Copy number variation

Examples of types of chromosome mutation

Copy number variation (short CNV , German copy number variation ) describes a form of structural variation of the genetic material (short SV , English structural variation ), which generates deviations in the number of copies of a certain DNA segment within a genome . If it was initially assumed that genes in the genome are usually present in two copies (one copy per chromosome set), some genes showed a variation in the number of gene copies between different individuals. A gene can be present in just one copy number ( gene deletion ) or in more than three or four copies ( gene duplication ). Genes can also be completely absent ( homozygous gene deletion). Similar to single nucleotide polymorphisms (or SNPs ), individuals can also be clearly distinguished from one another based on the presence or absence of CNVs. CNVs can affect one's predisposition to certain diseases. Compared to SNPs, CNVs generate a greater number of genetic differences between people, based on the number of DNA building blocks ( nucleotides ) affected by CNVs .

Analytical methods

For CNV identification in the genome, both microarray- based techniques and, increasingly, DNA sequencing , in particular methods of "second generation sequencing", are used. Analysis of data from a pilot study of the 1000 Genome Project enabled the identification of 28,000 CNVs in the genomes of 185 individuals using four different DNA sequence-based analysis methods. These four methods include end-pair sequencing and its bioinformatic analysis ( paired-end mapping ), the direct alignment of DNA sequences via the terminals (or "breakpoints") of CNVs ( split-read analysis ), sequence depth analysis ( read-depth analysis ) and the use of bioinformatic methods for sequence assembly ( sequence assembly ). In contrast to microarray-based techniques, DNA sequencing enables the detection of a greater number of classes of structural variations, including inversions and translocations .

Medical importance

Schematic representation of the nicotinic ACh receptor

Duplications and deletions can have very different effects depending on the size (length) of the affected DNA segment and depending on the gene density of the affected chromosome region. Initially, gene-free zones, part of a gene, a complete gene or several genes can be affected. Then the consequences depend on the function of the affected genes. The spectrum ranges from fatal ( miscarriage ) to harmless. In addition - even within a family - the penetration ( penetrance and expressivity ) of such a genetic deviation can vary greatly from person to person (0–100%).

Since part of the genetic information in deletions is only present once instead of twice or is even completely absent, the possibility of disorders caused by this is obvious. Duplication disorders are harder to explain. There have been observations here that an additional copy of a gene can result in excessive gene activity ( gene expression ). For example, an excessive number of components for a receptor can be produced in a certain time window , which can lead to stress and incorrect development of cells.

Many developmental disorders, such as disorders in the autism spectrum , are often caused by copy number variations - often several at the same time in different locations.

literature

• M. Saitou, O. Gokcumen: An Evolutionary Perspective on the Impact of Genomic Copy Number Variation on Human Health. In: Journal of molecular evolution. Volume 88, Number 1, January 2020, pp. 104-119, doi : 10.1007 / s00239-019-09911-6 , PMID 31522275 (review).
• V. Salpietro, A. Manole, S. Efthymiou, H. Houlden: A Review of Copy Number Variants in Inherited Neuropathies. In: Current genomics. Volume 19, number 6, September 2018, pp. 412-419, doi : 10.2174 / 1389202919666180330153316 , PMID 30258273 , PMC 6128387 (free full text) (review).
• AB Wilfert, A. Sulovari, TN Turner, BP Coe, EE Eichler: Recurrent de novo mutations in neurodevelopmental disorders: properties and clinical implications. In: Genome medicine. Volume 9, number 1, 11 2017, p. 101, doi : 10.1186 / s13073-017-0498-x , PMID 29179772 , PMC 5704398 (free full text) (review).
• S2k guideline for human genetic diagnostics and genetic advice from the German Society for Human Genetics . In: AWMF online (as of December 31, 2018).

Web links

• University Clinic Halle (Saale) - Institute for Human Genetics: Array-CGH-Diagnostics (method and application of the determination of copy number variations, CNV).
• Database of Genomic Variants
• Database of Genomic Structural Variation
• A Deep Catalog of Human Genetic Variation by the 1000 Genomes Project
• German Society for Human Genetics eV: Directory of genetic counseling centers

Individual evidence

1. ↑ Conrad, DF et al. (2010). Origins and functional impact of copy number variation in the human genome. In: Nature . Vol. 464, pp. 704-712. PMID 19812545
2. ↑ ^{a b} Mills, RE et al. (2011). Mapping copy number variation by population-scale genome sequencing. In: Nature . Vol. 470, pp. 59-65. PMID 21293372
3. ↑ Sudmant, P. et al. (2015). An integrated map of structural variation in 2,504 human genomes In: Nature . Vol. 526, pp. 75-81. PMID 26432246
4. ↑ McCarroll, DF et al. (2008). Integrated detection and population-genetic analysis of SNPs and copy number variation. In: Nat Genet . Vol. 40, pp. 66-74. PMID 18776908
5. ↑ Korbel, JO et al. (2007). Paired-end mapping reveals extensive structural variation in the human genome . In: Science . Vol. 318, pp. 420-426. PMID 17901297
6. ↑ Kidd, JM et al. (2008). Mapping and sequencing of structural variation from eight human genomes. In: Nature . Vol. 453, pp. 56-64. PMID 18451855
7. ↑ Ye, K. et al. (2009): Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads. In: Bioinformatics . Vol. 25, pp. 2865-2871. PMID 19561018
8. ↑ Lam, HY et al. (2010): Nucleotide-resolution analysis of structural variants using BreakSeq and a breakpoint library. In: Nat Biotechnol . Vol. 28, pp. 47-55. PMID 20037582 .
9. ↑ Yoon, S. (2009): Sensitive and accurate detection of copy number variants using read depth of coverage . In: Genome Res . Vol. 19, pp. 1586-1592. PMID 19657104
10. ^ Alkan, C. (2009): Personalized copy number and segmental duplication maps using next-generation sequencing . In: Nat Genet . Vol. 41, pp. 1061-1067. PMID 19718026
11. ↑ MA gillentine, J. Yin, A. Bajic, P. Zhang, S. Cummock, JJ Kim, CP Schaaf: Functional Consequences of CHRNA7 Copy Number Alterations in Induced Pluripotent Stem Cells and Neural Progenitor Cells. In: American Journal of Human Genetics . Volume 101, number 6, December 2017, pp. 874-887, doi : 10.1016 / j.ajhg.2017.09.024 , PMID 29129316 , PMC 5812918 (free full text).
12. ↑ MA gillentine, CP Schaaf: The human clinical phenotypes of altered CHRNA7 copy number. In: Biochemical pharmacology. Volume 97, number 4, October 2015, pp. 352-362, doi : 10.1016 / j.bcp.2015.06.012 , PMID 26095975 , PMC 4600432 (free full text) (review).
13. ↑ G. Ramaswami, DH Geschwind: Genetics of autism spectrum disorder. In: Handbook of clinical neurology. Volume 147, 2018, pp. 321-329, doi : 10.1016 / B978-0-444-63233-3.00021-X , PMID 29325621 (review), PDF .
14. ↑ M. Woodbury-Smith, SW Scherer: Progress in the genetics of autism spectrum disorder. In: Developmental medicine and child neurology. Volume 60, number 5, 05 2018, pp. 445–451, doi : 10.1111 / dmcn.13717 , PMID 29574884 (review) (free full text).

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