title: Large multiallelic copy number variations in humans.
abstract: Thousands of genomic segments appear to be present in widely varying copy numbers in different human genomes. We developed ways to use increasingly abundant whole-genome sequence data to identify the copy numbers, alleles and haplotypes present at most large multiallelic CNVs (mCNVs). We analyzed 849 genomes sequenced by the 1000 Genomes Project to identify most large (>5-kb) mCNVs, including 3,878 duplications, of which 1,356 appear to have 3 or more segregating alleles. We find that mCNVs give rise to most human variation in gene dosage-seven times the combined contribution of deletions and biallelic duplications-and that this variation in gene dosage generates abundant variation in gene expression. We describe 'runaway duplication haplotypes' in which genes, including HPR and ORM1, have mutated to high copy number on specific haplotypes. We also describe partially successful initial strategies for analyzing mCNVs via imputation and provide an initial data resource to support such analyses.
authors.affiliation: 1] Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Robert E
authors.identifier: 0000000231283547
authors.initials: RE
authors.lastname: Handsaker
authors.affiliation: 1] Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Van Doren
authors.affiliation: Digital Biology Center, Bio-Rad Laboratories, Inc., Pleasanton, California, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Berman
authors.affiliation: 1] Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Giulio
authors.initials: G
authors.lastname: Genovese
authors.affiliation: 1] Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Seva
authors.initials: S
authors.lastname: Kashin
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Boettger
authors.affiliation: 1] Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: McCarroll
mesh_terms: D000483:Alleles; D056915:DNA Copy Number Variations; D018628:Gene Dosage; D015894:Genome, Human; D055106:Genome-Wide Association Study / Q000379:methods*; D006239:Haplotypes; D006801:Humans