Deletions and duplications of chromosomal segments (copy number variants, CNVs) are a major source of variation between individual humans and are an underlying factor in human evolution and in many diseases, including mental illness, developmental disorders and cancer. CNVs form at a faster rate than other types of mutation, and seem to do so by similar mechanisms in bacteria, yeast and humans. Here we review current models of the mechanisms that cause copy number variation. Non-homologous end-joining mechanisms are well known, but recent models focus on perturbation of DNA replication and replication of non-contiguous DNA segments. For example, cellular stress might induce repair of broken replication forks to switch from high-fidelity homologous recombination to non-homologous repair, thus promoting copy number change.
Replication stress induces genome-wide copy number changes in human cells that resemble polymorphic and pathogenic variants.Am J Hum Genet. 2009 Mar;84(3):339-50. doi: 10.1016/j.ajhg.2009.01.024. Epub 2009 Feb 19. Am J Hum Genet. 2009. PMID: 19232554 Free PMC article.
Analysis of copy number variants and segmental duplications in the human genome: Evidence for a change in the process of formation in recent evolutionary history.Genome Res. 2008 Dec;18(12):1865-74. doi: 10.1101/gr.081422.108. Epub 2008 Oct 8. Genome Res. 2008. PMID: 18842824 Free PMC article.
Ionizing radiation and genetic risks XIV. Potential research directions in the post-genome era based on knowledge of repair of radiation-induced DNA double-strand breaks in mammalian somatic cells and the origin of deletions associated with human genomic disorders.Mutat Res. 2005 Oct 15;578(1-2):333-70. doi: 10.1016/j.mrfmmm.2005.06.020. Epub 2005 Aug 5. Mutat Res. 2005. PMID: 16084534 Review.
A microhomology-mediated break-induced replication model for the origin of human copy number variation.PLoS Genet. 2009 Jan;5(1):e1000327. doi: 10.1371/journal.pgen.1000327. Epub 2009 Jan 30. PLoS Genet. 2009. PMID: 19180184 Free PMC article. Review.
Origins and breakpoint analyses of copy number variations: up close and personal.Cytogenet Genome Res. 2011;135(3-4):271-6. doi: 10.1159/000330267. Epub 2011 Aug 12. Cytogenet Genome Res. 2011. PMID: 21846967 Review.
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