title: Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants.
abstract: We compared whole-exome sequencing (WES) and whole-genome sequencing (WGS) in six unrelated individuals. In the regions targeted by WES capture (81.5% of the consensus coding genome), the mean numbers of single-nucleotide variants (SNVs) and small insertions/deletions (indels) detected per sample were 84,192 and 13,325, respectively, for WES, and 84,968 and 12,702, respectively, for WGS. For both SNVs and indels, the distributions of coverage depth, genotype quality, and minor read ratio were more uniform for WGS than for WES. After filtering, a mean of 74,398 (95.3%) high-quality (HQ) SNVs and 9,033 (70.6%) HQ indels were called by both platforms. A mean of 105 coding HQ SNVs and 32 indels was identified exclusively by WES whereas 692 HQ SNVs and 105 indels were identified exclusively by WGS. We Sanger-sequenced a random selection of these exclusive variants. For SNVs, the proportion of false-positive variants was higher for WES (78%) than for WGS (17%). The estimated mean number of real coding SNVs (656 variants, ∼3% of all coding HQ SNVs) identified by WGS and missed by WES was greater than the number of SNVs identified by WES and missed by WGS (26 variants). For indels, the proportions of false-positive variants were similar for WES (44%) and WGS (46%). Finally, WES was not reliable for the detection of copy-number variations, almost all of which extended beyond the targeted regions. Although currently more expensive, WGS is more powerful than WES for detecting potential disease-causing mutations within WES regions, particularly those due to SNVs.
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France;
authors.forename: Aziz
authors.initials: A
authors.lastname: Belkadi
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065;
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bolze
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065;
authors.forename: Yuval
authors.initials: Y
authors.lastname: Itan
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France;
authors.forename: Aurélie
authors.initials: A
authors.lastname: Cobat
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France;
authors.forename: Quentin B
authors.initials: QB
authors.lastname: Vincent
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065;
authors.forename: Alexander
authors.initials: A
authors.lastname: Antipenko
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065;
authors.forename: Lei
authors.initials: L
authors.lastname: Shang
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065;
authors.forename: Bertrand
authors.initials: B
authors.lastname: Boisson
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; Howard Hughes Medical Institute, New York, NY 10065; and Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France laurent.abel@inserm.fr Jean-Laurent.Casanova@rockefeller.edu.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; laurent.abel@inserm.fr Jean-Laurent.Casanova@rockefeller.edu.
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
mesh_terms: D059472:Exome; D005260:Female; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide
keywords: Mendelian disorders; exome; genetic variants; genome; next-generation sequencing
references.citation: Nucleic Acids Res. 2014 Jan;42(Database issue):D865-72
references.pmid: 24217909
references.citation: BMC Bioinformatics. 2014;15:125
references.pmid: 24884706
references.citation: Brief Bioinform. 2015 May;16(3):380-92
references.pmid: 25169955
references.citation: Sci Transl Med. 2012 Oct 3;4(154):154ra135
references.pmid: 23035047
references.citation: Sci Transl Med. 2014 Dec 3;6(265):265ra168
references.pmid: 25473036
references.citation: Genome Med. 2014 Oct 28;6(10):89
references.pmid: 25426171
references.citation: Nature. 2014 Jul 17;511(7509):344-7
references.pmid: 24896178
references.citation: Science. 2013 May 24;340(6135):976-8
references.pmid: 23579497
references.citation: Nature. 2012 Nov 1;491(7422):56-65
references.pmid: 23128226
references.citation: Am J Hum Genet. 2010 Dec 10;87(6):873-81
references.pmid: 21109225
references.citation: Science. 2012 Jul 6;337(6090):64-9
references.pmid: 22604720
references.citation: Genome Res. 2012 Aug;22(8):1525-32
references.pmid: 22585873
references.citation: Nat Genet. 2014 Aug;46(8):818-25
references.pmid: 24974849
references.citation: Hum Mutat. 2014 Jul;35(7):899-907
references.pmid: 24599517
references.citation: J Exp Med. 2014 Oct 20;211(11):2137-49
references.pmid: 25311508
references.citation: Am J Hum Genet. 2012 Oct 5;91(4):597-607
references.pmid: 23040492
references.citation: BMC Res Notes. 2014;7:864
references.pmid: 25435282
references.citation: J Pediatr. 2011 Jan;158(1):142-8, 148.e1
references.pmid: 20846672
references.citation: Hum Mutat. 2012 Jul;33(7):1045-50
references.pmid: 22431159
references.citation: Genome Res. 2010 Sep;20(9):1297-303
references.pmid: 20644199
references.citation: Brief Bioinform. 2013 Mar;14(2):178-92
references.pmid: 22517427
references.citation: Nature. 2009 Sep 10;461(7261):272-6
references.pmid: 19684571
references.citation: Nucleic Acids Res. 2014 Jan;42(Database issue):D749-55
references.pmid: 24316576
references.citation: Nat Biotechnol. 2011 Oct;29(10):908-14
references.pmid: 21947028
references.citation: Brain. 2010 Dec;133(Pt 12):3510-8
references.pmid: 21106500
references.citation: J Mol Biol. 1990 Oct 5;215(3):403-10
references.pmid: 2231712
references.citation: Nat Genet. 2011 May;43(5):491-8
references.pmid: 21478889
references.citation: Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5558-63
references.pmid: 23509278
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 10;106(45):19096-101
references.pmid: 19861545
references.citation: BMC Bioinformatics. 2014;15:247
references.pmid: 25038816
references.citation: Nat Genet. 2014 Mar;46(3):310-5
references.pmid: 24487276
references.citation: Nat Protoc. 2009;4(8):1184-91
references.pmid: 19617889
references.citation: J Exp Med. 2010 Oct 25;207(11):2307-12
references.pmid: 20876309
references.citation: Nat Genet. 2011 Mar;43(3):269-76
references.pmid: 21317889
references.citation: Nat Rev Genet. 2011 Nov;12(11):745-55
references.pmid: 21946919
references.citation: Nucleic Acids Res. 2010 Sep;38(16):e164
references.pmid: 20601685
references.citation: Nucleic Acids Res. 2014 Jan;42(Database issue):D986-92
references.pmid: 24174537
references.citation: Cell. 2013 Sep 26;155(1):27-38
references.pmid: 24074859