Biology subjects

Keightley, P. D.

Publications and source records attributed to Keightley, P. D..

11 recordsLinked to original sources

bioRxiv2022

Variation in mutation, recombination, and transposition rates in Drosophila melanogaster and Drosophila simulans

Mutation, recombination, and transposition occurring during meiosis provide the variation on which natural selection can act and the rates at which they occur are important parameters in models of evolution. The de novo mutation rate determines levels of genetic diversity, responses to ongoing selection, and levels of genetic load. Recombination breaks up haplotypes and reduces the effects of linkage, helping to spread beneficial alleles and purge deleterious ones. Transposable elements (TE) selfishly replicate themselves through the genome, imposing fitness costs on the host and introducing complex mutations that can affect gene expression and give rise to new genes. However, even for key evolutionary models such as Drosophila melanogaster and D. simulans few estimates of these parameters are available, and we have little idea of how rates vary between individuals, sexes, populations, or species. Here, we provide direct estimates of mutation, recombination, and transposition rates and their variation in a West African and a European population of D. melanogaster and a European population of D. simulans. Across 89 flies, we observe 58 single nucleotide mutations, 286 crossovers, and 89 TE insertions. Compared to the European D. melanogaster, we find the West African population has a lower mutation rate (1.67 vs. 4.86 x 10-9 site-1 gen-1) and transposition rate (8.99 vs. 23.36 x 10-5 copy-1 gen-1), but a higher recombination rate (3.44 vs. 2.06 cM/Mb). The European D. simulans population has a similar mutation rate to European D. melanogaster but a significantly higher recombination rate and a lower but not significantly different transposition rate. Overall, we find paternal-derived mutations are more frequent than maternal ones in both species. HighlightsO_LIDe novo mutation rates are 1.67 x 10-9 site-1 gen-1 (95% HPD CI: 0.54 - 3.14 x 10-9), 4.86 x 10-9 site-1 gen-1 (2.11 - 8.02 x 10-9), and 4.51 x 10-9 site-1 gen-1 (1.94 - 7.75 x 10-9) for the West African D. melanogaster, the European D. melanogaster and the European D. simulans population, respectively. C_LIO_LIIn females, recombination rates in the absence of large genomic inversions are 3.44 cM/Mb (2.72 - 4.18), 2.06 cM/Mb (1.57 - 2.57), and 3.04 cM/Mb (2.45 - 3.73) for the three populations, respectively. There was no strong evidence of recombination observed in males. C_LIO_LIMutations (SNMs and indels) are male-biased. C_LIO_LIThe West African D. melanogaster population has a lower TE activity than the other populations and CMC-Transib is the dominant active TE. The European D. melanogaster population has multiple active TEs: Gypsy, CMC-Transib, Pao, Jockey and hAT-hobo; while in European D. simulans, they are Gypsy, CMC-Transib, Pao, hAT-hobo, Copia and TcMar-Mariner. C_LI

evolutionary biology↗

bioRxiv2022

Rates and spectra of de novo structural mutation in Chlamydomonas reinhardtii

Genetic variation originates from several types of spontaneous mutation, including single nucleotide substitutions, short insertions and deletions (INDELs), and larger structural changes. Structural mutations (SMs) drive genome evolution and are thought to play major roles in evolutionary adaptation, speciation and genetic disease, including cancers. Sequencing of mutation accumulation (MA) lines has provided estimates of rates and spectra of single nucleotide and INDEL mutations in many species, yet the rate of new SMs is largely unknown. Here, we use long-read sequencing to determine the full mutation spectrum in MA lines derived from two strains (CC-1952 and CC-2931) of the green alga Chlamydomonas reinhardtii. The SM rate is highly variable between strains and MA lines, and SMs represent a substantial proportion of all mutations in both strains (CC-1952 6%; CC-2931 12%). The SM spectra also differs considerably between the two strains, with almost all inversions and translocations occurring in CC-2931 MA lines. This variation is associated with heterogeneity in the number and type of active transposable elements (TEs), which comprise major proportions of SMs in both strains (CC-1952 22% and CC-2931 38% of SMs). In CC-2931, a Crypton and a previously undescribed type of DNA element caused 71% of chromosomal rearrangements, while in CC-1952 a Dualen LINE was associated with 87% of duplications. Other SMs, notably many large duplications in CC-2931, were likely products of various double-strand break repair pathways. Our results demonstrate that diverse types of SMs occur at substantial rates and support prominent roles for SMs and TEs in evolution.

evolutionary biology↗

bioRxiv2021

Statistical inference in population genomics

The field of population genomics has grown rapidly in response to the recent advent of affordable, large-scale sequencing technologies. As opposed to the situation during the majority of the 20th century, in which the development of theoretical and statistical population-genetic insights out-paced the generation of data to which they could be applied, genomic data are now being produced at a far greater rate than they can be meaningfully analyzed and interpreted. With this wealth of data has come a tendency to focus on fitting specific (and often rather idiosyncratic) models to data, at the expense of a careful exploration of the range of possible underlying evolutionary processes. For example, the approach of directly investigating models of adaptive evolution in each newly sequenced population or species often neglects the fact that a thorough characterization of ubiquitous non-adaptive processes is a prerequisite for accurate inference. We here describe the perils of these tendencies, present our consensus views on current best practices in population genomic data analysis, and highlight areas of statistical inference and theory that are in need of further attention. Thereby, we argue for the importance of defining a biologically relevant baseline model tuned to the details of each new analysis, of skepticism and scrutiny in interpreting model-fitting results, and of carefully defining addressable hypotheses and underlying uncertainties.

evolutionary biology↗

bioRxiv2021

The distribution of fitness effects of spontaneous mutations in Chlamydomonas reinhardtii inferred using frequency changes under experimental evolution

The distribution of fitness effects (DFE) for new mutations is fundamental for many aspects of population and quantitative genetics. In this study, we have inferred the DFE in the single-celled alga Chlamydomonas reinhardtii by estimating changes in the frequencies of 254 spontaneous mutations under experimental evolution and equating the frequency changes of linked mutations with their selection coefficients. We generated seven populations of recombinant haplotypes by crossing seven independently derived mutation accumulation lines carrying an average of 36 mutations in the homozygous state to a mutation-free strain of the same genotype. We then allowed the populations to evolve under natural selection in the laboratory by serial transfer in liquid culture. We observed substantial and repeatable changes in the frequencies of many groups of linked mutations, and, surprisingly, as many mutations were observed to increase as decrease in frequency. We developed a Bayesian Monte Carlo Markov Chain method to infer the DFE. This computes the likelihood of the observed distribution of changes of frequency, and obtains the posterior distribution of the selective effects of individual mutations, while assuming a two-sided gamma distribution of effects. We infer that the DFE is a highly leptokurtic distribution, and that approximately equal proportions of mutations have positive and negative effects on fitness. This result is consistent with what we have observed in previous work on a different C. reinhardtii strain, and suggests that a high fraction of new spontaneously arisen mutations are advantageous in a simple laboratory environment.

evolutionary biology↗

bioRxiv2021

Selective sweeps influence diversity over large regions of the mouse genome

To what extent do substitutions in protein-coding versus gene-regulatory regions contribute to fitness change over time? Answering this question requires estimates of the extent of selection acting on beneficial mutations in the two classes of sites. New mutations that have advantageous or deleterious fitness effects can induce selective sweeps and background selection, respectively, causing variation in the level of neutral genetic diversity along the genome. In this study, we analyse the profiles of genetic variability around protein-coding and regulatory elements in the genomes of wild mice to estimate the parameters of positive selection. We find patterns of diversity consistent with the effects of selection at linked sites, which are similar across mouse taxa, despite differences in effective population size and demographic history. By fitting a model that combines the effects of selective sweeps and background selection, we estimate the strength of positive selection and the frequency of advantageous mutations. We find that strong positive selection is required to explain variation in genetic diversity across the murid genome. In particular, we estimate that beneficial mutations in protein-coding regions have stronger effects on fitness than do mutations in gene-regulatory regions, but that mutations in gene-regulatory regions are more common. Overall though, our parameter estimates suggest that the cumulative fitness changes brought about by beneficial mutations in protein-coding may be greater than those in gene-regulatory elements.

evolutionary biology↗

bioRxiv2020

Cis-regulatory evolution spotlights species differences in the adaptive potential of gene expression plasticity

Phenotypic plasticity is the variation in phenotype that a single genotype can produce in different environments and, as such, is an important component of individual fitness. However, whether the effect of new mutations, and hence evolution, depends on the direction of plasticity remains controversial. Here, we identify the cis-acting modifications that have reshaped gene expression in response to dehydration stress in three Arabidopsis species. Our study shows that the direction of effects of most cis-regulatory variants differentiating the response between A. thaliana and the sister species A. lyrata and A. halleri depends on the direction of pre-existing plasticity in gene expression. A comparison of the rate of cis-acting variant accumulation in each lineage indicates that the selective forces driving adaptive evolution in gene expression favors regulatory changes that magnify the stress response in A. lyrata. The evolutionary constraints measured on the amino-acid sequence of these genes support this interpretation. In contrast, regulatory changes that mitigate the plastic response to stress evolved more frequently in A. halleri. Our results demonstrate that pre-existing plasticity can be a stepping stone for adaptation, but its selective remodeling differs between lineages.

evolutionary biology↗

bioRxiv2020

Comparative genomics of Chlamydomonas

Despite its fundamental role as a model organism in plant sciences, the green alga Chlamydomonas reinhardtii entirely lacks genomic resources for any closely related species, obstructing its development as a study system in several fields. We present highly contiguous and well-annotated genome assemblies for the two closest known relatives of the species, Chlamydomonas incerta and Chlamydomonas schloesseri, and a third more distantly related species, Edaphochlamys debaryana. We find the three Chlamydomonas genomes to be highly syntenous with similar gene contents, although the 129.2 Mb C. incerta and 130.2 Mb C. schloesseri assemblies are more repeat-rich than the 111.1 Mb C. reinhardtii genome. We identify the major centromeric repeat in C. reinhardtii as an L1 LINE transposable element homologous to Zepp (the centromeric repeat in Coccomyxa subellipsoidea) and infer that centromere locations and structure are likely conserved in C. incerta and C. schloesseri. We report extensive rearrangements, but limited gene turnover, between the minus mating-type loci of the Chlamydomonas species, potentially representing the early stages of mating-type haplotype reformation. We produce an 8-species whole-genome alignment of unicellular and multicellular volvocine algae and identify evolutionarily conserved elements in the C. reinhardtii genome. We find that short introns (<~100 bp) are extensively overlapped by conserved elements, and likely represent an important functional class of regulatory sequence in C. reinhardtii. In summary, these novel resources enable comparative genomics analyses to be performed for C. reinhardtii, significantly developing the analytical toolkit for this important model system.

genomics↗

bioRxiv2019

Direct inference of the distribution of fitness effects of spontaneous mutations in Chlamydomonas reinhardtii

Spontaneous mutations are the source of new genetic variation and are thus central to the evolutionary process. In molecular evolution and quantitative genetics, the nature of genetic variation depends critically on the distribution of fitness effects (DFE) of mutations. Spontaneous mutation accumulation (MA) experiments have been the principal approach for investigating the overall rate of occurrence and cumulative effect of mutations, but have not allowed the effects of individual mutations to be studied directly. Here, we crossed MA lines of the green alga Chlamydomonas reinhardtii with its unmutated ancestral strain to create haploid recombinant lines, each carrying an average of 50% of the accumulated mutations in a variety of combinations. With the aid of the genome sequences of the MA lines, we inferred the genotypes of the mutations, assayed their growth rate as a measure of fitness, and inferred the DFE using a novel Bayesian mixture model that allows the effects of individual mutations to be estimated. We infer that the DFE is highly leptokurtic (L-shaped), and that a high proportion of mutations increase fitness in the laboratory environment. The inferred distribution of effects for deleterious mutations is consistent with a strong role for nearly neutral evolution. Specifically, such a distribution predicts that nucleotide variation and genetic variation for quantitative traits will be insensitive to change in the effective population size.

evolutionary biology↗

bioRxiv2018

Understanding the factors that shape patterns of nucleotide diversity in the house mouse genome

A major goal of population genetics has been to determine the extent to which selection at linked sites influences patterns of neutral nucleotide diversity in the genome. Multiple lines of evidence suggest that diversity is influenced by both positive and negative selection. For example, in many species there are troughs in diversity surrounding functional genomic elements, consistent with the action of either background selection (BGS) or selective sweeps. In this study, we investigated the causes of the diversity troughs that are observed in the wild house mouse genome. Using the unfolded site frequency spectrum (uSFS), we estimated the strength and frequencies of deleterious and advantageous mutations occurring in different functional elements in the genome. We then used these estimates to parameterize forward-in-time simulations of chromosomes, using realistic distributions of functional elements and recombination rate variation in order to determine if selection at linked sites can explain the observed patterns of nucleotide diversity. The simulations suggest that BGS alone cannot explain the dips in diversity around either exons or conserved non-coding elements (CNEs). A combination of BGS and selective sweeps, however, can explain the troughs in diversity around CNEs. This is not the case for protein-coding exons, where observed dips in diversity cannot be explained by parameter estimates obtained from the uSFS. We discuss the extent to which our results provide evidence of sweeps playing a role in shaping patterns of nucleotide diversity and the limitations of using the uSFS for obtaining inferences of the frequency and effects of advantageous mutations.\n\nAuthor SummaryWe present a study examining the causes of variation in nucleotide diversity across the mouse genome. The status of mice as a model organism in the life sciences makes them an excellent model system for studying molecular evolution in mammals. In our study, we analyse how natural selection acting on new mutations can affect levels of nucleotide diversity through the processes of background selection and selective sweeps. To perform our analyses, we first estimated the rate and strengths of selected mutations from a sample of wild mice and then use our estimates in realistic population genetic simulations. Analysing simulations, we find that both harmful and beneficial mutations are required to explain patterns of nucleotide diversity in regions of the genome close to gene regulatory elements. For protein-coding genes, however, our approach is not able to fully explain observed patterns and we think that this is because there are strongly advantageous mutations that occur in protein-coding genes that we were not able to detect.

evolutionary biology↗

bioRxiv2018

Inferring the probability of the derived versus the ancestral allelic state at a polymorphic site

It is known that the allele ancestral to the variation at a polymorphic nucleotide site cannot be assigned with certainty, and that the most frequently used method to assign the ancestral state - maximum parsimony - is prone to mis-inference. Estimates of counts of sites that have a certain number of copies of the derived allele (the unfolded site frequency spectrum, uSFS) made by parsimony are therefore also biased. We previously developed a maximum likelihood method to estimate the uSFS for a focal species, using information from two outgroups and assuming simple models of nucleotide substitution. Here, we extend this approach to infer the uSFS, allowing multiple outgroups, potentially any phylogenetic tree topology and more complex models of nucleotide substitution. We find, however, that two outgroups and assuming the Kimura 2-parameter model is adequate for uSFS inference in most cases. We show that using parsimony for ancestral state inference at a specific site seriously breaks down in two situations. The first is where the outgroups provide no information about the ancestral state of variation in the focal species. In this case, nucleotide variation will be under-estimated if such sites are removed from the data. The second is where the minor allele in the focal species agrees with the allelic state of the outgroups. In this situation, parsimony tends to over-estimate the probability of the major allele being derived, because it fails to account for the fact that sites with a high frequency of the derived allele tend to be rare in most data sets. We present a method that corrects this deficiency, which is capable of providing unbiased estimates of ancestral state probabilities on a site-by-site basis and the uSFS.

evolutionary biology↗

bioRxiv2017

The recombination landscape in wild house mice inferred using population genomic data

Characterizing variation in the rate of recombination across the genome is important for understanding many evolutionary processes. The landscape of recombination has been studied previously in the house mouse, Mus musculus, and it is known that the different subspecies exhibit different suites of recombination hotspots. However, it is not established whether broad-scale variation in the rate of recombination is conserved between the subspecies. In this study, we construct a fine-scale recombination map for the Eastern house mouse subspecies, M. m. castaneus, using 10 individuals sampled from its ancestral range. After inferring phase, we use LDhelmet to construct recombination maps for each autosome. We find that the spatial distribution of recombination rate is strongly positively between our castaneus map and a map constructed using inbred lines of mice derived predominantly from M. m. domesticus. We also find that levels of genetic diversity in M. m. castaneus are positively correlated with the rate of recombination, consistent with pervasive natural selection acting in the genome. Our study suggests that recombination rate variation is conserved at broad scales between M. musculus subspecies.

evolutionary biology↗