Structural Diversity of the Human Genome and Disease Susceptibility


Structural genomic variants (SGVs) can span in size from the large microscopically visible chromosomal aberrations (>5 Mb) to variants identified at the DNA (deoxyribonucleic acid) sequence level (e.g. small insertions/deletions of a few base pairs). It has recently been shown that SGVs are widespread among humans, have some degree of specificity within human continental groups, and likely contribute significantly to differential disease susceptibility. Currently, the most common prevalent form of SGVs is copy number variants (CNVs), which are defined as DNA segments greater than 1 kb in length that exist in variable copy numbers between individuals. In this review, we provide an overview of our current understanding of human structural genomic variation, with a particular focus on CNVs and their associations in disease susceptibility.

Keywords: copy number variants; segmental duplications; disease susceptibility; structural genomic variation; complex disease

Figure 1.

Different types and sizes of structural variation in the genome.

Figure 2.

Examples of balanced and unbalanced (SGV). (a) An example of a balanced SGV. Here a region on 7p is exchanged with a region on 10p. (b) An example of an unbalanced SGV. Here a deletion is visualized on 5q and a duplication on 5p.

Figure 3.

A simplistic view of NAHR. Normally this would include initital double strand breaks in each chromosome and formation of a Holliday junction. (a) NAHR between repeated regions of misaligned chromosomes results in a gain of ‘abcd’ on one chromatid of a chromosome and a loss of the same ‘abcd’ on one chromatid of the other chromosome. Additionally, intrachromosomal NAHR can produce (b) deletions or (c) inversions depending on the orientation of the repeats that serve as substrates.

Figure 4.

Nonhomologous end‐joining (NHEJ) can result in the rearrangement or loss of genetic material after multiple double strand breaks (DSBs) occur because the ends of DSBs do not require extensive sequence homology for the ligation repair mechanism. (a) A balanced translocation can occur because the DSB between ‘abcd’ and ‘ef’ on the red chromosome and ‘ab’ and ‘cdef’ on the blue chromosome results in chromosome fragments that are incorrectly ligated together. (b) An unbalanced translocation can occur when two DSBs are on the same chromosome and the genomic material between them is lost during ligation as visualized by the loss of the ‘cd’ region (the acentric fragment).

Figure 5.

Array‐based comparative genomic hybridization (aCGH) (a) A test genome (labelled with a red dye) and a reference genome (labelled with a green dye) are hybridized to an array of probes representing different regions of the genome. Cot‐1 DNA is also added to block repetitive elements that may produce background signals. Fluorescence intensities of the spots on the microarray are quantitated to reflect relative copy number differences between the test subject and the reference at a particular genomic region. Red and green spots on the enlarged portion of the array represent excess of the relative intensity of one probe over the other probe. Green spots represent an excess of DNA from the reference sample indicating a relative loss in the test sample, while red spots represent an excess of DNA from the test sample indicating a relative gain. (b) The log2 values of the fluorescence ratios (y‐axis) for each DNA segment on the array are plotted from one end of a chromosome to the other (x‐axis). CNVs are usually called by the presence of multiple consecutive probes that deviate significantly from the expected log2 of 0.

Figure 6.

Quantitative PCR (qPCR) validation of CNVs. A duplicated region in the test individual (blue) relative to the reference individual (grey) is validated by performing qPCR using primers (black arrows) that amplify a small region located inside the CNV. The right panel shows the 2‐fold increase of the amount of fluorescent intensity generated in the test DNA generated by qPCR, compared to the reference.

Figure 7.

Fluorescent in situ hybridization (FISH) of human metaphase chromosomes. Shown are subtelomeric probes in green and red that hybridize to the end of the short and long arms of chromosome 6, respectively. One chromosome 6 has a deletion of the long arm subtelomere segment, identified by the absence of the red fluorescent signal.



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Further Reading

Conrad DF and Hurles ME (2007) The population genetics of structural variation. Nature Genetics 39(suppl. 7): S30–S36.

Lee C, Iafrate AJ and Brothman AR (2007) Copy number variations and clinical cytogenetic diagnosis of constitutional disorders. Nature Genetics 39(suppl. 7): S48–S54.

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Smith, Richard S, Gutiérrez‐Arcelus, María, Tran, Charles W, Park, Stephanie, Couter, Cheryn J, and Lee, Charles(Jul 2008) Structural Diversity of the Human Genome and Disease Susceptibility. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0020764]