A selectively driven molecular clock

It is shown that the method used by Jukes and Holmquist [Science177, 530 (1972)] is not able to lead to any conclusion on the rate of evolution of rattlesnake cytochromec because the method does not consider the time period over which the observed differences occurred. In an attempt to overcome this problem the phylogenetic relationship between rattlesnake, turtle and birds is examined from the paleontological evidence and from phylogenetic trees constructed from cytochromec sequences by “matrix methods” and by “ancestral sequence” methods. The paleonto-logical evidence and the “ancestral sequence tree” are in agreement for the positioning of rattlesnake. This ancestral sequence tree is used to estimate the rate of amino acid substitution and minimum base changes for different lines of descent among 20 vertebrate species. The rate of amino acid substitution is faster than average on the rattlesnake line but is not the fastest among the vertebrates and it is concluded that no “species specific” effect has yet been demonstrated for rattlesnake. However there is a large amount of diversity in the rates of amino acid substitution and this is discussed from the concept that at any point in time only a few codons (the covarions) are able to accept an amino acid substitution. It is suggested that some fluctuations in the rate of amino acid substitutions should occur.

Episodic evolution of RNA viruses.

Molecular evolution in papova viruses and in bacteriophages.

Hepatitis C virus (HCV) causes persistent infection in most patients. To clarify the mechanisms underlying establishment of this persistent infection, nucleotide sequences of the E1/E2 region were characterized in 5 patients with acute and chronic HCV infection. We used direct DNA sequencing methods to identify the major sequence of HCV in each patient. Each HCV genome displayed a high frequency of nucleotide sequence variation in the hypervariable region (HVR) of E2. However, patient-specific conserved nucleotide sequences were identified in the E1/E2 region during the course of infection and conserved the higher-order protein structure. In the acute phase HCV infection, amino acid substitution in HVR-1 as the monthly rate of amino acids substitution per site (%) between each point exceeded 10.2%. In the chronic phase HCV infection, a significantly lower rate of amino acid substitution was observed in patients. The host immune responses to HVR-1 of each HCV isolates from all clinical courses were characterized using synthetic peptides and ELISA. One chronic patient serum (genotype 1b) did not react at all to its own HVR-1 peptides, however another patient (genotype 2b) reacted to all clinical course. These results indicated that HVR-1 might not always exhibit neutralizing epitopes of HCV infection. The sequence variation in HVR-1 may instead indicate the existence of various clones in acute phase infection and the adaption of these clones is thought to have caused persistent and chronic infection in each patient.

Simple SummaryThe relative rates of amino acid substitution over evolutionary time reflect the chemical properties of amino acids. Substitutions that result in an amino acid similar to an ancestral residue accumulate more rapidly than those resulting in a dissimilar amino acid. The substitution rates for each amino acid pair are the parameters in models of evolutionary change for proteins. Although the best-fitting model of protein evolution is known to differ among taxa, a comprehensive picture of model changes across the tree of life is not available. In principle, models of protein change might reflect evolutionary history (i.e., closely related taxa have similar models) or the environment (i.e., taxa living in similar environments have similar models). We estimated models of amino acid evolution for organisms across the tree of life, finding evidence that history and the environment have both contributed to model differences. Bacterial models differed from archaeal and eukaryotic models. Models for Halobacteriaceae (archaea that live in highly saline environments) and Thermoprotei (a group of thermophilic archaea) were found to be very distinctive. The rates of substitution for pairs of aromatic amino acids were especially variable. Overall, these results paint a picture of the “evolutionary model space” for proteins across the tree of life.The factors that determine the relative rates of amino acid substitution during protein evolution are complex and known to vary among taxa. We estimated relative exchangeabilities for pairs of amino acids from clades spread across the tree of life and assessed the historical signal in the distances among these clade-specific models. We separately trained these models on collections of arbitrarily selected protein alignments and on ribosomal protein alignments. In both cases, we found a clear separation between the models trained using multiple sequence alignments from bacterial clades and the models trained on archaeal and eukaryotic data. We assessed the predictive power of our novel clade-specific models of sequence evolution by asking whether fit to the models could be used to identify the source of multiple sequence alignments. Model fit was generally able to correctly classify protein alignments at the level of domain (bacterial versus archaeal), but the accuracy of classification at finer scales was much lower. The only exceptions to this were the relatively high classification accuracy for two archaeal lineages: Halobacteriaceae and Thermoprotei. Genomic GC content had a modest impact on relative exchangeabilities despite having a large impact on amino acid frequencies. Relative exchangeabilities involving aromatic residues exhibited the largest differences among models. There were a small number of exchangeabilities that exhibited large differences in comparisons among major clades and between generalized models and ribosomal protein models. Taken as a whole, these results reveal that a small number of relative exchangeabilities are responsible for much of the structure of the “model space” for protein sequence evolution. The clade-specific models we generated may be useful tools for protein phylogenetics, and the structure of evolutionary model space that they revealed has implications for phylogenomic inference across the tree of life.

Adaptation of hepatitis C virus for persistent infection in patients with acute hepatitis

Functional Side Chain Interactions in ABCC Transporters Inferred by Improved Coevolution Analysis

Relaxed molecular clocks for dating historical plant dispersal events

Do the properties of amino acids affect their rates of substitution? The neutral theory predicts that greater selective constraint leads to slower rates of evolution; similarly, we expect amino acids that are more different from each other to have lower rates of exchange because such changes are most likely to affect protein structure and function. Here, we test these predictions, using substitution rates estimated from empirical amino acid exchangeability matrices. To measure degree of amino acid difference, we focused on two physicochemical properties, charge and size, uncorrelated metrics that are known to have important implications for protein structure and function. We find that for both charge and size, amino acid pairs with large differences had lower rates of substitution. We also found that amino acids that differed in both properties had the lowest rates of substitution, suggesting that both physicochemical properties are under selective constraint. Mutation properties, such as the number of mutations or the number of transitions as opposed to transversions separating amino acid pairs, were also important predictors of substitution rates. The relationship between amino acid substitution rates and differences in their physiochemical properties holds across several taxonomically restricted datasets. This finding suggests that purifying selection affects amino acid substitution rates in a similar manner across taxonomic groups with different effective population sizes.

Genetic Variation in Neuraminidase Genes of Influenza A (H3N2) Viruses

Norovirus is the leading viral agent of gastroenteritis in humans. RNA-dependent RNA polymerase (RdRp) is essential in the replication of norovirus RNA. Here, we present a comprehensive evolutionary analysis of the norovirus GI RdRp gene. Our results show that the norovirus GI RdRp gene can be divided into three groups, and that the most recent common ancestor was 1484. The overall evolutionary rate of GI RdRp is 1.821 × 10−3 substitutions/site/year. Most of the amino acids of the GI RdRp gene were under negative selection, and only a few positively selected sites were recognized. Amino acid substitutions in the GI RdRp gene accumulated slowly over time. GI.P1, GI.P3 and GI.P6 owned the higher evolutionary rates. GI.P11 and GI.P13 had the faster accumulation rate of amino acid substitutions. GI.P2, GI.P3, GI.P4, GI.P6 and GI.P13 presented a strong linear evolution. These results reveal that the norovirus GI RdRp gene evolves conservatively, and that the molecular evolutionary characteristics of each P-genotype are diverse. Sequencing in RdRp and VP1 of norovirus should be advocated in the surveillance system to explore the effect of RdRp on norovirus activity.

Light environments differ dramatically between day and night. The transition between diurnal and nocturnal visual ecology has happened repeatedly throughout evolution in many species. However, the molecular mechanism underlying the evolution of vision in recent diurnal-nocturnal transition is poorly understood. Here, we focus on hawkmoths (Lepidoptera: Sphingidae) to address this question by investigating five nocturnal and five diurnal species. We performed RNA-sequencing analysis and identified opsin genes corresponding to the ultraviolet (UV), short-wavelength (SW) and long-wavelength (LW)-absorbing visual pigments. We found no significant differences in the expression patterns of opsin genes between the nocturnal and diurnal species. We then constructed the phylogenetic trees of hawkmoth species and opsins. The diurnal lineages had emerged at least three times from the nocturnal ancestors. The evolutionary rates of amino acid substitutions in the three opsins differed between the nocturnal and diurnal species. We found an excess number of parallel amino acid substitutions in the opsins in three independent diurnal lineages. The numbers were significantly more than those inferred from neutral evolution, suggesting that positive selection acted on these parallel substitutions. Moreover, we predicted the visual pigment absorption spectra based on electrophysiologically determined spectral sensitivity in two nocturnal and two diurnal species belonging to different clades. In the diurnal species, the LW pigments shift 10 nm towards shorter wavelengths, and the SW pigments shift 10 nm in the opposite direction. Taken together, our results suggest that parallel evolution of opsins may have enhanced the colour discrimination properties of diurnal hawkmoths in ambient light.

1. Theoretical works on Nei's genetic distance and its extensions are discussed. New formulae for the sampling variances of genetic distance estimates are presented. Formulae for the genetic identity of genes at the electrophoretic level when the mutation rate varies from locus to locus are also presented. 2. Empirical data suggests that the rate of gene substitution or mutation rate per locus varies considerably among protein loci, and if this factor is taken into account, the rate of decline of genetic identity (I) is no longer constant but decreases with evolutionary time. Using both the infiniteallele model and the stepwise mutation model, the numerical relationship betweenI and evolutionary time is presented. This relationship may be used for estimating the time after divergence between populations. The value of genetic distance or genetic identity is also affected considerably by the bottleneck effect. The bottleneck effect generally accelerates the increase of genetic distance with time, and the effect remains for a long time after the population size returns to the original level. A method for correcting for this effect is presented. 3. Application of the theory of genetic distance to data on protein polymorphism in man indicates that the genetic variation between the three major races, Caucasoid, Negroid, and Mongoloid, is much smaller than the variation within them, despite the fact that there is a conspicuous difference in some morphological characters such as pigmentation, facial structure, and hair texture. It is proposed that the differentiation of these morphological characters was brought about by relatively strong natural selection through a small number of gene substitutions, whereas general protein loci are subject to little or very weak selection. Analysis of blood group gene frequency data gives essentially the same result as those from protein loci, though they are likely to have been affected by nonrandom sampling of the loci. It is also shown that at the protein level the racial differences in man correspond to those between local races in other organisms. 4. Rough estimates of the number of codon differences between an individual of man and his various relatives are presented. It seems that the mean number of codon differences between man and chimpanzee is about 10 times larger than that between second degree relatives in Caucasians or Japanese, but about 1/19 of that between man and horse. 5. Genetic distance estimates suggest that among the three major races of man the first divergence occurred about 120,000 years ago between Negroid and a group of Caucasoid and Mongoloid and then the latter group split into Caucasoid and Mongoloid around 60,000 years ago. It is also shown that the genetic identity between man and chimpanzee corresponds to a divergence time of 4–6 million years if the assumption of constant rate of amino acid substitution is correct. 6. Methods of constructing a phylogenetic tree from genetic distance estimates are discussed. For constructing the topology of a tree, Fitch and Margoliash's method is quite efficient. For estimating branch lengths, however, Nei's method of averaging distances seems to be better. 7. A phylogenetic tree for twelve races of man is constructed by using gene frequency data for 11 protein and 11 blood group loci. This tree roughly agrees with what we expect intuitively from the morphological characters and the historical record of these races.

Eukaryotic nuclear structure explains the evolutionary rate difference of ribosome export factors

The influence of the memory effects on the Poissonian clocks with fluctuating counting rates is investigated by using the technique of characteristic functionals. A general approach for computing all cumulants of the number of counts is suggested based on an analogy with the theory of rate processes with dynamical disorder. The large time behavior of the cumulants is investigated for stationary random processes with short and long memory, respectively. For short memory in the long run all cumulants increase linearly in time and the averaged stochastic process describing the statistics of the number of counts, although generally non-Poissonian, is non-intermittent and can be used as a clock. For finite long memory described by a stationary fractal random process, even though the cumulants of the number of events increase faster than linearly in time, the fluctuations are still non-intermittent and the averaged random process is also a clock. For infinite memory, however, the fluctuations of the number of counts are intermittent and the averaged random process is not a clock any more. An alternative stochastic approach is developed based on the use of a dynamical analogue of the Porter-Thomas formula; the results are consistent with the first version of the theory. Three applications of the general theory are presented. The first application is related to the connection between the Kimura's neutral theory of molecular evolution and the Gillespie's episodic clock for the rate of amino acid substitutions through the evolutionary process. If the fluctuations of the rate of substitution have short memory or long finite memory then Gillespie's episodic clock is consistent with Kimura's theory. Only the infinite memory is not consistent with the neutral hypothesis. The second application is the study of a hopping mechanism for enhanced diffusion. A biased random walk is investigated by assuming that the distribution of the number of jumps is given by a Poissonian process with a fluctuating counting rate. If the fluctuations of the counting rate have short memory then the resulting biased diffusion is normal and obeys Einstein's linear equation for the mean square displacement of the moving particle. For long memory the mean square displacement of the moving particle increases faster than linearly in time and the diffusion is enhanced. An alternative approach for a random walk in the velocity space is developed. In this case the diffusion process is even more efficient than for a random walk in the real space. The third application is the study of Porter-Thomas relaxation for systems with dynamical disorder. It is shown that for small and moderately long times the relaxation function obeys a scaling law of the negative power law type followed by a fast decaying exponential tail which is determined by the fluctuation dynamics. This type of relaxation behavior is of interest both for nuclear and molecular physics and corresponds to a non-ideal statistical fractal.