title: Optimized filtering reduces the error rate in detecting genomic variants by short-read sequencing.
abstract: Distinguishing single-nucleotide variants (SNVs) from errors in whole-genome sequences remains challenging. Here we describe a set of filters, together with a freely accessible software tool, that selectively reduce error rates and thereby facilitate variant detection in data from two short-read sequencing technologies, Complete Genomics and Illumina. By sequencing the nearly identical genomes from monozygotic twins and considering shared SNVs as 'true variants' and discordant SNVs as 'errors', we optimized thresholds for 12 individual filters and assessed which of the 1,048 filter combinations were effective in terms of sensitivity and specificity. Cumulative application of all effective filters reduced the error rate by 290-fold, facilitating the identification of genetic differences between monozygotic twins. We also applied an adapted, less stringent set of filters to reliably identify somatic mutations in a highly rearranged tumor and to identify variants in the NA19240 HapMap genome relative to a reference set of SNVs.
authors.affiliation: Vesalius Research Center, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.
authors.forename: Joke
authors.initials: J
authors.lastname: Reumers
authors.forename: Peter
authors.initials: P
authors.lastname: De Rijk
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.forename: Anthony
authors.initials: A
authors.lastname: Liekens
authors.forename: Dominiek
authors.initials: D
authors.lastname: Smeets
authors.forename: John
authors.initials: J
authors.lastname: Cleary
authors.forename: Peter
authors.initials: P
authors.lastname: Van Loo
authors.forename: Maarten
authors.initials: M
authors.lastname: Van Den Bossche
authors.forename: Kirsten
authors.initials: K
authors.lastname: Catthoor
authors.forename: Bernard
authors.initials: B
authors.lastname: Sabbe
authors.forename: Evelyn
authors.initials: E
authors.lastname: Despierre
authors.forename: Ignace
authors.initials: I
authors.lastname: Vergote
authors.forename: Brian
authors.initials: B
authors.lastname: Hilbush
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.forename: Jurgen
authors.initials: J
authors.lastname: Del-Favero
mesh_terms: D005260:Female; D015894:Genome, Human / Q000235:genetics*; D060148:HapMap Project; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012107:Research Design; D017422:Sequence Analysis, DNA / Q000379:methods*; D012984:Software; D014430:Twins, Monozygotic / Q000235:genetics