Copy number variation in human health, disease, and evolution

Abstract

Copy number variation (CNV) is a source of genetic diversity in humans. Numerous CNVs are being identified with various genome analysis platforms, including array comparative genomic hybridization (aCGH), single nucleotide polymorphism (SNP) genotyping platforms, and next-generation sequencing. CNV formation occurs by both recombination-based and replication-based mechanisms and de novo locus-specific mutation rates appear much higher for CNVs than for SNPs. By various molecular mechanisms, including gene dosage, gene disruption, gene fusion, position effects, etc., CNVs can cause Mendelian or sporadic traits, or be associated with complex diseases. However, CNV can also represent benign polymorphic variants. CNVs, especially gene duplication and exon shuffling, can be a predominant mechanism driving gene and genome evolution.

Figure 1

Size distribution of copy number variations (CNVs) larger than 100 bp. Red, CNVs in the Venter genome (81); purple, CNVs in the Watson genome (177); blue, CNVs in Redon et al. (132); green, deletion CNVs in Korbel et al. (68); yellow, deletion CNVs in Kidd et al. (64). Note the greater detection of smaller-sized CNVs with higher-resolution genome analysis.

Figure 2

Low-copy repeats (LCRs) or segmental duplications (SDs) in the human genome. (a) LCR orientations (direct, reverse, and complex LCRs). (b) Examples of complex LCR. NPHP1, the shaded blue representing the inverted 330-kb repeats and the green arrows for the direct 45-kb repeats (adapted from Reference 135). The WBS locus at 7q11.23, Blocks A, B, and C of centromeric (c), medial (m), and telomeric (t) LCRs represented by black arrows (adapted from Reference 9). The Sos locus, six subunit LCRs between the proximal and the distal Sos-REPs (A-F) and their orientation depicted by the arrowhead (adapted from Reference 72).

Figure 3

Comparisons and characteristics of the four major mechanisms underlying human genomic rearrangements and CNV formation. (a) Models for Non-Allelic Homologous Recombination (NAHR) between repeat sequences (LCRs/SDs, Alu, or L1 elements); Non-Homologous End-Joining (NHEJ), recombination repair of double strand break; Fork Stalling and Template Switching (FoSTeS), multiple FoSTeS events (×2 or more) resulting in complex rearrangement and single FoSTeS event (×1) causing simple rearrangement; and retrotransposition. TS, target site; TSD, duplicated target site. Adapted from References (47, 123). Thick bars of different colors indicate different genomic fragments; completely different colors (as orange and red or orange/red/green in FoSTeS×2) symbolize that no homology between the two fragments is required. The two bars in two similar shades of blue indicate that the two fragments involved in NAHR should have extensive homology with each other. The triangles symbolize short sequences sharing microhomologies. Each group of triangles (either filled or empty) indicates one group of sequences sharing the same microhomology with each other. (b) Characteristic features for each rearrangement mechanism. Specific features of certain mechanisms are shown in red. Abbreviations: dup, duplication; del, deletion; inv, inversion; ins, insertion.

Figure 4

New mutation rates for SNP versus CNV. Constant SNP mutation rates and variable CNV mutation rates across the human genome. Examples of human disease traits (OMIM numbers are shown) with different contribution of CNV versus SNP. Note that for some diseases at specific loci, CNVs outweigh SNPs as a mutational cause for disease. CNV de novo locus-specific rates can vary throughout the genome, whereas SNP rates are essentially constant. The SNP rate for CpG dinucleotides is constant but about ten times higher than other bases because of methyl-mediated deamination of cytosine to uracil, causing transition mutations.