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      PoPoolation: A Toolbox for Population Genetic Analysis of Next Generation Sequencing Data from Pooled Individuals

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          Abstract

          Recent statistical analyses suggest that sequencing of pooled samples provides a cost effective approach to determine genome-wide population genetic parameters. Here we introduce PoPoolation, a toolbox specifically designed for the population genetic analysis of sequence data from pooled individuals. PoPoolation calculates estimates of θ Watterson, θ π, and Tajima's D that account for the bias introduced by pooling and sequencing errors, as well as divergence between species. Results of genome-wide analyses can be graphically displayed in a sliding window plot. PoPoolation is written in Perl and R and it builds on commonly used data formats. Its source code can be downloaded from http://code.google.com/p/popoolation/. Furthermore, we evaluate the influence of mapping algorithms, sequencing errors, and read coverage on the accuracy of population genetic parameter estimates from pooled data.

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          Most cited references11

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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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            A test of neutral molecular evolution based on nucleotide data.

            The neutral theory of molecular evolution predicts that regions of the genome that evolve at high rates, as revealed by interspecific DNA sequence comparisons, will also exhibit high levels of polymorphism within species. We present here a conservative statistical test of this prediction based on a constant-rate neutral model. The test requires data from an interspecific comparison of at least two regions of the genome and data on levels of intraspecific polymorphism in the same regions from at least one species. The model is rejected for data from the region encompassing the Adh locus and the 5' flanking sequence of Drosophila melanogaster and Drosophila sechellia. The data depart from the model in a direction that is consistent with the presence of balanced polymorphism in the coding region.
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              Levels of naturally occurring DNA polymorphism correlate with recombination rates in D. melanogaster.

              Two genomic regions with unusually low recombination rates in Drosophila melanogaster have normal levels of divergence but greatly reduced nucleotide diversity, apparently resulting from the fixation of advantageous mutations and the associated hitch-hiking effect. Here we show that for 20 gene regions from across the genome, the amount of nucleotide diversity in natural populations of D. melanogaster is positively correlated with the regional rate of recombination. This cannot be explained by variation in mutation rates and/or functional constraint, because we observe no correlation between recombination rates and DNA sequence divergence between D. melanogaster and its sibling species, D. simulans. We suggest that the correlation may result from genetic hitch-hiking associated with the fixation of advantageous mutants. Hitch-hiking thus seems to occur over a large fraction of the Drosophila genome and may constitute a major constraint on levels of genetic variation in nature.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                6 January 2011
                : 6
                : 1
                : e15925
                Affiliations
                [1 ]Institute of Population Genetics, Vetmeduni Vienna, Vienna, Austria
                [2 ]Department of Statistics, University of Vienna, Vienna, Austria
                Erasmus University Medical Center, Netherlands
                Author notes

                Conceived and designed the experiments: CS CK. Performed the experiments: VN RK. Analyzed the data: PO-t RK RVP NDM. Contributed reagents/materials/analysis tools: AF. Wrote the paper: CS. Read and approved the final manuscript: RK PO-t NDM RVP VN AF CK CS.

                Article
                PONE-D-10-01734
                10.1371/journal.pone.0015925
                3017084
                21253599
                a77dab5d-c182-4807-87b8-090fc583023b
                Kofler et al. 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
                : 7 September 2010
                : 30 November 2010
                Page count
                Pages: 9
                Categories
                Research Article
                Biology
                Computational Biology
                Population Genetics
                Gene Pool
                Genetic Drift
                Genetic Polymorphism
                Natural Selection
                Sequence Analysis
                Evolutionary Biology
                Population Genetics
                Gene Pool
                Genetic Drift
                Genetic Polymorphism
                Natural Selection
                Evolutionary Genetics
                Genomics
                Genome Analysis Tools
                Genome Scans
                Computer Science
                Software Engineering
                Software Tools

                Uncategorized
                Uncategorized

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