Attempts to detect retrotransposition and de novo deletion of Alus and other dispersed repeats at specific loci in the human genome

Hollies, Caroline R. H.; Monckton, Darren G.; Jeffreys, Alec J.

doi:10.1038/sj.ejhg.5200590

Cited by 7 publications

(5 citation statements)

References 14 publications

(14 reference statements)

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“…The two deletion patterns detected in a single sarcoma cannot possibly correspond to independent events that occurred initially in different cells and were followed by separate clonal growth because the incidence of deletions is extremely low. From preliminary PCR-based experiments (not shown), we roughly estimate that the frequency of occurrence of deletion events, which could vary between tissue types, is lower than 1 per million cells, consistent with previous reports (Seperack et al, 1988;Hollies et al, 2001). We think, therefore, that our observations are most compatible with the interpretation that precise excisions occur first and are followed by secondary microdeletions during tumor evolution.…”

Section: Cre-independent Excision Of Floxed Dna In Micesupporting

confidence: 91%

‘Designer’ tumors in mice

et al. 2003

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We have developed and tested successfully a general method based on Cre-mediated recombination that can be used for ubiquitous or tissue-specific expression of protein products, including tumor-inducing oncoproteins. Depending on the specificity of a chosen promoter driving cre expression, tumors develop by design in bitransgenic mouse progeny derived by crossing Cre-producing mice with partners carrying a dormant oncogenic transgene (targeted into the 3 0 noncoding region of the cytoplasmic b-actin locus) that becomes functional after excision of a 'floxed' DNA segment. To provide proof-of-principle, we have used as models transgenes encoding the polyomavirus middle T antigen (PVMT) and the T antigens of the SV40 early region (SVER). Cre-dependent activation of widespread SVER expression resulted in hyperplasias or invasive tumors affecting particular visceral smooth muscles, whereas Cre-dependent, mammary gland-specific expression of PVMT-induced adenocarcinomas, according to plan. Unexpectedly, we also encountered spontaneous (Cre-independent) oncogene expression occurring as a rare event, which simulates the initiation of sporadic tumors and leads to PVMT-induced hemangiomas and mammary carcinomas or SVER-induced disseminated sarcomas, thus, revealing particular tissue susceptibilities to the actions of these oncoproteins.

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Section: Cre-independent Excision Of Floxed Dna In Micesupporting

confidence: 91%

‘Designer’ tumors in mice

et al. 2003

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“…It has also been shown that the frequency of Alu ‐mediated deletions in undamaged DNA is relatively low, with deletion rates in sperm of 3 × 10 −7 and 7 × 10 −7 and maximum frequencies of somatic mutation of less than 10 −6 per cell (Hollies et al, 2001). It seems that chromosomal DNA breaks may be necessary inducers of recombination and therefore increase the frequency of HR (Rouet et al, 1994) and chromosomal rearrangements.…”

Section: Influence Of Chromatin Structure and Repeat‐mediated Rearranmentioning

confidence: 99%

The role of Alu repeat clusters as mediators of recurrent chromosomal aberrations in tumors

Kolomietz

Meyn

Pandita

et al. 2002

Genes Chromosomes & Cancer

236

184

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There is increasing evidence for the involvement of repetitive DNA sequences as facilitators of some of the recurrent chromosomal rearrangements observed in human tumors. The high densities of repetitive DNA, such as Alu elements, at some chromosomal translocation breakpoint regions has led to the suggestion that these sequences could provide hot spots for homologous recombination, and could mediate the translocation process and elevate the likelihood of other types of chromosomal rearrangements taking place. The Alu core sequence itself has been suggested to promote DNA strand exchange and genomic rearrangement, and it has striking sequence similarity to (which has been shown to stimulate recBCD-mediated recombination in Escherichia coli). Alu repeats have been shown to be involved in the generation of many constitutional gene mutations in meiotic cells, attributed to unequal homologous recombination and consequent deletions and/or duplication events. It has recently been demonstrated that similar deletion events can take place in neoplasia because several types of leukemia-associated chromosomal rearrangements frequently have submicroscopic deletions immediately adjacent to the translocation breakpoint regions. Significantly, these types of deletions appear to be more likely to take place when the regions subject to rearrangement contain a high density of Alu repeats. With the completion of the Human Genome Project, it will soon be possible to create more comprehensive maps of the distribution and densities of repetitive sequences, such as Alu, throughout the genome. Such maps will offer unique insights into the relative distribution of cancer translocation breakpoints and the localization of clusters of repetitive DNA.

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“…Alternatively, techniques of sperm small-pool PCR (SP-PCR) could be used to detect de novo conversion events [13]; however, homogenization could occur at many possible sites within most paralogous repeats, making detection problematic. An alternative to these lab-based methods is to use available sequence data to explore whether gene conversion processes have played a role in the evolution of these repeats.…”

Section: Introductionmentioning

confidence: 99%

Gene conversion homogenizes the CMT1A paralogous repeats

Hurles

2001

BMC Genomics

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Background: Non-allelic homologous recombination between paralogous repeats is increasingly being recognized as a major mechanism causing both pathogenic microdeletions and duplications, and structural polymorphism in the human genome. It has recently been shown empirically that gene conversion can homogenize such repeats, resulting in longer stretches of absolute identity that may increase the rate of non-allelic homologous recombination.

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Attempts to detect retrotransposition and de novo deletion of Alus and other dispersed repeats at specific loci in the human genome

Cited by 7 publications

References 14 publications

‘Designer’ tumors in mice

‘Designer’ tumors in mice

The role of Alu repeat clusters as mediators of recurrent chromosomal aberrations in tumors

Gene conversion homogenizes the CMT1A paralogous repeats

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