{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T15:05:57Z","timestamp":1776697557009,"version":"3.51.2"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Motivation: Population low-coverage whole-genome sequencing is rapidly emerging as a prominent approach for discovering genomic variation and genotyping a cohort. This approach combines substantially lower cost than full-coverage sequencing with whole-genome discovery of low-allele frequency variants, to an extent that is not possible with array genotyping or exome sequencing. However, a challenging computational problem arises of jointly discovering variants and genotyping the entire cohort. Variant discovery and genotyping are relatively straightforward tasks on a single individual that has been sequenced at high coverage, because the inference decomposes into the independent genotyping of each genomic position for which a sufficient number of confidently mapped reads are available. However, in low-coverage population sequencing, the joint inference requires leveraging the complex linkage disequilibrium (LD) patterns in the cohort to compensate for sparse and missing data in each individual. The potentially massive computation time for such inference, as well as the missing data that confound low-frequency allele discovery, need to be overcome for this approach to become practical.<\/jats:p>\n                  <jats:p>Results: Here, we present Reveel, a novel method for single nucleotide variant calling and genotyping of large cohorts that have been sequenced at low coverage. Reveel introduces a novel technique for leveraging LD that deviates from previous Markov-based models, and which is aimed at computational efficiency as well as accuracy in capturing LD patterns present in rare haplotypes. We evaluate Reveel\u2019s performance through extensive simulations as well as real data from the 1000 Genomes Project, and show that it achieves higher accuracy in low-frequency allele discovery and substantially lower computation cost than previous state-of-the-art methods.<\/jats:p>\n                  <jats:p>Availability and implementation: \u00a0http:\/\/reveel.stanford.edu\/.<\/jats:p>\n                  <jats:p>Contact: serafim@cs.stanford.edu<\/jats:p>\n                  <jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btv530","type":"journal-article","created":{"date-parts":[[2015,9,10]],"date-time":"2015-09-10T09:37:06Z","timestamp":1441877826000},"page":"1686-1696","source":"Crossref","is-referenced-by-count":9,"title":["Reveel: large-scale population genotyping using low-coverage sequencing data"],"prefix":"10.1093","volume":"32","author":[{"given":"Lin","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Computer Science, Stanford University, CA 94305, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Stanford University, CA 94305, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruitang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Stanford University, CA 94305, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sivan","family":"Bercovici","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Stanford University, CA 94305, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Serafim","family":"Batzoglou","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Stanford University, CA 94305, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2015,9,9]]},"reference":[{"key":"2023020112283365400_btv530-B1","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/nature09298","article-title":"Integrating common and rare genetic variation in diverse human populations","volume":"467","author":"Altshuler","year":"2010","journal-title":"Nature"},{"key":"2023020112283365400_btv530-B2","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/nature07517","article-title":"Accurate whole human genome sequencing using reversible terminator chemistry","volume":"456","author":"Bentley","year":"2008","journal-title":"Nature"},{"key":"2023020112283365400_btv530-B3","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1111\/j.1749-6632.2010.05838.x","article-title":"The genetics of type 2 diabetes: what have we learned from GWAS? 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Med."},{"key":"2023020112283365400_btv530-B9","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.tplants.2010.10.005","article-title":"Crop genome sequencing: lessons and rationales","volume":"16","author":"Feuillet","year":"2011","journal-title":"Trends Plant Sci."},{"key":"2023020112283365400_btv530-B10","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1038\/ng.717","article-title":"Genome-wide meta-analysis increases to 71 the number of confirmed crohn\u2019s disease susceptibility loci","volume":"42","author":"Franke","year":"2010","journal-title":"Nat. Genet."},{"key":"2023020112283365400_btv530-B11","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1023\/A:1007465528199","article-title":"Bayesian network classifiers","volume":"29","author":"Friedman","year":"1997","journal-title":"Mach. Learn"},{"key":"2023020112283365400_btv530-B12","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/nrg3118","article-title":"Rare and common variants: twenty arguments","volume":"13","author":"Gibson","year":"2012","journal-title":"Nat. Rev. Genet."},{"key":"2023020112283365400_btv530-B13","doi-asserted-by":"crossref","DOI":"10.1142\/p351","article-title":"Mesh Enhancement: Selected Elliptic Methods, Foundations and Applications","author":"Hansen","year":"2005"},{"key":"2023020112283365400_btv530-B14","doi-asserted-by":"crossref","first-page":"9362","DOI":"10.1073\/pnas.0903103106","article-title":"Potential etiologic and functional implications of genome-wide association loci for human diseases and traits","volume":"106","author":"Hindorff","year":"2009","journal-title":"PNAS"},{"key":"2023020112283365400_btv530-B15","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1146\/annurev-arplant-050213-035715","article-title":"Natural variations and genome-wide association studies in crop plants","volume":"65","author":"Huang","year":"2014","journal-title":"Annu. Rev. Plant Biol."},{"key":"2023020112283365400_btv530-B16","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1109\/34.667881","article-title":"On combining classifiers","volume":"20","author":"Kittler","year":"1998","journal-title":"IEEE Trans. Pattern Anal. Mach. Intell."},{"key":"2023020112283365400_btv530-B17","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1101\/gr.113084.110","article-title":"SNP detection and genotyping from low-coverage sequencing data on multiple diploid samples","volume":"21","author":"Le","year":"2011","journal-title":"Genome Res."},{"key":"2023020112283365400_btv530-B43","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":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"2023020112283365400_btv530-B18","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.ajhg.2014.06.009","article-title":"Rare-variant association analysis: study designs and statistical tests","volume":"95","author":"Lee","year":"2014","journal-title":"Am. J. Hum. Genet."},{"key":"2023020112283365400_btv530-B19","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The sequence alignment\/map format and samtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"2023020112283365400_btv530-B20","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1101\/gr.117259.110","article-title":"Low-coverage sequencing: implications for design of complex trait association studies","volume":"21","author":"Li","year":"2011","journal-title":"Genome Res."},{"key":"2023020112283365400_btv530-B21","doi-asserted-by":"crossref","first-page":"2213","DOI":"10.1093\/genetics\/165.4.2213","article-title":"Modeling linkage disequilibrium and identifying recombination hotspots using single-nucleotide polymorphism data","volume":"165","author":"Li","year":"2003","journal-title":"Genetics"},{"key":"2023020112283365400_btv530-B22","doi-asserted-by":"crossref","first-page":"19872","DOI":"10.1073\/pnas.1319590110","article-title":"High-throughput DNA sequencing errors are reduced by orders of magnitude using circle sequencing","volume":"110","author":"Lou","year":"2013","journal-title":"PNAS"},{"key":"2023020112283365400_btv530-B23","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/nature08494","article-title":"Finding the missing heritability of complex diseases","volume":"461","author":"Manolio","year":"2009","journal-title":"Nature"},{"key":"2023020112283365400_btv530-B24","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":"McKenna","year":"2010","journal-title":"Genome Res."},{"key":"2023020112283365400_btv530-B25","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/nrg2986","article-title":"Genotype and snp calling from next-generation sequencing data","volume":"12","author":"Nielsen","year":"2012","journal-title":"Nat. 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Genet."},{"key":"2023020112283365400_btv530-B29","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1101\/gr.3709305","article-title":"Calibrating a coalescent simulation of human genome sequence variation","volume":"15","author":"Schaffner","year":"2005","journal-title":"Genome Res."},{"key":"2023020112283365400_btv530-B30","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1534\/genetics.166.1.505","article-title":"Linkage disequilibrium testing when linkage phase is unknown","volume":"166","author":"Schaid","year":"2004","journal-title":"Genetics"},{"key":"2023020112283365400_btv530-B31","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":"Tennessen","year":"2012","journal-title":"Science"},{"key":"2023020112283365400_btv530-B32","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1038\/nature09534","article-title":"A map of human genome variation from population-scale sequencing","volume":"467","author":"The 1000 Genomes Project Consortium","year":"2010","journal-title":"Nature"},{"key":"2023020112283365400_btv530-B33","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nature11632","article-title":"An integrated map of genetic variation from 1\u2009092 human genomes","volume":"491","author":"The 1000 Genomes Project Consortium","year":"2012","journal-title":"Nature"},{"key":"2023020112283365400_btv530-B34","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1126\/science.1167936","article-title":"Genome-wide survey of snp variation uncovers the genetic structure of cattle breeds","volume":"324","author":"The Bovine HapMap Consortium","year":"2009","journal-title":"Science"},{"key":"2023020112283365400_btv530-B35","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1038\/nature05911","article-title":"Genome-wide association study of 14\u2009000 cases of seven common diseases and 3\u2009000 shared controls","volume":"447","author":"The Wellcome Trust Case Control Consortium","year":"2007","journal-title":"Nature"},{"key":"2023020112283365400_btv530-B36","doi-asserted-by":"crossref","first-page":"11.10.1","DOI":"10.1002\/0471250953.bi1110s43","article-title":"From FastQ data to high-confidence variant calls: the genome analysis toolkit best practices pipeline","volume":"43","author":"Van der Auwera","year":"2013","journal-title":"Curr. Protoc. Bioinformat"},{"key":"2023020112283365400_btv530-B37","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.ajhg.2011.11.029","article-title":"Five years of GWAS discovery","volume":"90","author":"Visscher","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"2023020112283365400_btv530-B38","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms2256","article-title":"A fast and accurate SNP detection algorithm for next-generation sequencing data","author":"Xu","year":"2012","journal-title":"Nat. Commun."},{"key":"2023020112283365400_btv530-B39","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1109\/21.155943","article-title":"Methods of combining multiple classifiers and their applications to handwriting recognition","volume":"22","author":"Xu","year":"1992","journal-title":"IEEE Trans. Syst Man Cybern. Syst."},{"key":"2023020112283365400_btv530-B40","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1101\/gr.146084.112","article-title":"An integrative variant analysis pipeline for accurate genotype\/haplotype inference in population NGS data","volume":"23","author":"Wang","year":"2013","journal-title":"Genome Res."},{"key":"2023020112283365400_btv530-B41","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1109\/TSMCA.2012.2189880","article-title":"Knowledge engineering for bayesian networks: how common are noisy-max distributions in practice? IEEE Trans","volume":"43","author":"Zagorecki","year":"2013","journal-title":"Syst. Man Cybernet. Syst."},{"key":"2023020112283365400_btv530-B42","doi-asserted-by":"crossref","first-page":"E455","DOI":"10.1073\/pnas.1322563111","article-title":"Searching for missing heritability: designing rare variant association studies","volume":"111","author":"Zuk","year":"2014","journal-title":"PNAS"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/32\/11\/1686\/49019118\/bioinformatics_32_11_1686.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/32\/11\/1686\/49019118\/bioinformatics_32_11_1686.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T17:32:05Z","timestamp":1675272725000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/32\/11\/1686\/2240186"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,9,9]]},"references-count":43,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2016,6,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btv530","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/011882","asserted-by":"object"}]},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2016,6,1]]},"published":{"date-parts":[[2015,9,9]]}}}