Adam Eyre-Walker

The distribution of fitness effects of new mutations

The distribution of fitness effects (DFE) of new mutations is a fundamental entity in genetics that has implications ranging from the genetic basis of complex disease to the stability of the molecular clock. It has been studied by two different approaches: mutation accumulation and mutagenesis experiments, and the analysis of DNA sequence data. The proportion of mutations that are advantageous, effectively neutral and deleterious varies between species, and the DFE differs between coding and non-coding DNA. Despite these differences between species and genomic regions, some general principles have emerged: advantageous mutations are rare, and those that are strongly selected are exponentially distributed; and the DFE of deleterious mutations is complex and multi-modal.

Adaptive protein evolution in Drosophila

For over 30 years a central question in molecular evolution has been whether natural selection plays a substantial role in evolution at the DNA sequence level. Evidence has accumulated over the last decade that adaptive evolution does occur at the protein level, but it has remained unclear how prevalent adaptive evolution is. Here we present a simple method by which the number of adaptive substitutions can be estimated and apply it to data from Drosophila simulans and D. yakuba. We estimate that 45% of all amino-acid substitutions have been fixed by natural selection, and that on average one adaptive substitution occurs every 45 years in these species.

High genomic deleterious mutation rates in hominids

It has been suggested that humans may suffer a high genomic deleterious mutation rate,. Here we test this hypothesis by applying a variant of a molecular approach to estimate the deleterious mutation rate in hominids from the level of selective constraint in DNA sequences. Under conservative assumptions, we estimate that an average of 4.2 amino-acid-altering mutations per diploid per generation have occurred in the human lineage since humans separated from chimpanzees. Of these mutations, we estimate that at least 38% have been eliminated by natural selection, indicating that there have been more than 1.6 new deleterious mutations per diploid genome per generation. Thus, the deleterious mutation rate specific to protein-coding sequences alone is close to the upper limit tolerable by a species such as humans that has a low reproductive rate, indicating that the effects of deleterious mutations may have combined synergistically. Furthermore, the level of selective constraint in hominid protein-coding sequences is atypically low. A large number of slightly deleterious mutations may therefore have become fixed in hominid lineages.

Estimating the Rate of Adaptive Molecular Evolution in the Presence of Slightly Deleterious Mutations and Population Size Change

The prevalence of adaptive evolution relative to genetic drift is a central problem in molecular evolution. Methods to estimate the fraction of adaptive nucleotide substitutions (alpha) have been developed, based on the McDonald-Kreitman test, that contrast polymorphism and divergence between selectively and neutrally evolving sites. However, these methods are expected to give downwardly biased estimates of alpha if there are slightly deleterious mutations, because these inflate polymorphism relative to divergence. Here, we estimate alpha by simultaneously estimating the distribution of fitness effects of new mutations at selected sites from the site frequency spectrum and the number of adaptive substitutions. We test the method using simulations. If data meet the assumptions of the analysis model, estimates of alpha show little bias, even when there is little or no recombination. However, population size differences between the divergence and polymorphism phases may cause alpha to be over or underestimated by a predictable factor that depends on the magnitude of the population size change and the shape of the distribution of effects of deleterious mutations. We analyze several data sets of protein-coding genes and noncoding regions from hominids and Drosophila. In Drosophila genes, we estimate that approximately 50% of amino acid substitutions and approximately 20% of substitutions in introns are adaptive. In protein-coding and noncoding data sets of humans, comparison to macaque sequences reveals little evidence for adaptive substitutions. However, the true frequency of adaptive substitutions in human-coding DNA could be as high as 40%, because estimates based on current polymorphism may be strongly downwardly biased by a decrease in the effective population size along the human lineage.

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 ∼9 × 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.

Joint Inference of the Distribution of Fitness Effects of Deleterious Mutations and Population Demography Based on Nucleotide Polymorphism Frequencies

The distribution of fitness effects of new mutations (DFE) is important for addressing several questions in genetics, including the nature of quantitative variation and the evolutionary fate of small populations. Properties of the DFE can be inferred by comparing the distributions of the frequencies of segregating nucleotide polymorphisms at selected and neutral sites in a population sample, but demographic changes alter the spectrum of allele frequencies at both neutral and selected sites, so can bias estimates of the DFE if not accounted for. We have developed a maximum-likelihood approach, based on the expected allele-frequency distribution generated by transition matrix methods, to estimate parameters of the DFE while simultaneously estimating parameters of a demographic model that allows a population size change at some time in the past. We tested the method using simulations and found that it accurately recovers simulated parameter values, even if the simulated demography differs substantially from that assumed in our analysis. We use our method to estimate parameters of the DFE for amino acid-changing mutations in humans and Drosophila melanogaster. For a model of unconditionally deleterious mutations, with effects sampled from a gamma distribution, the mean estimate for the distribution shape parameter is ∼0.2 for human populations, which implies that the DFE is strongly leptokurtic. For Drosophila populations, we estimate that the shape parameter is ∼0.35. Differences in the shape of the distribution and the mean selection coefficient between humans and Drosophila result in significantly more strongly deleterious mutations in Drosophila than in humans, and, conversely, nearly neutral mutations are significantly less frequent.

Variation in the mutation rate across mammalian genomes

It has been known for many years that the mutation rate varies across the genome. However, only with the advent of large genomic data sets is the full extent of this variation becoming apparent. The mutation rate varies over many different scales, from adjacent sites to whole chromosomes, with the strongest variation seen at the smallest scales. Some of these patterns have clear mechanistic bases, but much of the rate variation remains unexplained, and some of it is deeply perplexing. Variation in the mutation rate has important implications in evolutionary biology and underexplored implications for our understanding of hereditary disease and cancer.

Evidence of selection upon genomic GC-content in bacteria

The genomic GC-content of bacteria varies dramatically, from less than 20% to more than 70%. This variation is generally ascribed to differences in the pattern of mutation between bacteria. Here we test this hypothesis by examining patterns of synonymous polymorphism using datasets from 149 bacterial species. We find a large excess of synonymous GC→AT mutations over AT→GC mutations segregating in all but the most AT-rich bacteria, across a broad range of phylogenetically diverse species. We show that the excess of GC→AT mutations is inconsistent with mutation bias, since it would imply that most GC-rich bacteria are declining in GC-content; such a pattern would be unsustainable. We also show that the patterns are probably not due to translational selection or biased gene conversion, because optimal codons tend to be AT-rich, and the excess of GC→AT SNPs is observed in datasets with no evidence of recombination. We therefore conclude that there is selection to increase synonymous GC-content in many species. Since synonymous GC-content is highly correlated to genomic GC-content, we further conclude that there is selection on genomic base composition in many bacteria.

Direct Measure of the De Novo Mutation Rate in Autism and Schizophrenia Cohorts

The role of de novo mutations (DNMs) in common diseases remains largely unknown. Nonetheless, the rate of de novo deleterious mutations and the strength of selection against de novo mutations are critical to understanding the genetic architecture of a disease. Discovery of high-impact DNMs requires substantial high-resolution interrogation of partial or complete genomes of families via resequencing. We hypothesized that deleterious DNMs may play a role in cases of autism spectrum disorders (ASD) and schizophrenia (SCZ), two etiologically heterogeneous disorders with significantly reduced reproductive fitness. We present a direct measure of the de novo mutation rate (μ) and selective constraints from DNMs estimated from a deep resequencing data set generated from a large cohort of ASD and SCZ cases (n = 285) and population control individuals (n = 285) with available parental DNA. A survey of ∼430 Mb of DNA from 401 synapse-expressed genes across all cases and 25 Mb of DNA in controls found 28 candidate DNMs, 13 of which were cell line artifacts. Our calculated direct neutral mutation rate (1.36 × 10(-8)) is similar to previous indirect estimates, but we observed a significant excess of potentially deleterious DNMs in ASD and SCZ individuals. Our results emphasize the importance of DNMs as genetic mechanisms in ASD and SCZ and the limitations of using DNA from archived cell lines to identify functional variants.

Recombination and mammalian genome evolution

Several lines of evidence are presented which suggest that sequence G + C content and recombination frequency are related in mammals: (i) chromosome G + C content is positively correlated to chiasmata density; (ii) the non-pairing region of the Y chromosome has one of the lowest G + C contents of any chromosomal segment; (iii) a reduction in the rate of recombination at several loci is mirrored by a decrease in G + C content; and (iv) when compared with humans, mice have a lower variance in chiasmata density which is reflected in a lower variance in G + C content. The observed relation between recombination frequency and sequence G + C content provides an elegant explanation of why gene density is higher in G + C rich isochores than in other parts of the genome, and why long interspersed elements (lines) are exclusive to G + C poor isochores. However, the cause of the relation is as yet unknown. Several possibilities are considered, including gene conversion.