{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T23:06:14Z","timestamp":1773702374848,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1008397","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2020,12,7]],"date-time":"2020-12-07T00:00:00Z","timestamp":1607299200000}}],"reference-count":36,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2020,11,23]],"date-time":"2020-11-23T00:00:00Z","timestamp":1606089600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010663","name":"H2020 European Research Council","doi-asserted-by":"publisher","award":["ERC-AdG 789256"],"award-info":[{"award-number":["ERC-AdG 789256"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Genetic diseases are driven by aberrations of the human genome. Identification of such aberrations including structural variations (SVs) is key to our understanding. Conventional short-reads whole genome sequencing (cWGS) can identify SVs to base-pair resolution, but utilizes only short-range information and suffers from high false discovery rate (FDR). Linked-reads sequencing (10XWGS) utilizes long-range information by linkage of short-reads originating from the same large DNA molecule. This can mitigate alignment-based artefacts especially in repetitive regions and should enable better prediction of SVs. However, an unbiased evaluation of this technology is not available. In this study, we performed a comprehensive analysis of different types and sizes of SVs predicted by both the technologies and validated with an independent PCR based approach. The SVs commonly identified by both the technologies were highly specific, while validation rate dropped for uncommon events. A particularly high FDR was observed for SVs only found by 10XWGS. To improve FDR and sensitivity, statistical models for both the technologies were trained. Using our approach, we characterized SVs from the MCF7 cell line and a primary breast cancer tumor with high precision. This approach improves SV prediction and can therefore help in understanding the underlying genetics in various diseases.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1008397","type":"journal-article","created":{"date-parts":[[2020,11,23]],"date-time":"2020-11-23T19:37:28Z","timestamp":1606160248000},"page":"e1008397","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Integrative analysis of structural variations using short-reads and linked-reads yields highly specific and sensitive predictions"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2948-9711","authenticated-orcid":true,"given":"Riccha","family":"Sethi","sequence":"first","affiliation":[]},{"given":"Julia","family":"Becker","sequence":"additional","affiliation":[]},{"given":"Jos de","family":"Graaf","sequence":"additional","affiliation":[]},{"given":"Martin","family":"L\u00f6wer","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6625-6162","authenticated-orcid":true,"given":"Martin","family":"Suchan","sequence":"additional","affiliation":[]},{"given":"Ugur","family":"Sahin","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9631-8459","authenticated-orcid":true,"given":"David","family":"Weber","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2020,11,23]]},"reference":[{"issue":"5","key":"pcbi.1008397.ref001","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.tig.2008.03.001","article-title":"The functional impact of structural variation in humans","volume":"24","author":"ME Hurles","year":"2008","journal-title":"Trends Genet"},{"issue":"2","key":"pcbi.1008397.ref002","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/BF01630378","article-title":"The minute chromosome (Ph1) in chronic granulocytic leukemia","volume":"8","author":"C Nowell","year":"1962","journal-title":"Blut"},{"issue":"1","key":"pcbi.1008397.ref003","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/nrg3117","article-title":"Repetitive DNA and next-generation sequencing: Computational challenges and solutions","volume":"13","author":"TJ SSL Treangen","year":"2011","journal-title":"Nat Rev Genet"},{"issue":"1","key":"pcbi.1008397.ref004","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1038\/s41467-018-08148-z","article-title":"Multi-platform discovery of haplotype-resolved structural variation in human genomes","volume":"10","author":"MJ Chaisson","year":"2019","journal-title":"Nat Commun"},{"issue":"6","key":"pcbi.1008397.ref005","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/s41576-018-0003-4","article-title":"Piercing the dark matter: bioinformatics of long-range sequencing and mapping","volume":"19","author":"FJ Sedlazeck","year":"2018","journal-title":"Nature reviews Genetics"},{"issue":"8","key":"pcbi.1008397.ref006","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1038\/ng.3021","article-title":"Whole-genome sequence variation, population structure and demographic history of the Dutch population","volume":"46","author":"Genome of the Netherlands C","year":"2014","journal-title":"Nat Genet"},{"issue":"3","key":"pcbi.1008397.ref007","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/nbt.3432","article-title":"Haplotyping germline and cancer genomes with high-throughput linked-read sequencing","volume":"34","author":"GX Zheng","year":"2016","journal-title":"Nat Biotechnol"},{"issue":"19","key":"pcbi.1008397.ref008","doi-asserted-by":"crossref","first-page":"e162","DOI":"10.1093\/nar\/gkx712","article-title":"Chromosome-scale mega-haplotypes enable digital karyotyping of cancer aneuploidy","volume":"45","author":"JM Bell","year":"2017","journal-title":"Nucleic acids research"},{"issue":"4","key":"pcbi.1008397.ref009","doi-asserted-by":"crossref","first-page":"e19","DOI":"10.1093\/nar\/gkx1193","article-title":"Identification of large rearrangements in cancer genomes with barcode linked reads","volume":"46","author":"LC Xia","year":"2018","journal-title":"Nucleic acids research"},{"issue":"2","key":"pcbi.1008397.ref010","doi-asserted-by":"crossref","first-page":"e1007858","DOI":"10.1371\/journal.pgen.1007858","article-title":"Comprehensive structural variation genome map of individuals carrying complex chromosomal rearrangements","volume":"15","author":"J Eisfeldt","year":"2019","journal-title":"PLoS genetics"},{"key":"pcbi.1008397.ref011","doi-asserted-by":"crossref","first-page":"160025","DOI":"10.1038\/sdata.2016.25","article-title":"Extensive sequencing of seven human genomes to characterize benchmark reference materials.","volume":"3","author":"JM Zook","year":"2016","journal-title":"Sci Data"},{"issue":"1","key":"pcbi.1008397.ref012","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s13073-017-0447-8","article-title":"Linked read sequencing resolves complex genomic rearrangements in gastric cancer metastases","volume":"9","author":"SU Greer","year":"2017","journal-title":"Genome medicine"},{"issue":"2","key":"pcbi.1008397.ref013","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.cell.2018.05.036","article-title":"Structural alterations driving castration-resistant prostate cancer revealed by linked-read genome sequencing","volume":"174","author":"SR Viswanathan","year":"2018","journal-title":"Cell"},{"issue":"1","key":"pcbi.1008397.ref014","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s13059-017-1158-6","article-title":"Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome","volume":"18","author":"RL Collins","year":"2017","journal-title":"Genome biology"},{"issue":"14","key":"pcbi.1008397.ref015","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows-Wheeler transform","volume":"25","author":"H Li","year":"2009","journal-title":"Bioinformatics"},{"issue":"17","key":"pcbi.1008397.ref016","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.1093\/bioinformatics\/btu314","article-title":"SAMBLASTER: Fast duplicate marking and structural variant read extraction","volume":"30","author":"HI Faust GG","year":"2014","journal-title":"Bioinformatics"},{"issue":"16","key":"pcbi.1008397.ref017","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence Alignment\/Map format and SAMtools","volume":"25","author":"H Li","year":"2009","journal-title":"Bioinformatics"},{"key":"pcbi.1008397.ref018","doi-asserted-by":"crossref","first-page":"3240","DOI":"10.1038\/s41467-019-11146-4","article-title":"Comprehensive evaluation and characterisation of short read general-purpose structural variant calling software","volume":"10","author":"DL Cameron","year":"2019","journal-title":"Nat Commun"},{"issue":"1","key":"pcbi.1008397.ref019","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/s13059-019-1720-5","article-title":"Comprehensive evaluation of structural variation detection algorithms for whole genome sequencing","volume":"20","author":"S Kosugi","year":"2019","journal-title":"Genome biology"},{"issue":"18","key":"pcbi.1008397.ref020","doi-asserted-by":"crossref","first-page":"i333","DOI":"10.1093\/bioinformatics\/bts378","article-title":"DELLY: Structural variant discovery by integrated paired-end and split-read analysis","volume":"28","author":"T Rausch","year":"2012","journal-title":"Bioinformatics"},{"issue":"6","key":"pcbi.1008397.ref021","doi-asserted-by":"crossref","first-page":"R84","DOI":"10.1186\/gb-2014-15-6-r84","article-title":"LUMPY: a probabilistic framework for structural variant discovery","volume":"15","author":"RM Layer","year":"2014","journal-title":"Genome biology"},{"issue":"4","key":"pcbi.1008397.ref022","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1101\/gr.221028.117","article-title":"SvABA: genome-wide detection of structural variants and indels by local assembly","volume":"28","author":"JA Wala","year":"2018","journal-title":"Genome research"},{"issue":"4","key":"pcbi.1008397.ref023","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/j.cell.2013.04.010","article-title":"Diverse mechanisms of somatic structural variations in human cancer genomes","volume":"153","author":"L Yang","year":"2013","journal-title":"Cell"},{"issue":"2","key":"pcbi.1008397.ref024","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1093\/bioinformatics\/btx712","article-title":"Identifying structural variants using linked-read sequencing data","volume":"34","author":"R Elyanow","year":"2018","journal-title":"Bioinformatics"},{"issue":"9","key":"pcbi.1008397.ref025","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1038\/nmeth.4366","article-title":"Genome-wide reconstruction of complex structural variants using read clouds","volume":"14","author":"N Spies","year":"2017","journal-title":"Nat Methods"},{"key":"pcbi.1008397.ref026","first-page":"e30377","article-title":"Umap and Bismap: Quantifying genome and methylome mappability","volume":"7","author":"M Karimzadeh","year":"2018","journal-title":"Nucleic acids research"},{"issue":"3","key":"pcbi.1008397.ref027","doi-asserted-by":"crossref","first-page":"319","DOI":"10.3102\/1076998609332754","article-title":"Using Dominance Analysis to Determine Predictor Importance in Logistic Regression","volume":"34","author":"R Azen","year":"2009","journal-title":"Journal of Educational and Behavioral Statistics"},{"issue":"1","key":"pcbi.1008397.ref028","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.cels.2016.05.007","article-title":"Allele-Specific Quantification of Structural Variations in Cancer Genomes","volume":"3","author":"Y Li","year":"2016","journal-title":"Cell Syst"},{"issue":"5","key":"pcbi.1008397.ref029","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1101\/gr.113555.110","article-title":"Comprehensive long-span paired-end-tag mapping reveals characteristic patterns of structural variations in epithelial cancer genomes","volume":"21","author":"AM Hillmer","year":"2011","journal-title":"Genome research"},{"issue":"7809","key":"pcbi.1008397.ref030","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/s41586-020-2287-8","article-title":"A structural variation reference for medical and population genetics","volume":"581","author":"RL Collins","year":"2020","journal-title":"Nature"},{"key":"pcbi.1008397.ref031","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1186\/s12864-015-1479-3","article-title":"Assessing structural variation in a personal genome-towards a human reference diploid genome","volume":"16","author":"AC English","year":"2015","journal-title":"BMC Genomics"},{"issue":"8","key":"pcbi.1008397.ref032","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1038\/nmeth.3454","article-title":"Assembly and diploid architecture of an individual human genome via single-molecule technologies","volume":"12","author":"M Pendleton","year":"2015","journal-title":"Nat Methods"},{"issue":"7571","key":"pcbi.1008397.ref033","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/nature15394","article-title":"An integrated map of structural variation in 2,504 human genomes","volume":"526","author":"PH Sudmant","year":"2015","journal-title":"Nature"},{"key":"pcbi.1008397.ref034","article-title":"A robust benchmark for germline structural variant detection","author":"JM Zook","year":"2019","journal-title":"bioRxiv"},{"issue":"4","key":"pcbi.1008397.ref035","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1101\/gr.234443.118","article-title":"Resolving the full spectrum of human genome variation using Linked-Reads","volume":"29","author":"P Marks","year":"2019","journal-title":"Genome research"},{"issue":"12","key":"pcbi.1008397.ref036","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.cancergen.2013.11.002","article-title":"Detection of structural DNA variation from next generation sequencing data: A review of informatic approaches","volume":"206","author":"HJ DEJ Abel","year":"2013","journal-title":"Cancer Genet"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1008397","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2020,12,7]],"date-time":"2020-12-07T00:00:00Z","timestamp":1607299200000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1008397","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,12,7]],"date-time":"2020-12-07T23:26:30Z","timestamp":1607383590000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1008397"}},"subtitle":[],"editor":[{"given":"Florian","family":"Markowetz","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2020,11,23]]},"references-count":36,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11,23]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1008397","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pcbi.1008397","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,23]]}}}