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      Background Selection as Baseline for Nucleotide Variation across the Drosophila Genome

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      PLoS Genetics
      Public Library of Science

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          Abstract

          The constant removal of deleterious mutations by natural selection causes a reduction in neutral diversity and efficacy of selection at genetically linked sites (a process called Background Selection, BGS). Population genetic studies, however, often ignore BGS effects when investigating demographic events or the presence of other types of selection. To obtain a more realistic evolutionary expectation that incorporates the unavoidable consequences of deleterious mutations, we generated high-resolution landscapes of variation across the Drosophila melanogaster genome under a BGS scenario independent of polymorphism data. We find that BGS plays a significant role in shaping levels of variation across the entire genome, including long introns and intergenic regions distant from annotated genes. We also find that a very large percentage of the observed variation in diversity across autosomes can be explained by BGS alone, up to 70% across individual chromosome arms at 100-kb scale, thus indicating that BGS predictions can be used as baseline to infer additional types of selection and demographic events. This approach allows detecting several outlier regions with signal of recent adaptive events and selective sweeps. The use of a BGS baseline, however, is particularly appropriate to investigate the presence of balancing selection and our study exposes numerous genomic regions with the predicted signature of higher polymorphism than expected when a BGS context is taken into account. Importantly, we show that these conclusions are robust to the mutation and selection parameters of the BGS model. Finally, analyses of protein evolution together with previous comparisons of genetic maps between Drosophila species, suggest temporally variable recombination landscapes and, thus, local BGS effects that may differ between extant and past phases. Because genome-wide BGS and temporal changes in linkage effects can skew approaches to estimate demographic and selective events, future analyses should incorporate BGS predictions and capture local recombination variation across genomes and along lineages.

          Author Summary

          The removal of deleterious mutations from natural populations has potential consequences on patterns of variation across genomes. Population genetic analyses, however, often assume that such effects are negligible across recombining regions of species like Drosophila. We use simple models of purifying selection and current knowledge of recombination rates and gene distribution across the genome to obtain a baseline of variation predicted by the constant input and removal of deleterious mutations. We find that purifying selection alone can explain a major fraction of the observed variance in nucleotide diversity across the genome. The use of a baseline of variation predicted by linkage to deleterious mutations as null expectation exposes genomic regions under other selective regimes, including more regions showing the signature of balancing selection than would be evident when using traditional approaches. Our study also indicates that most, if not all, nucleotides across the D. melanogaster genome are significantly influenced by the removal of deleterious mutations, even when located in the middle of highly recombining regions and distant from genes. Additionally, the study of rates of protein evolution confirms previous analyses suggesting that the recombination landscape across the genome has changed in the recent history of D. melanogaster. All these reported factors can skew current analyses designed to capture demographic events or estimate the strength and frequency of adaptive mutations, and illustrate the need for new and more realistic theoretical and modeling approaches to study naturally occurring genetic variation.

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          The hitch-hiking effect of a favourable gene.

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            Soft sweeps: molecular population genetics of adaptation from standing genetic variation.

            A population can adapt to a rapid environmental change or habitat expansion in two ways. It may adapt either through new beneficial mutations that subsequently sweep through the population or by using alleles from the standing genetic variation. We use diffusion theory to calculate the probabilities for selective adaptations and find a large increase in the fixation probability for weak substitutions, if alleles originate from the standing genetic variation. We then determine the parameter regions where each scenario-standing variation vs. new mutations-is more likely. Adaptations from the standing genetic variation are favored if either the selective advantage is weak or the selection coefficient and the mutation rate are both high. Finally, we analyze the probability of "soft sweeps," where multiple copies of the selected allele contribute to a substitution, and discuss the consequences for the footprint of selection on linked neutral variation. We find that soft sweeps with weaker selective footprints are likely under both scenarios if the mutation rate and/or the selection coefficient is high.
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              The effect of deleterious mutations on neutral molecular variation.

              Selection against deleterious alleles maintained by mutation may cause a reduction in the amount of genetic variability at linked neutral sites. This is because a new neutral variant can only remain in a large population for a long period of time if it is maintained in gametes that are free of deleterious alleles, and hence are not destined for rapid elimination from the population by selection. Approximate formulas are derived for the reduction below classical neutral values resulting from such background selection against deleterious mutations, for the mean times to fixation and loss of new mutations, nucleotide site diversity, and number of segregating sites. These formulas apply to random-mating populations with no genetic recombination, and to populations reproducing exclusively asexually or by self-fertilization. For a given selection regime and mating system, the reduction is an exponential function of the total mutation rate to deleterious mutations for the section of the genome involved. Simulations show that the effect decreases rapidly with increasing recombination frequency or rate of outcrossing. The mean time to loss of new neutral mutations and the total number of segregating neutral sites are less sensitive to background selection than the other statistics, unless the population size is of the order of a hundred thousand or more. The stationary distribution of allele frequencies at the neutral sites is correspondingly skewed in favor of rare alleles, compared with the classical neutral result. Observed reductions in molecular variation in low recombination genomic regions of sufficiently large size, for instance in the centromere-proximal regions of Drosophila autosomes or in highly selfing plant populations, may be partly due to background selection against deleterious mutations.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                June 2014
                26 June 2014
                : 10
                : 6
                : e1004434
                Affiliations
                [1 ]Department of Biology, University of Iowa, Iowa City, Iowa, United States of America
                [2 ]Interdisciplinary Program in Genetics, University of Iowa, Iowa City, Iowa, United States of America
                University of California Davis, United States of America
                Author notes

                The author has declared that no competing interests exist.

                Conceived and designed the experiments: JMC. Performed the experiments: JMC. Analyzed the data: JMC. Contributed reagents/materials/analysis tools: JMC. Wrote the paper: JMC.

                Article
                PGENETICS-D-13-02693
                10.1371/journal.pgen.1004434
                4072542
                24968283
                0a5042c3-60f9-4c0a-865c-5d6cbd743b8c
                Copyright @ 2014

                Comeron. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 1 October 2013
                : 28 April 2014
                Page count
                Pages: 18
                Funding
                This research was funded by US National Institutes of Health grant RC2GM092501 and National Science Foundation grant DEB1354921. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Evolutionary Biology
                Evolutionary Processes
                Genetic Drift
                Natural Selection
                Evolutionary Genetics
                Evolutionary Theory
                Population Genetics
                Organisms
                Animals
                Invertebrates
                Arthropoda
                Insects
                Drosophila
                Drosophila Melanogaster

                Genetics
                Genetics

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