Neutral mutation

Last updated

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 be lost or will replace all other alleles of the gene. That 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.

Contents

While many mutations in a genome may decrease an organism’s ability to survive and reproduce, also known as fitness, those mutations are selected against and are not passed on to future generations. The most commonly-observed mutations that are detectable as variation in the genetic makeup of organisms and populations appear to have no visible effect on the fitness of individuals and are therefore neutral. The identification and study of neutral mutations has led to the development of the neutral theory of molecular evolution, which is an important and often-controversial theory that proposes that most molecular variation within and among species is essentially neutral and not acted on by selection. Neutral mutations are also the basis for using molecular clocks to identify such evolutionary events as speciation and adaptive or evolutionary radiations.

History

Charles Darwin in 1868 Charles Darwin by Julia Margaret Cameron, c. 1868.jpg
Charles Darwin in 1868

Charles Darwin commented on the idea of neutral mutation in his work, hypothesizing that mutations that do not give an advantage or disadvantage may fluctuate or become fixed apart from natural selection. "Variations neither useful nor injurious would not be affected by natural selection, and would be left either a fluctuating element, as perhaps we see in certain polymorphic species, or would ultimately become fixed, owing to the nature of the organism and the nature of the conditions." While Darwin is widely credited with introducing the idea of natural selection which was the focus of his studies, he also saw the possibility for changes that did not benefit or hurt an organism. [1]

Darwin's view of change being mostly driven by traits that provide advantage was widely accepted until the 1960s. [2] While researching mutations that produce nucleotide substitutions in 1968, Motoo Kimura found that the rate of substitution was so high that if each mutation improved fitness, the gap between the most fit and typical genotype would be implausibly large. However, Kimura explained this rapid rate of mutation by suggesting that the majority of mutations were neutral, i.e. had little or no effect on the fitness of the organism. Kimura developed mathematical models of the behavior of neutral mutations subject to random genetic drift in biological populations. This theory has become known as the neutral theory of molecular evolution. [3]

As technology has allowed for better analysis of genomic data, research has continued in this area. While natural selection may encourage adaptation to a changing environment, neutral mutation may push divergence of species due to nearly random genetic drift. [2]

Impact on evolutionary theory

Neutral mutation has become a part of the neutral theory of molecular evolution, proposed in the 1960s. This theory suggests that neutral mutations are responsible for a large portion of DNA sequence changes in a species. For example, bovine and human insulin, while differing in amino acid sequence are still able to perform the same function. The amino acid substitutions between species were seen therefore to be neutral or not impactful to the function of the protein. 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. [4]

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. [2]

Types

Synonymous mutation of bases

When an incorrect nucleotide is inserted during replication or transcription of a coding region, it can affect the eventual translation of the sequence into amino acids. Since multiple codons are used for the same amino acids, a change in a single base may still lead to translation of the same amino acid. This phenomenon is referred to as degeneracy and allows for a variety of codon combinations leading to the same amino acid being produced. For example, the codes TCT, TCC, TCA, TCG, AGT, and AGC all code for the amino acid serine. This can be explained by the wobble concept. Francis Crick proposed this theory to explain why specific tRNA molecules could recognize multiple codons. The area of the tRNA that recognizes the codon called the anticodon is able to bind multiple interchangeable bases at its 5' end due to its spatial freedom. A fifth base called inosine can also be substituted on a tRNA and is able to bind with A, U, or C. This flexibility allows for changes in bases in codons leading to translation of the same amino acid. [5] The changing of a base in a codon without the changing of the translated amino acid is called a synonymous mutation. Since the amino acid translated remains the same a synonymous mutation has traditionally been considered a neutral mutation. [6] Some research has suggested that there is bias in selection of base substitution in synonymous mutation. This could be due to selective pressure to improve translation efficiency associated with the most available tRNAs or simply mutational bias. [7] If these mutations influence the rate of translation or an organism’s ability to manufacture protein they may actually influence the fitness of the affected organism. [6]

Amino-acid biochemical propertiesNonpolarPolarBasicAcidicTermination: stop codon
Standard genetic code (NCBI table 1) [8]
1st
base		2nd base3rd
base
TCAG
TTTT(Phe/F) Phenylalanine TCT(Ser/S) Serine TAT(Tyr/Y) Tyrosine TGT(Cys/C) Cysteine T
TTCTCCTACTGCC
TTA(Leu/L) Leucine TCATAA Stop (Ochre) [B] TGA Stop (Opal) [B] A
TTG [A] TCGTAG Stop (Amber) [B] TGG(Trp/W) Tryptophan G
CCTTCCT(Pro/P) Proline CAT(His/H) Histidine CGT(Arg/R) Arginine T
CTCCCCCACCGCC
CTACCACAA(Gln/Q) Glutamine CGAA
CTGCCGCAGCGGG
AATT(Ile/I) Isoleucine ACT(Thr/T) Threonine AAT(Asn/N) Asparagine AGT(Ser/S) Serine T
ATCACCAACAGCC
ATAACAAAA(Lys/K) Lysine AGA(Arg/R) Arginine A
ATG [A] (Met/M) Methionine ACGAAGAGGG
GGTT(Val/V) Valine GCT(Ala/A) Alanine GAT(Asp/D) Aspartic acid GGT(Gly/G) Glycine T
GTCGCCGACGGCC
GTAGCAGAA(Glu/E) Glutamic acid GGAA
GTG [A] GCGGAGGGGG
A Possible start codons in NCBI table 1. ATG is most common. [9] The two other start codons listed by table 1 (GTG and TTG) are rare in eukaryotes. [10] Prokaryotes have less strigent start codon requirements; they are described by NCBI table 11.
B ^ ^ ^ The historical basis for designating the stop codons as amber, ochre and opal is described in an autobiography by Sydney Brenner [11] and in a historical article by Bob Edgar. [12]

Neutral amino acid substitution

While substitution of a base in a noncoding area of a genome may make little difference and be considered neutral, base substitutions in or around genes may impact the organism. Some base substitutions lead to synonymous mutation and no difference in the amino acid translated as noted above. However, a base substitution can also change the genetic code so that a different amino acid is translated. This sort of substitution usually has a negative effect on the protein being formed and will be eliminated from the population through purifying selection. However, if the change has a positive influence, the mutation may become more and more common in a population until it becomes a fixed genetic piece of that population. Organisms changing via these two options comprise the classic view of natural selection. A third possibility is that the amino acid substitution makes little or no positive or negative difference to the affected protein. [13] Proteins demonstrate some tolerance to changes in amino acid structure. This is somewhat dependent on where in the protein the substitution takes place. If it occurs in an important structural area or in the active site, one amino acid substitution may inactivate or substantially change the functionality of the protein. Substitutions in other areas may be nearly neutral and drift randomly over time. [14]

Identification and measurement of neutrality

Neutral mutations are measured in population and evolutionary genetics often by looking at variation in populations. These have been measured historically by gel electrophoresis to determine allozyme frequencies. [15] Statistical analyses of this data is used to compare variation to predicted values based on population size, mutation rates and effective population size. Early observations that indicated higher than expected heterozygosity and overall variation within the protein isoforms studied, drove arguments as to the role of selection in maintaining this variation versus the existence of variation through the effects of neutral mutations arising and their random distribution due to genetic drift. [16] [17] [18] The accumulation of data based on observed polymorphism led to the formation of the neutral theory of evolution. [16] According to the neutral theory of evolution, the rate of fixation in a population of a neutral mutation will be directly related to the rate of formation of the neutral allele. [19]

In Kimura’s original calculations, mutations with |2 Ns|<1 or |s|≤1/(2N) are defined as neutral. [16] [18] In this equation, N is the effective population size and is a quantitative measurement of the ideal population size that assumes such constants as equal sex ratios and no emigration, migration, mutation nor selection. [20] Conservatively, it is often assumed that effective population size is approximately one fifth of the total population size. [21] s is the selection coefficient and is a value between 0 and 1. It is a measurement of the contribution of a genotype to the next generation where a value of 1 would be completely selected against and make no contribution and 0 is not selected against at all. [22] This definition of neutral mutation has been criticized due to the fact that very large effective population sizes can make mutations with small selection coefficients appear non neutral. Additionally, mutations with high selection coefficients can appear neutral in very small populations. [18] The testable hypothesis of Kimura and others showed that polymorphism within species are approximately that which would be expected in a neutral evolutionary model. [18] [23] [24]

For many molecular biology approaches, as opposed to mathematical genetics, neutral mutations are generally assumed to be those mutations that cause no appreciable effect on gene function. This simplification eliminates the effect of minor allelic differences in fitness and avoids problems when a selection has only a minor effect. [18]

Early convincing evidence of this definition of neutral mutation was shown through the lower mutational rates in functionally important parts of genes such as cytochrome c versus less important parts [25] and the functionally interchangeable nature of mammalian cytochrome c in in vitro studies. [26] Nonfunctional pseudogenes provide more evidence for the role of neutral mutations in evolution. The rates of mutation in mammalian globin pseudogenes has been shown to be much higher than rates in functional genes. [27] [28] According to neo-Darwinian evolution, such mutations should rarely exist as these sequences are functionless and positive selection would not be able to operate. [18]

The McDonald-Kreitman test [29] has been used to study selection over long periods of evolutionary time. This is a statistical test that compares polymorphism in neutral and functional sites and estimates what fraction of substitutions have been acted on by positive selection. [30] The test often uses synonymous substitutions in protein coding genes as the neutral component; however, synonymous mutations have been shown to be under purifying selection in many instances. [31] [32]

Molecular clocks

Molecular clocks can be used to estimate the amount of time since divergence of two species and for placing evolutionary events in time. [33] Pauling and Zuckerkandl, proposed the idea of the molecular clock in 1962 based on the observation that the random mutation process occurs at an approximate constant rate. Individual proteins were shown to have linear rates of amino acid changes over evolutionary time. [34] Despite controversy from some biologists arguing that morphological evolution would not proceed at a constant rate, many amino acid changes were shown to accumulate in a constant fashion. Kimura and Ohta explained these rates as part of the framework of the neutral theory. These mutations were reasoned to be neutral as positive selection should be rare and deleterious mutations should be eliminated quickly from a population. [35] By this reasoning, the accumulation of these neutral mutations should only be influenced by the mutation rate. Therefore, the neutral mutation rate in individual organisms should match the molecular evolution rate in species over evolutionary time. The neutral mutation rate is affected by the amount of neutral sites in a protein or DNA sequence versus the amount of mutation in sites that are functionally constrained. By quantifying these neutral mutations in protein and/or DNA and comparing them between species or other groups of interest, rates of divergence can be determined. [33] [36]

Molecular clocks have caused controversy due to the dates they derive for events such as explosive radiations seen after extinction events like the Cambrian explosion and the radiations of mammals and birds. Two-fold differences exist in dates derived from molecular clocks and the fossil record. While some paleontologists argue that molecular clocks are systemically inaccurate, others attribute the discrepancies to lack of robust fossil data and bias in sampling. [37] While not without constancy and discrepancies with the fossil record, the data from molecular clocks have shown how evolution is dominated by the mechanisms of a neutral model and is less influenced by the action of natural selection. [33]

See also

Related Research Articles

<span class="mw-page-title-main">Genetic code</span> Rules by which information encoded within genetic material is translated into proteins

The genetic code is the set of rules used by living cells to translate information encoded within genetic material into proteins. Translation is accomplished by the ribosome, which links proteinogenic amino acids in an order specified by messenger RNA (mRNA), using transfer RNA (tRNA) molecules to carry amino acids and to read the mRNA three nucleotides at a time. The genetic code is highly similar among all organisms and can be expressed in a simple table with 64 entries.

<span class="mw-page-title-main">Mutation</span> 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 describes how inherited DNA and/or RNA change over evolutionary time, and the consequences of this for proteins and other components of cells and organisms. Molecular evolution is the basis of phylogenetic approaches to describing the tree of life. Molecular evolution also overlaps with population genetics, especially on shorter timescales. Topics in molecular evolution also include the origins of new genes, the genetic nature of complex traits, the genetic basis of speciation, the evolution of development, and patterns and processes underlying genomic changes during evolution.

<span class="mw-page-title-main">Neutral theory of molecular evolution</span> Theory of evolution by changes at the molecular level

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.

Population genetics is a subfield of genetics that deals with genetic differences within and among populations, and is a part of evolutionary biology. Studies in this branch of biology examine such phenomena as adaptation, speciation, and population structure.

<span class="mw-page-title-main">Codon usage bias</span> Genetic bias in coding DNA

Codon usage bias refers to differences in the frequency of occurrence of synonymous codons in coding DNA. A codon is a series of three nucleotides that encodes a specific amino acid residue in a polypeptide chain or for the termination of translation.

The molecular clock is a figurative term for a technique that uses the mutation rate of biomolecules to deduce the time in prehistory when two or more life forms diverged. The biomolecular data used for such calculations are usually nucleotide sequences for DNA, RNA, or amino acid sequences for proteins.

<span class="mw-page-title-main">Point mutation</span> Replacement, insertion, or deletion of a single DNA or RNA nucleotide

A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences that are moderately predictable based upon the specifics of the mutation. These consequences can range from no effect to deleterious effects, with regard to protein production, composition, and function.

<span class="mw-page-title-main">Silent mutation</span> DNA mutation with no observable effect on an organisms phenotype

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.

<span class="mw-page-title-main">Synonymous substitution</span>

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.

<i>The Neutral Theory of Molecular Evolution</i>

The Neutral Theory of Molecular Evolution is an influential monograph written in 1983 by Japanese evolutionary biologist Motoo Kimura. While the neutral theory of molecular evolution existed since his article in 1968, Kimura felt the need to write a monograph with up-to-date information and evidences showing the importance of his theory in evolution.

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 Ka/Ks estimates the degree of evolutionary constraint.

<span class="mw-page-title-main">Masatoshi Nei</span> Japanese-American geneticist (1931–2023)

Masatoshi Nei was a Japanese-born American evolutionary biologist.

The nearly neutral theory of molecular evolution is a modification of the neutral theory of molecular evolution that accounts for the fact that not all mutations are either so deleterious such that they can be ignored, or else neutral. Slightly deleterious mutations are reliably purged only when their selection coefficient are greater than one divided by the effective population size. In larger populations, a higher proportion of mutations exceed this threshold for which genetic drift cannot overpower selection, leading to fewer fixation events and so slower 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.

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.

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.

Weak selection in evolutionary biology is when individuals with different phenotypes possess similar fitness, i.e. one phenotype is weakly preferred over the other. Weak selection, therefore, is an evolutionary theory to explain the maintenance of multiple phenotypes in a stable population.

A neutral network is a set of genes all related by point mutations that have equivalent function or fitness. Each node represents a gene sequence and each line represents the mutation connecting two sequences. Neutral networks can be thought of as high, flat plateaus in a fitness landscape. During neutral evolution, genes can randomly move through neutral networks and traverse regions of sequence space which may have consequences for robustness and evolvability.

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.

References

  1. ↑ Darwin, C. (1987; 1859). On the origin of species by means of natural selection : Or the preservation of favoured races in the struggle for life (Special ed.). Birmingham, Ala.: Gryphon Editions.
  2. 1 2 3 Duret, L. (2008). "Neutral theory: The null hypothesis of molecular evolution". Nature Education. 1 (1): 803–6. 218.
  3. ↑ Kimura, Motoo (1983). The Neutral Theory of Molecular Evolution. Cambridge University Press. ISBN   978-1-139-93567-8.
  4. ↑ Nei, M; Suzuki, Y; Nozawa, M (2010). "The neutral theory of molecular evolution in the genomic era". Annual Review of Genomics and Human Genetics. 11: 265–89. doi:10.1146/annurev-genom-082908-150129. PMID   20565254. S2CID   207591378.
  5. ↑ Watson, James D.; Baker, Tania A.; Bell, Stephen P.; Gann, Alexander; Levine, Michael; Losik, Richard; Harrison, Stephen C. (2013). Molecular biology of the gene (7th ed.). Benjamin-Cummings. pp. 573–6. ISBN   978-0321762436.
  6. 1 2 Venetianer, Pál (1 January 2012). "Are synonymous codons indeed synonymous?". Biomolecular Concepts. 3 (1): 21–8. doi: 10.1515/bmc.2011.050 . PMID   25436522. S2CID   3765747.
  7. ↑ Duret, L (December 2002). "Evolution of synonymous codon usage in metazoans". Current Opinion in Genetics & Development. 12 (6): 640–9. doi:10.1016/s0959-437x(02)00353-2. PMID   12433576.
  8. ↑ Elzanowski A, Ostell J (7 January 2019). "The Genetic Codes". National Center for Biotechnology Information. Archived from the original on 5 October 2020. Retrieved 21 February 2019.
  9. ↑ Nakamoto T (March 2009). "Evolution and the universality of the mechanism of initiation of protein synthesis". Gene. 432 (1–2): 1–6. doi:10.1016/j.gene.2008.11.001. PMID   19056476.
  10. ↑ Asano, K (2014). "Why is start codon selection so precise in eukaryotes?". Translation (Austin, Tex.). 2 (1): e28387. doi:10.4161/trla.28387. PMID   26779403.
  11. ↑ Brenner S. A Life in Science (2001) Published by Biomed Central Limited ISBN   0-9540278-0-9 see pages 101-104
  12. ↑ Edgar B (2004). "The genome of bacteriophage T4: an archeological dig". Genetics. 168 (2): 575–82. PMC   1448817 . PMID   15514035. see pages 580-581
  13. ↑ Ng, PC; Henikoff, S (2006). "Predicting the effects of amino acid substitutions on protein function". Annual Review of Genomics and Human Genetics. 7: 61–80. doi:10.1146/annurev.genom.7.080505.115630. PMID   16824020. S2CID   1172309.
  14. ↑ Guo, HH; Choe, J; Loeb, LA (22 June 2004). "Protein tolerance to random amino acid change". Proc. Natl. Acad. Sci. U.S.A. 101 (25): 9205–10. Bibcode:2004PNAS..101.9205G. doi: 10.1073/pnas.0403255101 . PMC   438954 . PMID   15197260.
  15. ↑ Lewontin, RC (August 1991). "Twenty-five years ago in Genetics: electrophoresis in the development of evolutionary genetics: milestone or millstone?". Genetics. 128 (4): 657–62. doi:10.1093/genetics/128.4.657. PMC   1204540 . PMID   1916239.
  16. 1 2 3 Kimura, Motoo (17 February 1968). "Evolutionary Rate at the Molecular Level". Nature. 217 (5129): 624–6. Bibcode:1968Natur.217..624K. doi:10.1038/217624a0. PMID   5637732. S2CID   4161261.
  17. ↑ Lewontin, RC; Hubby, JL (August 1966). "A molecular approach to the study of genic heterozygosity in natural populations. II. Amount of variation and degree of heterozygosity in natural populations of Drosophila pseudoobscura". Genetics. 54 (2): 595–609. doi:10.1093/genetics/54.2.595. PMC   1211186 . PMID   5968643.
  18. 1 2 3 4 5 6 Nei, M (December 2005). "Selectionism and neutralism in molecular evolution". Molecular Biology and Evolution. 22 (12): 2318–42. doi:10.1093/molbev/msi242. PMC   1513187 . PMID   16120807.
  19. ↑ Tomizawa, J (20 June 2000). "Derivation of the relationship between neutral mutation and fixation solely from the definition of selective neutrality". Proc. Natl. Acad. Sci. U.S.A. 97 (13): 7372–5. Bibcode:2000PNAS...97.7372T. doi: 10.1073/pnas.97.13.7372 . PMC   16552 . PMID   10861006.
  20. ↑ Harmon, Luke J.; Braude, Stanton (2009). "12: Conservation of Small Populations: Effective Population Sizes, Inbreeding, and the 50/500 Rule". In Braude, Stanton; Low, Bobbi S. (eds.). An introduction to methods and models in ecology, evolution, and conservation biology. Princeton University Press. pp. 125–8. ISBN   9780691127248.
  21. ↑ Mace, Georgina M.; Lande, Russell (June 1991). "Assessing Extinction Threats: Toward a Reevaluation of IUCN Threatened Species Categories". Conservation Biology. 5 (2): 148–157. doi: 10.1111/j.1523-1739.1991.tb00119.x . JSTOR   2386188. S2CID   53450189.
  22. ↑ Ridley, Mark (2004). Evolution (3rd ed.). Blackwell. ISBN   978-1-4051-0345-9.
  23. ↑ Yamazaki, T.; Maruyama, T. (6 October 1972). "Evidence for the Neutral Hypothesis of Protein Polymorphism". Science. 178 (4056): 56–58. Bibcode:1972Sci...178...56Y. doi:10.1126/science.178.4056.56. PMID   5070515. S2CID   5944402.
  24. ↑ Nei, M; Graur, D (1984). "Extent of Protein Polymorphism and the Neutral Mutation Theory". Evolutionary Biology. Vol. 17. pp. 73–118. doi:10.1007/978-1-4615-6974-9_3 (inactive 2024-04-27). ISBN   978-1-4615-6976-3.{{cite book}}: CS1 maint: DOI inactive as of April 2024 (link)
  25. ↑ Dickerson, RE (1971). "The structures of cytochrome c and the rates of molecular evolution". Journal of Molecular Evolution. 1 (1): 26–45. Bibcode:1971JMolE...1...26D. doi:10.1007/bf01659392. PMID   4377446. S2CID   24992347.
  26. ↑ Jacobs, EE; Sanadi, DR (February 1960). "The reversible removal of cytochrome c from mitochondria". The Journal of Biological Chemistry. 235 (2): 531–4. doi: 10.1016/S0021-9258(18)69561-4 . PMID   14406362.
  27. ↑ Li, Wen-Hsiung; Gojobori, Takashi; Nei, Masatoshi (16 July 1981). "Pseudogenes as a paradigm of neutral evolution". Nature. 292 (5820): 237–9. Bibcode:1981Natur.292..237L. doi:10.1038/292237a0. PMID   7254315. S2CID   23519275.
  28. ↑ Miyata, T; Yasunaga, T (September 1980). "Molecular evolution of mRNA: a method for estimating evolutionary rates of synonymous and amino acid substitutions from homologous nucleotide sequences and its application". Journal of Molecular Evolution. 16 (1): 23–36. Bibcode:1980JMolE..16...23M. doi:10.1007/bf01732067. PMID   6449605. S2CID   22507222.
  29. ↑ McDonald, JH; Kreitman, M (20 June 1991). "Adaptive protein evolution at the Adh locus in Drosophila". Nature. 351 (6328): 652–4. Bibcode:1991Natur.351..652M. doi:10.1038/351652a0. PMID   1904993. S2CID   205024070.
  30. ↑ Egea, R; Casillas, S; Barbadilla, A (1 July 2008). "Standard and generalized McDonald-Kreitman test: a website to detect selection by comparing different classes of DNA sites". Nucleic Acids Research. 36 (Web Server issue): W157–62. doi:10.1093/nar/gkn337. PMC   2447769 . PMID   18515345.
  31. ↑ Hellmann, I; Zollner, S; Enard, W; Ebersberger, I; Nickel, B; Paabo, S (May 2003). "Selection on human genes as revealed by comparisons to chimpanzee cDNA". Genome Research. 13 (5): 831–7. doi:10.1101/gr.944903. PMC   430916 . PMID   12727903.
  32. ↑ Zhou, T; Gu, W; Wilke, CO (August 2010). "Detecting positive and purifying selection at synonymous sites in yeast and worm". Molecular Biology and Evolution. 27 (8): 1912–22. doi:10.1093/molbev/msq077. PMC   2915641 . PMID   20231333.
  33. 1 2 3 Bromham, L; Penny, D (March 2003). "The modern molecular clock". Nature Reviews Genetics. 4 (3): 216–24. doi:10.1038/nrg1020. hdl: 1885/35737 . PMID   12610526. S2CID   205482778.
  34. ↑ Zuckerkandl, E.; Pauling, L. (1962). "Molecular Disease, Evolution and Genetic Heterogeneity". In Kasha, M.; Pullman, B. (eds.). Horizons in Biochemistry: Albert Szent-Györgyi dedicatory volume. New York: Academic Press. pp. 189–225. OCLC   174774459.
  35. ↑ Kimura, Motoo; Ohta, Tomoko (March 1971). "On the rate of molecular evolution". Journal of Molecular Evolution. 1 (1): 1–17. Bibcode:1971JMolE...1....1K. doi:10.1007/BF01659390. PMID   5173649. S2CID   30339157.
  36. ↑ Kumar, S (August 2005). "Molecular clocks: four decades of evolution". Nature Reviews Genetics. 6 (8): 654–62. doi:10.1038/nrg1659. PMID   16136655. S2CID   14261833.
  37. ↑ Smith, Andrew B.; Peterson, Kevin J. (May 2002). "DATING THE TIME OF ORIGIN OF MAJOR CLADES: Molecular Clocks and the Fossil Record". Annual Review of Earth and Planetary Sciences. 30 (1): 65–88. Bibcode:2002AREPS..30...65S. doi:10.1146/annurev.earth.30.091201.140057. S2CID   53992597.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.