Copy number variations in East-Asian population and their evolutionary and functional implications

Abstract

Recent discovery of the copy number variation (CNV) in normal individuals has widened our understanding of genomic variation. However, most of the reported CNVs have been identified in Caucasians, which may not be directly applicable to people of different ethnicities. To profile CNV in East-Asian population, we screened CNVs in 3578 healthy, unrelated Korean individuals, using the Affymetrix Genome-Wide Human SNP array 5.0. We identified 144,207 CNVs using a pooled data set of 100 randomly chosen Korean females as a reference. The average number of CNVs per genome was 40.3, which is higher than that of CNVs previously reported using lower resolution platforms. The median size of CNVs was 18.9 kb (range 0.2-5406 kb). Copy number losses were 4.7 times more frequent than copy number gains. CNV regions (CNVRs) were defined by merging overlapping CNVs identified in two or more samples. In total, 4003 CNVRs were defined encompassing 241.9 Mb accounting for approximately 8% of the human genome. A total of 2077 CNVRs (51.9%) were potentially novel. Known CNVRs were larger and more frequent than novel CNVRs. Sixteen percent of the CNVRs were observed in > or =1% of study subjects and 24% overlapped with the OMIM genes. A total of 476 (11.9%) CNVRs were associated with segmental duplications. CNVS/CNVRs identified in this study will be valuable resources for studying human genome diversity and its association with disease.

Figure 1.

Size distribution of CNVs (A) and CNVRs (B) from this study with corresponding CNV/CNVRs from the DGV (August 2009 version). X-axis, the sizes in kilobases. Y-axis, the proportions of CNV/CNVRs within each size bin.

Figure 2.

Examples of signal intensity ratio plots of CNVRs. (A) A CNVR on 2p12, gain only. (B) A CNVR on 10g21.1, loss only. (C) A CNVR on 4p11, gain/loss complex. X-axis, genomic coordinates (Mb). Y-axis, signal intensity ratios (test/reference) in log₂ scale.

Figure 3.

Degree of match between CNVRs from this study and DGV CNVRs with respect to the allele frequency. X-axis, the degree of match (%). Y-axis, the allele frequency of CNVRs.

Figure 4.

Association of retrotransposons with CNVRs. (A) The mean regional fractions of the three retrotransposons around CNVRs by distance from the CNVRs. X-axis, the separating distance from the CNVRs. Y-axis, the fractions (%) of the retroelements. 95% confidence intervals are shown with error bars. (B) Divergence rates of the three retrotransposons around the CNVRs. X-axis, the separating distance from the CNVRs. Y-axis, the mean milliDivergence of the retroelements. 250 milliDivergence corresponds to 25.0% of divergence rates. The orientation of repeat sequences was determined with respect to the corresponding CNVRs; concordant elements are those whose tails are more closely located to CNVRs; divergent elements are those with opposite orientation. Calculation of milliDivergence was performed following the description at the RepeatMaskers (http://www.repeatmasker.org/).