title: Population-genetic nature of copy number variations in the human genome.
abstract: Copy number variations (CNVs) are universal genetic variations, and their association with disease has been increasingly recognized. We designed high-density microarrays for CNVs, and detected 3000-4000 CNVs (4-6% of the genomic sequence) per population that included CNVs previously missed because of smaller sizes and residing in segmental duplications. The patterns of CNVs across individuals were surprisingly simple at the kilo-base scale, suggesting the applicability of a simple genetic analysis for these genetic loci. We utilized the probabilistic theory to determine integer copy numbers of CNVs and employed a recently developed phasing tool to estimate the population frequencies of integer copy number alleles and CNV-SNP haplotypes. The results showed a tendency toward a lower frequency of CNV alleles and that most of our CNVs were explained only by zero-, one- and two-copy alleles. Using the estimated population frequencies, we found several CNV regions with exceptionally high population differentiation. Investigation of CNV-SNP linkage disequilibrium (LD) for 500-900 bi- and multi-allelic CNVs per population revealed that previous conflicting reports on bi-allelic LD were unexpectedly consistent and explained by an LD increase correlated with deletion-allele frequencies. Typically, the bi-allelic LD was lower than SNP-SNP LD, whereas the multi-allelic LD was somewhat stronger than the bi-allelic LD. After further investigation of tag SNPs for CNVs, we conclude that the customary tagging strategy for disease association studies can be applicable for common deletion CNVs, but direct interrogation is needed for other types of CNVs.
authors: Center for Genomic Medicine, RIKEN, 1-7-22 Suehiro, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors: Mamoru
authors: M
authors: Kato
authors: Takahisa
authors: T
authors: Kawaguchi
authors: Shumpei
authors: S
authors: Ishikawa
authors: Takayoshi
authors: T
authors: Umeda
authors: Reiichiro
authors: R
authors: Nakamichi
authors: Michael H
authors: MH
authors: Shapero
authors: Keith W
authors: KW
authors: Jones
authors: Yusuke
authors: Y
authors: Nakamura
authors: Hiroyuki
authors: H
authors: Aburatani
authors: Tatsuhiko
authors: T
authors: Tsunoda
mesh_terms: D056915:DNA Copy Number Variations; D018628:Gene Dosage; D005787:Gene Frequency; D005828:Genetics, Population; D015894:Genome, Human; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D044382:Population Groups / Q000235:genetics