved sequences are identical or similar sequences in nucleic acids or proteins across species, or within a genome, or between donor and receptor taxa. Conservation indicates that a sequence has been maintained by natural selection.

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. If beneficial mutations are assumed to make little contribution, then Ks estimates the degree of evolutionary constraint.

Neutral mutations are changes in DNA sequence that are neither beneficial nor detrimental to the ability of an organism to survive and reproduce. In population genetics, mutations in which natural selection does not affect the spread of the mutation in a species are termed neutral mutations. Neutral mutations that are inheritable and not linked to any genes under selection will either be lost or will replace all other alleles of the gene. This loss or fixation of the gene proceeds based on random sampling known as genetic drift. A neutral mutation that is in linkage disequilibrium with other alleles that are under selection may proceed to loss or fixation via genetic hitchhiking and/or background selection.

Masatoshi Nei American geneticist

Masatoshi Nei is a Japanese-born American evolutionary biologist currently affiliated with the Department of Biology at Temple University as a Carnell Professor. He was, until recently, Evan Pugh Professor of Biology at Pennsylvania State University and Director of the Institute of Molecular Evolutionary Genetics; he was there from 1990 to 2015.

History of molecular evolution History of the field of study of molecular evolution

The history of molecular evolution starts in the early 20th century with "comparative biochemistry", but the field of molecular evolution came into its own in the 1960s and 1970s, following the rise of molecular biology. The advent of protein sequencing allowed molecular biologists to create phylogenies based on sequence comparison, and to use the differences between homologous sequences as a molecular clock to estimate the time since the last common ancestor. In the late 1960s, the neutral theory of molecular evolution provided a theoretical basis for the molecular clock, though both the clock and the neutral theory were controversial, since most evolutionary biologists held strongly to panselectionism, with natural selection as the only important cause of evolutionary change. After the 1970s, nucleic acid sequencing allowed molecular evolution to reach beyond proteins to highly conserved ribosomal RNA sequences, the foundation of a reconceptualization of the early history of life.

Adaptive evolution results from the propagation of advantageous mutations through positive selection. This is the modern synthesis of the process which Darwin and Wallace originally identified as the mechanism of evolution. However, in the last half century, there has been considerable debate as to whether evolutionary changes at the molecular level are largely driven by natural selection or random genetic drift. Unsurprisingly, the forces which drive evolutionary changes in our own species’ lineage have been of particular interest. Quantifying adaptive evolution in the human genome gives insights into our own evolutionary history and helps to resolve this neutralist-selectionist debate. Identifying specific regions of the human genome that show evidence of adaptive evolution helps us find functionally significant genes, including genes important for human health, such as those associated with diseases.

The McDonald–Kreitman test is a statistical test often used by evolutionary and population biologists to detect and measure the amount of adaptive evolution within a species by determining whether adaptive evolution has occurred, and the proportion of substitutions that resulted from positive selection. To do this, the McDonald–Kreitman test compares the amount of variation within a species (polymorphism) to the divergence between species (substitutions) at two types of sites, neutral and nonneutral. A substitution refers to a nucleotide that is fixed within one species, but a different nucleotide is fixed within a second species at the same base pair of homologous DNA sequences. A site is nonneutral if it is either advantageous or deleterious. The two types of sites can be either synonymous or nonsynonymous within a protein-coding region. In a protein-coding sequence of DNA, a site is synonymous if a point mutation at that site would not change the amino acid, also known as a silent mutation. Because the mutation did not result in a change in the amino acid that was originally coded for by the protein-coding sequence, the phenotype, or the observable trait, of the organism is generally unchanged by the silent mutation. A site in a protein-coding sequence of DNA is nonsynonymous if a point mutation at that site results in a change in the amino acid, resulting in a change in the organism's phenotype. Typically, silent mutations in protein-coding regions are used as the "control" in the McDonald–Kreitman test.

Ziheng Yang FRS is a Chinese biologist. He holds the R.A. Fisher Chair of Statistical Genetics at University College London, and is the Director of R.A. Fisher Centre for Computational Biology at UCL. He was elected a Fellow of the Royal Society in 2006.

Degeneracy or redundancy of codons is the redundancy of the genetic code, exhibited as the multiplicity of three-base pair codon combinations that specify an amino acid. The degeneracy of the genetic code is what accounts for the existence of synonymous mutations.

A conservative replacement is an amino acid replacement in a protein that changes a given amino acid to a different amino acid with similar biochemical properties.

The rate of evolution is quantified as the speed of genetic or morphological change in a lineage over a period of time. The speed at which a molecular entity evolves is of considerable interest in evolutionary biology since determining the evolutionary rate is the first step in characterizing its evolution. Calculating rates of evolutionary change is also useful when studying phenotypic changes in phylogenetic comparative biology. In either case, it can be beneficial to consider and compare both genomic data and paleontological data, especially in regards to estimating the timing of divergence events and establishing geological time scales.

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.

References

  1. ↑ Ting Hu and Wolfgang Banzhaf. "Nonsynonymous to Synonymous Substitution Ratio ka/ks: Measurement for Rate of Evolution in Evolutionary Computation" (PDF).{{cite journal}}: Cite journal requires |journal= (help)
  2. ↑ Herron, Jon C. (2014). Evolutionary analysis. Freeman, Scott, 1955-, Hodin, Jason A., 1969-, Miner, Brooks Erin,, Sidor, Christian A. (Fifth ed.). Boston. ISBN   978-0321616678. OCLC   859267755.
  3. 1 2 3 4 5 Nature encyclopedia of the human genome. Cooper, David N. (David Neil), 1957-, Nature Publishing Group. London: Nature Pub. Group. 2003. ISBN   978-0333803868. OCLC   51668320.{{cite book}}: CS1 maint: others (link)
  4. ↑ Li, W.H. (1997). Molecular Evolution. Sunderland, MA: Sinauer Associates.
  5. ↑ Tomoko, Ohta (1995-01-01). "Synonymous and nonsynonymous substitutions in mammalian genes and the nearly neutral theory". Journal of Molecular Evolution. 40 (1): 56–63. Bibcode:1995JMolE..40...56T. doi:10.1007/bf00166595. ISSN   0022-2844. PMID   7714912.
  6. ↑ Kimura, Motoo (1968). "Evolutionary Rate at the Molecular Level" (PDF). Nature. 217 (5129): 624–626. Bibcode:1968Natur.217..624K. doi:10.1038/217624a0. PMID   5637732. S2CID   4161261.
  7. ↑ Akashi, Hiroshi; Osada, Naoki; Ohta, Tomoko (2012-09-01). "Weak Selection and Protein Evolution". Genetics. 192 (1): 15–31. doi:10.1534/genetics.112.140178. ISSN   0016-6731. PMC   3430532 . PMID   22964835.
  8. ↑ Ohta, Tomoko (2002-12-10). "Near-neutrality in evolution of genes and gene regulation". Proceedings of the National Academy of Sciences. 99 (25): 16134–16137. Bibcode:2002PNAS...9916134O. doi: 10.1073/pnas.252626899 . ISSN   0027-8424. PMC   138577 . PMID   12461171.
  9. ↑ Ziheng Yang and Rasmus Nielsen. "Estimating Synonymous and Nonsynonymous Substitution Rates Under Realistic Evolutionary Models" (PDF). Archived from the original (PDF) on 2015-10-20. Retrieved 2017-12-02.
  10. ↑ Ziheng Yang and Rasmus Nielsen (1998). "Synonymous and Nonsynonymous Rate Variation in Nuclear Genes of Mammals" (PDF). Journal of Molecular Evolution. 46 (4): 409–418. Bibcode:1998JMolE..46..409Y. CiteSeerX   10.1.1.19.7744 . doi:10.1007/pl00006320. PMID   9541535. S2CID   13917969.
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