title: Comprehensive variation discovery in single human genomes.
abstract: Complete knowledge of the genetic variation in individual human genomes is a crucial foundation for understanding the etiology of disease. Genetic variation is typically characterized by sequencing individual genomes and comparing reads to a reference. Existing methods do an excellent job of detecting variants in approximately 90% of the human genome; however, calling variants in the remaining 10% of the genome (largely low-complexity sequence and segmental duplications) is challenging. To improve variant calling, we developed a new algorithm, DISCOVAR, and examined its performance on improved, low-cost sequence data. Using a newly created reference set of variants from the finished sequence of 103 randomly chosen fosmids, we find that some standard variant call sets miss up to 25% of variants. We show that the combination of new methods and improved data increases sensitivity by several fold, with the greatest impact in challenging regions of the human genome.
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Neil I
authors.initials: NI
authors.lastname: Weisenfeld
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Shuangye
authors.identifier: 0000000227792584
authors.initials: S
authors.lastname: Yin
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Ted
authors.initials: T
authors.lastname: Sharpe
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Bayo
authors.initials: B
authors.lastname: Lau
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Hegarty
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Laurie
authors.initials: L
authors.lastname: Holmes
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Sogoloff
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Tabbaa
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Louise
authors.initials: L
authors.lastname: Williams
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Carsten
authors.initials: C
authors.lastname: Russ
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Chad
authors.initials: C
authors.lastname: Nusbaum
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Iain
authors.initials: I
authors.lastname: MacCallum
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Jaffe
mesh_terms: D000465:Algorithms; D001483:Base Sequence; D002874:Chromosome Mapping; D005787:Gene Frequency; D014644:Genetic Variation; D016678:Genome; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D012984:Software