Abstract
To examine copy number variations among the Korean population, we compared individual genomes with the Korean reference genome assembly using the publicly available Korean HapMap SNP 50 k chip data from 90 individuals. Korean individuals exhibited 123 copy number variation regions (CNVRs) covering 27.2 mb, equivalent to 1.0% of the genome in the copy number variation (CNV) analysis using the combined criteria of P value (P<0.01) and standard deviation of copy numbers (SD>or= 0.25) among study subjects. In contrast, when compared to the Affymetrix reference genome assembly from multiple ethnic groups, considerably more CNVRs (n=643) were detected in larger proportions (5.0%) of the genome covering 135.1 mb even by more stringent criteria (P<0.001 and SD>or=0.25), reflecting ethnic diversity of structural variations between Korean and other populations. Some CNVRs were validated by the quantitative multiplex PCR of short fluorescent fragment (QMPSF) method, and then copy number invariant regions were detected among the study subjects. These copy number invariant regions would be used as good internal controls for further CNV studies. Lastly, we demonstrated that the CNV information could stratify even a single ethnic population with a proper reference genome assembly from multiple heterogeneous populations.
Highlights
Human genetic variations comprise various types of structural genomic changes and single nucleotide polymorphisms (SNPs)
Two different reference sets were used to detect copy number variations (CNVs) from study subjects (n = 90); 1) the Korean reference set generated from all the genomes of 90 individuals, 2) the Affymetrix reference set provided as a copy number reference from multiple ethnic groups by Affymetrix Inc
Our P value-based CNV analysis using the Korean reference set showed that 90 Korean individuals represented 435 copy number variation regions (CNVRs) covering 123 mb equivalent to 4.1% of the genome using a cutoff of P < 0.01, while the choice of a more stringent cutoff of P < 0.001 allowed detection of less CNVRs (n = 126) covering 35 mb (1.2%) (Supplemental Data Table S1)
Summary
Human genetic variations comprise various types of structural genomic changes and single nucleotide polymorphisms (SNPs). Large microscopic changes affect more than tens of millions of bases (mb) in the genome, and are rare in healthy individuals, but smaller structural variations ranging from 1 kb to hundreds of kb are frequent and widespread even in normal individuals, contributing to human genetic diversity or disease susceptibility (Feuk et al, 2006; Freeman et al, 2006) Such submicroscopic genomic variations have been defined in terms of copy number variations (CNVs) and include large-scale copy number variants (LCVs) (Iafrate et al, 2004), copy number polymorphisms (CNPs) (Sebat et al, 2004), and intermediate-sized variants (ISVs) (Tuzun et al, 2005), as well as other types of genomic variations such as low copy repeats (LCRs) (Lupski and Stankiewicz, 2005), multisite variants (MSVs) (Fredman et al, 2004), and paralogous sequence variants (PSV) (Eichler 2001). Recent studies have shown that DNA copy number variations are implicated in human diseases including glomerulonephritis (FCGR3B) (Aitman et al, 2006), HIV-1/AIDS (CCL3L1) (Gonzalez et al, 2005), bipolar disorder and schizophrenia (GLUR7, CACNG2 and AKAP5) (Wilson et al, 2006), muscular atrophy (SMN) (Kesari et al, 2005) and neoplasia (14q12) (Braude et al, 2006)
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