Genome-Wide Inference of Ancestral Recombination Graphs
Publication Date
May 15, 2014
Journal
PLOS Genetics
Authors
Matthew D. Rasmussen, Melissa J. Hubisz, Ilan Gronau & Adam Siepel
Volume
10
Issue
5
Pages
e1004342
DOI
http://doi.org/10.1371/journal.pgen.1004342
Publisher URL
http://journals.plos.org/plosgenetics/article?id=10.1371%2Fjournal.pgen.1004342
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/24831947
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022496
Europe PMC
http://europepmc.org/abstract/MED/24831947
Web of Science
000337145100040
Scopus
84901640930
Mendeley
http://www.mendeley.com/research/genomewide-inference-ancestral-recombination-graphs-1
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Mendeley | Further Information

{"title"=>"Genome-Wide Inference of Ancestral Recombination Graphs", "type"=>"journal", "authors"=>[{"first_name"=>"Matthew D.", "last_name"=>"Rasmussen", "scopus_author_id"=>"22980672500"}, {"first_name"=>"Melissa J.", "last_name"=>"Hubisz", "scopus_author_id"=>"55397727300"}, {"first_name"=>"Ilan", "last_name"=>"Gronau", "scopus_author_id"=>"36625164700"}, {"first_name"=>"Adam", "last_name"=>"Siepel", "scopus_author_id"=>"6701428520"}], "year"=>2014, "source"=>"PLoS Genetics", "identifiers"=>{"isbn"=>"1553-7404", "doi"=>"10.1371/journal.pgen.1004342", "pui"=>"373197051", "sgr"=>"84901640930", "arxiv"=>"q-bio.PE/1306.5110", "scopus"=>"2-s2.0-84901640930", "pmid"=>"24831947", "issn"=>"15537404"}, "id"=>"b671e356-85ee-30a1-b789-519218b47cb2", "abstract"=>"The complex correlation structure of a collection of orthologous DNA sequences is uniquely captured by the \"ancestral recombination graph\" (ARG), a complete record of coalescence and recombination events in the history of the sample. However, existing methods for ARG inference are computationally intensive, highly approximate, or limited to small numbers of sequences, and, as a consequence, explicit ARG inference is rarely used in applied population genomics. Here, we introduce a new algorithm for ARG inference that is efficient enough to apply to dozens of complete mammalian genomes. The key idea of our approach is to sample an ARG of [Formula: see text] chromosomes conditional on an ARG of [Formula: see text] chromosomes, an operation we call \"threading.\" Using techniques based on hidden Markov models, we can perform this threading operation exactly, up to the assumptions of the sequentially Markov coalescent and a discretization of time. An extension allows for threading of subtrees instead of individual sequences. Repeated application of these threading operations results in highly efficient Markov chain Monte Carlo samplers for ARGs. We have implemented these methods in a computer program called ARGweaver. Experiments with simulated data indicate that ARGweaver converges rapidly to the posterior distribution over ARGs and is effective in recovering various features of the ARG for dozens of sequences generated under realistic parameters for human populations. In applications of ARGweaver to 54 human genome sequences from Complete Genomics, we find clear signatures of natural selection, including regions of unusually ancient ancestry associated with balancing selection and reductions in allele age in sites under directional selection. The patterns we observe near protein-coding genes are consistent with a primary influence from background selection rather than hitchhiking, although we cannot rule out a contribution from recurrent selective sweeps.", "link"=>"http://www.mendeley.com/research/genomewide-inference-ancestral-recombination-graphs-1", "reader_count"=>186, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>12, "Researcher"=>52, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>64, "Student > Postgraduate"=>8, "Student > Master"=>17, "Other"=>4, "Student > Bachelor"=>11, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>11}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>12, "Researcher"=>52, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>64, "Student > Postgraduate"=>8, "Student > Master"=>17, "Other"=>4, "Student > Bachelor"=>11, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>11}, "reader_count_by_subject_area"=>{"Unspecified"=>5, "Environmental Science"=>3, "Biochemistry, Genetics and Molecular Biology"=>19, "Mathematics"=>8, "Agricultural and Biological Sciences"=>132, "Medicine and Dentistry"=>5, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Computer Science"=>13}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>5}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>132}, "Computer Science"=>{"Computer Science"=>13}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>19}, "Mathematics"=>{"Mathematics"=>8}, "Unspecified"=>{"Unspecified"=>5}, "Environmental Science"=>{"Environmental Science"=>3}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Austria"=>1, "Sweden"=>1, "United States"=>22, "Brazil"=>3, "United Kingdom"=>4, "France"=>2, "Portugal"=>3, "Germany"=>2}, "group_count"=>2}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1500004"], "description"=>"a<p>Genomic coordinates in hg19 assembly.</p>b<p>Posterior expected TMRCA in generations, averaged across unfiltered genomic positions in region.</p>c<p>Number of polymorphisms in Complete Genomics dataset in region per kilobase of unfiltered sequence.</p>d<p>Normalized polymorphism rate: number of polymorphisms per unfiltered kilobase divided first by the local mutation rate (as estimated from divergence to nonhuman primate outgroup genomes) then by the average of the same polymorphism/divergence ratio in designated neutral regions (see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004342#s4\" target=\"_blank\">Methods</a>). The resulting value can be interpreted as a fold increase in the mutation-normalized polymorphism rate compared with the expectation under neutrality.</p>e<p>Possible copy number variant (CNV), based on Complete Genomics “hypervariable” or “invariant” labels (see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004342#s4\" target=\"_blank\">Methods</a>). Polymorphism rates in these regions may be inflated. Few of these regions were identified in the Leffler et al. data set, probably because the authors were careful to filter out duplicated regions from their analysis <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004342#pgen.1004342-Leffler1\" target=\"_blank\">[77]</a>.</p>", "links"=>[], "tags"=>["Computational biology", "genome analysis", "Genome scans", "Evolutionary modeling", "ecology", "Ecological metrics", "Population size", "Effective population size", "Evolutionary biology", "Evolutionary processes", "Genetic drift", "natural selection", "population genetics", "Gene flow", "Genetic polymorphism", "haplotypes", "neutral theory", "genetics", "genomics", "Human genetics", "mutation", "mathematics", "Statistics (mathematics)", "Biostatistics", "regions"], "article_id"=>1028597, "categories"=>["Biological Sciences"], "users"=>["Matthew D. Rasmussen", "Melissa J. Hubisz", "Ilan Gronau", "Adam Siepel"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004342.t003", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Top_twenty_regions_of_shared_human_chimpanzee_haplotypes_by_estimated_TMRCA_/1028597", "title"=>"Top twenty regions of shared human/chimpanzee haplotypes by estimated TMRCA.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-05-15 03:59:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/1500003"], "description"=>"a<p>Genomic coordinates in hg19 assembly. The genome was simply partitioned into nonoverlapping 10 kb intervals in hg19 coordinates.</p>b<p>Posterior expected TMRCA in generations, averaged across unfiltered genomic positions in region.</p>c<p>Number of polymorphisms in Complete Genomics dataset in region per kilobase of unfiltered sequence.</p>d<p>Normalized polymorphism rate: number of polymorphisms per unfiltered kilobase divided first by the local mutation rate (as estimated from divergence to nonhuman primate outgroup genomes) then by the average of the same polymorphism/divergence ratio in designated neutral regions. The resulting value can be interpreted as a fold increase in the mutation-normalized polymorphism rate compared with the expectation under neutrality. The same measure was computed from the much larger 1000 Genomes Project Phase 1 data set, and was significantly elevated in these 20 high-TMRCA regions (Supplementary <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004342#pgen.1004342.s013\" target=\"_blank\">Figure S13</a>).</p>e<p>Possible copy number variant (CNV), based on Complete Genomics “hypervariable” or “invariant” labels (see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004342#s4\" target=\"_blank\">Methods</a>). Polymorphism rates in these regions may be over-estimated.</p>", "links"=>[], "tags"=>["Computational biology", "genome analysis", "Genome scans", "Evolutionary modeling", "ecology", "Ecological metrics", "Population size", "Effective population size", "Evolutionary biology", "Evolutionary processes", "Genetic drift", "natural selection", "population genetics", "Gene flow", "Genetic polymorphism", "haplotypes", "neutral theory", "genetics", "genomics", "Human genetics", "mutation", "mathematics", "Statistics (mathematics)", "Biostatistics", "10", "kb", "regions", "genome"], "article_id"=>1028596, "categories"=>["Biological Sciences"], "users"=>["Matthew D. Rasmussen", "Melissa J. Hubisz", "Ilan Gronau", "Adam Siepel"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004342.t002", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Top_twenty_10_kb_regions_in_the_human_genome_by_estimated_TMRCA_/1028596", "title"=>"Top twenty 10 kb regions in the human genome by estimated TMRCA.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-05-15 03:59:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/1500000"], "description"=>"<p>(A) Recovery of global features of simulated ARGs from sequence data. This plot is based on sets of 20 1-Mb sequences generated under our standard simulation parameters (see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004342#s4\" target=\"_blank\">Methods</a>) with (see Supplementary Figure 10 for additional results). From left to right are shown true (-axis) versus inferred (-axis) values of the log joint probability (the logarithm of <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004342#pgen.1004342.e196\" target=\"_blank\">equation 2</a>), the total number of recombinations, and the total branch length of the ARG. Each data point in each plot represents one of 100 simulated data sets. In the vertical dimension, circles represent averages across 100 sampled ARGs based on the corresponding data sets, sampled at intervals of 10 after a burn-in of 200 iterations, and error bars represent the interval between the 2.5 and 97.5 percentiles. In the second and third plots, circles are interpretable as posterior expected values and error bars as 95% Bayesian credible intervals. (B) Posterior mean TMRCA (dark red line, with 95% credible intervals in light red) versus true TMRCA (black line) along a simulated genomic segment of 1 Mb. This plot is based on a single representative data set of 20 1-Mb sequences generated under our standard simulation parameters with (see Supplementary <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004342#pgen.1004342.s005\" target=\"_blank\">Figure S5</a> for additional results).</p>", "links"=>[], "tags"=>["Computational biology", "genome analysis", "Genome scans", "Evolutionary modeling", "ecology", "Ecological metrics", "Population size", "Effective population size", "Evolutionary biology", "Evolutionary processes", "Genetic drift", "natural selection", "population genetics", "Gene flow", "Genetic polymorphism", "haplotypes", "neutral theory", "genetics", "genomics", "Human genetics", "mutation", "mathematics", "Statistics (mathematics)", "Biostatistics"], "article_id"=>1028593, "categories"=>["Biological Sciences"], "users"=>["Matthew D. Rasmussen", "Melissa J. Hubisz", "Ilan Gronau", "Adam Siepel"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004342.g004", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Simulation_results_/1028593", "title"=>"Simulation results.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-15 03:59:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/1499998"], "description"=>"<p>The threading operation adds an th sequence to an ARG of sequences under a discretized version of the SMC (the DSMC) that requires all coalescence and recombination events to occur precisely at pre-defined time points, (horizontal dashed lines). In this example, the fourth sequence has been removed from ARG from <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004342#pgen-1004342-g001\" target=\"_blank\">Figure 1</a>, leaving a tree with leaves at each position (; shown in black). The fourth sequence (shown in red) is re-threaded through the remaining portion of the ARG by a two-step process that first samples a coalescence point for this sequence at each (dark blue points), thereby defining a new tree , and second, samples a recombination point to reconcile each adjacent pair of trees, (light blue points). For simplicity, only the distinct local trees for the four nonrecombining segments (after threading) are shown. The gray box highlights the pair of trees immediately flanking the breakpoint . Notice that the first recombination from <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004342#pgen-1004342-g001\" target=\"_blank\">Figure 1</a> is retained (dark gray nodes and dashed line in left-most tree). In general, new recombinations are prohibited at the locations of “given” recombinations (see text). Note that it is possible for the attachment point of the th sequence in the local trees to move due to old recombinations as well as new ones (not shown in this example).</p>", "links"=>[], "tags"=>["Computational biology", "genome analysis", "Genome scans", "Evolutionary modeling", "ecology", "Ecological metrics", "Population size", "Effective population size", "Evolutionary biology", "Evolutionary processes", "Genetic drift", "natural selection", "population genetics", "Gene flow", "Genetic polymorphism", "haplotypes", "neutral theory", "genetics", "genomics", "Human genetics", "mutation", "mathematics", "Statistics (mathematics)", "Biostatistics"], "article_id"=>1028591, "categories"=>["Biological Sciences"], "users"=>["Matthew D. Rasmussen", "Melissa J. Hubisz", "Ilan Gronau", "Adam Siepel"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004342.g002", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_8220_threading_8221_operation_/1028591", "title"=>"The “threading” operation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-15 03:59:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/1499999"], "description"=>"<p>(A) Full DSMC model for samples with local trees, , recombinations, , and alignment columns, . Together, and define an ancestral recombination graph, . Solid circles indicate observed variables and empty circles indicate latent variables. Arrows indicate direct dependencies between variables and correspond to conditional probability distributions described in the text. Notice that the variables can be integrated out of this model, leading to the conventional graph topology for a hidden Markov model. (B) The same model as in (A), but now partitioning the latent variables into components that describe the history of the first sequences ( and ) and components specific to the th sequence ( and ). The and variables are represented by solid circles because they are now “clamped” at specific values. A sample of represents a threading of the th sequence through the ARG. (C) Reduced model after elimination of by integration, enabling efficient sampling of coalescent threadings . This is the model used by the first step in our two-step sampling approach. In the second step, the variables are sampled conditional on , separately for each . In this model, the grouped nodes have complex joint dependencies, leading to a heterogeneous state space and normalization structure, but the linear conditional independence structure of an HMM is retained.</p>", "links"=>[], "tags"=>["Computational biology", "genome analysis", "Genome scans", "Evolutionary modeling", "ecology", "Ecological metrics", "Population size", "Effective population size", "Evolutionary biology", "Evolutionary processes", "Genetic drift", "natural selection", "population genetics", "Gene flow", "Genetic polymorphism", "haplotypes", "neutral theory", "genetics", "genomics", "Human genetics", "mutation", "mathematics", "Statistics (mathematics)", "Biostatistics", "discretized", "sequentially", "markov", "coalescent"], "article_id"=>1028592, "categories"=>["Biological Sciences"], "users"=>["Matthew D. Rasmussen", "Melissa J. Hubisz", "Ilan Gronau", "Adam Siepel"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004342.g003", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Graphical_models_for_Discretized_Sequentially_Markov_Coalescent_DSMC_models_/1028592", "title"=>"Graphical models for Discretized Sequentially Markov Coalescent (DSMC) models.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-15 03:59:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/1499997"], "description"=>"<p>(A) Going backwards in time (from bottom to top), the graph shows how lineages that lead to modern-day chromosomes (bottom) either “coalesce” into common ancestral lineages (dark blue circles), or split into the distinct parental chromosomes that were joined (in forward time) by recombination events (light blue circles). Each coalescence and recombination event is associated with a specific time (dashed lines), and each recombination event is also associated with a specific breakpoint along the chromosomes (here, and ). Each non-recombining interval of the sequences (shown in red, green, and purple) corresponds to a “local tree” embedded in the ARG (shown in matching colors). Recombinations cause these trees to change along the length of the sequences, making the correlation structure of the data set highly complex. The ARG for four sequences is denoted in our notation. (B) Representation of in terms of a sequence of local trees and recombination events . A local tree is shown for each nonrecombining segment in colors matching those in (A). Each tree, , can be viewed as being constructed from the previous tree, , by placing a recombination event along the branches of (light blue circles), breaking the branch at this location, and then allowing the broken lineage to re-coalesce to the rest of the tree (dashed lines in matching colors; new coalescence points are shown in gray). Together, the local trees and recombinations provide a complete description of the ARG. The Sequentially Markov Coalescent (SMC) approximate the full coalescent-with-recombination by assuming that is statistically independent of all previous trees given . (C) An alignment of four sequences, , corresponding to the linearized ARG shown in (B). For simplicity, only the derived alleles at polymorphic sites are shown. The sequences are assumed to be generated by a process that samples an ancestral sequences from a suitable background distribution, then allows each nonrecombining segment of this sequence to mutate stochastically along the branches of the corresponding local tree. Notice that the correlation structure of the sequences is fully determined by the local trees; that is, is conditionally independent of the recombinations given the local trees .</p>", "links"=>[], "tags"=>["Computational biology", "genome analysis", "Genome scans", "Evolutionary modeling", "ecology", "Ecological metrics", "Population size", "Effective population size", "Evolutionary biology", "Evolutionary processes", "Genetic drift", "natural selection", "population genetics", "Gene flow", "Genetic polymorphism", "haplotypes", "neutral theory", "genetics", "genomics", "Human genetics", "mutation", "mathematics", "Statistics (mathematics)", "Biostatistics", "ancestral", "recombination", "graph"], "article_id"=>1028590, "categories"=>["Biological Sciences"], "users"=>["Matthew D. Rasmussen", "Melissa J. Hubisz", "Ilan Gronau", "Adam Siepel"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004342.g001", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_An_ancestral_recombination_graph_ARG_for_four_sequences_/1028590", "title"=>"An ancestral recombination graph (ARG) for four sequences.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-15 03:59:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/1500026", "https://ndownloader.figshare.com/files/1500028", "https://ndownloader.figshare.com/files/1500030", "https://ndownloader.figshare.com/files/1500032", "https://ndownloader.figshare.com/files/1500034", "https://ndownloader.figshare.com/files/1500036", "https://ndownloader.figshare.com/files/1500038", "https://ndownloader.figshare.com/files/1500040", "https://ndownloader.figshare.com/files/1500041", "https://ndownloader.figshare.com/files/1500042", "https://ndownloader.figshare.com/files/1500044", "https://ndownloader.figshare.com/files/1500045", "https://ndownloader.figshare.com/files/1500046", "https://ndownloader.figshare.com/files/1500047", "https://ndownloader.figshare.com/files/1500048", "https://ndownloader.figshare.com/files/1500049", "https://ndownloader.figshare.com/files/1500050", "https://ndownloader.figshare.com/files/1500051", "https://ndownloader.figshare.com/files/1500052", "https://ndownloader.figshare.com/files/1500053", "https://ndownloader.figshare.com/files/1500054", "https://ndownloader.figshare.com/files/1500055"], "description"=>"<div><p>The complex correlation structure of a collection of orthologous DNA sequences is uniquely captured by the “ancestral recombination graph” (ARG), a complete record of coalescence and recombination events in the history of the sample. However, existing methods for ARG inference are computationally intensive, highly approximate, or limited to small numbers of sequences, and, as a consequence, explicit ARG inference is rarely used in applied population genomics. Here, we introduce a new algorithm for ARG inference that is efficient enough to apply to dozens of complete mammalian genomes. The key idea of our approach is to sample an ARG of chromosomes conditional on an ARG of chromosomes, an operation we call “threading.” Using techniques based on hidden Markov models, we can perform this threading operation exactly, up to the assumptions of the sequentially Markov coalescent and a discretization of time. An extension allows for threading of subtrees instead of individual sequences. Repeated application of these threading operations results in highly efficient Markov chain Monte Carlo samplers for ARGs. We have implemented these methods in a computer program called <i>ARGweaver</i>. Experiments with simulated data indicate that <i>ARGweaver</i> converges rapidly to the posterior distribution over ARGs and is effective in recovering various features of the ARG for dozens of sequences generated under realistic parameters for human populations. In applications of <i>ARGweaver</i> to 54 human genome sequences from Complete Genomics, we find clear signatures of natural selection, including regions of unusually ancient ancestry associated with balancing selection and reductions in allele age in sites under directional selection. The patterns we observe near protein-coding genes are consistent with a primary influence from background selection rather than hitchhiking, although we cannot rule out a contribution from recurrent selective sweeps.</p></div>", "links"=>[], "tags"=>["Computational biology", "genome analysis", "Genome scans", "Evolutionary modeling", "ecology", "Ecological metrics", "Population size", "Effective population size", "Evolutionary biology", "Evolutionary processes", "Genetic drift", "natural selection", "population genetics", "Gene flow", "Genetic polymorphism", "haplotypes", "neutral theory", "genetics", "genomics", "Human genetics", "mutation", "mathematics", "Statistics (mathematics)", "Biostatistics", "inference", "ancestral", "recombination"], "article_id"=>1028600, "categories"=>["Biological Sciences"], "users"=>["Matthew D. Rasmussen", "Melissa J. Hubisz", "Ilan Gronau", "Adam Siepel"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004342.s001", "https://dx.doi.org/10.1371/journal.pgen.1004342.s002", "https://dx.doi.org/10.1371/journal.pgen.1004342.s003", "https://dx.doi.org/10.1371/journal.pgen.1004342.s004", "https://dx.doi.org/10.1371/journal.pgen.1004342.s005", "https://dx.doi.org/10.1371/journal.pgen.1004342.s006", "https://dx.doi.org/10.1371/journal.pgen.1004342.s007", "https://dx.doi.org/10.1371/journal.pgen.1004342.s008", "https://dx.doi.org/10.1371/journal.pgen.1004342.s009", "https://dx.doi.org/10.1371/journal.pgen.1004342.s010", "https://dx.doi.org/10.1371/journal.pgen.1004342.s011", "https://dx.doi.org/10.1371/journal.pgen.1004342.s012", "https://dx.doi.org/10.1371/journal.pgen.1004342.s013", "https://dx.doi.org/10.1371/journal.pgen.1004342.s014", "https://dx.doi.org/10.1371/journal.pgen.1004342.s015", "https://dx.doi.org/10.1371/journal.pgen.1004342.s016", "https://dx.doi.org/10.1371/journal.pgen.1004342.s017", "https://dx.doi.org/10.1371/journal.pgen.1004342.s018", "https://dx.doi.org/10.1371/journal.pgen.1004342.s019", "https://dx.doi.org/10.1371/journal.pgen.1004342.s020", "https://dx.doi.org/10.1371/journal.pgen.1004342.s021", "https://dx.doi.org/10.1371/journal.pgen.1004342.s022"], "stats"=>{"downloads"=>91, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Genome_Wide_Inference_of_Ancestral_Recombination_Graphs_/1028600", "title"=>"Genome-Wide Inference of Ancestral Recombination Graphs", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-05-15 03:59:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/1500005"], "description"=>"a<p>Model allows for a separate for each time interval l but all analyses in this paper assume a constant across time intervals.</p>", "links"=>[], "tags"=>["Computational biology", "genome analysis", "Genome scans", "Evolutionary modeling", "ecology", "Ecological metrics", "Population size", "Effective population size", "Evolutionary biology", "Evolutionary processes", "Genetic drift", "natural selection", "population genetics", "Gene flow", "Genetic polymorphism", "haplotypes", "neutral theory", "genetics", "genomics", "Human genetics", "mutation", "mathematics", "Statistics (mathematics)", "Biostatistics"], "article_id"=>1028598, "categories"=>["Biological Sciences"], "users"=>["Matthew D. Rasmussen", "Melissa J. Hubisz", "Ilan Gronau", "Adam Siepel"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004342.t001", "stats"=>{"downloads"=>5, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Key_to_notation_/1028598", "title"=>"Key to notation.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-05-15 03:59:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/1500002"], "description"=>"<p>(A) Estimated age of derived allele in generations, averaged across polymorphic sites of various annotation classes. Estimates were derived from ARGs sampled by <i>ARGweaver</i> based on the Complete Genomics data set (see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004342#s4\" target=\"_blank\">Methods</a>). Error bars represent one standard deviation above and below the mean. Neut = putatively neutral sites; 4d = fourfold degenerate sites in coding regions; CNS = conserved noncoding sequences identified by phastCons; PPh:{Benign,PosDam,ProbDam} = missense mutations identified by PolyPhen-2 as “benign”, “possibly damaging”, or “probably damaging”, respectively; CV:{NonPath,Path} = mutations in “nonpathogenic” (categories 1–3) or “pathogenic” (categories 4 & 5) classes in the ClinVar database, respectively. (B) Similar plot with categories further divided by derived allele frequencies (DAF) in numbers of chromosomes out of 108. Error bars represent 95% confidence intervals, as assessed by bootstrapping. In categories that combine multiple frequencies (e.g., 4–5, 6–8), a subsampling strategy was used to ensure that the relative contributions of the different frequencies matched those of the Neut class. Estimates for DAF>20 were excluded due to sparse data. Notice that ages generally increase with DAF, as expected (see Supplementary <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004342#pgen.1004342.s007\" target=\"_blank\">Figure S7</a>), but at a considerably reduced rate in categories under strong selection.</p>", "links"=>[], "tags"=>["Computational biology", "genome analysis", "Genome scans", "Evolutionary modeling", "ecology", "Ecological metrics", "Population size", "Effective population size", "Evolutionary biology", "Evolutionary processes", "Genetic drift", "natural selection", "population genetics", "Gene flow", "Genetic polymorphism", "haplotypes", "neutral theory", "genetics", "genomics", "Human genetics", "mutation", "mathematics", "Statistics (mathematics)", "Biostatistics", "allele", "annotation", "derived"], "article_id"=>1028595, "categories"=>["Biological Sciences"], "users"=>["Matthew D. Rasmussen", "Melissa J. Hubisz", "Ilan Gronau", "Adam Siepel"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004342.g006", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mean_allele_age_as_a_function_of_annotation_class_and_derived_allele_frequency_/1028595", "title"=>"Mean allele age as a function of annotation class and derived allele frequency.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-15 03:59:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/1500001"], "description"=>"<p>Shown (from top to bottom) are nucleotide diversity (), time to most recent common ancestry (TMRCA), and relative TMRCA halflife (RTH) for the 13 individuals (26 haploid genomes) of European descent (CEU and TSI populations) in the Complete Genomics data set (similar plots for African population are shown in Supplementary <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004342#pgen.1004342.s011\" target=\"_blank\">Figure S11</a>). Nucleotide diversity was computed as the average rate of nucleotide differences per site across all pairs of chromosomes, whereas sitewise values of the TMRCA and RTH were computed by averaging over local trees sampled by <i>ARGweaver</i>. (A) Estimates for 17,845 protein-coding genes from the Consensus Coding Sequence (CCDS) track in the UCSC Genome Browser (hg19). Estimates for noncoding regions were computed by averaging in a sliding window of size 300 bp then averaging across genes. Estimates for coding exons were computed by first averaging over fourfold degenerate (4d) sites of each exonic type (first, middle, last), then averaging across genes (see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004342#s4\" target=\"_blank\">Methods</a>). Only 4d sites were considered to focus on the influence of selection from linked sites rather than direct selection. Nevertheless, the decreased values for the exons suggest some influence from direct selection. The differences between exons and flanking sites may also be influenced by windowing in the noncoding regions. “First exon” is taken to begin at the annotated start codon and “last exon” to end at the stop codon, so that both exclude untranslated regions. The TMRCA is measured in thousands of generations. RTH is ratio of the time required for the first 50% of lineages to find a most recent common ancestor to the full TMRCA (see Supplementary <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004342#pgen.1004342.s010\" target=\"_blank\">Figure S10</a>). Error bars (dashed lines for noncoding regions) indicate 95% confidence intervals as estimated by bootstrapping over regions. (B) Similar plots for 255 100-kb regions predicted to have undergone partial selective sweeps in the CEU population based on the iHS statistic <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004342#pgen.1004342-Voight2\" target=\"_blank\">[72]</a>. In this case, all measures are computed in a sliding window of 10,000 bases. Notice that both protein-coding genes and putative selective sweeps display substantial reductions in nucleotide diversity, but the genes show a much more prominent reduction in TMRCA, whereas the sweeps show a much more prominent reduction in RTH. These signatures are consistent with a dominant influence from background selection rather than hitchhiking in protein-coding genes (see text).</p>", "links"=>[], "tags"=>["Computational biology", "genome analysis", "Genome scans", "Evolutionary modeling", "ecology", "Ecological metrics", "Population size", "Effective population size", "Evolutionary biology", "Evolutionary processes", "Genetic drift", "natural selection", "population genetics", "Gene flow", "Genetic polymorphism", "haplotypes", "neutral theory", "genetics", "genomics", "Human genetics", "mutation", "mathematics", "Statistics (mathematics)", "Biostatistics", "protein-coding", "genes", "selective"], "article_id"=>1028594, "categories"=>["Biological Sciences"], "users"=>["Matthew D. Rasmussen", "Melissa J. Hubisz", "Ilan Gronau", "Adam Siepel"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004342.g005", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Measures_of_genetic_variation_near_protein_coding_genes_and_partial_selective_sweeps_/1028594", "title"=>"Measures of genetic variation near protein-coding genes and partial selective sweeps.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-15 03:59:23"}

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Relative Metric

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