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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
mutation 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, ...
s 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 The effective population size (''N'e'') is the size of an idealised population that would experience the same rate of genetic drift as the real population. Idealised populations are those following simple one- locus models that comply with ass ...
. In larger populations, a higher proportion of mutations exceed this threshold for which
genetic drift Genetic drift, also known as random genetic drift, allelic drift or the Wright effect, is the change in the Allele frequency, frequency of an existing gene variant (allele) in a population due to random chance. Genetic drift may cause gene va ...
cannot overpower selection, leading to fewer fixation events and so slower molecular evolution. The nearly neutral theory was proposed by Tomoko Ohta in 1973. The population-size-dependent threshold for purging mutations has been called the "drift barrier" by Michael Lynch, and used to explain differences in genomic architecture among species.


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 time In population biology and demography Demography () is the statistical study of human populations: their size, composition (e.g., ethnic group, age), and how they change through the interplay of fertility (births), mortality (deaths), and mi ...
s, 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 Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
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 Non-coding DNA (ncDNA) sequences are components of an organism's DNA that do not encode protein sequences. Some non-coding DNA is transcribed into functional non-coding RNA molecules (e.g. transfer RNA, microRNA, piRNA, ribosomal RNA, and regu ...
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. 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) In 1973, Ohta published a short letter in ''Nature'' 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. 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 DNA sequencing is the process of determining the nucleic acid sequence – the order of nucleotides in DNA. It includes any method or technology that is used to determine the order of the four bases: adenine, thymine, cytosine, and guanine. The ...
. 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.


Theory

The rate of substitution, \rho is : \rho = ugN_e \bar P_, 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_ = \frac , where s is the selection coefficient of a mutation. When , s, \ll \frac (completely neutral), P_= \frac , and when - s \gg \frac (extremely deleterious), P_ decreases almost exponentially with N_e . Mutations with -s \simeq \frac are called nearly neutral mutations. These mutations can fix in small- N_e populations through
genetic drift Genetic drift, also known as random genetic drift, allelic drift or the Wright effect, is the change in the Allele frequency, frequency of an existing gene variant (allele) in a population due to random chance. Genetic drift may cause gene va ...
. In large- N_e populations, these mutations are purged by selection. If nearly neutral mutations are common, then the proportion for which P_ \ll \frac 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” 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 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. 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 Proofreading is a phase in the process of publishing where galley proofs are compared against the original manuscripts or graphic artworks, to identify transcription errors in the typesetting process. In the past, proofreaders would place corr ...
, and hence have higher rates of error. This may explain why ''
Escherichia coli ''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Escherichia'' that is commonly fo ...
'' has higher rates of transcription error than ''
Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungal microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have be ...
''. 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 Deamination is the removal of an amino group from a molecule. Enzymes that catalysis, catalyse this reaction are called deaminases. In the human body, deamination takes place primarily in the liver; however, it can also occur in the kidney. In s ...
errors in ''S. cerevisiae''.


See also

*
History 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 sequ ...


References

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External links


The Nearly Neutral Theory of Molecular Evolution
- Perspectives on Molecular Evolution Molecular evolution Population genetics Neutral theory