title: Towards a comprehensive structural variation map of an individual human genome.
abstract: BACKGROUND
  Several genomes have now been sequenced, with millions of genetic variants annotated. While significant progress has been made in mapping single nucleotide polymorphisms (SNPs) and small (<10 bp) insertion/deletions (indels), the annotation of larger structural variants has been less comprehensive. It is still unclear to what extent a typical genome differs from the reference assembly, and the analysis of the genomes sequenced to date have shown varying results for copy number variation (CNV) and inversions.
  
  
  RESULTS
  We have combined computational re-analysis of existing whole genome sequence data with novel microarray-based analysis, and detect 12,178 structural variants covering 40.6 Mb that were not reported in the initial sequencing of the first published personal genome. We estimate a total non-SNP variation content of 48.8 Mb in a single genome. Our results indicate that this genome differs from the consensus reference sequence by approximately 1.2% when considering indels/CNVs, 0.1% by SNPs and approximately 0.3% by inversions. The structural variants impact 4,867 genes, and >24% of structural variants would not be imputed by SNP-association.
  
  
  CONCLUSIONS
  Our results indicate that a large number of structural variants have been unreported in the individual genomes published to date. This significant extent and complexity of structural variants, as well as the growing recognition of their medical relevance, necessitate they be actively studied in health-related analyses of personal genomes. The new catalogue of structural variants generated for this genome provides a crucial resource for future comparison studies.
authors.affiliation: Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada. andypang@sickkids.ca
authors.forename: Andy W
authors.initials: AW
authors.lastname: Pang
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: MacDonald
authors.forename: Dalila
authors.initials: D
authors.lastname: Pinto
authors.forename: John
authors.initials: J
authors.lastname: Wei
authors.forename: Muhammad A
authors.initials: MA
authors.lastname: Rafiq
authors.forename: Donald F
authors.initials: DF
authors.lastname: Conrad
authors.forename: Hansoo
authors.initials: H
authors.lastname: Park
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.forename: J Craig
authors.initials: JC
authors.lastname: Venter
authors.forename: Ewen F
authors.initials: EF
authors.lastname: Kirkness
authors.forename: Samuel
authors.initials: S
authors.lastname: Levy
authors.forename: Lars
authors.initials: L
authors.lastname: Feuk
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
mesh_terms: D020029:Base Pairing / Q000235:genetics; D002874:Chromosome Mapping / Q000379:methods*; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics; D030541:Databases, Genetic; D005787:Gene Frequency / Q000235:genetics; D015723:Gene Library; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009154:Mutation / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA