Copy Number Variations in the Human Genome: Potential Source for Individual Diversity and Disease Association Studies

Abstract The widespread presence of large-scale genomic varia-tions, termed copy number variation (CNVs), has been recently recognized in phenotypically normal individuals. Judging by the growing number of reports on CNVs, it is now evident that these variants contribute significantly to genetic diversity in the human genome. Like single nucleotide polymorphisms (SNPs), CNVs are expected to serve as potential biomarkers for disease suscepti-bility or drug responses. However, the technical and practical concerns still remain to be tackled. In this re-view, we examine the current status of CNV DBs and research, including the ongoing efforts of CNV screening in the human genome. We also discuss the character-istics of platforms that are available at the moment and suggest the potential of CNVs in clinical research and application. Keywords: array-CGH, Copy number variation (CNV), Genome-wide association study (GWAS) Introduction Traditionally, large-scale genomic variants that are visi-ble in conventional karyotyping have been thought to be associated with early-onset, highly penetrant genetic disorders, while they are incompatible in normal, dis-ease-free individuals (Lupski, 1998; Stankiewicz and Lupski, 2002). The construction of the 'reference ge-nome' by the human genome sequencing project is based on the belief that human genome sequences are virtually identical, even in different individuals, except for well-known single nucleotide polymorphisms (SNP) or size-variants of tandem repeats such as mini- or micro-satellites (variable number of tandem repeats or VNTR) (Przeworski et al., 2000). This traditional concept has been recently challenged by the discovery that large structural variations are more prevalent than previously presumed (Check, 2005). Using high-resolution whole- genome scanning technologies such as array-based comparative genomic hybridization (array-CGH), two groups of pioneering scientists have identified wide-spread copy number variations (CNVs) in apparently healthy, normal individuals (Iafrate et al., 2004; Sebat et al., 2004). It proposes that our genome is more diverse than has ever been recognized, and subsequent studies have identified up to 11,000 CNVs across the whole ge-nome (Tuzun et al., 2005; Hinds et al., 2006; Mills et al., 2006; McCarroll et al., 2006; Conrad et al., 2006; Sharp et al., 2005; Wong et al., 2007; de Smith et al., 2007). Although the current understanding of CNVs is still limited for practical use and technical challenges still re-main to be tackled, recent studies already have demon-strated the potential association of CNVs with various diseases, suggesting plausible functional significances and highlighting the promising utility of CNVs. The current coverage of CNVs in the human genome already has exceeded that of SNPs (approximately 600 Mb comprising ∼12% of human genome) and is still in-creasing (Cooper et al., 2007). These large-scale struc-tural variants, in addition to SNPs, will serve as powerful sources to help our understanding of human genetic variation and of differences in disease susceptibility for various diseases. This paper reviews the current knowl-edge and future perspectives of CNVs.