Analysis of Spontaneous Gene Conversion Tracts within and between Mammalian Chromosomes

Rukść, Ania; Bell-Rogers, Patricia; Smith, Jillian D.L.; Baker, Mark D.

doi:10.1016/j.jmb.2008.01.036

Cited by 12 publications

(8 citation statements)

References 59 publications

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“…For the four data sets of yeast, the estimates are within a quite small range from ∼50 to several hundred bp, which seems to be much smaller than allelic gene conversion [73]. The results for rodents are similar; our estimates are around 100 bp except for the data of Rukść et al [72], which provide an estimate of >1 kb with a much wider confidence interval (roughly 1 kp) than the others. This may be partly because the marker density is very low (the average interval is 375 bp for this data set, while the average of the others is ∼160 bp).…”

Section: The Tract Length Of Gene Conversionsupporting

confidence: 60%

The Rate and Tract Length of Gene Conversion between Duplicated Genes

Mansai

Kado

Innan

2011

Genes

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Interlocus gene conversion occurs such that a certain length of DNA fragment is non-reciprocally transferred (copied and pasted) between paralogous regions. To understand the rate and tract length of gene conversion, there are two major approaches. One is based on mutation-accumulation experiments, and the other uses natural DNA sequence variation. In this review, we overview the two major approaches and discuss their advantages and disadvantages. In addition, to demonstrate the importance of statistical analysis of empirical and evolutionary data for estimating tract length, we apply a maximum likelihood method to several data sets.

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Section: The Tract Length Of Gene Conversionsupporting

confidence: 60%

The Rate and Tract Length of Gene Conversion between Duplicated Genes

Mansai

Kado

Innan

2011

Genes

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“…These studies indicated that the crossovers were more likely to occur near the initiation site of strand invasion, probably as a result of branch migration. Although similar studies have been undertaken in mammalian systems [10]–[13], [40], [48] the generality of the conclusions were restricted by the limited scale of the data. Taking advantage of the high targeting efficiency of rAAV, we performed a SNP retention analysis for non-DSB (Figure 1E and F) and DSB-induced (Figure 5G and H) gene targeting in human cells with unprecedented resolution.…”

Section: Discussionmentioning

confidence: 99%

“…However, because of the robust competing pathway of DSBR known as non-homologous end joining [8], gene targeting events occur rarely in mammals [9]–[11]. Indeed, despite valiant efforts — in particular by the Baker laboratory [10], [12], [13] — the low targeting efficiency of plasmid-based dsDNA vectors has prohibited a systematic characterization of recombination intermediates in mammalian cells. To gain better insight into the mechanism of human gene targeting it is crucial to establish a more vigorous gene targeting system.…”

Section: Introductionmentioning

confidence: 99%

The Mechanism of Gene Targeting in Human Somatic Cells

et al. 2014

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Gene targeting in human somatic cells is of importance because it can be used to either delineate the loss-of-function phenotype of a gene or correct a mutated gene back to wild-type. Both of these outcomes require a form of DNA double-strand break (DSB) repair known as homologous recombination (HR). The mechanism of HR leading to gene targeting, however, is not well understood in human cells. Here, we demonstrate that a two-end, ends-out HR intermediate is valid for human gene targeting. Furthermore, the resolution step of this intermediate occurs via the classic DSB repair model of HR while synthesis-dependent strand annealing and Holliday Junction dissolution are, at best, minor pathways. Moreover, and in contrast to other systems, the positions of Holliday Junction resolution are evenly distributed along the homology arms of the targeting vector. Most unexpectedly, we demonstrate that when a meganuclease is used to introduce a chromosomal DSB to augment gene targeting, the mechanism of gene targeting is inverted to an ends-in process. Finally, we demonstrate that the anti-recombination activity of mismatch repair is a significant impediment to gene targeting. These observations significantly advance our understanding of HR and gene targeting in human cells.

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“…In yeast, Drosophila and mouse, the majority of recombination‐associated crossovers exhibit continuous gene conversion associated with simple conversion tracts, where all sequence mismatches within a given tract have been converted from the same donor template (Fig. B) [Haber et al., ; Lee et al., ; Mancera et al., ; Pâques and Haber, ; Rukść et al., ; Weng et al., ]. Similarly in humans, most characterized AHR crossovers have been found to be associated with continuous gene conversion [Jeffreys et al., , , ; Jeffreys and Neumann, ; Webb et al., ].…”

Section: Introductionmentioning

confidence: 99%

Analysis of Crossover Breakpoints Yields New Insights into the Nature of the Gene Conversion Events Associated with LargeNF1Deletions Mediated by Nonallelic Homologous Recombination

et al. 2013

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Large NF1 deletions are mediated by nonallelic homologous recombination (NAHR). An in-depth analysis of gene conversion operating in the breakpoint-flanking regions of large NF1 deletions was performed to investigate whether the rate of discontinuous gene conversion during NAHR with crossover is increased, as has been previously noted in NAHR-mediated rearrangements. All 20 germline type-1 NF1 deletions analyzed were mediated by NAHR associated with continuous gene conversion within the breakpoint-flanking regions. Continuous gene conversion was also observed in 31/32 type-2 NF1 deletions investigated. In contrast to the meiotic type-1 NF1 deletions, type-2 NF1 deletions are predominantly of post-zygotic origin. Our findings therefore imply that the mitotic as well as the meiotic NAHR intermediates of large NF1 deletions are processed by long-patch mismatch repair (MMR), thereby ensuring gene conversion tract continuity instead of the discontinuous gene conversion that is characteristic of short-patch repair. However, the single type-2 NF1 deletion not exhibiting continuous gene conversion was processed without MMR, yielding two different deletion-bearing chromosomes, which were distinguishable in terms of their breakpoint positions. Our findings indicate that MMR failure during NAHR, followed by post-meiotic/mitotic segregation, has the potential to give rise to somatic mosaicism in human genomic rearrangements by generating breakpoint heterogeneity.

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Analysis of Spontaneous Gene Conversion Tracts within and between Mammalian Chromosomes

Cited by 12 publications

References 59 publications

The Rate and Tract Length of Gene Conversion between Duplicated Genes

The Rate and Tract Length of Gene Conversion between Duplicated Genes

The Mechanism of Gene Targeting in Human Somatic Cells

Analysis of Crossover Breakpoints Yields New Insights into the Nature of the Gene Conversion Events Associated with LargeNF1Deletions Mediated by Nonallelic Homologous Recombination

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