The minimum amount of homology required for homologous recombination in mammalian cells.

Rubnitz, Jeffrey E.; Subramani, Suresh

doi:10.1128/mcb.4.11.2253

Cited by 247 publications

(188 citation statements)

References 44 publications

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“…These studies also challenge the notion of minimum pairing segments of uninterrupted homology required for such exchanges (38)(39)(40). Finally, direct comparisons of germ-line mutation rates and population frequencies can provide insights into historical levels of selection operating in human populations.…”

Section: Discussionmentioning

confidence: 99%

Processes of copy-number change in human DNA: The dynamics of α-globin gene deletion

Lam

Jeffreys²

2006

Proc. Natl. Acad. Sci. U.S.A.

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Ectopic recombination between locally repeated DNA sequences is of fundamental importance in the evolution of gene families, generating copy-number variation in human DNA and often leading to pathological rearrangements. Despite its importance, little is known about the dynamics and processes of these unequal crossovers and the degree to which meiotic recombination plays a role in instability. We address this issue by using as a highly informative system the duplicated ␣-globin genes in which ectopic recombination can lead to gene deletions, often very prevalent in populations affected by malaria, as well as reduplications. Here we show that spontaneous deletions can be accessed directly in genomic DNA by using single-DNA-molecule methods. These deletions proved to be remarkably common in both blood and sperm. Somatic deletions arise by a strictly intrachromosomal pathway of homologous exchange that also operates in the germ line and can generate mutational mosaicism, whereas sperm deletions frequently involve recombinational interactions between homologous chromosomes that most likely occur at meiosis. Ectopic recombination frequencies show surprisingly little requirement for long, identical homology blocks shared by paralogous sequences, and exchanges can occur even between short regions of sequence identity. Finally, direct knowledge of germ-line deletion rates can give insights into the fitness of individuals with these ␣-globin gene deletions, providing a new approach to investigating historical levels of selection operating in human populations.ectopic ͉ recombination ͉ selection ͉ mutation ͉ mosaicism

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Section: Discussionmentioning

confidence: 99%

Processes of copy-number change in human DNA: The dynamics of α-globin gene deletion

Lam

Jeffreys²

2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Illegitimate recombination and the origin of satDNA Â satDNA junctions In mammals and plants, in vivo and in vitro experiments showed that efficient recombination between sequences requires a minimum of approximately 200 bp of uninterrupted homology (Rubnitz and Subramani, 1984;Opperman et al, 2004). Below this threshold, sequence divergence has an inhibitory effect on homologous recombination and can decrease threefold with a divergence level as low as 0.16%.…”

Section: Discussionmentioning

confidence: 99%

Evolutionary dynamics and sites of illegitimate recombination revealed in the interspersion and sequence junctions of two nonhomologous satellite DNAs in cactophilic Drosophila species

et al. 2009

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Satellite DNA (satDNA) is a major component of genomes but relatively little is known about the fine-scale organization of unrelated satDNAs residing at the same chromosome location, and the sequence structure and dynamics of satDNA junctions. We studied the organization and sequence junctions of two nonhomologous satDNAs, pBuM and DBC-150, in three species from the neotropical Drosophila buzzatii cluster (repleta group). In situ hybridization to microchromosomes, interphase nuclei and extended DNA fibers showed frequent interspersion of the two satellites in D. gouveai, D. antonietae and, to a lesser extent, D. seriema. We isolated by PCR six pBuM Â DBC-150 junctions: four are exclusive to D. gouveai and two are exclusive to D. antonietae. The six junction breakpoints occur at different positions within monomers, suggesting independent origin. Four junctions showed abrupt transitions between the two satellites, whereas two junctions showed a distinct 10 bp tandem duplication before the junction. Unlike pBuM, DBC-150 junction repeats are more variable than randomly cloned monomers and showed diagnostic features in common to a 3-monomer higher-order repeat seen in the sister species D. serido. The high levels of interspersion between pBuM and DBC-150 repeats suggest extensive rearrangements between the two satellites, maybe favored by specific features of the microchromosomes. Our interpretation is that the junctions evolved by multiples events of illegitimate recombination between nonhomologous satDNA repeats, with subsequent rounds of unequal crossing-over expanding the copy number of some of the junctions.

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“…It was established that at least 50-to 100-bp homology is required for it (see, e.g., refs. [5][6][7]. This ensures that the fragments belong to 2 alleles of the same gene rather than to different genes.…”

Section: Homology Recognition Enigmamentioning

confidence: 99%

The homology recognition well as an innate property of DNA structure

Kornyshev

Wynveen

2009

Proc. Natl. Acad. Sci. U.S.A.

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Mutual recognition of homologous sequences of DNA before strand exchange is considered to be the most puzzling stage of recombination of genes. In 2001, a mechanism was suggested for a doublestranded DNA molecule to recognize from a distance its homologous match in electrolytic solution without unzipping [Kornyshev AA, Leikin S (2001) Phys Rev Lett 86:3666 -3669]. Based on a theory of electrostatic interactions between helical molecules, the difference in the electrostatic interaction energy between homologous duplexes and between nonhomologous duplexes, called the recognition energy, was calculated. Here, we report a theoretical investigation of the form of the potential well that DNA molecules may feel sliding along each other. This well, the bottom of which is determined by the recognition energy, leads to trapping of the molecular tracks of the same homology in direct juxtaposition. A simple formula for the shape of the well is obtained. The well is quasi-exponential. Its half-width is determined by the helical coherence length, introduced first in the same 2001 article, the value of which, as the latest study shows, is Ϸ10 nm.Decades of research into homologous recombination have unraveled many of the details concerning the transfer of information between 2 homologous sequences. By contrast, the processes by which the interacting molecules initially colocalize are largely unknown. How can 2 homologous needles find each other in the genomic haystack?- Barzel and Kupiec (2008) R ecombination of genes is a process in which sequences are exchanged between 2 DNA molecules. In homologous recombination fragments of the same homology, those that have almost identical sequences are swapped. This makes possible gene shuffling between 2 parental copies of DNA, crucial for evolution and genetic diversity. A similar process is used in DNA repair, when the cell uses a backup copy of the genome as a template for repairs. It is generally accepted that understanding recombination of genes is one of the key challenges of the ''postgenomic era'' (1). Homology Recognition EnigmaThe key point in homologous recombination is the swapping of correct genes: only regions with homologous sequences should be exchanged or used as a template for repair. Recombination mistakes are known to cause a variety of severe genetic diseases (2, 3) and contribute to aging (4). Fortunately, such errors are rare. The recognition of sequence homology occurs with amazing precision. In site-specific recombination, the exchange happens at specific, designated loci recognized by the complex recombination machinery of the cell (involving multiple proteins). In homologous recombination the exchange can occur anywhere. It was established that at least 50-to 100-bp homology is required for it (see, e.g., refs. 5-7). This ensures that the fragments belong to 2 alleles of the same gene rather than to different genes. The long-range goal is an in-depth understanding of the recognition mechanism to be able to develop procedures that could further minimize these ...

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The minimum amount of homology required for homologous recombination in mammalian cells.

Cited by 247 publications

References 44 publications

Processes of copy-number change in human DNA: The dynamics of α-globin gene deletion

Processes of copy-number change in human DNA: The dynamics of α-globin gene deletion

Evolutionary dynamics and sites of illegitimate recombination revealed in the interspersion and sequence junctions of two nonhomologous satellite DNAs in cactophilic Drosophila species

The homology recognition well as an innate property of DNA structure

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