title: Genome assembly comparison identifies structural variants in the human genome.
abstract: Numerous types of DNA variation exist, ranging from SNPs to larger structural alterations such as copy number variants (CNVs) and inversions. Alignment of DNA sequence from different sources has been used to identify SNPs and intermediate-sized variants (ISVs). However, only a small proportion of total heterogeneity is characterized, and little is known of the characteristics of most smaller-sized (<50 kb) variants. Here we show that genome assembly comparison is a robust approach for identification of all classes of genetic variation. Through comparison of two human assemblies (Celera's R27c compilation and the Build 35 reference sequence), we identified megabases of sequence (in the form of 13,534 putative non-SNP events) that were absent, inverted or polymorphic in one assembly. Database comparison and laboratory experimentation further demonstrated overlap or validation for 240 variable regions and confirmed >1.5 million SNPs. Some differences were simple insertions and deletions, but in regions containing CNVs, segmental duplication and repetitive DNA, they were more complex. Our results uncover substantial undescribed variation in humans, highlighting the need for comprehensive annotation strategies to fully interpret genome scanning and personalized sequencing projects.
authors.affiliation: Program in Genetics and Genomic Biology, The Hospital for Sick Children and Department of Molecular and Medical Genetics, University of Toronto and The Centre for Applied Genomics, MaRS Centre, Toronto, Ontario, M5G 1L7, Canada.
authors.forename: Razi
authors.initials: R
authors.lastname: Khaja
authors.forename: Junjun
authors.initials: J
authors.lastname: Zhang
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: MacDonald
authors.forename: Yongshu
authors.initials: Y
authors.lastname: He
authors.forename: Ann M
authors.initials: AM
authors.lastname: Joseph-George
authors.forename: John
authors.initials: J
authors.lastname: Wei
authors.forename: Muhammad A
authors.initials: MA
authors.lastname: Rafiq
authors.forename: Cheng
authors.initials: C
authors.lastname: Qian
authors.forename: Mary
authors.initials: M
authors.lastname: Shago
authors.forename: Lorena
authors.initials: L
authors.lastname: Pantano
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Keith
authors.initials: K
authors.lastname: Jones
authors.forename: Richard
authors.initials: R
authors.lastname: Redon
authors.forename: Matthew
authors.initials: M
authors.lastname: Hurles
authors.forename: Lluis
authors.initials: L
authors.lastname: Armengol
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Mural
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.forename: Lars
authors.initials: L
authors.lastname: Feuk
mesh_terms: D001483:Base Sequence; D004247:DNA / Q000235:genetics; D014644:Genetic Variation; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D016133:Polymerase Chain Reaction; D016415:Sequence Alignment
chemical_list: D004247:DNA