title: Population analysis of large copy number variants and hotspots of human genetic disease.
abstract: Copy number variants (CNVs) contribute to human genetic and phenotypic diversity. However, the distribution of larger CNVs in the general population remains largely unexplored. We identify large variants in approximately 2500 individuals by using Illumina SNP data, with an emphasis on "hotspots" prone to recurrent mutations. We find variants larger than 500 kb in 5%-10% of individuals and variants greater than 1 Mb in 1%-2%. In contrast to previous studies, we find limited evidence for stratification of CNVs in geographically distinct human populations. Importantly, our sample size permits a robust distinction between truly rare and polymorphic but low-frequency copy number variation. We find that a significant fraction of individual CNVs larger than 100 kb are rare and that both gene density and size are strongly anticorrelated with allele frequency. Thus, although large CNVs commonly exist in normal individuals, which suggests that size alone can not be used as a predictor of pathogenicity, such variation is generally deleterious. Considering these observations, we combine our data with published CNVs from more than 12,000 individuals contrasting control and neurological disease collections. This analysis identifies known disease loci and highlights additional CNVs (e.g., 3q29, 16p12, and 15q25.2) for further investigation. This study provides one of the first analyses of large, rare (0.1%-1%) CNVs in the general population, with insights relevant to future analyses of genetic disease.
authors.affiliation: Department of Genome Sciences, School of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Andy
authors.initials: A
authors.lastname: Itsara
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Cooper
authors.forename: Carl
authors.initials: C
authors.lastname: Baker
authors.forename: Santhosh
authors.initials: S
authors.lastname: Girirajan
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Devin
authors.initials: D
authors.lastname: Absher
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Krauss
authors.forename: Richard M
authors.initials: RM
authors.lastname: Myers
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ridker
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
authors.forename: Heather
authors.initials: H
authors.lastname: Mefford
authors.forename: Phyllis
authors.initials: P
authors.lastname: Ying
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
mesh_terms: D018628:Gene Dosage; D020440:Gene Duplication; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D014644:Genetic Variation; D005828:Genetics, Population; D015894:Genome, Human; D005838:Genotype; D005843:Geography; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D017384:Sequence Deletion