Methylated cytosines, in turn, tend to mutate rapidly to thymines due to chemical instability Bird Because mutations caused by DNA methylation occur largely independently of DNA replication, such mutations may follow different molecular clocks than others. To test this hypothesis, Kim et al. The human-chimpanzee pair the hominoid pair has much longer generation times compared to the macaque-baboon pair the Old World monkey pair. In contrast, molecular clocks at CpG sites showed similar numbers of substitutions in hominoid and Old World monkey pairs Figure 3.
Thus, time-dependent and generation time-dependent molecular clocks co-exist within the same genomes. The assumption that a single molecular clock may exist for a given lineage is no longer valid, because the predominant mutational forces vary among genomic regions. Figure 3 A Phylogeny of the four taxa analyzed in Kim et al. T O denotes the time since the split between the two Old World monkey species, and T H denotes the time since the split between the two hominoids.
Fossil records suggest that T O and T H are approximately similar. X and Y denote the common ancestors of the human-chimpanzee pair and of the macaque-baboon pair, respectively. B Contrasting molecular clocks of transitions at CpG sites vs. The Y-axis shows the ratio of the numbers of substitutions accumulated in the baboon-macaque pair K O to that in the human-chimpanzee pair K H. For non-CpG sites, this ratio is around 1.
In contrast, transitions at CpG sites, which are primarily of methylation origin, show no difference between the two pairs. Bailey, W. Molecular evolution of the psi eta-globin gene locus: Gibbon phylogeny and the hominoid slowdown. Molecular Biology and Evolution 8 , Bedford, T, I.
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Molecular Biology and Evolution 25 , Kimura, M. For example, consider a theoretical population in which all individuals, or genotypes, have exactly the same fitness. In this situation, natural selection does not operate, because all genotypes have the same chance to contribute to the next generation.
Given that populations do not grow infinitely and that each individual produces many gametes , it follows that only a fraction of the gametes that are produced will succeed in developing into adults. Thus, in each generation, allelic frequencies may change simply as a consequence of this random process of gamete sampling. This process is called genetic drift.
The difference between genetic drift and natural selection is that changes in allele frequency caused by genetic drift are random, rather than directional. Ultimately, genetic drift leads to the fixation of some alleles and the loss of others. But what about mutations that do not affect the fitness of individuals?
These so-called neutral mutations are not affected by natural selection and, hence, their fate is essentially driven by genetic drift. Interestingly, Darwin himself recognized that some traits might evolve without being affected by natural selection:. It is important to note, however, that the impact of genetic drift is not limited to neutral mutations. Because of genetic drift, most advantageous mutations are eventually lost, whereas some weakly deleterious mutations may become fixed.
Beyond selection and drift, biased gene conversion BGC is a third process that can cause changes in allele frequency in sexual populations. BGC is linked to meiotic crossing-over.
When crossing-over occurs between two homologous chromosomes, the intermediate includes heteroduplex DNA—a region in which one DNA strand is from one homologue and the other strand is from the other homologue. Regardless of the ultimate resolution of the crossover intermediate in other words, whether the regions on either side of the crossover junction recombine , base-pairing mismatches in the heteroduplex region must be resolved.
As a consequence, when a given locus resides in the heteroduplex region, one allele can be "copied and pasted" onto the other one during gene conversion. BGC is said to be biased if one allele has a higher probability of conversion than the other. In that situation, the donor allele will occur at higher frequency in the gamete pool than the converted allele. Hence, BGC tends to increase the frequency of such donor alleles within populations.
There is evidence that BGC occurs in many eukaryotic species, and various observations suggest that it might result from a bias in the repair of DNA mismatches in the heteroduplex DNA formed during recombination Marais, Until the s, the prevailing view was that natural selection played a dominant role.
According to this view, differences between species were thought to consist mainly of mutations that had been fixed by positive selection—mutations that contributed to the adaptation of a species to its environment. In contrast, the existing polymorphism within populations was thought to reflect balancing selection.
Thus, according to this so-called selectionist theory, nonadaptive processes were at best minor contributors to evolution. However, the analysis of sequence data that became available in the late s considerably challenged this view. In , these empirical data and new theoretical developments led Motoo Kimura to propose a new hypothesis, now known as the neutral theory of molecular evolution Kimura, Kimura subsequently summarized his theory as follows:.
Immediately, this theory caused controversy and gave rise to opposition from many evolutionary biologists. However, the theory also made several strong predictions that could be tested against actual data. Notably, if most of the sequence divergence between species is due to neutral evolution, then one should expect more changes in functionally less important sequences.
When Kimura proposed the neutral theory in , only a few protein sequences were available. By the s, however, the much larger amount of DNA sequence data that had accumulated largely validated this prediction. In fact, in light of these new sequence data, Kimura himself published a review of his theory in In his paper, he pointed out several important observations that had been recently reported, including the following:. All of these observations have been widely confirmed with the genomic data that are now available Figure 1.
These observations are consistent with the neutral theory but contradict selectionist theory. After all, if most substitutions were adaptive, as argued by selectionist theory, one would expect fewer substitutions in DNA regions where changes have little or no effect on phenotype e.
It must be stressed that the neutral theory of molecular evolution is not an anti-Darwinian theory. Both the selectionist and neutral theories recognize that natural selection is responsible for the adaptation of organisms to their environment. Both also recognize that most new mutations in functionally important regions are deleterious and that purifying selection quickly removes these deleterious mutations from populations.
Thus, these mutations do not contribute—or contribute very little—to sequence divergence between species and to polymorphisms within species. Rather, the dispute between selectionists and neutralists relates only to the relative proportion of neutral and advantageous mutations that contribute to sequence divergence and polymorphism. Analysis of genomic sequence data reveals that there is no "all or nothing" answer to this dispute.
In fact, the proportion of neutral substitutions varies widely among taxa. However, it is now clearly established that nonadaptive processes cannot be neglected. Even in taxa in which selection is very effective, a large fraction of substitutions are indeed neutral. The classification of mutations into three distinct types—deleterious, neutral, and advantageous—is of course an oversimplification.
In reality, there is a continuum from highly deleterious to weakly deleterious, nearly neutral, neutral, weakly advantageous, and strongly advantageous mutations. It is important to note that the effectiveness of selection on a mutation depends both on the fitness effect of this mutation the selection coefficient s and on the effective population size N e. Specifically, when the product N e s is much less than 1, the fate of mutations is essentially determined by random genetic drift. In other words, in small populations, the stochastic effects of random genetic drift overcome the effects of selection.
Thus, all mutations for which N e s is much less than 1 can be considered effectively neutral. Missense mutations or nonsynonymous mutations are types of point mutations where a single nucleotide is changed to cause substitution of a different amino acid. This in turn can render the resulting protein nonfunctional. A neutral mutation is a mutation that occurs in an amino acid codon presumably within an mRNA molecule which results in the use of a different, but chemically similar, amino acid.
This is similar to a silent mutation , where a codon mutation may encode the same amino acid see Wobble Hypothesis ; for example, a change from AUU to AUC will still encode leucine, so no discernable change occurs a silent mutation. A nonsense mutation is a frameshift mutation in a sequence of DNA that results in a premature stop codon , or a nonsense codon in the transcribed mRNA, and possibly a truncated, and often nonfunctional protein product. A point mutation , or substitution , is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide.
Often the term point mutation also includes insertions or deletions of a single base pair which have more of an adverse effect on the synthesized protein due to nucleotides still being read in triplets, but in different frames- a mutation called a frameshift mutation.
Silent mutations are DNA mutations that do not result in a change to the amino acid sequence of a protein. They may occur in a non-coding region outside of a gene or within an intron , or they may occur within an exon in a manner that does not alter the final amino acid sequence.
The phrase silent mutation is often used interchangeably with the phrase synonymous mutation ; however, synonymous mutations are a subcategory of the former, occurring only within exons. Changes in DNA caused by mutation can cause errors in protein sequence, creating partially or completely non-functional proteins. To function correctly, each cell depends on thousands of proteins to function in the right places at the right times.
When a mutation alters a protein that plays a critical role in the body, a medical condition can result. A condition caused by mutations in one or more genes is called a genetic disorder. However, only a small percentage of mutations cause genetic disorders; most have no impact on health. If a mutation is present in a germ cell, it can give rise to offspring that carries the mutation in all of its cells.
This is the case in hereditary diseases. On the other hand, a mutation can occur in a somatic cell of an organism. Such mutations will be present in all descendants of this cell, and certain mutations can cause the cell to become malignant, and thus cause cancer [5]. Often, gene mutations that could cause a genetic disorder are repaired by the DNA repair system of the cell. Each cell has a number of pathways through which enzymes recognize and repair mistakes in DNA. Because DNA can be damaged or mutated in many ways, the process of DNA repair is an important way in which the body protects itself from disease.
Although the neutral theory turned 50 this year, this seemingly basic question is still a topic of hot debate Rands et al.
Even the question of what it means for a mutation to evolve neutrally is more complicated than Kimura could have imagined in Unlike adaptive mutations, which spread through populations as fast as their fitness advantages can carry them, neutral mutations diffuse at a slow, steady rate that is easy to model mathematically Fisher, In theory, it is possible to: i sample DNA sequences from humans worldwide; ii count and compare the neutral mutations that can be found on multiple continents, one continent, and one individual; iii use this information to reconstruct details about human migration across the globe Gutenkunst et al.
In practice, however, it can be hard to deduce whether a given mutation is evolving neutrally or not. When variation under selection is misclassified as neutral and used to study past migrations and changes in population size, the results can be misleading Ewing and Jensen, ; Schrider et al.
In an ambitious undertaking, Pouyet et al. Superficially, this might seem like a death knell for the neutral theory, but it is nothing of the kind.
To understand why, we have to revisit the question of what it means to evolve neutrally. A mutation will not evolve neutrally if it provides a direct fitness advantage, but the converse does not apply. A mutation can appear to evolve non-neutrally if it is merely located close to a mutation that affects fitness.
In sexual organisms like humans, each child inherits DNA from its parents in big, continuous chunks. Even distant cousins will share large chunks of DNA that were inherited from recent common ancestors. If that part of DNA happens to contain a beneficial mutation, hundreds of nearby mutations might hitchhike along for the ride as the beneficial DNA spreads quickly through a population Smith and Haigh, ; Charlesworth et al.
These hitchhikers confer no fitness advantage but, equally, they do not behave the way we expect neutral mutations to do. Because of this hitchhiking effect, Pouyet et al.
In regions with high recombination rates, on the other hand, neutral mutations are quickly separated from nearby mutations that are under selection.
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