Nearly neutral theory of molecular evolution

Last updated December 09, 2023

The nearly neutral theory of molecular evolution is a modification of the neutral theory of molecular evolution ^[1] 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.

Origins

According to the neutral theory of molecular evolution, the rate at which molecular changes accumulate between species should be equal to the rate of neutral mutations and hence relatively constant across species. However, this is a per-generation rate. Since larger organisms have longer generation times, the neutral theory predicts that their rate of molecular evolution should be slower. However, molecular evolutionists found that rates of protein evolution were fairly independent of generation time.

Noting that population size is generally inversely proportional to generation time, Tomoko Ohta proposed that if most amino acid substitutions are slightly deleterious, this would increase the rate of effectively neutral mutation rate in small populations, which could offset the effect of long generation times. However, because noncoding DNA substitutions tend to be more neutral, independent of population size, their rate of evolution is correctly predicted to depend on population size / generation time, unlike the rate of non-synonymous changes.^[3]

In this case, the faster rate of neutral evolution in proteins expected in small populations (due to a more lenient threshold for purging deleterious mutations) is offset by longer generation times (and vice versa), but in large populations with short generation times, noncoding DNA evolves faster while protein evolution is retarded by selection (which is more significant than drift for large populations)^[3] In 1973, Ohta published a short letter in Nature^[2] suggesting that a wide variety of molecular evidence supported the theory that most mutation events at the molecular level are slightly deleterious rather than strictly neutral.

Between then and the early 1990s, many studies of molecular evolution used a "shift model" in which the negative effect on the fitness of a population due to deleterious mutations shifts back to an original value when a mutation reaches fixation. In the early 1990s, Ohta developed a "fixed model" that included both beneficial and deleterious mutations, so that no artificial "shift" of overall population fitness was necessary.^[3] According to Ohta, however, the nearly neutral theory largely fell out of favor in the late 1980s, because the mathematically simpler neutral theory for the widespread molecular systematics research that flourished after the advent of rapid DNA sequencing. As more detailed systematics studies started to compare the evolution of genome regions subject to strong selection versus weaker selection in the 1990s, the nearly neutral theory and the interaction between selection and drift have once again become an important focus of research.^[4]

Theory

The rate of substitution, $\rho$ is

\rho =ugN_{e}{\bar {P}}_{fix}

,

where $u$ is the mutation rate, $g$ is the generation time, and $N_{e}$ is the effective population size. The last term is the probability that a new mutation will become fixed. Early models assumed that $u$ is constant between species, and that $g$ increases with $N_{e}$ . Kimura’s equation for the probability of fixation in a haploid population gives:

P_{fix}={\frac {1-e^{-s}}{1-e^{-sN_{e}}}}

,

where $s$ is the selection coefficient of a mutation. When $|s|\ll {\frac {1}{N_{e}}}$ (completely neutral), $P_{fix}={\frac {1}{N_{e}}}$ , and when $-s\gg {\frac {1}{N_{e}}}$ (extremely deleterious), $P_{fix}$ decreases almost exponentially with $N_{e}$ . Mutations with $-s\simeq {\frac {1}{N_{e}}}$ are called nearly neutral mutations. These mutations can fix in small- $N_{e}$ populations through genetic drift. In large- $N_{e}$ populations, these mutations are purged by selection. If nearly neutral mutations are common, then the proportion for which $P_{fix}\ll {\frac {1}{N_{e}}}$ is dependent on $N_{e}$

The effect of nearly neutral mutations can depend on fluctuations in $s$ . Early work used a “shift model” in which $s$ can vary between generations but the mean fitness of the population is reset to zero after fixation. This basically assumes the distribution of $s$ is constant (in this sense, the argument in the previous paragraphs can be regarded as based on the “shift model”). This assumption can lead to indefinite improvement or deterioration of protein function. Alternatively, the later “fixed model”^[5] fixes the distribution of mutations’ effect on protein function, but allows the mean fitness of population to evolve. This allows the distribution of $s$ to change with the mean fitness of population.

The “fixed model” provides a slightly different explanation for the rate of protein evolution. In large $N_{e}$ populations, advantageous mutations are quickly picked up by selection, increasing the mean fitness of the population. In response, the mutation rate of nearly neutral mutations is reduced because these mutations are restricted to the tail of the distribution of selection coefficients.

The “fixed model” expands the nearly neutral theory. Tachida^[6] classified evolution under the “fixed model” based on the product of $N_{e}$ and the variance in the distribution of $s$ : a large product corresponds to adaptive evolution, an intermediate product corresponds to nearly neutral evolution, and a small product corresponds to almost neutral evolution. According to this classification, slightly advantageous mutations can contribute to nearly neutral evolution.

The "drift barrier" theory

Michael Lynch has proposed that variation in the ability to purge slightly deleterious mutations (i.e. variation in $N_{e}$ ) can explain variation in genomic architecture among species, e.g. the size of the genome, or the mutation rate.^[7] Specifically, larger populations will have lower mutation rates, more streamlined genomic architectures, and generally more finely tuned adaptations. However, if robustness to the consequences of each possible error in processes such as transcription and translation substantially reduces the cost of making such errors, larger populations might evolve lower rates of global proofreading, and hence have higher rates of error.^[8] This may explain why Escherichia coli has higher rates of transcription error than Saccharomyces cerevisiae .^[9]^[10] This is supported by the fact that transcriptional error rates in E. coli depend on protein abundance (which is responsible for modulating the locus-specific strength of selection), but do so only for high-error-rate C to U deamination errors in S. cerevisiae.^[11]

Related Research Articles

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.

Genetic drift, also known as random genetic drift, allelic drift or the Wright effect, is the change in the frequency of an existing gene variant (allele) in a population due to random chance.

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, the evolution of development, and ways that evolutionary forces influence genomic and phenotypic changes.

<span class="mw-page-title-main">Neutral theory of molecular evolution</span>

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.

In evolutionary genetics, Muller's ratchet is a process which, in the absence of recombination, results in an accumulation of irreversible deleterious mutations. This happens because in the absence of recombination, and assuming reverse mutations are rare, offspring bear at least as much mutational load as their parents. Muller proposed this mechanism as one reason why sexual reproduction may be favored over asexual reproduction, as sexual organisms benefit from recombination and consequent elimination of deleterious mutations. The negative effect of accumulating irreversible deleterious mutations may not be prevalent in organisms which, while they reproduce asexually, also undergo other forms of recombination. This effect has also been observed in those regions of the genomes of sexual organisms that do not undergo recombination.

<span class="mw-page-title-main">Motoo Kimura</span> Japanese biologist

Motoo Kimura was a Japanese biologist best known for introducing the neutral theory of molecular evolution in 1968. He became one of the most influential theoretical population geneticists. He is remembered in genetics for his innovative use of diffusion equations to calculate the probability of fixation of beneficial, deleterious, or neutral alleles. Combining theoretical population genetics with molecular evolution data, he also developed the neutral theory of molecular evolution in which genetic drift is the main force changing allele frequencies. James F. Crow, himself a renowned population geneticist, considered Kimura to be one of the two greatest evolutionary geneticists, along with Gustave Malécot, after the great trio of the modern synthesis, Ronald Fisher, J. B. S. Haldane, and Sewall Wright.

Haldane's dilemma, also known as the waiting time problem, is a limit on the speed of beneficial evolution, calculated by J. B. S. Haldane in 1957. Before the invention of DNA sequencing technologies, it was not known how much polymorphism DNA harbored, although alloenzymes were beginning to make it clear that substantial polymorphism existed. This was puzzling because the amount of polymorphism known to exist seemed to exceed the theoretical limits that Haldane calculated, that is, the limits imposed if polymorphisms present in the population generally influence an organism's fitness. Motoo Kimura's landmark paper on neutral theory in 1968 built on Haldane's work to suggest that most molecular evolution is neutral, resolving the dilemma. Although neutral evolution remains the consensus theory among modern biologists, and thus Kimura's resolution of Haldane's dilemma is widely regarded as correct, some biologists argue that adaptive evolution explains a large fraction of substitutions in protein coding sequence, and they propose alternative solutions to Haldane's dilemma.

The effective population size (N_e) is size of an idealised population would experience the same rate of genetic drift or increase in inbreeding as in the real population. Idealised populations are based on unrealistic but convenient assumptions including random mating, simultaneous birth of each new generation, constant population size. For most quantities of interest and most real populations, N_e is smaller than the census population size N of a real population. The same population may have multiple effective population sizes for different properties of interest, including genetic drift and inbreeding.

Genetic load is the difference between the fitness of an average genotype in a population and the fitness of some reference genotype, which may be either the best present in a population, or may be the theoretically optimal genotype. The average individual taken from a population with a low genetic load will generally, when grown in the same conditions, have more surviving offspring than the average individual from a population with a high genetic load. Genetic load can also be seen as reduced fitness at the population level compared to what the population would have if all individuals had the reference high-fitness genotype. High genetic load may put a population in danger of extinction.

Mutation–selection balance is an equilibrium in the number of deleterious alleles in a population that occurs when the rate at which deleterious alleles are created by mutation equals the rate at which deleterious alleles are eliminated by selection. The majority of genetic mutations are neutral or deleterious; beneficial mutations are relatively rare. The resulting influx of deleterious mutations into a population over time is counteracted by negative selection, which acts to purge deleterious mutations. Setting aside other factors, the equilibrium number of deleterious alleles is then determined by a balance between the deleterious mutation rate and the rate at which selection purges those mutations.

Tomoko Ohta is a Japanese scientist and Professor Emeritus of the National Institute of Genetics. Ohta works on population genetics/molecular evolution and is known for developing the nearly neutral theory of evolution.

Coalescent theory is a model of how alleles sampled from a population may have originated from a common ancestor. In the simplest case, coalescent theory assumes no recombination, no natural selection, and no gene flow or population structure, meaning that each variant is equally likely to have been passed from one generation to the next. The model looks backward in time, merging alleles into a single ancestral copy according to a random process in coalescence events. Under this model, the expected time between successive coalescence events increases almost exponentially back in time. Variance in the model comes from both the random passing of alleles from one generation to the next, and the random occurrence of mutations in these alleles.

Genetic hitchhiking, also called genetic draft or the hitchhiking effect, is when an allele changes frequency not because it itself is under natural selection, but because it is near another gene that is undergoing a selective sweep and that is on the same DNA chain. When one gene goes through a selective sweep, any other nearby polymorphisms that are in linkage disequilibrium will tend to change their allele frequencies too. Selective sweeps happen when newly appeared mutations are advantageous and increase in frequency. Neutral or even slightly deleterious alleles that happen to be close by on the chromosome 'hitchhike' along with the sweep. In contrast, effects on a neutral locus due to linkage disequilibrium with newly appeared deleterious mutations are called background selection. Both genetic hitchhiking and background selection are stochastic (random) evolutionary forces, like genetic drift.

<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.

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.

In population genetics, fixation is the change in a gene pool from a situation where there exists at least two variants of a particular gene (allele) in a given population to a situation where only one of the alleles remains. That is, the allele becomes fixed. In the absence of mutation or heterozygote advantage, any allele must eventually be lost completely from the population or fixed. Whether a gene will ultimately be lost or fixed is dependent on selection coefficients and chance fluctuations in allelic proportions. Fixation can refer to a gene in general or particular nucleotide position in the DNA chain (locus).

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.

References

↑ Kimura M (February 1968). "Evolutionary rate at the molecular level". Nature. 217 (5129): 624–626. Bibcode:1968Natur.217..624K. doi:10.1038/217624a0. PMID 5637732. S2CID 4161261.
1 2 Ohta T (November 1973). "Slightly deleterious mutant substitutions in evolution". Nature. 246 (5428): 96–98. Bibcode:1973Natur.246...96O. doi:10.1038/246096a0. PMID 4585855. S2CID 4226804.
1 2 3 Ohta T, Gillespie JH (April 1996). "Development of Neutral and Nearly Neutral Theories". Theoretical Population Biology. 49 (2): 128–142. CiteSeerX 10.1.1.332.2080 . doi:10.1006/tpbi.1996.0007. PMID 8813019.
↑ Ohta T (August 1996). "The current significance and standing of neutral and neutral theories". BioEssays. 18 (8): 673–7, discussion 683. doi:10.1002/bies.950180811. PMID 8779656.
↑ Ohta T, Tachida H (September 1990). "Theoretical study of near neutrality. I. Heterozygosity and rate of mutant substitution". Genetics. 126 (1): 219–229. doi:10.1093/genetics/126.1.219. PMC 1204126 . PMID 2227381.
↑ Tachida H (May 1991). "A study on a nearly neutral mutation model in finite populations". Genetics. 128 (1): 183–192. doi:10.1093/genetics/128.1.183. PMC 1204447 . PMID 2060776.
↑ Lynch M (2007). The origins of genome architecture. Sunderland: Sinauer Associates.
↑ Rajon E, Masel J (January 2011). "Evolution of molecular error rates and the consequences for evolvability". Proceedings of the National Academy of Sciences of the United States of America. 108 (3): 1082–1087. Bibcode:2011PNAS..108.1082R. doi: 10.1073/pnas.1012918108 . PMC 3024668 . PMID 21199946.
↑ "Correction for Traverse and Ochman, Conserved rates and patterns of transcription errors across bacterial growth states and lifestyles". Proceedings of the National Academy of Sciences of the United States of America. 113 (29): E4257–E4258. July 2016. Bibcode:2016PNAS..113E4257.. doi: 10.1073/pnas.1609677113 . PMC 4961203 . PMID 27402746.
↑ Xiong K, McEntee JP, Porfirio DJ, Masel J (January 2017). "Drift Barriers to Quality Control When Genes Are Expressed at Different Levels". Genetics. 205 (1): 397–407. doi: 10.1534/genetics.116.192567 . PMC 5223517 . PMID 27838629.
↑ Meer KM, Nelson PG, Xiong K, Masel J (January 2020). "High Transcriptional Error Rates Vary as a Function of Gene Expression Level". Genome Biology and Evolution. 12 (1): 3754–3761. doi: 10.1093/gbe/evz275 . PMC 6988749 . PMID 31841128.

External links

The Nearly Neutral Theory of Molecular Evolution - Perspectives on Molecular Evolution

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[1] Kimura M (February 1968). "Evolutionary rate at the molecular level". Nature. 217 (5129): 624–626. Bibcode:1968Natur.217..624K. doi:10.1038/217624a0. PMID 5637732. S2CID 4161261.

[Ohta_1973-2] 1 2 Ohta T (November 1973). "Slightly deleterious mutant substitutions in evolution". Nature. 246 (5428): 96–98. Bibcode:1973Natur.246...96O. doi:10.1038/246096a0. PMID 4585855. S2CID 4226804.

[Ohta_1996-3] 1 2 3 Ohta T, Gillespie JH (April 1996). "Development of Neutral and Nearly Neutral Theories". Theoretical Population Biology. 49 (2): 128–142. CiteSeerX 10.1.1.332.2080 . doi:10.1006/tpbi.1996.0007. PMID 8813019.

[pmid8779656-4] Ohta T (August 1996). "The current significance and standing of neutral and neutral theories". BioEssays. 18 (8): 673–7, discussion 683. doi:10.1002/bies.950180811. PMID 8779656.

[5] Ohta T, Tachida H (September 1990). "Theoretical study of near neutrality. I. Heterozygosity and rate of mutant substitution". Genetics. 126 (1): 219–229. doi:10.1093/genetics/126.1.219. PMC 1204126 . PMID 2227381.

[6] Tachida H (May 1991). "A study on a nearly neutral mutation model in finite populations". Genetics. 128 (1): 183–192. doi:10.1093/genetics/128.1.183. PMC 1204447 . PMID 2060776.

[7] Lynch M (2007). The origins of genome architecture. Sunderland: Sinauer Associates.

[8] Rajon E, Masel J (January 2011). "Evolution of molecular error rates and the consequences for evolvability". Proceedings of the National Academy of Sciences of the United States of America. 108 (3): 1082–1087. Bibcode:2011PNAS..108.1082R. doi: 10.1073/pnas.1012918108 . PMC 3024668 . PMID 21199946.

[9] "Correction for Traverse and Ochman, Conserved rates and patterns of transcription errors across bacterial growth states and lifestyles". Proceedings of the National Academy of Sciences of the United States of America. 113 (29): E4257–E4258. July 2016. Bibcode:2016PNAS..113E4257.. doi: 10.1073/pnas.1609677113 . PMC 4961203 . PMID 27402746.

[10] Xiong K, McEntee JP, Porfirio DJ, Masel J (January 2017). "Drift Barriers to Quality Control When Genes Are Expressed at Different Levels". Genetics. 205 (1): 397–407. doi: 10.1534/genetics.116.192567 . PMC 5223517 . PMID 27838629.

[11] Meer KM, Nelson PG, Xiong K, Masel J (January 2020). "High Transcriptional Error Rates Vary as a Function of Gene Expression Level". Genome Biology and Evolution. 12 (1): 3754–3761. doi: 10.1093/gbe/evz275 . PMC 6988749 . PMID 31841128.

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