Table 1.
Associations Identified in GWASs for Common Disorders Using Genotyping Arrays
Figure 1.
Types of Genomic Structural Changes Affecting Segments of DNA, Leading to Deletions, Duplications, Inversions, and CNV Changes (Biallelic, Multillelic, and Complex)
The only segment that is constant is “A.” Segment “B” varies in orientation in the inversion. Segments “C” and “D” show different types of variation.
Table 2.
Summary of Genome Scans to Study Structural Variations and CNVs of the Human Genome
Figure 2.
Approaches Used for the Identification of CNVs and Other Types of Structural Changes in the Human Genome
Myriad methods and technologies have been employed to identify structural variants in the human genome. They are based on completely different experimental procedures and provide very different levels of resolution. The majority of findings (>80%) are attributable to a restricted number of high-throughput experiments with a limited resolution.
Table 3.
Summary of Common Disorders for Which Associations to CNVs Have Been Reported
Figure 3.
Expected and Observed Size Distribution of CNV Changes Identified to Date
Blue bars represent the frequencies of the currently identified CNVs in the size ranges depicted in the x-axis. A plausible scenario of variation in CNV size frequency is depicted as red vertical bars. An under-detection of variable fragments of small size (<50 kb) can be observed, which is likely due to technological limitations in the high-throughput assays used so far to identify CNVs, largely based on array CGH (Figure 2). Observed and expected CNVs that are >50 kb coincide, due to the powerful array methods, which cover the medium-to-large-size CNVs well. Dark blue bars represent the small-sized CNVs, which are more of a challenge to detect.
Figure 4.
Genomic Organization of the Chemokine Cluster on Human Chromosome 17, Containing the CCL3L1 Gene (Red Arrows), Which Shows Variability in Copy Number and Association to HIV-1 Infectivity and AIDS Susceptibility
This region contains several segmental duplications and has been reported to vary in copy number in several studies. The Affymetrix 500K and Illumina HumanHap 550 arrays do not cover this region well, and completely lack SNPs in the CCL3L1/L3 gene (red dotted lines). A large number of gains and losses have been reported in the HapMap samples. Numbers in parentheses indicate the number of events involving genomic changes.
CEU, European; HCB, Chinese; JPT, Japanese; YRI, African.
Figure 5.
Schematic Representation of Two Genomic Regions That Involve CNVs Associated with SLE [65,66]
(A) The region of Chromosome 1 containing the FCGR3 gene cluster is highly variable and contains segmental duplications with a high sequence identity. Several CNVs have been reported that span this region. The genomic organization of the cluster is highly complex and not well solved in the current assembly of the genome sequence. The Affymetrix 500K and Illumina HumanHap 550 arrays do not cover this region well (red dotted lines).
(B) The region of Chromosome 6p21, containing the C4A and C4B genes, is embedded in a region of complex genomic organization [67,69,70]. The region has been shown to contain segmental duplications and CNVs. The Affymetrix 500K and Illumina HumanHap 550 genotyping platforms do not cover this region, either (red dotted lines).
Figure 6.
CNV Characterization Strategies
(A) Scales of resolution at the nucleotide level and maximum number of loci interrogated by the different methods (only the most widely used approaches are shown).
(B) Diagram of different approaches in CNV analysis, either at the genome-wide scale or at individual/multiplex loci. Arrows indicate the deeper analysis that is needed after initial detection by one methodology or another.
DASH, dynamic allele-specific hybridization [80]; PRT, paralogue ratio test [81]; MAQ, multiple amplicon quantification [82]; qPCR, quantitative PCR.