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Adam Eyre-Walker

Publications and source records attributed to Adam Eyre-Walker.

At least 19 recordsLinked to original sources
PubMed2006

Searching for sequence directed mutagenesis in eukaryotes.

Sequence directed mutagenesis is a mechanism by which imperfect repeats "repair" each other to become perfect, generating mutations. This process is known to be prevalent in prokaryotes and it has been implicated in several human genetic diseases. Here we test whether sequence directed mutagenesis occurs in the protein coding sequences of eukaryotes using extensive DNA sequence data from humans, mice, Drosophila, nematodes, yeast, and Arabidopsis. Using two tests we find little evidence of sequence directed mutagenesis. We conclude that sequence directed mutagenesis is not prevalent in eukaryotes and that the examples of human diseases, apparently caused by sequence directed mutagenesis, are probably coincidental.

Animals↗
PubMed2006

Synonymous codon usage in Escherichia coli: selection for translational accuracy.

In many organisms, selection acts on synonymous codons to improve translation. However, the precise basis of this selection remains unclear in the majority of species. Selection could be acting to maximize the speed of elongation, to minimize the costs of proofreading, or to maximize the accuracy of translation. Using several data sets, we find evidence that codon use in Escherichia coli is biased to reduce the costs of both missense and nonsense translational errors. Highly conserved sites and genes have higher codon bias than less conserved ones, and codon bias is positively correlated to gene length and production costs, both indicating selection against missense errors. Additionally, codon bias increases along the length of genes, indicating selection against nonsense errors. Doublet mutations or replacement substitutions do not explain our observations. The correlations remain when we control for expression level and for conflicting selection pressures at the start and end of genes. Considering each amino acid by itself confirms our results. We conclude that selection on synonymous codon use in E. coli is largely due to selection for translational accuracy, to reduce the costs of both missense and nonsense errors.

Codon↗
PubMed2006

A new perspective on isochore evolution.

The genomes of mammals and birds show dramatic variation in base composition over large scales, the so called isochore structure of the genome. The origin of isochores is still controversial: various neutral and selectionist models have been proposed--and criticized--since the discovery of isochores in the 1970s. The availability of complete mammalian genomes has yielded new opportunities for addressing this question. In particular, it was recently proposed that (i) the isochore structure is declining in many mammalian groups, and that (ii) GC-content is influenced by local recombination rate, possibly via the mechanism of GC-biased gene conversion. In this article we review the existing support for these two hypotheses, and discuss how they can be combined to provide a new perspective on isochore evolution.

Animals↗
PubMed2006

The genomic rate of adaptive evolution.

The role of positive darwinian selection in evolution at the molecular level has been keenly debated for many years, with little resolution. However, a recent increase in DNA sequence data and the development of new methods of analysis have finally made this question tractable. Here, I review the current state-of-play of the field. Initial estimates in Drosophila suggest that approximately 50% of all amino acid substitutions, and a substantial fraction of substitutions in non-coding DNA, have been fixed as a consequence of adaptive evolution. Estimates in microorganisms are even higher. By contrast, there is little evidence of widespread adaptive evolution in our own species.

Adaptation, Physiological↗
PubMed2006

The rate of adaptive evolution in enteric bacteria.

Here we estimate the rate of adaptive substitution in a set of 410 genes that are present in 6 Escherichia coli and 6 Salmonella enterica genomes. We estimate that more than 50% of amino acid substitutions in this set of genes have been fixed by positive selection between the E. coli and S. enterica lineages. We also show that the proportion of adaptive substitutions is uncorrelated with the rate of amino acid substitution or gene function but that it may be correlated with levels of synonymous codon usage bias.

Adaptation, Biological↗
PubMed2006

The distribution of fitness effects of new deleterious amino acid mutations in humans.

The distribution of fitness effects of new mutations is a fundamental parameter in genetics. Here we present a new method by which the distribution can be estimated. The method is fairly robust to changes in population size and admixture, and it can be corrected for any residual effects if a model of the demography is available. We apply the method to extensively sampled single-nucleotide polymorphism data from humans and estimate the distribution of fitness effects for amino acid changing mutations. We show that a gamma distribution with a shape parameter of 0.23 provides a good fit to the data and we estimate that >50% of mutations are likely to have mild effects, such that they reduce fitness by between one one-thousandth and one-tenth. We also infer that <15% of new mutations are likely to have strongly deleterious effects. We estimate that on average a nonsynonymous mutation reduces fitness by a few percent and that the average strength of selection acting against a nonsynonymous polymorphism is approximately 9 x 10(-5). We argue that the relaxation of natural selection due to modern medicine and reduced variance in family size is not likely to lead to a rapid decline in genetic quality, but that it will be very difficult to locate most of the genes involved in complex genetic diseases.

Alleles↗
PubMed2005

An investigation of the variation in the transition bias among various animal mitochondrial DNA.

The transition:transversion ratio (ts/tv) is known to be very high in human mitochondrial DNA, but we have little information about this ratio in other species. Here we investigate the transition bias in animal mitochondrial DNA using single nucleotide polymorphism data at four-fold degenerate sites. We investigate this pattern of polymorphism in the cytochrome b gene (cyt-b) in 70 species using a total of 1823 mutations. We show that most species show a bias towards transitions but that the ratio varies significantly between species. There is little evidence for variation within orders or genera and between closely related species such as the great apes. The majority of the variation appears to be at a higher phylogenetic levels: between orders and classes. We test whether the variation in ts/tv ratio could be due to variation in the metabolic rate by considering whether the ratio is correlated to base composition. We find no evidence that the metabolic rate affects the ts/tv ratio. We also investigate the relative frequencies of C to T or T to C (C<-->T) mutations and A to G or G to A (A<-->G) mutations. We show that overall they occur at significantly different frequencies, and that there is significant variation in their relative frequency between species and between classes. We find no evidence in support of the hypothesis that this variation could be due to different metabolic rates.

Animals↗
PubMed2005

A dissection of volatility in yeast.

It has been suggested that volatility, the proportion of mutations which change an amino acid, can be used to infer the level of natural selection acting upon a gene. This conjecture is supported by a correlation between volatility and the rate of nonsynonymous substitution (dN), or the ratio of nonsynonymous and synonymous substitution rates, in a variety of organisms. These organisms include yeast, in which the correlations are quite strong. Here we show that these correlations are a by-product of a correlation between synonymous codon bias toward translationally optimal codons and dN. Although this analysis suggests that volatility is not a good measure of the selection, we suggest that it might be possible to infer something about the level of natural selection, from a single genome sequence, using translational codon bias.

Base Sequence↗
PubMed2005

Evidence for widespread degradation of gene control regions in hominid genomes.

Although sequences containing regulatory elements located close to protein-coding genes are often only weakly conserved during evolution, comparisons of rodent genomes have implied that these sequences are subject to some selective constraints. Evolutionary conservation is particularly apparent upstream of coding sequences and in first introns, regions that are enriched for regulatory elements. By comparing the human and chimpanzee genomes, we show here that there is almost no evidence for conservation in these regions in hominids. Furthermore, we show that gene expression is diverging more rapidly in hominids than in murids per unit of neutral sequence divergence. By combining data on polymorphism levels in human noncoding DNA and the corresponding human-chimpanzee divergence, we show that the proportion of adaptive substitutions in these regions in hominids is very low. It therefore seems likely that the lack of conservation and increased rate of gene expression divergence are caused by a reduction in the effectiveness of natural selection against deleterious mutations because of the low effective population sizes of hominids. This has resulted in the accumulation of a large number of deleterious mutations in sequences containing gene control elements and hence a widespread degradation of the genome during the evolution of humans and chimpanzees.

Animals↗
PubMed2005

Why are young and old repetitive elements distributed differently in the human genome?

Alu elements are not distributed homogeneously throughout the human genome: old elements are preferentially found in the GC-rich parts of the genome, while young Alus are more often found in the GC-poor parts of the genome. The process giving rise to this differential distribution remains poorly understood. Here we investigate whether this pattern could be due to a preferential degradation of Alu elements integrated in GC-poor regions by small indel mutations. We aligned 5.1 Mb of human and chimpanzee sequences and examined whether the rate of insertion and deletion inside Alu elements differed according to the base composition surrounding them. We found that Alu elements are not preferentially degraded in GC-poor regions by indel events. We also looked at whether very young L1 elements show the same change in distribution compared to older ones. This analysis indicated that L1 elements also show a shift in their distribution, although we could not assess it as precisely as for Alu elements. We propose that the differential distribution of Alu elements is likely to be due to a change in their pattern of insertion or their probability of fixation through evolutionary time.

Alu Elements↗
PubMed2004

A broad survey of recombination in animal mitochondria.

Recombination in mitochondrial DNA (mtDNA) remains a controversial topic. Here we present a survey of 279 animal mtDNA data sets, of which 12 were from asexual species. Using four separate tests, we show that there is widespread evidence of recombination; for one test as many as 14.2% of the data sets reject a model of clonal inheritance and in several data sets, including primates, the recombinants can be identified visually. We show that none of the tests give significant results for obligate clonal species (apomictic pathogens) and that the sexual species show significantly greater evidence of recombination than asexual species. For some data sets, such as Macaca nemestrina, additional data sets suggest that the recombinants are not artifacts. For others, it cannot be determined whether the recombinants are real or produced by laboratory error. Either way, the results have important implications for how mtDNA is sequenced and used.

Analysis of Variance↗
PubMed2004

The genomic rate of adaptive amino acid substitution in Drosophila.

The proportion of amino acid substitutions driven by adaptive evolution can potentially be estimated from polymorphism and divergence data by an extension of the McDonald-Kreitman test. We have developed a maximum-likelihood method to do this and have applied our method to several data sets from three Drosophila species: D. melanogaster, D. simulans, and D. yakuba. The estimated number of adaptive substitutions per codon is not uniformly distributed among genes, but follows a leptokurtic distribution. However, the proportion of amino acid substitutions fixed by adaptive evolution seems to be remarkably constant across the genome (i.e., the proportion of amino acid substitutions that are adaptive appears to be the same in fast-evolving and slow-evolving genes; fast-evolving genes have higher numbers of both adaptive and neutral substitutions). Our estimates do not seem to be significantly biased by selection on synonymous codon use or by the assumption of independence among sites. Nevertheless, an accurate estimate is hampered by the existence of slightly deleterious mutations and variations in effective population size. The analysis of several Drosophila data sets suggests that approximately 25% +/- 20% of amino acid substitutions were driven by positive selection in the divergence between D. simulans and D. yakuba.

Adaptation, Biological↗
PubMed2004

The decline of isochores in mammals: an assessment of the GC content variation along the mammalian phylogeny.

Whether isochores, the large-scale variation of the GC content in mammalian genomes, are being maintained has recently been questioned. It has been suggested that GC-rich isochores originated in the ancestral amniote genome but that whatever force gave rise to them is no longer effective and that isochores are now disappearing from mammalian genomes. Here we investigated the evolution of the GC content of 41 coding genes in 6 to 66 species of mammals by estimating the ancestral GC content using a method which allows for different rates of substitution between sites. We found a highly significant decrease in the GC content during early mammalian evolution, as well as a weaker but still significant decrease in the GC content of GC-rich genes later in at least three groups of mammals: primates, rodents, and carnivores. These results are of interest because they confirm the recently suggested disappearance of GC-rich isochores in some mammalian genomes, and more importantly, they suggest that this disappearance started very early in mammalian evolution.

Animals↗
PubMed2004

Patterns of evolutionary constraints in intronic and intergenic DNA of Drosophila.

We develop methods to infer levels of evolutionary constraints in the genome by comparing rates of nucleotide substitution in noncoding DNA with rates predicted from rates of synonymous site evolution in adjacent genes or other putatively neutrally evolving sites, while accounting for differences in base composition. We apply the methods to estimate levels of constraint in noncoding DNA of Drosophila. In introns, constraint (the estimated fraction of mutations that are selectively eliminated) is absolute at the 5' and 3' splice junction dinucleotides, and averages 72% in base pairs 3-6 at the 5'-end. Constraint at the 5' base pairs 3-6 is significantly lower in the lineage leading to Drosophila melanogaster than in Drosophila simulans, a finding that agrees with other features of genome evolution in Drosophila and indicates that the effect of selection on intron function has been weaker in the melanogaster lineage. Elsewhere in intron sequences, the rate of nucleotide substitution is significantly higher than at synonymous sites. By using intronic sites outside splice control regions as a putative neutrally evolving standard, constraint in the 500 bp of intergenic DNA upstream and downstream regions of protein-coding genes averages approximately 44%. Although the estimated level of constraint in intergenic regions close to genes is only about one-half of that of amino acid sites, selection against single-nucleotide mutations in intergenic DNA makes a substantial contribution to the mutation load in Drosophila.

Animals↗
PubMed2003

Human disease genes: patterns and predictions.

We compared genes at which mutations are known to cause human disease (disease genes) with other human genes (nondisease genes) using a large set of human-rodent alignments to infer evolutionary patterns. Such comparisons may be of use both in predicting disease genes and in understanding the general evolution of human genes. Four features were found to differ significantly between disease and nondisease genes, with disease genes (i) evolving with higher nonsynonymous/synonymous substitution rate ratios (Ka/Ks), (ii) evolving at higher synonymous substitution rates, (iii) with longer protein-coding sequences, and (iv) expressed in a narrower range of tissues. Discriminant analysis showed that these differences may help to predict human disease genes. We also investigated other factors affecting the mode of evolution in the disease genes: Ka/Ks is significantly affected by protein function, mode of inheritance, and the reduction of life expectancy caused by disease.

Adolescent↗
PubMed2003

Estimating the distribution of fitness effects from DNA sequence data: implications for the molecular clock.

We present a method for estimating the distribution of fitness effects of new amino acid mutations when those mutations can be assumed to be slightly advantageous, slightly deleterious, or strongly deleterious. We apply the method to mitochondrial data from several different species. In the majority of the data sets, the shape of the distribution is approximately exponential. Our results provide an estimate of the distribution of fitness effects of weakly selected mutations and provide a possible explanation for why the molecular clock is fairly constant across taxa and time.

Animals↗