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Recombination hotspot

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Recombination hotspots are regions in a genome that exhibit elevated rates of recombination relative to a neutral expectation. The recombination rate within hotspots can be hundreds of times that of the surrounding region.[1] Recombination hotspots result from higher DNA break formation in these regions, and apply to both mitotic and meiotic cells. In practice, this appellation traditionally refers to recombination events resulting from the uneven distribution of programmed meiotic double-strand breaks.[2]

Meiotic Recombination

Meiotic recombination through crossing over is thought to be the mechanism by which a cell ensures correct segregation of homologous chromosomes. Crossing over requires a DNA double-stranded break followed by strand invasion of the homolog and subsequent repair.[3] Initiation sites for recombination are usually identified by mapping crossing over events through pedigree analysis or through analysis of linkage disequilibrium. Linkage disequilibrium has identified more than 30,000 hotspots within the human genome.[3] In humans, the average number of crossover recombination events per hotspot is one crossover per 1,300 meioses, and the most extreme hotspot has a crossover frequency of one per 110 meioses.[4]

Genomic Rearrangements

Recombination can also occur due to errors in DNA replication that lead to genomic rearrangements. These events are often associated with pathology. However, genomic rearrangement is also thought to be a driving force in evolutionary development as it gives rise to novel gene combinations.[5] Recombination hotspots are thought to arise from the interaction of the following selective forces: the benefit of driving genetic diversity through genomic rearrangement coupled with selection acting to maintain favorable gene combinations.[6]

Initiation Sites

DNA contains “fragile sites” within the sequence that are more prone to recombination. These fragile sites are associated with the following trinucleotide repeats: CGG-CCG, GAG-CTG, GAA-TTC, and GCN-NGC.[5] These fragile sites are conserved in mammals and in yeast, suggesting that the instability is caused by something inherent to the molecular structure of DNA and is associated with DNA-repeat instability.[5] These fragile sites are thought to form hairpin structures on the lagging strand during replication from single-stranded DNA base-pairing with itself in the trinucleotide repeat region.[5] These hairpin structures cause DNA breaks that lead to a higher frequency of recombination at these sites.[5]

Recombination hotspots are also thought to arise due to higher-order chromosome structure that make some areas of the chromosome more accessible to recombination than others.[6] A double stranded-break initiation site was identified in mice and yeast, located at a common chromatin feature: the trimethylation of lysine 4 of histone H3 (H3K4me3).[3]

Interestingly, recombination hotspots do not seem to be solely caused by DNA sequence arrangements or chromosome structure. Alternatively, initiation sites of recombination hotspots can be coded for in the genome. Through the comparison of recombination between different mouse strains, locus Dsbc1 was identified as a locus that contributes to the specification of initiation sites in the genome in at least two recombination hotspot locations.[3] Additional crossing over mapping located the Dsbc1 locus to the 12.2 to 16.7-Mb region of mouse chromosome 17, which contains the PRDM9 gene. The PRDM9 gene encodes a histone methyltransferase in the Dsbc1 region, providing evidence of a non-random, genetic basis for recombination initiation sites in mice.[3]

See also

Further reading

References

  1. ^ Jeffreys AJ, Kauppi L, Neumann R (October 2001). "Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex". Nat. Genet. 29 (2): 217–22. doi:10.1038/ng1001-217. PMID 11586303.
  2. ^ Székvölgyi, Lóránt; Ohta, Kunihiro; Nicolas, Alain (2015-05-01). "Initiation of meiotic homologous recombination: flexibility, impact of histone modifications, and chromatin remodeling". Cold Spring Harbor Perspectives in Biology. 7 (5). doi:10.1101/cshperspect.a016527. ISSN 1943-0264. PMC 4448624. PMID 25934010.
  3. ^ a b c d e Baudat, F., et al. "Prdm9 Is a Major Determinant of Meiotic Recombination Hotspots in Humans and Mice." Science 327.5967 (2010): 836-40. Print.
  4. ^ Myers S, Spencer CC, Auton A, et al. (August 2006). "The distribution and causes of meiotic recombination in the human genome". Biochem. Soc. Trans. 34 (Pt 4): 526–30. doi:10.1042/BST0340526. PMID 16856851.
  5. ^ a b c d e Aguilera, A., and B. Gomez-Gonzalez. "Genome Instability: A Mechanistic View of Its Causes and Consequences." Nature Reviews Genetics 9.3 (2008): 204-17. Print.
  6. ^ a b Lichten, M., and A. S. H. Goldman. "Meiotic Recombination Hotspots." Annual Review of Genetics 29 (1995): 423-44. Print.
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