Structural Biochemistry/Copy Number Variants

Copy Number Variants (CNVs) are a type of genetic mutation that results in an abnormal number genes or regions on a specific chromosome. CNVs contrast with Single Nucleotide Polymorphisms, which result in only a single mutated nucleotide. The development of SNPs outnumber CNVs by three orders of magnitude, their significance and contributions to variations are roughly similar. This is due to the fact that CNVs affect tens or thousands of kilobases, and thus its mutation impacts are large.

Importance of CNVs

Since CNVs contribute to a significant amount of differences between human genomes, they have been found to be important in both human disease and drug response. A better understanding of CNVs and how they work may help scientists better understand drug targets as well as human genome evolution.

Mutation Mechanisms

CNVs can arise from four different mechanisms: Nonallelic Homologous Recombination, Nonhomologous End-Joining, Fork Stalling and Template Switching, and Retrotransposition.

Nonallelic Homologous Recombination (NAHR), most commonly occurs during meiosis when two homologous chromosome pairs in the genome line up for crossing over. The positions of these chromosomes affect the rate at which a CNV mutation occurs. A slight mismatch of homologous chromosomes may result in the extra copy of a specific gene. Nonhomologous End-Joining (NHEJ) occurs when an abnormal repairing of a break of the DNA strand occurs. The repair results in either a deletion or more commonly a duplication of a segment in the genome. Forkstalling and Template Switching (FoSTeS) is induced by errors during DNA replication processes. These variants vary in both size and complexity. Retrotransposition of a DNA element may also result in an abnormal number of genes on a chromosome.

According to the 1000 Genomes Project, approximately 70.8% of deletions were attributed to NHEJ and 89.6% of small insertions were attributable to retrotransposition activity.

Clinical Significance

Most genetic mutations are benign. However, there have been few clinical studies showing that some of these genetic mutations may contribute to the onset of diseases. CNVs have been related to onsets of a prevalent amount of neuropsychiatric diseases, as a good proportion of schizophrenia, autism and bipolar cases are linked to CNVs. CNVs have also been found as an underlying cause elevated cancer cells.

References

Malhotra, Dheeraj, and Jonathan Sebat. "CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics." Cell 148.6 (2012): 1223-241. CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics. 16 Mar. 2012. Web. 15 June 2012. <http://www.cell.com/abstract/S0092-8674(12)00277-2>.

Daar AS, Scherer SW, Hegele RA. Implications for copy-number variation in the human genome: a time for questions. Nature Reviews Genetics, 2006, 7:414