The rate of molecular evolution

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The importance of understanding what determines the rate of molecular evolution allows us to have a better understanding of molecular evolution itself. This is fundamental in providing a better understanding of genetic diseases, phylogenetic analysis and in predicting patterns of evolution. Molecular evolution includes evolution of eukaryotic nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) and DNA and RNA of prokaryotes and viruses. DNA can be coding and non-coding for proteins essential for survival thus proteins are also considered in molecular evolution. Rates of evolution of nDNA and mtDNA vary due to differences such as in recombination rates, presence of introns and repair mechanisms (Nabholz et al 2009) therefore rate determinants and their degree of effect also differ. The rate of molecular evolution depends firstly on the rate at which mutations take place and secondly the rate of fixation of these changes into the species genome, the substitution rate (Bromham 2009). This report will discuss how the latter rate is influenced by neutral, nearly neutral and non-neutral mutation rates associated with population size and dynamics, affect of body size, life history including generation time, functional aspects of proteins and gene expression. All of these factors have shown evidence to be by some measure inter-linked with one-another in determining rates of molecular evolution.

Population Size and Dynamics

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Molecular evolution cannot exist without the presence of mutation (Barton et al; Evolution), and so forces that drive mutations to fixation are also examined; random genetic drift, neutral theory, nearly neutral theory and natural selection. Effective population size, Ne (Woolfit 2009) which is defined as the average number of individuals in a population that contribute genes to following generations, and dynamics have shown in many studies to influence rate of molecular evolution (Woolfit and Bromham 2005, DeSalle and Templeton 1988). Population size is key to molecular evolution in view of the fact that populations evolve, not individuals, as polymorphisms that are fixed due to natural selection are permitted to do so subsequent to sampling a subset of alleles present in one generation and allowing them to spread in successive generations (Bromham 2009) implying Ne as one of the determinants for rate of molecular evolution. Germline mutations can be lost through DNA repair or removed from populations by natural selection or random drift, it is the fixation of these mutations through generations that causes evolution.

A large fraction of evolutionary changes consist of neutral and nearly neutral mutations (Ohta 1972). These involve synonymous or silent (a DNA mutation that despite altering the codon do not change the amino acid that is coded for) and slightly deleterious/advantageous non-synonymous (a DNA mutation that changes the codon and so changes the amino acid it codes for) mutations. Ne strongly impacts substitution rates of synonymous and non-synonymous mutations. A negative correlation exists between Ne and portion of mutations that are neutral; populations with smaller Ne have a larger fraction of effectively neutral substitutions in comparison to populations with larger Ne (Popadin et al 2007) and so non-synonymous mutations become fixed more easily in small Ne. No significant difference in number of neutral mutations is present between large and small populations, neutral substitution rates are independent of Ne, it is the proportion of these types of mutation in overall substitution rate (Woolfit and Bromham 2005) that is considered to differ between large and small Ne. The same relationship is also present between nearly neutral mutations and Ne (Woolfit and Bromham 2005, Woolfit 2009). This difference in ratios between neutral and nearly neutral mutations is presumed to be observed as random genetic drift dominates in species with smaller Ne. Random genetic drift results in increasing substitution rates of slightly deleterious mutations (mutations that are effectively neutral, that is in the context of the nearly neutral theory) (Woolfit 2009) instead of removal of them by purifying selection as in populations with larger Ne (Popadin et al 2007) where natural selection is the chief driving force for molecular evolution. This theory is also assumed for populations decreasing in size (as opposed to populations with pre-established small Ne as discussed above) as slightly deleterious mutations, that may have previously been inhibited by natural selection, reach fixation (Popadin et al 2007) as the driving force of random drift begins to dominate. It can then be deduced that the ratio of non-synonymous to synonymous substitution rates (?) is greater in a population of small Ne (Ohta 1992, Woolfit and Bromham 2005). Species with large Ne are affected predominantly by natural selection (Popadin et al 2007) where rates of molecular evolution are determined by how intense the need to adapt is thus ? is smaller. Due to their size, smaller populations frequently have limited gene pools (the total number of genes of every individual in an interbreeding population); there is a restricted number and type of genes that are able to circulate within the population, are more isolated (for example on an island) and are spread over environments that are less varied ultimately resulting in faster rate of molecular evolution (Ohta 1972) than species with large Ne that inhabit more varied environments. As the environment of populations with small Ne are, as a result, more uniform an advantageous mutation is likely to benefit the entire population thus elevation of overall substitution rates are expected as advantageous substitution rates increase (Ohta 1972), alternatively it has recently been suggested if these types of mutations are rare there is a higher probability of them being lost by random genetic drift instead of being positively selected for fixation (Woolfit 2009). Slightly advantageous non-synonymous substitution rates would consequently decrease however, provided all mutation rates between populations of large and small Ne are equal, overall substitution rate would still rise compared to larger Ne, as slightly deleterious fixation rates compensate for this loss (Woolfit 2009). Regardless of these two theories (Ohta 1972, Woolfit 2009) the net result is still equivalent in that populations with smaller Ne have greater substitution rates, representing faster rates of molecular evolution than in populations with larger Ne.

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Evidence for greater ? in smaller populations include observed rapid phenotypic evolution of populations with small Ne and at the molecular level in invertebrate and vertebrate lineages on islands in comparison to their mainland relatives (Woolfit and Bromham 2005). Phenotypic evolution is the result of non-synonymous substitutions changing amino acid sequences and their corresponding proteins, therefore morphological/physical changes can be linked to ?. Comparison of island and mainland lineages is ideal for analysing effects of Ne on molecular rate of evolution as the islands are isolated from many factors that could impact evolutionary change other than alteration of Ne. A larger ? in island lineage inhabitants can be explained by relaxed selective constraints (Woolfit and Bromham 2005) that reduce variability of the selection coefficients, s (Ohta 1972), of non-synonymous mutations resulting in an increase of nearly neutral substitution rates. This study (Woolfit and Bromham 2005) although having results of greater ? with decreased Ne did not show an increase in overall substitution rate of island lineages in comparison to their mainland relatives, however other studies have seen a significant rise (for example Wu and Li 1985, Woolfit and Bromham 2003). It has been suggested that in endosymbiotic bacteria A and T bases experience a mutational bias and so their content increases (due to a reduction in Ne) in comparison to non-endosymbiotic bacteria (Wernegreen, J. J., and N. A. Moran. 1999. Evidence for genetic drift in endosymbionts (Buchnera): analyses of protein-coding genes. Mol. Biol. Evol. 16:83-97). Woolfit and Bromham's (2003) analyses of A and T content in whole genomes of endosymbiotic bacteria were found to be higher and had a significant increase in overall substitution rate than in non-endosymbiotic bacteria. Conversely, in a study of cytochrome b nucleotide composition in mtDNA results concluded no relationship with population size and rate of mtDNA evolution in birds and mammals therefore it has been proposed to evolve independently of Ne (Nabholz et al 2009), suggesting further investigation is required to confirm the theory of faster rates of molecular evolution in smaller Ne than in larger Ne.

Endosymbiotic bacteria, when transfected to a host, experience a population bottleneck pattern at which point there is a substantial increase in substitution rate (Woolfit and Bromham 2003). This is subsequent to a reduction in Ne which is in turn due to an alteration in lifestyle as the environment from external to internal host has changed, thus is a strong indication for lifestyle changes affecting rates of molecular evolution through changes in Ne. It is also important to consider that lifestyles changes such as this relax environmental constraints on fixation of polymorphisms as revealed in faster rates of molecular evolution in parasites (Dowtan and Austin 1995). This is a result of functions needed for parasitic survival now being carried out by their host, therefore is likely to allow an increased number of nearly neutral mutations to reach fixation increasing overall substitution rates (Bromham 2009). The change of environment and lifestyle can adjust the extent to which a single mutation is neutral, accordingly neutral mutations allowed to fixate at higher rates in one environment may be deleterious and substitute less in another again demonstrating lifestyle changes in part determine rate of molecular evolution. This provides a clear example of how factors such as Ne and lifestyle interact to influence rate of molecular evolution; the change in environment results in a change in Ne.

Body Size and correlations with Metabolic Rate and Generation Time in part determine Rate of Molecular Evolution

Species with small body sizes frequently exist in large populations whilst smaller populations consist of species with greater body size (Popadin et al 2007). It can therefore be deduced that natural selection consequently acts more powerfully on smaller organisms and random drift on larger organisms resulting in a higher ? in larger organisms as substitution rates of slightly deleterious mutations rise in comparison.

Bromham (2009) theorised that larger mammals evolve at a slower rate than their smaller relatives due to the selection against the higher number of slightly deleterious substitutions that occur as a result of the tendency of larger mammals to have a longer reproductive lifespan, consist of a higher number of cells and require more cell generations to produce gametes. This higher number of cell generations allows for DNA to be checked and repaired more frequently before cells become gametes and so work more strongly against mutation. These among several other factors (Bromham 2009) allow more opportunities for genetic error to arise, consequently negative selection will act more powerfully against these by improving DNA replication and repair mechanisms causing mutations to reduce and thereby restraining evolutionary rate. Larger organisms typically reproduce less than smaller organisms, which can be further decreased by deleterious mutations thus reducing rate of molecular evolution.

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Body size is often associated with life history traits that potentially determine rates of molecular evolution in organisms, such as metabolic rate (Martin and Palumbi 1993), generation time, figure 2, (Nunn and Stanley 1998, Bromham 2009) and lifespan, complicating the search to reveal true determinants of rate of molecular evolution. These traits correlate with one another leading Martin and Palumbi (1993) to create the metabolic rate hypothesis and more recently Gilooly et al (2005) to generate a molecular evolutionary model based on the interrelation of life history traits in connection with the neutral theory of evolution (Kimura 1983).

Metabolic Rate Hypothesis

The metabolic rate hypothesis (Martin and Palumbi 1993) states that an inverse relationship is present between body size and metabolic rate, and a positive correlation exists between metabolic rate and substitution rate; as body size decreases metabolic rate is accelerated and rate of molecular evolution is more rapid (figure 1). Metabolism inevitably generates highly reactive oxygen radicals containing damaging free electrons that are able to compromise DNA integrity by causing mutation; thus as metabolic rate increases, rate of DNA mutation rises as a result of increased free radical abundance (Shigenaga et al 1989). The oxidative radicals are able to react with the sugar-phosphate backbone or bases in DNA strands causing mutation. This effect has been found to occur five to ten times more rapidly in mtDNA compared to nDNA (Brown et al 1982) as 90% of cellular oxygen is consumed and used by mitochondria, increasing the organelle's internal free radical abundance. The ability of free radicals generated from mitochondrial activity to cause mutations in nDNA is negligible (Hoffmann et al 2004) also explaining the reduced damage to nDNA resulting in a slower rate of molecular evolution in comparison to mtDNA. The hypothesis suggests DNA mutations as being a result of harmful free radical reactions and the inability of the DNA repair mechanism to function fully as the damage is not recognised and corrected as well as increased DNA synthesis in organisms with higher metabolic rates. mtDNA is independent of the cell cycle, unlike nDNA, and undergoes replication to a higher extent than nDNA allowing more room for error, promoting substitution and consequently a faster rate of evolution than in nDNA. In summary as body size decreases metabolic rate increases, this in turn produces higher amounts of oxidative free radicals resulting in more germline mutations, increasing the number of mutations going to fixation and so ultimately increases substitution rate; smaller organisms evolve faster than their larger relatives.

Figure 1 uses silent rates calibrated from fossil data and clearly demonstrates as body size increases (and so metabolic rate decreases) the synonymous mutation rate in mammalian mitochondrial cytochrome b DNA reduces as predicted by the hypothesis. Results of the study (Martin and Palumbi 1993) correspond directly to the metabolic rate hypothesis displayed most apparently by slow substitution rates in whales compared to rodents. There was, however, a significant difference opposing the theory as substitution rates in rats were recorded as higher than mice, which is assumed to be a result of oxidative radical production being higher in rats. This result indicates a divergence to the metabolic rate hypothesis may be more credible; species-specific variation in the rate of production of free radicals influences DNA evolutionary rate, not metabolic rate, supported by increasing rate of oxygen consumption raising overall substitution rates in mammals (Martin 1995). Overall the study found substitutions to accumulate at a faster rate in smaller then larger animals (also supported by Bromham 2009). Nunn and Stanley's (1998) findings in the cytochrome b of tube-nosed seabirds provide evidence supporting the metabolic rate hypothesis as a negative correlation was recorded between body size and rate of molecular evolution. Procellariiform birds possess a strong positive relationship of body size with metabolic rate thus the faster rate of cytochrome b evolution was attributed to the increase in metabolic rate as opposed to generation time.

Gilooly et al (2005) present a model that elaborates on the metabolic rate hypothesis stating that as free radical production and generation time are associated with metabolic rate, which is in turn associated with body size and physiological thermal environment, it is too complex to assign influence on evolutionary rate to metabolic rate alone. Rate of evolution is predicted in the model to be controlled by a combination of body size and temperature effects on metabolism. Using the factors of body size and temperature drew parallel to causes of variation in rate of protein evolution for the mitochondrial genes NADH and cytochrome b in Gilooly et al (2007). The model considers that although the unpredictability of natural selection on rate of fixation of mutations causes difficulty in obtaining a rate of molecular evolution, this rate is also limited by generation time and genomic variation between individuals each of which is associated with metabolic rate allowing the degree of effect of these factors on rate of evolution to be calculated (see equation 1 in Gilooly et al 2005). These factors alone do not determine rate of molecular evolution (Nunn and Stanley 1998) and only contribute to a fraction of it.

Some studies have been found to contradict the hypothesis; Bromham et al (1996) revealed a relationship between mammalian body size and rate of molecular evolution, yet found no evidence to suggest a relationship with metabolic rate whereas Thomas (2006) found no correlation between body size and substitution rate in invertebrates, strongly enforcing the caution that conclusions drawn from vertebrate data should not be generalised to all organisms. Welch et al (2008) uncovered the opposite relationship in Euarchontoglires (group containing rodents and primates), a positive correlation between body mass and synonymous substitution rate was clear. However this relationship was not true for all other mammalian groups studied in this investigation. The collection of these oppositions to the theory and the physiology behind the relationship between free radical production, metabolic rate and mtDNA mutations being unclear (Galtier et al 2009) concludes the effect of body mass (and so metabolic rate) on rate of molecular evolution is not the only determinant however does influence a portion of it.

Generation Time Hypothesis

Another accountable factor for the relationship between body mass and rate of molecular evolution is generation time. As body mass increases, generation time also increases:

The generation time hypothesis (Kohne 1970) states that organisms with shorter generation times have higher mutation rates than organisms with longer generation times. Shorter generation time organisms have an accelerated rate of cell division; there is a larger number of cell division per unit time leading to increase in accumulation of mutations. There are, however, assumptions the theory works within, firstly the majority of mutations must be neutral and a result of error in DNA replication and secondly the number of germ cell divisions within a lifespan of all organisms must be similar (Nunn and Stanley 1998). Smaller organisms are more likely to have shorter generation times (figure 2) as well as greater numbers of offspring (Bromham 2009) resulting in faster rates of molecular evolution. Evidence for the hypothesis is provided by higher molecular evolutionary rates in rodents - shorter generation times - than humans - longer generation times - (Wu and Li 1985), in mammalian protein sequences (Bromham et al 1996), in bird DNA sequences where no other factor including metabolic rate has no results indicating a relationship with the pattern observed (Mooers and Harvey 1994) and between plants (Smith and Donoghue 2008). The generation time effect is more clearly demonstrated in synonymous substitution rates (Ohta 1993). Nabholz et al (2007) suggest generation time is the strongest predictor for rate of molecular evolution in mtDNA when other factors are taken into account separately. On a more molecular level Martin and Palumbi (1993) associated generation time with time taken to copy a nucleotide position; shorter nucleotide generation times imply a faster replication rate, raising the probability of replication and repair error ultimately accelerating rate of evolution.

Arguments against the hypothesis include the assumption in the theory that all organisms undergo a similar amount of DNA substitutions during their respective generation times however nearly neutral mutations under weak selection may be an exception to this (Martin and Palumbi 1993) and so give reason for the theory being more applicable to synonymous rather than non-synonymous substitutions. The generation time effect should apply to both nDNA and mtDNA however studies have shown significantly varying rates of the two between and within species (Nunn and Stanley 1998, Welch et al 2008, Brown et al 1982, Nabholz et al 2007). Although the difference between rate of evolution in nDNA and mtDNA cannot be explained by this theory, it can be by the metabolic rate hypothesis. Results are also inconsistent for the hypothesis in Nunn and Stanley's (1998) recording of four out of seven tube-nosed seabird taxa directly opposing the theory's predictions.

Overall it can be deduced that mammals of small body mass generally have shorter generation times, higher metabolic rate and greater number of offspring (Bromham 2009) all contributing to accelerated rates of evolution in comparison to their larger sized relatives. Exceptions to individual theories may be compensated for by another single factor or the interactions of them.

Protein Evolution and Gene Expression

In all the above discussed factors both non-synonymous and synonymous substitution rates have been considered however it is the non-synonymous mutations altering coding sequences for amino acids that is the basis for protein evolution. Nabholz et al (2009) found no significant relationship present between evolutionary rate of proteins encoded by mtDNA and population size or metabolic rate; instead results recorded were correlated with rate of mutation. A positive relationship between mutation rate and substitution rate compels observation of determinants of germline mutations so that ultimately influences on rate of molecular evolution can be detected. The potential of a gene to mutate, mutability, can vary throughout the human and chimpanzee genomes (Kelkar et al 2008). Increasing mutability accelerates mutation rate, thus the accumulation of these highly mutatible genes overall increases substitution rate and so rate of molecular evolution. The generation of variation by mutation is amplified by genetic recombination (Barton et al; Evolution) and so increase in recombination rates may speed rate of DNA evolution as analysed in the wheat genome (Akhunov et al 2003). As discussed in the effect of Ne on rate of molecular evolution, natural selection drives the fraction of substitutions that are adaptive, these are non-synonymous mutations that have altered codons and so change amino acid sequences. Each amino acid has a function on which adaptive selection will act upon (Brookfield 2000) thereby in part determining rate of protein evolution. Contradictory to Nabholz et al (2009)'s finding in mtDNA, rate of evolution may slow due to strong selective pressure on genes and in doing so can eliminate the positive relationship between mutation rate and evolutionary rate (Gilooly et al 2007). This provides a clear example of factors acting simultaneously and more or less predominantly to generate various outcomes on rate of molecular evolution.

Wilson et al (1977) established the concept of more functionally important DNA sequences used in protein synthesis being conserved more and so evolve at a slower rate. Functional significance to fitness was assessed by determining gene dispensability; the ability of the organism to live without the gene. Low gene dispensability slows rate of evolution as shown in yeast by Wall et al (2005). Studies have also shown an inverse relationship between functional importance of a gene and its corresponding evolutionary rate (Wang and Zhang 2009) which follow the translational robustness hypothesis as opposed to gene dispensability. This hypothesis is also applicable to slow rates of evolution in highly expressed genes (Drummond et al 2005) stating as highly expressed genes undergo increased levels of expression, there is a higher probability of error resulting in translational misfolding of proteins, which can be harmful to the organism's survival, to be selected against whilst mechanisms and nucleotide sequences improving translational folding are selected for. Overall this strengthens gene expression and protein synthesis against mutation and misfolding thus reducing rate of evolution. Drummond et al (2005) showed highly expressed genes although having slow rates of evolution do not match expectations of the translation efficiency hypothesis as does data recorded by Akashi (2003). The translational efficiency hypothesis on rate of evolution states a decrease in rate due to increasingly efficient mechanisms of translation being employed as well as synonymous codons that are able to be translated at a faster rate being selected for. The sum of these actions allows the wildtype protein to be synthesised more efficiently with less potential for mutation and so acts against evolution by decelerating it. The ability of a synonymous mutation in a codon to increase efficiency questions whether or not silent mutations can in practise be considered as "silent" due to the theoretical effect on rate of evolution. Drummond et al (2005) found the slower rate of evolution of highly expressed genes to be largely a consequence of expression level and had no relation to functional importance or functional density (Zuckerkandl 1976) of paralogs of proteins synthesised in Saccharomyces cerevisiae. Zuckerkandl (1976) proposed the widely accepted determinant of evolutionary rate being functional density; the proportion of amino acid sequences involved in specific functions. As functional density increases, rate of molecular evolution decreases as selection for the wildtype protein strengthens. Functional density may be an incorrect term as selection pressure can also act positively toward mutation fixation as stated in the translational efficiency hypothesis, an action unrelated to protein function leading to the suggestion of "fitness density" instead by Pál et al (2006). Distribution of gene expression has also been shown by Yang et al (2005) to effect rate of molecular evolution as broadly expressed genes evolved at a slower rate in comparison to more narrowly expressed genes with results being found as unrelated to gene function.

The rate of molecular evolution in yeast has been suggested to be driven by a single determinant. More recent analysis of DNA evolution in Saccharomyces cerevisiae have demonstrated rate of evolution being affected by nearly every factor, such as expression level and gene dispensability (Plotkin and Fraser 2007), however the authors insist that the data do not exclude the possibility of a single determinant for rate of yeast evolution. This study does however support the concept of many factors integrating to influence rate of molecular evolution, the extent of each single aspect's effect has not been confirmed however is suggested as being 5% or less for functional significance and gene dispensability whereas expression level has been calculated to have a more predominant effect (Drummond et al 2005).

Summary

The rate of molecular evolution cannot be deduced from a single determinant. Multiple factors with varying degrees of effect dependent on different situations determine the overall rate of molecular evolution. Analysis of each determinant individually has not yet been achieved however it can be concluded that the factors of Ne, body mass (metabolic rate, free radical production and generation time) as well as expression level, translational robustness and distribution of gene expression influence, at minimum a fraction, of the rate of molecular evolution. Studies have provided data strongly suggesting the ratio of the rate of non-synonymous substitution to rate of synonymous substitution, ?, is predominantly decided by effective population size and dynamics through the driving forces of random drift and natural selection in relation to the nearly neutral and neutral theories of evolution. Body mass and temperature and, in turn, correlates with it appear to integrate to determine overall substitution rate and so overall rate of DNA evolution. Areas where the generation time hypothesis is not consistent with results such as the significant difference between mtDNA and nDNA substitution rates is compensated for by the metabolic rate hypothesis, both of which predict the same negative relationship between body size and evolutionary rate. Non-synonymous substitutions contribute to changes in gene expression and protein evolution rate. Some synonymous substitutions are capable of increasing efficiency of gene expression and so can be considered non-neutral as this effects rate of molecular evolution. The ability of expressed genes to strengthen against error in replication or protein synthesis, for example as stated in the translational robustness hypothesis, acts against evolution by slowing its rate as mutations are increasingly protected against. Other factors such as effect of linkage to effect of latitude on molecular rate of evolution have not been considered in this report due to lack of supporting evidence, however are becoming more apparent as analysis is continued on them. Evolution does not exist in the absence of mutation. Despite mutation rate not consistently being directly linked to rate of molecular evolution it retains a vital role in determining it. It can be concluded that any influence on mutation rate and fixation will in part determine overall rate of molecular evolution. Factors discussed in this report do individually and collectively determine rate of molecular evolution however further study is required to calculate to what degree each determinant effects rate and if this can be generalised to not only both mtDNA and nDNA but across the majority of organisms.

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