Yeast Spontaneous Mutation Rate and Spectrum Vary with Environment

1. Download : Download high-res image (229KB)
2. Download : Download full-size image

     

Compositional Properties of Green-Plant Plastid Genomes

We studied variation of GC contents among plastid (Pt) genomes of green plants. In the green plants, the GC contents of the whole Pt genomes range from 42.14 to 28.81%. These values are similar to those observed in the mitochondrial (Mt) genomes of the green plants, however, the GC contents in the Pt genomes are not related to those in the Mt genomes or the nuclear (Nc) genomes. In addition, some compositional properties of the three types of genomes are different. Thus, it is suggested that the GC contents of the Pt genomes are maintained independently of the other genomes within a cell. We found that the compositional bias toward AT is strong at the third codon position and in intergenic spacer (IGS) regions in the Pt genomes, and the GC contents (GC3 and GCIGS) at these sites are generally similar within each genome. Additionally, the GC3 and GCIGS are strongly related to the whole-genome GC content. Therefore, the interspecific variation of the GC contents in the Pt genomes is suggested to be mainly caused by the variation of the GC3 and GCIGS, both of which are considered to be under weak selective constraints. Using a maximum likelihood approach, we estimated equilibrium GC3 (eqGC₃) of 12 genes in the land-plant Pt genomes. We found an increase in eqGC₃ after the divergence of liverworts. These results suggest that genome-wide factors such as GC mutational bias are important for the biased base composition in the Pt genomes.Reviewing Editor: Dr. Brian Morton     

Accumulation of Spontaneous Mutations in the Ciliate Tetrahymena thermophila

Knowledge of the rate and fitness effects of mutations is essential for understanding the process of evolution. Mutations are inherently difficult to study because they are rare and are frequently eliminated by natural selection. In the ciliate Tetrahymena thermophila, mutations can accumulate in the germline genome without being exposed to selection. We have conducted a mutation accumulation (MA) experiment in this species. Assuming that all mutations are deleterious and have the same effect, we estimate that the deleterious mutation rate per haploid germline genome per generation is U = 0.0047 (95% credible interval: 0.0015, 0.0125), and that germline mutations decrease fitness by s = 11% when expressed in a homozygous state (95% CI: 4.4%, 27%). We also estimate that deleterious mutations are partially recessive on average (h = 0.26; 95% CI: –0.022, 0.62) and that the rate of lethal mutations is <10% of the deleterious mutation rate. Comparisons between the observed evolutionary responses in the germline and somatic genomes and the results from individual-based simulations of MA suggest that the two genomes have similar mutational parameters. These are the first estimates of the deleterious mutation rate and fitness effects from the eukaryotic supergroup Chromalveolata and are within the range of those of other eukaryotes.     

The Rate and Molecular Spectrum of Spontaneous Mutations in the GC-Rich Multichromosome Genome of Burkholderia cenocepacia

Spontaneous mutations are ultimately essential for evolutionary change and are also the root cause of many diseases. However, until recently, both biological and technical barriers have prevented detailed analyses of mutation profiles, constraining our understanding of the mutation process to a few model organisms and leaving major gaps in our understanding of the role of genome content and structure on mutation. Here, we present a genome-wide view of the molecular mutation spectrum in Burkholderia cenocepacia, a clinically relevant pathogen with high %GC content and multiple chromosomes. We find that B. cenocepacia has low genome-wide mutation rates with insertion–deletion mutations biased toward deletions, consistent with the idea that deletion pressure reduces prokaryotic genome sizes. Unlike prior studies of other organisms, mutations in B. cenocepacia are not AT biased, which suggests that at least some genomes with high %GC content experience unusual base-substitution mutation pressure. Importantly, we also observe variation in both the rates and spectra of mutations among chromosomes and elevated G:C > T:A transversions in late-replicating regions. Thus, although some patterns of mutation appear to be highly conserved across cellular life, others vary between species and even between chromosomes of the same species, potentially influencing the evolution of nucleotide composition and genome architecture.     

De Novo Mutation Rate Variation and Its Determinants in Chlamydomonas

De novo mutations are central for evolution, since they provide the raw material for natural selection by regenerating genetic variation. However, studying de novo mutations is challenging and is generally restricted to model species, so we have a limited understanding of the evolution of the mutation rate and spectrum between closely related species. Here, we present a mutation accumulation (MA) experiment to study de novo mutation in the unicellular green alga Chlamydomonas incerta and perform comparative analyses with its closest known relative, Chlamydomonas reinhardtii. Using whole-genome sequencing data, we estimate that the median single nucleotide mutation (SNM) rate in C. incerta is μ = 7.6 × 10⁻¹⁰, and is highly variable between MA lines, ranging from μ = 0.35 × 10⁻¹⁰ to μ = 131.7 × 10⁻¹⁰. The SNM rate is strongly positively correlated with the mutation rate for insertions and deletions between lines (r > 0.97). We infer that the genomic factors associated with variation in the mutation rate are similar to those in C. reinhardtii, allowing for cross-prediction between species. Among these genomic factors, sequence context and complexity are more important than GC content. With the exception of a remarkably high C→T bias, the SNM spectrum differs markedly between the two Chlamydomonas species. Our results suggest that similar genomic and biological characteristics may result in a similar mutation rate in the two species, whereas the SNM spectrum has more freedom to diverge.     

A Novel Method Distinguishes Between Mutation Rates and Fixation Biases in Patterns of Single-Nucleotide Substitution

Analysis of the genome-wide patterns of single-nucleotide substitution reveals that the human GC content structure is out of equilibrium. The substitutions are decreasing the overall GC content (GC), at the same time making its range narrower. Investigation of single-nucleotide polymorphisms (SNPs) revealed that presently the decrease in GC content is due to a uniform mutational preference for A:T pairs, while its projected range is due to a variability in the fixation preference for G:C pairs. However, it is important to determine whether lessons learned about evolutionary processes operating at the present time (that is reflected in the SNP data) can be extended back into the evolutionary past. We describe here a new approach to this problem that utilizes the juxtaposition of forward and reverse substitution rates to determine the relative importance of variability in mutation rates and fixation probabilities in shaping long-term substitutional patterns. We use this approach to demonstrate that the forces shaping GC content structure over the recent past (since the appearance of the SNPs) extend all the way back to the mammalian radiation ∼90 million years ago. In addition, we find a small but significant effect that has not been detected in the SNP data—relatively high rates of C:G→A:T germline mutation in low-GC regions of the genome. Reviewing Editor: Dr. Nicolas Galfier An erratum to this article is available at .     

Study of Completed Archaeal Genomes and Proteomes： Hypothesis of Strong Mutational AT Pressure Existed in Their Common Predecessor

The number of completely sequenced archaeal genomes has been sufficient for a large-scale bioinformatic study.We have conducted analyses for each coding region from 36 archaeal genomes using the original CGS algorithm by calculating the total GC content(G+C),GC content in first,second and third codon positions as well as in fourfold and twofold degenerated sites from third codon positions,levels of arginine codon usage(Arg2:AGA/G;Arg4:CGX),levels of amino acid usage and the entropy of amino acid content distribution.In archaeal genomes with strong GC pressure,arginine is coded preferably by GC-rich Arg4 codons,whereas in most of archaeal genomes with G+C0.6,arginine is coded preferably by AT-rich Arg2 codons.In the genome of Haloquadratum walsbyi,which is closely related to GC-rich archaea,GC content has decreased mostly in third codon positions,while Arg4Arg2 bias still persists.Proteomes of archaeal species carry characteristic amino acid biases:levels of isoleucine and lysine are elevated,while levels of alanine,histidine,glutamine and cytosine are relatively decreased.Numerous genomic and proteomic biases observed can be explained by the hypothesis of previously existed strong mutational AT pressure in the common predecessor of all archaea.     

The Correlation Between Recombination Rate and Dinucleotide Bias in Drosophila melanogaster

Revealing how recombination affects genomic sequence is of great significance to our understanding of genome evolution. The present paper focuses on the correlation between recombination rate and dinucleotide bias in Drosophila melanogaster genome. Our results show that the overall dinucleotide bias is positively correlated with recombination rate for genomic sequences including untranslated regions, introns, intergenic regions, and coding sequences. The correlation patterns of individual dinucleotide biases with recombination rate are presented. Possible mechanisms of interaction between recombination and dinucleotide bias are discussed. Our data indicate that there may be a genome-wide universal mechanism acting between recombination rate and dinucleotide bias, which is likely to be neighbor-dependent biased gene conversion.     

DNA Isolation and GC Base Composition of Four Root-knot Nematode (Meloidogyne spp.) Genomes

Phenol extraction and cesium trifluoroacetate ultracentrifugation were compared for efficiency in the extraction of DNA from eggs and second-stage juveniles of four species of Meloidogyne. The second method proved to be more satisfactory in that it yielded larger amounts of DNA, shortened the extraction period, and reduced sample handling by eliminating phenol and ether extraction and RNAse treatment. It also made possible the extraction of DNA: from more than one sample at a time. The mean base compositions (% GC) of the total DNA of M. incognita, M. javanica, M. arenaria, and M. hapla, as determined by thermal denaturation tests, were quite similar, as they ranged only between 31 and 33%. Similarly, the thermal stability of the DNA of all four species covered a narrow range from 82.97 to 83.63 C.     

Proceedings of the SMBE Tri-National Young Investigators' Workshop 2005. Mutation rate and the cost of complexity

Two recent theoretical studies of adaptation suggest that more complex organisms tend to adapt more slowly. Specifically, in Fisher's "geometric" model of a finite population where multiple traits are under optimizing selection, the average progress ensuing from a single mutation decreases as the number of traits increases--the "cost of complexity." Here, I draw on molecular and histological data to assess the extent to which on a large phylogenetic scale, this predicted decrease in the rate of adaptation per mutation is mitigated by an increase in the number of mutations per generation as complexity increases. As an index of complexity for multicellular organisms, I use the number of visibly distinct types of cell in the body. Mutation rate is the product of mutational target size and population mutation rate per unit target. Despite much scatter, genome size appears to be positively correlated with complexity (as indexed by cell-type number), which along with other considerations suggests that mutational target size tends to increase with complexity. In contrast, effective population mutation rate per unit target appears to be negatively correlated with complexity. The net result is that mutation rate probably does tend to increase with complexity, although probably not fast enough to eliminate the cost of complexity.     

Low base‐substitution mutation rate and predominance of insertion‐deletion events in the acidophilic bacterium Acidobacterium capsulatum

Analyses of spontaneous mutation have shown that total genome‐wide mutation rates are quantitatively similar for most prokaryotic organisms. However, this view is mainly based on organisms that grow best around neutral pH values (6.0–8.0). In particular, the whole‐genome mutation rate has not been determined for an acidophilic organism. Here, we have determined the genome‐wide rate of spontaneous mutation in the acidophilic Acidobacterium capsulatum using a direct and unbiased method: a mutation‐accumulation experiment followed by whole‐genome sequencing. Evaluation of 69 mutation accumulation lines of A. capsulatum after an average of ~2900 cell divisions yielded a base‐substitution mutation rate of 1.22 × 10⁻¹⁰ per site per generation or 4 × 10⁻⁴ per genome per generation, which is significantly lower than the consensus value (2.5−4.6 × 10⁻³) of mesothermophilic (~15–40°C) and neutrophilic (pH 6–8) prokaryotic organisms. However, the insertion‐deletion rate (0.43 × 10⁻¹⁰ per site per generation) is high relative to the base‐substitution mutation rate. Organisms with a similar effective population size and a similar expected effect of genetic drift should have similar mutation rates. Because selection operates on the total mutation rate, it is suggested that the relatively high insertion‐deletion rate may be balanced by a low base‐substitution rate in A. capsulatum, with selection operating on the total mutation rate.     

The Response of Amino Acid Frequencies to Directional Mutation Pressure in Mitochondrial Genome Sequences Is Related to the Physical Properties of the Amino Acids and to the Structure of the Genetic Code

The frequencies of A, C, G, and T in mitochondrial DNA vary among species due to unequal rates of mutation between the bases. The frequencies of bases at fourfold degenerate sites respond directly to mutation pressure. At first and second positions, selection reduces the degree of frequency variation. Using a simple evolutionary model, we show that first position sites are less constrained by selection than second position sites and, therefore, that the frequencies of bases at first position are more responsive to mutation pressure than those at second position. We define a measure of distance between amino acids that is dependent on eight measured physical properties and a similarity measure that is the inverse of this distance. Columns 1, 2, 3, and 4 of the genetic code correspond to codons with U, C, A, and G in their second position, respectively. The similarity of amino acids in the four columns decreases systematically from column 1 to column 2 to column 3 to column 4. We then show that the responsiveness of first position bases to mutation pressure is dependent on the second position base and follows the same decreasing trend through the four columns. Again, this shows the correlation between physical properties and responsiveness. We determine a proximity measure for each amino acid, which is the average similarity between an amino acid and all others that are accessible via single point mutations in the mitochondrial genetic code structure. We also define a responsiveness for each amino acid, which measures how rapidly an amino acid frequency changes as a result of mutation pressure acting on the base frequencies. We show that there is a strong correlation between responsiveness and proximity, and that both these quantities are also correlated with the mutability of amino acids estimated from the mtREV substitution rate matrix. We also consider the variation of base frequencies between strands and between genes on a strand. These trends are consistent with the patterns expected from analysis of the variation among genomes. [Reviewing Editor: Dr. David Pollock]     

Mutational Load and the Transition between Diploidy and Haploidy in Experimental Populations of the Yeast Saccharomyces cerevisiae

Mutations were accumulated over hundreds of generations in a mutator strain of yeast in a constant laboratory environment. This ensured that mutations were frequent and that the quality of environment remained unchanged. Mutations were accumulated in asexual populations of diploids but their impact on fitness was tested both for the diploid clones and for haploid clones derived from them. Dozens of harmful and lethal mutations accumulated in diploids, but important phenotypic traits, such as maximum growth rate, did not deteriorate by more than 10%. There were no signs of decline in population size. In strong contrast, the populations of haploids derived from the diploids suffered from high mortality; their density was reduced by more than three orders of magnitude. These findings indicate how ineffective natural selection can be in removing deleterious mutations from populations of clonally reproducing diploids. They also suggest that phenotypic assays of heterozygous diploids may be of little value as indicators of increasing genetic degeneration.     

Dynamics of reductive genome evolution in mitochondria and obligate intracellular microbes

Reductive evolution in mitochondria and obligate intracellular microbes has led to a significant reduction in their genome size and guanine plus cytosine content (GC). We show that genome shrinkage during reductive evolution in prokaryotes follows an exponential decay pattern and provide a method to predict the extent of this decay on an evolutionary timescale. We validated predictions by comparison with estimated extents of genome reduction known to have occurred in mitochondria and Buchnera aphidicola, through comparative genomics and by drawing on available fossil evidences. The model shows how the mitochondrial ancestor would have quickly shed most of its genome, shortly after its incorporation into the protoeukaryotic cell and prior to codivergence subsequent to the split of eukaryotic lineages. It also predicts that the primary rickettsial parasitic event would have occurred between 180 and 425 million years ago (MYA), an event of relatively recent evolutionary origin considering the fact that Rickettsia and mitochondria evolved from a common alphaproteobacterial ancestor. This suggests that the symbiotic events of Rickettsia and mitochondria originated at different time points. Moreover, our model results predict that the ancestor of Wigglesworthia glossinidia brevipalpis, dated around the time of origin of its symbiotic association with the tsetse fly (50-100 MYA), was likely to have been an endosymbiont itself, thus supporting an earlier proposition that Wigglesworthia, which is currently a maternally inherited primary endosymbiont, evolved from a secondary endosymbiont.     

The Relationship Between the Rate of Molecular Evolution and the Rate of Genome Rearrangement in Animal Mitochondrial Genomes

Evolution of mitochondrial genes is far from clock-like. The substitution rate varies considerably between species, and there are many species that have a significantly increased rate with respect to their close relatives. There is also considerable variation among species in the rate of gene order rearrangement. Using a set of 55 complete arthropod mitochondrial genomes, we estimate the evolutionary distance from the common ancestor to each species using protein sequences, tRNA sequences, and breakpoint distances (a measure of the degree of genome rearrangement). All these distance measures are correlated. We use relative rate tests to compare pairs of related species in several animal phyla. In the majority of cases, the species with the more highly rearranged genome also has a significantly higher rate of sequence evolution. Species with higher amino acid substitution rates in mitochondria also have more variable amino acid composition in response to mutation pressure. We discuss the possible causes of variation in rates of sequence evolution and gene rearrangement among species and the possible reasons for the observed correlation between the two rates. [Reviewing Editor: Dr. David Pollock]     

Amelioration of Bacterial Genomes: Rates of Change and Exchange

Although bacterial species display wide variation in their overall GC contents, the genes within a particular species' genome are relatively similar in base composition. As a result, sequences that are novel to a bacterial genome—i.e., DNA introduced through recent horizontal transfer—often bear unusual sequence characteristics and can be distinguished from ancestral DNA. At the time of introgression, horizontally transferred genes reflect the base composition of the donor genome; but, over time, these sequences will ameliorate to reflect the DNA composition of the new genome because the introgressed genes are subject to the same mutational processes affecting all genes in the recipient genome. This process of amelioration is evident in a large group of genes involved in host-cell invasion by enteric bacteria and can be modeled to predict the amount of time required after transfer for foreign DNA to resemble native DNA. Furthermore, models of amelioration can be used to estimate the time of introgression of foreign genes in a chromosome. Applying this approach to a 1.43-megabase continuous sequence, we have calculated that the entire Escherichia coli chromosome contains more than 600 kb of horizontally transferred, protein-coding DNA. Estimates of amelioration times indicate that this DNA has accumulated at a rate of 31 kb per million years, which is on the order of the amount of variant DNA introduced by point mutations. This rate predicts that the E. coli and Salmonella enterica lineages have each gained and lost more than 3 megabases of novel DNA since their divergence. Received: 7 July 1996 / Accepted: 27 September 1996     

Comparative analysis of genome maintenance genes in naked mole rat,mouse, and human

Genome maintenance (GM) is an essential defense system against aging and cancer, as both are characterized by increased genome instability. Here, we compared the copy number variation and mutation rate of 518 GM‐associated genes in the naked mole rat (NMR), mouse, and human genomes. GM genes appeared to be strongly conserved, with copy number variation in only four genes. Interestingly, we found NMR to have a higher copy number of CEBPG, a regulator of DNA repair, and TINF2, a protector of telomere integrity. NMR, as well as human, was also found to have a lower rate of germline nucleotide substitution than the mouse. Together, the data suggest that the long‐lived NMR, as well as human, has more robust GM than mouse and identifies new targets for the analysis of the exceptional longevity of the NMR.