{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T20:01:11Z","timestamp":1787774471308,"version":"build-2784847793"},"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2015,12,7]],"date-time":"2015-12-07T00:00:00Z","timestamp":1449446400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"DOI":"10.1371\/journal.pcbi.1004647","type":"journal-article","created":{"date-parts":[[2015,12,8]],"date-time":"2015-12-08T14:16:49Z","timestamp":1449584209000},"page":"e1004647","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":38,"title":["The Characteristics of Heterozygous Protein Truncating Variants in the Human Genome"],"prefix":"10.1371","volume":"11","author":[{"given":"Istv\u00e1n","family":"Bartha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Rausell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"McLaren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pejman","family":"Mohammadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Tardaguila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nimisha","family":"Chaturvedi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques","family":"Fellay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amalio","family":"Telenti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2015,12,7]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1126\/science.1219240","article-title":"Evolution and functional impact of rare coding variation from deep sequencing of human exomes","volume":"337","author":"JA Tennessen","year":"2012","journal-title":"Science"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1126\/science.1217876","article-title":"An abundance of rare functional variants in 202 drug target genes sequenced in 14,002 people","volume":"337","author":"MR Nelson","year":"2012","journal-title":"Science"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1038\/nature13127","article-title":"Guidelines for investigating causality of sequence variants in human disease","volume":"508","author":"DG MacArthur","year":"2014","journal-title":"Nature"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1126\/science.1215040","article-title":"A systematic survey of loss-of-function variants in human protein-coding genes","volume":"335","author":"DG MacArthur","year":"2012","journal-title":"Science"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/ng.3243","article-title":"Identification of a large set of rare complete human knockouts","volume":"47","author":"P Sulem","year":"2015","journal-title":"Nat Genet"},{"key":"ref6","article-title":"Analysis of loss-of-function variants and 20 risk factor phenotypes in 8,554 individuals identifies loci influencing chronic disease","author":"AH Li","year":"2015","journal-title":"Nat Genet"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1126\/science.1261877","article-title":"Human genomics. Effect of predicted protein-truncating genetic variants on the human transcriptome","volume":"348","author":"MA Rivas","year":"2015","journal-title":"Science"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"e1004494","DOI":"10.1371\/journal.pgen.1004494","article-title":"Distribution and medical impact of loss-of-function variants in the Finnish founder population","volume":"10","author":"ET Lim","year":"2014","journal-title":"PLoS Genet"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/ng0594-5","article-title":"Human haploinsufficiency\u2014one for sorrow, two for joy","volume":"7","author":"E Fisher","year":"1994","journal-title":"Nat Genet"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"e1001154","DOI":"10.1371\/journal.pgen.1001154","article-title":"Characterising and predicting haploinsufficiency in the human genome","volume":"6","author":"N Huang","year":"2010","journal-title":"PLoS Genet"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1101\/gr.080531.108","article-title":"The consensus coding sequence (CCDS) project: Identifying a common protein-coding gene set for the human and mouse genomes","volume":"19","author":"KD Pruitt","year":"2009","journal-title":"Genome Res"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1038\/ng.3050","article-title":"A framework for the interpretation of de novo mutation in human disease","volume":"46","author":"KE Samocha","year":"2014","journal-title":"Nat Genet"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"e1003757","DOI":"10.1371\/journal.pcbi.1003757","article-title":"Analysis of stop-gain and frameshift variants in human innate immunity genes","volume":"10","author":"A Rausell","year":"2014","journal-title":"PLoS Comput Biol"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1126\/science.1247005","article-title":"Genome-scale CRISPR-Cas9 knockout screening in human cells","volume":"343","author":"O Shalem","year":"2014","journal-title":"Science"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"e1003709","DOI":"10.1371\/journal.pgen.1003709","article-title":"Genic intolerance to functional variation and the interpretation of personal genomes","volume":"9","author":"S Petrovski","year":"2013","journal-title":"PLoS Genet"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"D726","DOI":"10.1093\/nar\/gku967","article-title":"The Mouse Genome Database (MGD): facilitating mouse as a model for human biology and disease","volume":"43","author":"JT Eppig","year":"2015","journal-title":"Nucleic acids research"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1038\/ejhg.2008.111","article-title":"Identification of human haploinsufficient genes and their genomic proximity to segmental duplications","volume":"16","author":"VT Dang","year":"2008","journal-title":"Eur J Hum Genet"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1126\/science.1260791","article-title":"Immunology. Autoimmunity by haploinsufficiency","volume":"345","author":"F Rieux-Laucat","year":"2014","journal-title":"Science"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"e1001935","DOI":"10.1371\/journal.pbio.1001935","article-title":"The genomic landscape of compensatory evolution","volume":"12","author":"B Szamecz","year":"2014","journal-title":"PLoS Biol"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1101\/gr.168393.113","article-title":"Estimating genotype error rates from high-coverage next-generation sequence data","volume":"24","author":"JD Wall","year":"2014","journal-title":"Genome Res"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/s13073-014-0089-z","article-title":"Reducing INDEL calling errors in whole genome and exome sequencing data","volume":"6","author":"H Fang","year":"2014","journal-title":"Genome Med"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1038\/ng.3121","article-title":"Comprehensive variation discovery in single human genomes","volume":"46","author":"NI Weisenfeld","year":"2014","journal-title":"Nat Genet"},{"key":"ref23","article-title":"Haploinsufficiency predictions without study bias","author":"J Steinberg","year":"2015","journal-title":"Nucleic acids research: gkv474"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1007\/s00335-012-9418-y","article-title":"Mouse large-scale phenotyping initiatives: overview of the European Mouse Disease Clinic (EUMODIC) and of the Wellcome Trust Sanger Institute Mouse Genetics Project","volume":"23","author":"A Ayadi","year":"2012","journal-title":"Mamm Genome"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.cell.2013.06.022","article-title":"Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes","volume":"154","author":"JK White","year":"2013","journal-title":"Cell"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1126\/science.1255904","article-title":"Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4","volume":"345","author":"HS Kuehn","year":"2014","journal-title":"Science"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"2165","DOI":"10.1126\/science.286.5447.2165","article-title":"Global transposon mutagenesis and a minimal Mycoplasma genome","volume":"286","author":"CA Hutchison","year":"1999","journal-title":"Science"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1007\/s00335-012-9422-2","article-title":"The mammalian gene function resource: the International Knockout Mouse Consortium","volume":"23","author":"A Bradley","year":"2012","journal-title":"Mamm Genome"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.ymeth.2014.02.025","article-title":"Chemical mutagens, transposons, and transgenes to interrogate gene function in Drosophila melanogaster","volume":"68","author":"KJ Venken","year":"2014","journal-title":"Methods"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1126\/science.1246981","article-title":"Genetic screens in human cells using the CRISPR-Cas9 system","volume":"343","author":"T Wang","year":"2014","journal-title":"Science"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nature11632","article-title":"An integrated map of genetic variation from 1,092 human genomes","volume":"491","author":"GR Abecasis","year":"2012","journal-title":"Nature"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/ejhg.2013.118","article-title":"The Genome of the Netherlands: design, and project goals","volume":"22","author":"DI Boomsma","year":"2014","journal-title":"European journal of human genetics: EJHG"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1093\/ije\/dys064","article-title":"Cohort Profile: the &apos;children of the 90s&apos;\u2014the index offspring of the Avon Longitudinal Study of Parents and Children","volume":"42","author":"A Boyd","year":"2013","journal-title":"International journal of epidemiology"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"e1000791","DOI":"10.1371\/journal.pgen.1000791","article-title":"Common genetic variation and the control of HIV-1 in humans","volume":"5","author":"J Fellay","year":"2009","journal-title":"PLoS genetics"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1471-2261-8-6","article-title":"The CoLaus study: a population-based study to investigate the epidemiology and genetic determinants of cardiovascular risk factors and metabolic syndrome","volume":"8","author":"M Firmann","year":"2008","journal-title":"BMC cardiovascular disorders"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1371\/journal.pbio.0050254","article-title":"The diploid genome sequence of an individual human","volume":"5","author":"S Levy","year":"2007","journal-title":"PLoS Biology"},{"key":"ref37","unstructured":"NIEHS Environmental Genome Project UW, Seattle, WA (accessed 2013)."},{"key":"ref38","unstructured":"Exome Variant Server NGESPE, Seattle, WA (accessed 2014)."},{"key":"ref39","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"A McKenna","year":"2010","journal-title":"Genome Res"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1093\/bioinformatics\/btp698","article-title":"Fast and accurate long-read alignment with Burrows-Wheeler transform","volume":"26","author":"H Li","year":"2010","journal-title":"Bioinformatics"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"D527","DOI":"10.1093\/nar\/gki086","article-title":"SNPeffect: a database mapping molecular phenotypic effects of human non-synonymous coding SNPs","volume":"33","author":"J Reumers","year":"2005","journal-title":"Nucleic Acids Res"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"11983","DOI":"10.1073\/pnas.1019276108","article-title":"Demographic history and rare allele sharing among human populations","volume":"108","author":"S Gravel","year":"2011","journal-title":"Proc Natl Acad Sci U S A"}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pcbi.1004647","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2018,10,23]],"date-time":"2018-10-23T08:48:20Z","timestamp":1540284500000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1004647"}},"subtitle":[],"editor":[{"given":"Marco","family":"Punta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2015,12,7]]},"references-count":42,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2015,12,7]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1004647","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/010611","asserted-by":"object"}],"has-review":[{"id-type":"doi","id":"10.3410\/f.725996833.793512185","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,12,7]]}}}