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The McDonald–Kreitman test is a statistical test often used by evolution 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 (also known as directional 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.〔Futuyma, D. J. 2013. Evolution. Sinauer Associates, Inc.: Sunderland.〕 A site is nonneutral if it is either advantageous or deleterious.〔(), Charlesworth, J. Eyre-Walker, A. 2008. The McDonald–Kreitman Test and Slightly Deleterious Mutations. Molecular Biology and Evolution 25 (6): 1007-1015.〕 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.〔(), Kimchi-Sarfaty, C. Oh, J. M. Kim, I. Sauna, Z. E. Calcagno, A. M. Ambudkar, S. V. Gottesman, M. M. 2007. A "Silent" Polymorphism in the MDR1 Gene Changes Substrate Specificity. Science 315 (5811): 525-528.〕 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. In 1991, John H. McDonald and Martin Kreitman derived the McDonald–Kreitman test while performing an experiment with Drosophila (fruit flies) and their differences in amino acid sequence of the alcohol dehydrogenase gene. McDonald and Kreitman proposed this method to estimate the proportion of substitutions that are fixed by positive selection rather than by genetic drift.〔(), Eyre-Walker, A. 2006. The genomic rate of adaptive evolution. Trends in Ecology and Evolution 21 (10): 569-575.〕 In order to set up the McDonald–Kreitman test, we must first set up a two-way contingency table of our data on the species being investigated as shown below: * ''D''s: the number of synonymous substitutions per gene * ''D''n: the number of non-synonymous substitutions per gene * ''P''s: the number of synonymous polymorphisms per gene * ''P''n: the number of non-synonymous polymorphisms per gene To quantify the values for ''D''s, ''D''n, ''P''s, and ''P''n, you count the number of differences in the protein-coding region for each type of variable in the contingency table. The null hypothesis of the McDonald–Kreitman test is that the ratio of nonsynonymous to synonymous variation within a species is going to equal the ratio of nonsynonymous to synonymous variation between species (i.e. ''D''n/''D''s = ''P''n/''P''s). When positive or negative selection (natural selection) influences nonsynonymous variation, the ratios will no longer equal. The ratio of nonsynonymous to synonymous variation between species is going to be lower than the ratio of nonsynonymous to synonymous variation within species (i.e. ''D''n/''D''s < ''P''n/''P''s) when negative selection is at work, and deleterious mutations strongly affect polymorphism. The ratio of nonsynonymous to synonymous variation within species is lower than the ratio of nonsynonymous to synonymous variation between species (i.e. ''D''n/''D''s > ''P''n/''P''s) when we observe positive selection. Since mutations under positive selection spread through a population rapidly, they don't contribute to polymorphism but do have an effect on divergence.〔(), Barbadilla, A. Casillas, S. Egea, R. 2008. Standard and generalized McDonald-Kreitman test: a website to detect selection by comparing different classes of DNA sites. Nucleic Acids Research 36: 157-162.〕 Using an equation derived by Smith and Eyre-Walker, we can estimate the proportion of base substitutions fixed by natural selection, α, using the following formula: : Alpha represents the proportion of substitutions driven by positive selection. Alpha can be equal to any number between -∞ and 1. Negative values of alpha are produced by sampling error or violations of the model, such as the segregation of slightly deleterious amino acid mutations.〔(), Eyre-Walker, A. 2002. Changing Effective Population Size and the McDonald-Kreitman Test. Genetics Society of America 162: 2017-2024.〕 Similar to above, our null hypothesis here is that α=0, and we expect ''D''n/''D''s to equal ''P''n/''P''s.〔 ==The Neutrality Index== The neutrality index (NI) quantifies the direction and degree of departure from neutrality (where ''P''n/''P''s and ''D''n/''D''s ratios equal). When assuming that silent mutations are neutral, a neutrality index greater than 1 (i.e. NI > 1) indicates negative selection is at work, resulting in an excess of amino acid polymorphism. This occurs because natural selection is favoring the purifying selection, and the weeding out of deleterious alleles.〔(), Meiklejohns, C. D. Montooth, K. L. Rand, D. M. 2007. Positive and negative selection on the mitochondrial genome. Trends in Genetics 23 (6): 259-263.〕 Because silent mutations are neutral, a neutrality index lower than 1 (i.e. NI < 1) indicates an excess of nonsilent divergence, which occurs when positive selection is at work in the population. When positive selection is acting on the species, natural selection favors a specific phenotype over other phenotypes, and the favored phenotype begins to go to fixation in the species as the allele frequency for that phenotype increases.〔(), Stoletzki, N. Eyre-Walker, A. 2010. Estimation of the Neutrality Index. Molecular Biology and Evolution 28 (1): 63-70.〕 To find the neutrality index, we can use the following equation: : 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「McDonald–Kreitman test」の詳細全文を読む スポンサード リンク
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