K a / K s ratio

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In genetics , the K a / K s ratio (also called d N / d S ratio or ω ) is used to distinguish between neutral, negatively selecting or positively selecting mutations within a sequence of a gene . It is calculated from the so-called non-synonymous substitutions and the synonymous substitutions.

functionality

The genetic code provides a total of 64 codons, which, however, code for only 20 amino acids . Numerous codons are therefore synonymous with one another, i.e. they code for the same amino acid. In a so-called synonymous substitution (mostly a silent mutation ), a base in a codon is exchanged without changing the encoded amino acid. (e.g. AGG → CGG, both code for arginine ). In the case of a non-synonymous substitution, the change in the base also changes the coded amino acid. (e.g. UUU → UUA, the former codes for phenylalanine , but after the mutation the codon codes for leucine ). Evolutionary selection acts on changes in the phenotype , which are mostly caused by mutations in protein-coding gene segments.

Calculation and interpretation

There are various ways of calculating the ratio. The simplest are called approximate methods, as they make a variety of simplistic assumptions. The calculation for two sequences with which a sequence alignment was carried out is carried out according to the following scheme.

  1. Count the synonymous and non-synonymous substitution sites in both sequences
  2. Count the synonymous and nonsynonymous differences between the two sequences
  3. Correction for possible multiple substitutions

If the value calculated using a certain method is equal to 1, this speaks for a neutral mutation, if it is greater than 1 for a positive selection and if it is less than 1 for a negative selection.

Limitations

Despite its wide usage, the K a / K s ratio also has some limitations. First of all, only mutations in the coding region of a gene can or are considered with the K a / K s ratio. However, many evolutionary changes are based on regulatory gene segments that such an analysis does not include.

The K a / K s calculation also requires strong differences between the sequences in order to be able to recognize selection. This is particularly problematic when parts of the analyzed sequence are highly conserved and thus make it more difficult to achieve a K a / K s ratio greater than 1.

In addition, with certain non-synonymous substitutions, which change the amino acid sequence of the protein, changes of varying magnitude can occur, depending on whether the new amino acid is chemically similar to the original one or not. The former often leads to proteins that are functional, while the latter tends to lead to a disruption of the function of the protein.

In addition, a temporal component must also be considered, since depending on the strength of the selection pressure, the time or the number of generations that is necessary for a negative mutation to disappear from a population varies. This makes it particularly difficult to compare sequences of closely related populations or species .

Finally, the K a / K s ratio can only be used to compare differences between different populations , which is what it was originally used for. When trying to compare sequences within the same population, the ratio must not be compared as when comparing two evolutionarily separated sequences.

Web links

Individual evidence

  1. ^ Laurence D Hurst: The Ka / Ks ratio: diagnosing the form of sequence evolution . In: Trends in Genetics . tape 18 , no. 9 , September 2002, p. 486-487 , doi : 10.1016 / S0168-9525 (02) 02722-1 ( elsevier.com [accessed June 27, 2020]).
  2. ↑ Ziheng Yang, Joseph P. Bielawski: Statistical Methods for Detecting molecular adaptation . In: Trends in Ecology & Evolution . tape 15 , no. December 12 , 2000, pp. 496-503 , doi : 10.1016 / S0169-5347 (00) 01994-7 , PMID 11114436 , PMC 7134603 (free full text) - ( elsevier.com [accessed June 27, 2020]).
  3. ↑ Eduardo PC Rocha, John Maynard Smith, Laurence D. Hurst, Matthew TG Holden, Jessica E. Cooper: Comparisons of dN / dS are time dependent for closely related bacterial genomes . In: Journal of Theoretical Biology . tape 239 , no. 2 , March 2006, p. 226–235 , doi : 10.1016 / j.jtbi.2005.08.037 ( elsevier.com [accessed June 27, 2020]).
  4. ^ Carina F. Mugal, Jochen BW Wolf, Ingemar Kaj: Why Time Matters: Codon Evolution and the Temporal Dynamics of dN / dS . In: Molecular Biology and Evolution . tape 31 , no. 1 , January 2014, ISSN  1537-1719 , p. 212-231 , doi : 10.1093 / molbev / mst192 , PMID 24129904 , PMC 3879453 (free full text) - ( oup.com [accessed June 27, 2020]).
  5. ↑ Sergey Kryazhimskiy, Joshua B. Plotkin: The Population Genetics of dN / dS . In: PLoS Genetics . tape 4 , no. 12 , December 12, 2008, ISSN  1553-7404 , p. e1000304 , doi : 10.1371 / journal.pgen.1000304 , PMID 19081788 , PMC 2596312 (free full text) - ( plos.org [accessed June 27, 2020]).
  6. ↑ Zhang Zhang, Jun Li, Xiao-Qian Zhao, Jun Wang, Gane Ka-Shu Wong: KaKs_Calculator: Calculating Ka and Ks Through Model Selection and Model Averaging . In: Genomics, Proteomics & Bioinformatics . tape 4 , no. 4 , 2006, p. 259-263 , doi : 10.1016 / S1672-0229 (07) 60007-2 , PMID 17531802 , PMC 5054075 (free full text) - ( elsevier.com [accessed June 27, 2020]).