A Likelihood-Based Framework for Variant Calling and De Novo Mutation Detection in Families
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{"title"=>"A Likelihood-Based Framework for Variant Calling and De Novo Mutation Detection in Families", "type"=>"journal", "authors"=>[{"first_name"=>"Bingshan", "last_name"=>"Li", "scopus_author_id"=>"23479764000"}, {"first_name"=>"Wei", "last_name"=>"Chen", "scopus_author_id"=>"55574216631"}, {"first_name"=>"Xiaowei", "last_name"=>"Zhan", "scopus_author_id"=>"55849215100"}, {"first_name"=>"Fabio", "last_name"=>"Busonero", "scopus_author_id"=>"36804143600"}, {"first_name"=>"Serena", "last_name"=>"Sanna", "scopus_author_id"=>"16646989300"}, {"first_name"=>"Carlo", "last_name"=>"Sidore", "scopus_author_id"=>"36151309600"}, {"first_name"=>"Francesco", "last_name"=>"Cucca", "scopus_author_id"=>"55029470000"}, {"first_name"=>"Hyun M.", "last_name"=>"Kang", "scopus_author_id"=>"9739748700"}, {"first_name"=>"Gonçalo R.", "last_name"=>"Abecasis", "scopus_author_id"=>"56521788900"}], "year"=>2012, "source"=>"PLoS Genetics", "identifiers"=>{"pui"=>"365953651", "doi"=>"10.1371/journal.pgen.1002944", "pmid"=>"23055937", "issn"=>"15537390", "sgr"=>"84868138663", "scopus"=>"2-s2.0-84868138663", "isbn"=>"1553-7404 (Electronic)\\n1553-7390 (Linking)"}, "id"=>"6eaeba5a-bb65-3cde-a4f5-9ee352898d5d", "abstract"=>"Family samples, which can be enriched for rare causal variants by focusing on families with multiple extreme individuals and which facilitate detection of de novo mutation events, provide an attractive resource for next-generation sequencing studies. Here, we describe, implement, and evaluate a likelihood-based framework for analysis of next generation sequence data in family samples. Our framework is able to identify variant sites accurately and to assign individual genotypes, and can handle de novo mutation events, increasing the sensitivity and specificity of variant calling and de novo mutation detection. Through simulations we show explicit modeling of family relationships is especially useful for analyses of low-frequency variants and that genotype accuracy increases with the number of individuals sequenced per family. Compared with the standard approach of ignoring relatedness, our methods identify and accurately genotype more variants, and have high specificity for detecting de novo mutation events. The improvement in accuracy using our methods over the standard approach is particularly pronounced for low-frequency variants. Furthermore the family-aware calling framework dramatically reduces Mendelian inconsistencies and is beneficial for family-based analysis. We hope our framework and software will facilitate continuing efforts to identify genetic factors underlying human diseases.", "link"=>"http://www.mendeley.com/research/likelihoodbased-framework-variant-calling-novo-mutation-detection-families", "reader_count"=>130, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>12, "Researcher"=>48, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>36, "Student > Postgraduate"=>4, "Student > Master"=>13, "Other"=>7, "Student > Bachelor"=>1, "Professor"=>5}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>12, "Researcher"=>48, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>36, "Student > Postgraduate"=>4, "Student > Master"=>13, "Other"=>7, "Student > Bachelor"=>1, "Professor"=>5}, "reader_count_by_subject_area"=>{"Engineering"=>2, "Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>16, "Mathematics"=>2, "Agricultural and Biological Sciences"=>83, "Medicine and Dentistry"=>12, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Psychology"=>3, "Computer Science"=>8, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>2}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>12}, "Psychology"=>{"Psychology"=>3}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>83}, "Computer Science"=>{"Computer Science"=>8}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>16}, "Mathematics"=>{"Mathematics"=>2}, "Unspecified"=>{"Unspecified"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"New Zealand"=>2, "Colombia"=>1, "Sweden"=>1, "United States"=>13, "Japan"=>1, "China"=>1, "United Kingdom"=>3, "France"=>1, "Switzerland"=>1, "Germany"=>1, "Spain"=>1}, "group_count"=>9}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/563649"], "description"=>"<p>PolyMutt (ignoring relatedness) and GATK calls were obtained by jointly calling a trio assuming individuals in a trio are unrelated using Polymutt and GATK respectively.</p>", "links"=>[], "tags"=>["curves", "polymutt", "methods", "mutation", "detection", "empirically", "calibrated", "alignments", "simulated", "reads", "sequencing"], "article_id"=>234125, "categories"=>["Genetics"], "users"=>["Bingshan Li", "Wei Chen", "Xiaowei Zhan", "Fabio Busonero", "Serena Sanna", "Carlo Sidore", "Francesco Cucca", "Hyun M. Kang", "Gonçalo R. Abecasis"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002944.g004", "stats"=>{"downloads"=>1, "page_views"=>47, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_receiver_operating_characteristic_ROC_curves_of_PolyMutt_and_the_standard_methods_for_de_novo_mutation_DNM_detection_from_empirically_calibrated_alignments_of_simulated_reads_with_sequencing_coverage_of_30_with_base_quality_of_Q20_/234125", "title"=>"The receiver operating characteristic (ROC) curves of PolyMutt and the standard methods for <i>de novo</i> mutation (DNM) detection from empirically calibrated alignments of simulated reads with sequencing coverage of 30× with base quality of Q20.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 22:09:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/563561"], "description"=>"<p>Panel A) shows the power for trios with base quality Q20 and Q30 and panel B) shows the power comparisons of trios, nuclear families with 2 and 3 siblings, and 3-generation extended pedigrees (shown in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002944#pgen-1002944-g001\" target=\"_blank\">Figure 1</a>) for base quality Q20 without mapping error.</p>", "links"=>[], "tags"=>["detecting", "mutations", "pedigree", "structures"], "article_id"=>234051, "categories"=>["Genetics"], "users"=>["Bingshan Li", "Wei Chen", "Xiaowei Zhan", "Fabio Busonero", "Serena Sanna", "Carlo Sidore", "Francesco Cucca", "Hyun M. Kang", "Gonçalo R. Abecasis"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002944.g003", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Power_of_detecting_de_novo_mutations_DNM_in_different_pedigree_structures_for_coverage_from_5_to_40_/234051", "title"=>"Power of detecting <i>de novo</i> mutations (DNM) in different pedigree structures for coverage from 5× to 40×.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 22:09:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/563788"], "description"=>"<p>For all scenarios 300 sequenced individuals were simulated.</p>", "links"=>[], "tags"=>["non-reference", "genotypes", "variants", "called", "modeling", "ignoring", "relatedness", "sequencing", "phred-scaled", "20", "30"], "article_id"=>234260, "categories"=>["Genetics"], "users"=>["Bingshan Li", "Wei Chen", "Xiaowei Zhan", "Fabio Busonero", "Serena Sanna", "Carlo Sidore", "Francesco Cucca", "Hyun M. Kang", "Gonçalo R. Abecasis"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002944.t001", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Percentage_of_missing_non_reference_genotypes_i_e_false_negatives_per_individual_in_families_for_variants_called_by_joint_modeling_family_data_and_the_standard_approach_of_ignoring_relatedness_for_sequencing_coverage_between_5_215_and_30_215_and_for_inpu/234260", "title"=>"Percentage of missing non-reference genotypes (i.e. false negatives) per individual in families for variants called by joint modeling family data and the standard approach of ignoring relatedness for sequencing coverage between 5× and 30× and for input sequence data with Phred-scaled quality of 20 (error rate of 1% per base) or 30 (error rate of 0.1% per base) without mapping error.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-19 22:10:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/563843"], "description"=>"<p>The mismatch rates are shown for 4 genotype categories: all genotypes (All), homozygous reference allele (HomRef), heterozygotes (Het), and homozygous alternative allele (HomAlt).</p>", "links"=>[], "tags"=>["mismatch", "rates", "structures", "sequencing", "bases", "phred-scaled", "q20", "q30"], "article_id"=>234321, "categories"=>["Genetics"], "users"=>["Bingshan Li", "Wei Chen", "Xiaowei Zhan", "Fabio Busonero", "Serena Sanna", "Carlo Sidore", "Francesco Cucca", "Hyun M. Kang", "Gonçalo R. Abecasis"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002944.t002", "stats"=>{"downloads"=>2, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Genotype_mismatch_rates_for_different_family_structures_with_sequencing_coverage_of_5_215_15_215_and_30_215_and_input_bases_with_Phred_scaled_quality_Q20_1_error_rate_or_Q30_0_1_error_rate_without_mapping_error_/234321", "title"=>"Genotype mismatch rates (%) for different family structures with sequencing coverage of 5×, 15×, and 30× and input bases with Phred-scaled quality Q20 (1% error rate) or Q30 (0.1% error rate) without mapping error.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-19 22:11:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/563722"], "description"=>"<p>Comparisons of two variant callsets from SardiNIA low-pass sequencing data where variant calling was carried out by explicitly modeling family relatedness (family calls) and by the standard approach of ignoring relatedness (standard calls).</p>", "links"=>[], "tags"=>["variant", "callsets", "sardinia", "low-pass", "sequencing", "calling", "was", "carried", "explicitly", "modeling", "relatedness", "ignoring"], "article_id"=>234193, "categories"=>["Genetics"], "users"=>["Bingshan Li", "Wei Chen", "Xiaowei Zhan", "Fabio Busonero", "Serena Sanna", "Carlo Sidore", "Francesco Cucca", "Hyun M. Kang", "Gonçalo R. Abecasis"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002944.g005", "stats"=>{"downloads"=>3, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Comparisons_of_two_variant_callsets_from_SardiNIA_low_pass_sequencing_data_where_variant_calling_was_carried_out_by_explicitly_modeling_family_relatedness_family_calls_and_by_the_standard_approach_of_ignoring_relatedness_standard_calls_/234193", "title"=>"Comparisons of two variant callsets from SardiNIA low-pass sequencing data where variant calling was carried out by explicitly modeling family relatedness (family calls) and by the standard approach of ignoring relatedness (standard calls).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 22:10:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/563939"], "description"=>"<p>Number of false positive <i>de novo</i> mutations per billion bases detected by PolyMutt of jointly modeling for sequencing at coverage 5×–40× with Phred-scaled base quality Q20 (1% error rate) without mapping error in different pedigrees structures.</p>", "links"=>[], "tags"=>["mutations", "bases", "polymutt", "jointly", "modeling", "sequencing", "phred-scaled", "q20", "pedigrees"], "article_id"=>234416, "categories"=>["Genetics"], "users"=>["Bingshan Li", "Wei Chen", "Xiaowei Zhan", "Fabio Busonero", "Serena Sanna", "Carlo Sidore", "Francesco Cucca", "Hyun M. Kang", "Gonçalo R. Abecasis"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002944.t004", "stats"=>{"downloads"=>2, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Number_of_false_positive_de_novo_mutations_per_billion_bases_detected_by_PolyMutt_of_jointly_modeling_for_sequencing_at_coverage_5_40_with_Phred_scaled_base_quality_Q20_1_error_rate_without_mapping_error_in_different_pedigrees_structures_/234416", "title"=>"Number of false positive <i>de novo</i> mutations per billion bases detected by PolyMutt of jointly modeling for sequencing at coverage 5×–40× with Phred-scaled base quality Q20 (1% error rate) without mapping error in different pedigrees structures.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-19 22:11:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/563893"], "description"=>"<p>Mendelian inconsistency rates per triplet (father, mother and offspring) for the genotypes by joint modeling of family data (top panel) and by the standard approach where the relatedness was ignored, i.e. individuals were treated as unrelated (bottom panel) for sequencing coverage of 5× to 30× and bases with Phred-scaled quality Q20 (1% error rate) and 30 (0.1% error rate) without mapping error.</p>", "links"=>[], "tags"=>["inconsistency", "rates", "triplet", "genotypes", "modeling", "relatedness", "was", "individuals", "treated", "unrelated", "sequencing", "bases", "phred-scaled", "q20", "30"], "article_id"=>234365, "categories"=>["Genetics"], "users"=>["Bingshan Li", "Wei Chen", "Xiaowei Zhan", "Fabio Busonero", "Serena Sanna", "Carlo Sidore", "Francesco Cucca", "Hyun M. Kang", "Gonçalo R. Abecasis"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002944.t003", "stats"=>{"downloads"=>3, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mendelian_inconsistency_rates_per_triplet_father_mother_and_offspring_for_the_genotypes_by_joint_modeling_of_family_data_top_panel_and_by_the_standard_approach_where_the_relatedness_was_ignored_i_e_individuals_were_treated_as_unrelated_bottom_panel_for_s/234365", "title"=>"Mendelian inconsistency rates per triplet (father, mother and offspring) for the genotypes by joint modeling of family data (top panel) and by the standard approach where the relatedness was ignored, i.e. individuals were treated as unrelated (bottom panel) for sequencing coverage of 5× to 30× and bases with Phred-scaled quality Q20 (1% error rate) and 30 (0.1% error rate) without mapping error.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-19 22:11:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/564014"], "description"=>"<p>Heterozygous mismatch rates (%) and Mendelian inconsistency rates (%) per site of call sets generated by PolyMutt (family-aware) and the standard approaches using PolyMutt (ignoring relatedness) and GATK from empirically calibrated alignments of simulated reads with base quality of Q20 in the pedigree shown in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002944#pgen-1002944-g001\" target=\"_blank\">Figure 1</a>.</p>", "links"=>[], "tags"=>["mismatch", "rates", "mendelian", "inconsistency", "sets", "generated", "polymutt", "approaches", "gatk", "empirically", "calibrated", "alignments", "simulated", "reads", "q20", "pedigree", "shown"], "article_id"=>234475, "categories"=>["Genetics"], "users"=>["Bingshan Li", "Wei Chen", "Xiaowei Zhan", "Fabio Busonero", "Serena Sanna", "Carlo Sidore", "Francesco Cucca", "Hyun M. Kang", "Gonçalo R. Abecasis"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002944.t005", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Heterozygous_mismatch_rates_and_Mendelian_inconsistency_rates_per_site_of_call_sets_generated_by_PolyMutt_family_aware_and_the_standard_approaches_using_PolyMutt_ignoring_relatedness_and_GATK_from_empirically_calibrated_alignments_of_simulated_reads_with/234475", "title"=>"Heterozygous mismatch rates (%) and Mendelian inconsistency rates (%) per site of call sets generated by PolyMutt (family-aware) and the standard approaches using PolyMutt (ignoring relatedness) and GATK from empirically calibrated alignments of simulated reads with base quality of Q20 in the pedigree shown in Figure 1.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-19 22:11:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/563259"], "description"=>"<p>A) is a 3-generation extended pedigree with numbers labeling the individual heterozygous genotype mismatch rates (%) at coverage of 15× with base quality of Q20 without mapping error and panel B) labels the corresponding mismatch rates for the standard approach of ignoring relatedness. Panel C) and D) display the heterozygous mismatch rates (%) when a fixed sequencing effort of 150× is allocated differently to family members: Panel C) is for the situation where the founders are allocated 30× while non-founders have 5× and in Panel D) founders and non-founders have coverage of 6× and 21× respectively.</p>", "links"=>[], "tags"=>["genetics and genomics"], "article_id"=>233750, "categories"=>["Genetics"], "users"=>["Bingshan Li", "Wei Chen", "Xiaowei Zhan", "Fabio Busonero", "Serena Sanna", "Carlo Sidore", "Francesco Cucca", "Hyun M. Kang", "Gonçalo R. Abecasis"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002944.g001", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Three_generation_extended_pedigrees_/233750", "title"=>"Three-generation extended pedigrees.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 22:07:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/563477"], "description"=>"<p>The 4 categories are (A) overall genotypes, (B) homozygous alternative allele, (C) heterozygotes and (D) homozygous reference allele.</p>", "links"=>[], "tags"=>["rates", "categories", "genotypes", "allele", "frequencies", "pedigrees", "quartet", "siblings", "q20"], "article_id"=>233951, "categories"=>["Genetics"], "users"=>["Bingshan Li", "Wei Chen", "Xiaowei Zhan", "Fabio Busonero", "Serena Sanna", "Carlo Sidore", "Francesco Cucca", "Hyun M. Kang", "Gonçalo R. Abecasis"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002944.g002", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mismatch_rates_of_4_categories_of_genotypes_by_the_reference_allele_frequencies_for_pedigrees_of_quartet_two_siblings_and_their_parents_with_base_quality_Q20_at_15_215_without_mapping_error_/233951", "title"=>"Mismatch rates (%) of 4 categories of genotypes by the reference allele frequencies for pedigrees of quartet (two siblings and their parents) with base quality Q20 at 15× without mapping error.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 22:09:01"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"7", "full-text"=>"9", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"4"}
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Relative Metric

{"start_date"=>"2012-01-01T00:00:00Z", "end_date"=>"2012-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences", "average_usage"=>[322, 550, 671, 773, 864, 955, 1048, 1135, 1223, 1308, 1387, 1465, 1534, 1602, 1673, 1744, 1813, 1885, 1955, 2026, 2093, 2160, 2228, 2290, 2349]}, {"subject_area"=>"/Biology and life sciences/Computational biology", "average_usage"=>[375, 629, 760, 889, 1000, 1110, 1203, 1298, 1399, 1492, 1603, 1699, 1774, 1855, 1918, 1998, 2062, 2152, 2227, 2312, 2378, 2461, 2528, 2600, 2664]}, {"subject_area"=>"/Biology and life sciences/Genetics", "average_usage"=>[333, 576, 707, 814, 908, 1004, 1104, 1197, 1280, 1370, 1449, 1531, 1603, 1673, 1742, 1817, 1886, 1954, 2025, 2098, 2171, 2234, 2304, 2365, 2431]}]}
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