Human Copy Number Variation and Complex Genetic Disease

Copy number variants (CNVs) play an important role in human disease and population diversity. Advancements in technology have allowed for the analysis of CNVs in thousands of individuals with disease in addition to thousands of controls. These studies have identified rare CNVs associated with neuropsychiatric diseases such as autism, schizophrenia, and intellectual disability. In addition, copy number polymorphisms (CNPs) are present at higher frequencies in the population, show high diversity in copy number, sequence, and structure, and have been associated with multiple phenotypes, primarily related to immune or environmental response. However, the landscape of copy number variation still remains largely unexplored, especially for smaller CNVs and those embedded within complex regions of the human genome. An integrated approach including characterization of single nucleotide variants and CNVs in a large number of individuals with disease and normal genomes holds the promise of thoroughly elucidating the genetic basis of human disease and diversity. 203 A nn u. R ev . G en et . 2 01 1. 45 :2 03 -2 26 . D ow nl oa de d fr om w w w .a nn ua lr ev ie w s. or g by W as hi ng to n U ni ve rs ity S t. L ou is o n 09 /2 2/ 14 . F or p er so na l u se o nl y. GE45CH10-Eichler ARI 1 October 2011 15:57 Copy number variant (CNV): an imbalance of genomic sequence (>50 bp) that alters the diploid status of a particular locus Comparative genomic hybridization (CGH): a method where the DNA from two individuals are labeled with different fluorescent dyes and hybridized to a microarray INTRODUCTION Recent studies have indicated that copy number variants (CNVs) are widespread in the human genome and are a significant source of human genetic variation accounting for disease and population diversity. Advances in wholegenome technologies, including array comparative genomic hybridization (CGH), single nucleotide polymorphism (SNP) microarrays, and genome sequencing, have enabled the discovery and characterization of variants that are intermediate between large chromosomal aberrations (>1 Mbp) and smaller insertions or deletions (1–50 bp) (Figure 1). These intermediate-sized variants, essentially deletions and duplications in the human genome, are called CNVs. Between any two individuals the number of basepair differences due to CNVs is >100-fold higher compared with SNPs (72). Current advances have also led to large-scale association studies for common 1 bp 1 chr Fr eq ue nc y SNP Trisomy Monosomy Copy number variants Size of variant 1 kb 1 Mb