{"id":"https://openalex.org/W2207366299","doi":"https://doi.org/10.5281/zenodo.32710","title":"The Human Knockout Project: Identifying Loss Of Function Variants In Large Population Datasets","display_name":"The Human Knockout Project: Identifying Loss Of Function Variants In Large Population Datasets","publication_year":2015,"publication_date":"2015-10-26","ids":{"openalex":"https://openalex.org/W2207366299","doi":"https://doi.org/10.5281/zenodo.32710","mag":"2207366299"},"language":"en","primary_location":{"id":"doi:10.5281/zenodo.32710","doi":"https://doi.org/10.5281/zenodo.32710","is_oa":true,"landing_page_url":"https://doi.org/10.5281/zenodo.32710","pdf_url":null,"source":{"id":"https://openalex.org/S4306400562","display_name":"Zenodo (CERN European Organization for Nuclear Research)","issn_l":null,"issn":null,"is_oa":true,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I67311998","host_organization_name":"European Organization for Nuclear Research","host_organization_lineage":["https://openalex.org/I67311998"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":null,"is_accepted":false,"is_published":false,"raw_source_name":null,"raw_type":"article-journal"},"volume":null,"type":"article","indexed_in":["datacite"],"open_access":{"is_oa":true,"oa_status":"green","oa_url":"https://doi.org/10.5281/zenodo.32710","any_repository_has_fulltext":true},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5106691485","display_name":"Konrad J. Karczewski","orcid":"https://orcid.org/0000-0003-2878-4671","observed_orcids":["https://orcid.org/0000-0003-2878-4671"]},"institutions":[{"id":"https://openalex.org/I107606265","display_name":"Broad Institute","ror":"https://ror.org/05a0ya142","country_code":"US","type":"nonprofit","lineage":["https://openalex.org/I107606265"]},{"id":"https://openalex.org/I136199984","display_name":"Harvard University","ror":"https://ror.org/03vek6s52","country_code":"US","type":"education","lineage":["https://openalex.org/I136199984"]},{"id":"https://openalex.org/I4210087915","display_name":"Massachusetts General Hospital","ror":"https://ror.org/002pd6e78","country_code":"US","type":"healthcare","lineage":["https://openalex.org/I4210087915","https://openalex.org/I48633490"]},{"id":"https://openalex.org/I63966007","display_name":"Massachusetts Institute of Technology","ror":"https://ror.org/042nb2s44","country_code":"US","type":"education","lineage":["https://openalex.org/I63966007"]}],"countries":["US"],"is_corresponding":true,"raw_author_name":"Karczewski, Konrad","raw_affiliation_strings":["Massachusetts General Hospital and The Broad Institute of Harvard and MIT"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Massachusetts General Hospital and The Broad Institute of Harvard and MIT","institution_ids":["https://openalex.org/I107606265","https://openalex.org/I136199984","https://openalex.org/I4210087915","https://openalex.org/I63966007"]}]}],"institutions":[],"countries_distinct_count":1,"institutions_distinct_count":4,"corresponding_author_ids":["https://openalex.org/A5106691485"],"corresponding_institution_ids":["https://openalex.org/I107606265","https://openalex.org/I136199984","https://openalex.org/I4210087915","https://openalex.org/I63966007"],"apc_list":null,"apc_paid":null,"fwci":0.0,"has_fulltext":true,"cited_by_count":0,"citation_normalized_percentile":{"value":0.09021615,"is_in_top_1_percent":false,"is_in_top_10_percent":false},"cited_by_percentile_year":null,"biblio":{"volume":null,"issue":null,"first_page":null,"last_page":null},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T11642","display_name":"Genomics and Rare Diseases","score":0.9990000128746033,"subfield":{"id":"https://openalex.org/subfields/1311","display_name":"Genetics"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},"topics":[{"id":"https://openalex.org/T11642","display_name":"Genomics and Rare Diseases","score":0.9990000128746033,"subfield":{"id":"https://openalex.org/subfields/1311","display_name":"Genetics"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T10261","display_name":"Genetic Associations and Epidemiology","score":0.000699999975040555,"subfield":{"id":"https://openalex.org/subfields/1311","display_name":"Genetics"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T10015","display_name":"Genomics and Phylogenetic Studies","score":9.999999747378752e-05,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/loss-of-function-variants","display_name":"loss-of-function mutations","score":0.9629999995231628},{"id":"https://openalex.org/keywords/homozygous-variant","display_name":"homozygous variant","score":0.7450000047683716},{"id":"https://openalex.org/keywords/consanguinity","display_name":"consanguinity","score":0.5680000185966492},{"id":"https://openalex.org/keywords/splicing","display_name":"splicing","score":0.5979999899864197},{"id":"https://openalex.org/keywords/gtex","display_name":"GTEx","score":0.621999979019165},{"id":"https://openalex.org/keywords/therapeutic-target","display_name":"therapeutic target","score":0.5120000243186951},{"id":"https://openalex.org/keywords/pcsk9","display_name":"PCSK9","score":0.7379999756813049}],"concepts":[{"id":"https://openalex.org/C14036430","wikidata":"https://www.wikidata.org/wiki/Q3736076","display_name":"Function (biology)","level":2,"score":0.5973312854766846},{"id":"https://openalex.org/C2908647359","wikidata":"https://www.wikidata.org/wiki/Q2625603","display_name":"Population","level":2,"score":0.49667006731033325},{"id":"https://openalex.org/C70721500","wikidata":"https://www.wikidata.org/wiki/Q177005","display_name":"Computational biology","level":1,"score":0.479801207780838},{"id":"https://openalex.org/C177264268","wikidata":"https://www.wikidata.org/wiki/Q1514741","display_name":"Set (abstract data type)","level":2,"score":0.4426223933696747},{"id":"https://openalex.org/C105951970","wikidata":"https://www.wikidata.org/wiki/Q1036748","display_name":"Loss function","level":4,"score":0.43901771306991577},{"id":"https://openalex.org/C86803240","wikidata":"https://www.wikidata.org/wiki/Q420","display_name":"Biology","level":0,"score":0.43276816606521606},{"id":"https://openalex.org/C54355233","wikidata":"https://www.wikidata.org/wiki/Q7162","display_name":"Genetics","level":1,"score":0.3135722875595093},{"id":"https://openalex.org/C41008148","wikidata":"https://www.wikidata.org/wiki/Q21198","display_name":"Computer science","level":0,"score":0.28815561532974243},{"id":"https://openalex.org/C127716648","wikidata":"https://www.wikidata.org/wiki/Q104053","display_name":"Phenotype","level":3,"score":0.24639979004859924},{"id":"https://openalex.org/C71924100","wikidata":"https://www.wikidata.org/wiki/Q11190","display_name":"Medicine","level":0,"score":0.20874997973442078},{"id":"https://openalex.org/C99454951","wikidata":"https://www.wikidata.org/wiki/Q932068","display_name":"Environmental health","level":1,"score":0.13072249293327332},{"id":"https://openalex.org/C104317684","wikidata":"https://www.wikidata.org/wiki/Q7187","display_name":"Gene","level":2,"score":0.12353101372718811},{"id":"https://openalex.org/C199360897","wikidata":"https://www.wikidata.org/wiki/Q9143","display_name":"Programming language","level":1,"score":0.0}],"mesh":[],"locations_count":2,"locations":[{"id":"doi:10.5281/zenodo.32710","doi":"https://doi.org/10.5281/zenodo.32710","is_oa":true,"landing_page_url":"https://doi.org/10.5281/zenodo.32710","pdf_url":null,"source":{"id":"https://openalex.org/S4306400562","display_name":"Zenodo (CERN European Organization for Nuclear Research)","issn_l":null,"issn":null,"is_oa":true,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I67311998","host_organization_name":"European Organization for Nuclear Research","host_organization_lineage":["https://openalex.org/I67311998"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":null,"is_accepted":false,"is_published":false,"raw_source_name":null,"raw_type":"article-journal"},{"id":"mag:2207366299","doi":null,"is_oa":false,"landing_page_url":"https://zenodo.org/record/32710","pdf_url":null,"source":{"id":"https://openalex.org/S2764516455","display_name":"Basel Life Science Week","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":null,"host_organization_name":null,"host_organization_lineage":[],"host_organization_lineage_names":[],"type":"journal"},"license":null,"license_id":null,"version":null,"is_accepted":false,"is_published":false,"raw_source_name":"Basel Life Science Week","raw_type":null}],"best_oa_location":{"id":"doi:10.5281/zenodo.32710","doi":"https://doi.org/10.5281/zenodo.32710","is_oa":true,"landing_page_url":"https://doi.org/10.5281/zenodo.32710","pdf_url":null,"source":{"id":"https://openalex.org/S4306400562","display_name":"Zenodo (CERN European Organization for Nuclear Research)","issn_l":null,"issn":null,"is_oa":true,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I67311998","host_organization_name":"European Organization for Nuclear Research","host_organization_lineage":["https://openalex.org/I67311998"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":null,"is_accepted":false,"is_published":false,"raw_source_name":null,"raw_type":"article-journal"},"sustainable_development_goals":[{"score":0.9476000070571899,"id":"https://metadata.un.org/sdg/3","display_name":"Good health and well-being"}],"study_designs":[],"awards":[],"funders":[],"has_content":{"grobid_xml":false,"pdf":false},"content_urls":null,"referenced_works_count":0,"referenced_works":[],"related_works":["https://openalex.org/W2168412461","https://openalex.org/W4319029703","https://openalex.org/W2143602768","https://openalex.org/W2033320788","https://openalex.org/W4415195417","https://openalex.org/W2748225400","https://openalex.org/W2170411836","https://openalex.org/W2114617761","https://openalex.org/W7056098653","https://openalex.org/W3049591481"],"abstract_inverted_index":{"Every":[0],"human":[1,41,104],"carries":[2],"at":[3],"least":[4],"a":[5,93,107,158,218,232,298,305],"hundred":[6],"loss-of-function":[7,198],"(LoF)":[8],"variants":[9,26,57,64,75,112,209,271,296],"predicted":[10],"to":[11,81,87,139,166,196,202,217],"severely":[12],"disrupt":[13],"the":[14,22,36,52,88,103,150,204,253,267,286,292],"function":[15,37],"of":[16,29,38,54,90,152,161,171,206,220,234,261,269,294,300,314],"protein-coding":[17],"genes,":[18],"including":[19,226],"many":[20],"in":[21,58,69,76,102,142],"homozygous":[23,172,207],"state.":[24],"These":[25],"represent":[27],"?experiments":[28],"nature?":[30],"that":[31],"can":[32],"cast":[33],"light":[34],"on":[35,272],"currently":[39],"uncharacterized":[40],"genes:":[42],"indeed,":[43],"much":[44],"novel":[45],"biology":[46],"has":[47],"already":[48],"been":[49,78],"learned":[50],"from":[51,223,231,243,252,281,285],"involvement":[53],"rare":[55,173,235,315],"LoF":[56,74,174,208,270,301],"severe":[59],"Mendelian":[60,316],"disease.":[61,98],"Additionally,":[62],"these":[63,111,257,295],"have":[65,122,184,214],"also":[66],"proved":[67],"valuable":[68],"identifying":[70,177],"potential":[71],"therapeutic":[72,94],"targets:":[73],"PCSK9have":[77],"causally":[79],"linked":[80],"low":[82,124],"LDL":[83],"cholesterol":[84],"levels,":[85],"leading":[86],"development":[89],"PCSK9":[91],"as":[92,110],"target":[95],"for":[96,115,169,307],"cardiovascular":[97],"However,":[99],"discovering":[100],"LoFs":[101,141],"population":[105],"remains":[106],"significant":[108],"challenge,":[109],"are":[113,137,164],"enriched":[114],"sequencing":[116],"and":[117,120,129,155,236,247,265,312],"annotation":[118],"errors,":[119],"typically":[121],"very":[123],"frequency,":[125],"confounding":[126],"their":[127],"discovery":[128,170],"interpretation.":[130],"For":[131],"this":[132,181],"reason,":[133],"large":[134,221],"sample":[135],"sizes":[136],"required":[138],"discover":[140],"every":[143],"possible":[144],"gene.":[145],"Alternatively,":[146],"two":[147],"distinct":[148],"strategies,":[149],"use":[151],"bottlenecked":[153],"populations":[154,156],"with":[157,277],"high":[159],"rate":[160],"consanguineous":[162],"mating,":[163],"established":[165],"significantly":[167],"enrich":[168],"variants,":[175,264,302],"effectively":[176],"?knockout?":[178],"humans.":[179],"To":[180],"end,":[182],"we":[183,213,290],"developed":[185],"an":[186],"open-source":[187],"tool,":[188],"LOFTEE":[189,216],"(Loss":[190],"Of":[191],"Function":[192],"Transcript":[193],"Effect":[194],"Estimator),":[195],"annotate":[197],"variants.":[199],"In":[200],"order":[201],"characterize":[203],"landscape":[205],"(knockouts)":[210],"across":[211],"humans,":[212],"applied":[215],"number":[219],"datasets":[222],"collaborative":[224],"efforts,":[225],"over":[227,248,282],"91,000":[228],"exomes":[229,276],"aggregated":[230],"variety":[233],"complex":[237],"disease":[238,263],"consortia,":[239],"deeply":[240],"phenotyped":[241],"samples":[242],"Finnish":[244],"national":[245],"biobanks,":[246],"1,000":[249],"parentally-related":[250],"individuals":[251,284],"UK.":[254],"We":[255],"validate":[256],"methods":[258],"using":[259],"databases":[260],"known":[262],"investigate":[266],"role":[268],"splicing":[273],"by":[274],"intersecting":[275],"matched":[278],"RNA-Seq":[279],"data":[280],"500":[283],"GTEx":[287],"consortium.":[288],"Finally,":[289],"describe":[291],"aggregation":[293],"into":[297],"database":[299],"dbLoF,":[303],"providing":[304],"resource":[306],"pharmaceutical":[308],"development,":[309],"transplant":[310],"biology,":[311],"understanding":[313],"diseases.":[317]},"counts_by_year":[],"updated_date":"2026-10-29T09:56:32.521200","created_date":"2016-06-24T00:00:00"}