title: A reference data set of 5.4 million phased human variants validated by genetic inheritance from sequencing a three-generation 17-member pedigree.
abstract: Improvement of variant calling in next-generation sequence data requires a comprehensive, genome-wide catalog of high-confidence variants called in a set of genomes for use as a benchmark. We generated deep, whole-genome sequence data of 17 individuals in a three-generation pedigree and called variants in each genome using a range of currently available algorithms. We used haplotype transmission information to create a phased "Platinum" variant catalog of 4.7 million single-nucleotide variants (SNVs) plus 0.7 million small (1-50 bp) insertions and deletions (indels) that are consistent with the pattern of inheritance in the parents and 11 children of this pedigree. Platinum genotypes are highly concordant with the current catalog of the National Institute of Standards and Technology for both SNVs (>99.99%) and indels (99.92%) and add a validated truth catalog that has 26% more SNVs and 45% more indels. Analysis of 334,652 SNVs that were consistent between informatics pipelines yet inconsistent with haplotype transmission ("nonplatinum") revealed that the majority of these variants are de novo and cell-line mutations or reside within previously unidentified duplications and deletions. The reference materials from this study are a resource for objective assessment of the accuracy of variant calls throughout genomes.
authors.affiliation: Illumina Incorporated, San Diego, California 92122, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Eberle
authors.affiliation: Illumina Limited, Chesterford Research Park, Little Chesterford, Nr Saffron Walden, Essex, CB10 1XL, United Kingdom.
authors.forename: Epameinondas
authors.initials: E
authors.lastname: Fritzilas
authors.affiliation: Illumina Limited, Chesterford Research Park, Little Chesterford, Nr Saffron Walden, Essex, CB10 1XL, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Krusche
authors.affiliation: Illumina Limited, Chesterford Research Park, Little Chesterford, Nr Saffron Walden, Essex, CB10 1XL, United Kingdom.
authors.forename: Morten
authors.initials: M
authors.lastname: Källberg
authors.affiliation: Illumina Limited, Chesterford Research Park, Little Chesterford, Nr Saffron Walden, Essex, CB10 1XL, United Kingdom.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Moore
authors.affiliation: Illumina Limited, Chesterford Research Park, Little Chesterford, Nr Saffron Walden, Essex, CB10 1XL, United Kingdom.
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Bekritsky
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, United Kingdom.
authors.forename: Zamin
authors.initials: Z
authors.lastname: Iqbal
authors.affiliation: Illumina Incorporated, San Diego, California 92122, USA.
authors.forename: Han-Yu
authors.initials: HY
authors.lastname: Chuang
authors.affiliation: Illumina Limited, Chesterford Research Park, Little Chesterford, Nr Saffron Walden, Essex, CB10 1XL, United Kingdom.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Humphray
authors.affiliation: Illumina Incorporated, San Diego, California 92122, USA.
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Halpern
authors.affiliation: Illumina Incorporated, San Diego, California 92122, USA.
authors.forename: Semyon
authors.initials: S
authors.lastname: Kruglyak
authors.affiliation: Illumina Incorporated, San Diego, California 92122, USA.
authors.forename: Elliott H
authors.initials: EH
authors.lastname: Margulies
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, United Kingdom.|Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, OX3 7BN, United Kingdom.
authors.forename: Gil
authors.initials: G
authors.lastname: McVean
authors.affiliation: Illumina Limited, Chesterford Research Park, Little Chesterford, Nr Saffron Walden, Essex, CB10 1XL, United Kingdom.
authors.forename: David R
authors.initials: DR
authors.lastname: Bentley
mesh_terms: D000465:Algorithms; D030541:Databases, Genetic; D059472:Exome / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA / Q000379:methods*; D012984:Software