title: A thesaurus of genetic variation for interrogation of repetitive genomic regions.
abstract: Detecting genetic variation is one of the main applications of high-throughput sequencing, but is still challenging wherever aligning short reads poses ambiguities. Current state-of-the-art variant calling approaches avoid such regions, arguing that it is necessary to sacrifice detection sensitivity to limit false discovery. We developed a method that links candidate variant positions within repetitive genomic regions into clusters. The technique relies on a resource, a thesaurus of genetic variation, that enumerates genomic regions with similar sequence. The resource is computationally intensive to generate, but once compiled can be applied efficiently to annotate and prioritize variants in repetitive regions. We show that thesaurus annotation can reduce the rate of false variant calls due to mappability by up to three orders of magnitude. We apply the technique to whole genome datasets and establish that called variants in low mappability regions annotated using the thesaurus can be experimentally validated. We then extend the analysis to a large panel of exomes to show that the annotation technique opens possibilities to study variation in hereto hidden and under-studied parts of the genome.
authors.affiliation: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna, Austria.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kerzendorfer
authors.affiliation: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna, Austria tomasz.konopka@ludwig.ox.ac.uk.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Konopka
authors.affiliation: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna, Austria sebastian.nijman@ludwig.ox.ac.uk.
authors.forename: Sebastian M B
authors.initials: SM
authors.lastname: Nijman
mesh_terms: D045744:Cell Line, Tumor; D059472:Exome; D014644:Genetic Variation; D015894:Genome, Human; D023281:Genomics / Q000379:methods*; D006801:Humans; D058977:Molecular Sequence Annotation; D012091:Repetitive Sequences, Nucleic Acid; D018875:Vocabulary, Controlled
references.citation: Genome Res. 2012 Mar;22(3):568-76
references.pmid: 22300766
references.citation: Nat Rev Genet. 2012 Jan;13(1):36-46
references.pmid: 22124482
references.citation: Bioinformatics. 2012 Apr 1;28(7):907-13
references.pmid: 22285562
references.citation: Genome Biol. 2011;12(11):R112
references.pmid: 22067484
references.citation: Bioinformatics. 2012 Aug 15;28(16):2097-105
references.pmid: 22668792
references.citation: Genome Res. 2012 Sep;22(9):1760-74
references.pmid: 22955987
references.citation: Nature. 2012 Sep 6;489(7414):57-74
references.pmid: 22955616
references.citation: Nat Biotechnol. 2013 Mar;31(3):213-9
references.pmid: 23396013
references.citation: Nat Rev Genet. 2013 Jul;14(7):460-70
references.pmid: 23752795
references.citation: Bioinformatics. 2013 Jul 15;29(14):1734-41
references.pmid: 23677944
references.citation: Elife. 2013;2:e00569
references.pmid: 23840927
references.citation: Nature. 2013 Jul 11;499(7457):214-8
references.pmid: 23770567
references.citation: N Engl J Med. 2013 Oct 17;369(16):1502-11
references.pmid: 24088041
references.citation: Nature. 2013 Oct 17;502(7471):333-9
references.pmid: 24132290
references.citation: Nat Methods. 2013 Oct;10(10):965-71
references.pmid: 24161985
references.citation: Nat Biotechnol. 2013 Nov;31(11):1023-31
references.pmid: 24142049
references.citation: Nat Biotechnol. 2013 Dec;31(12):1111-8
references.pmid: 24185094
references.citation: PLoS One. 2014;9(1):e86664
references.pmid: 24489763
references.citation: Genome Biol. 2013;14(10):R110
references.pmid: 24176112
references.citation: Brief Bioinform. 2014 Mar;15(2):256-78
references.pmid: 23341494
references.citation: Nat Biotechnol. 2014 Mar;32(3):261-6
references.pmid: 24561555
references.citation: Nat Genet. 2014 Aug;46(8):912-8
references.pmid: 25017105
references.citation: Hum Genomics. 2014;8:14
references.pmid: 25078893
references.citation: Nat Genet. 2013 Oct;45(10):1127-33
references.pmid: 24071851
references.citation: Nucleic Acids Res. 2001 Jan 1;29(1):308-11
references.pmid: 11125122
references.citation: Genome Res. 2002 Apr;12(4):656-64
references.pmid: 11932250
references.citation: Bioinformatics. 2010 Apr 1;26(7):873-81
references.pmid: 20147302
references.citation: Genome Res. 2010 Sep;20(9):1297-303
references.pmid: 20644199
references.citation: Nature. 2010 Oct 28;467(7319):1061-73
references.pmid: 20981092
references.citation: Genet Med. 2011 Mar;13(3):255-62
references.pmid: 21173700
references.citation: Genome Biol. 2011;12(6):R55
references.pmid: 21689413
references.citation: Nat Methods. 2012 Apr;9(4):357-9
references.pmid: 22388286