Variable germline and embryonic instability of the human minisatellite MS32 (D1S8) in transgenic mice.

Collick, Andrew; Norris, M. L.; Allen, Maxine; Bois, Philippe R.J.; Barton, Sheila C.; Surani, M. Azim; Jeffreys, Alec J.

doi:10.1002/j.1460-2075.1994.tb06912.x

Cited by 15 publications

(8 citation statements)

References 34 publications

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“…Transminisatellitic mice hemizygous for single-copy MS32 integrations have shown a »100-fold reduction in the germline mutation frequency relative to that observed in humans (Collick et al 1994). It will be interesting to compare the present yeast data with results from mice in which MS32 has been bred to homozygosity.…”

Section: Discussionmentioning

confidence: 99%

Mutations at the human minisatellite MS32 integrated in yeast occur with high frequency in meiosis and involve complex recombination events

1997

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Minisatellites are composed of tandem repetitive DNA sequences and are present at many positions in the human genome. They frequently mutate to new length alleles in the germline, by complex and incompletely understood recombination mechanisms which may operate during meiosis. In several minisatellites the mutation events are restricted to one end of the repeat array, indicating a possible association with elements that act in cis. Mutant alleles do not show exchange of flanking regions. To construct a model system suitable for further investigations of the mutation process, we have integrated the human minisatellite MS32, flanked by synthetic markers, in the vicinity of a meiotic recombination hot spot upstream of the LEU2 locus in the yeast Saccharomyces cerevisiae. Here we provide direct evidence for a meiotic origin of MS32 mutations. Mutation events were polarised towards both ends of the minisatellite and varied from simple duplications and deletions to complex intra- and interallelic events. Interallelic events were frequently accompanied by exchange of regions flanking the minisatellite. The results also support the notion that cis-acting elements are involved in the mutational process. The fact that MS32 mutant structures are similar in yeast and human shows that meiotic recombination plays a crucial role in both organisms and emphasises the usefulness of yeast strains harbouring minisatellites as a model system for the study of minisatellite mutation.

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Section: Discussionmentioning

confidence: 99%

Mutations at the human minisatellite MS32 integrated in yeast occur with high frequency in meiosis and involve complex recombination events

1997

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“…Given the lack of instability of endogenous minisatellites in pig, rat and mouse, modelling has instead been attempted by creating mice transgenic for human minisatellites MS32 and CEB1 [63,108;J. Buard,unpublished data].…”

Section: Modelling Minisatellite Instabilitymentioning

confidence: 99%

“…Buard,unpublished data]. Initial constructs consisting of a short MS32 allele plus a few hundred base pairs of flanking human DNA yielded multicopy and single-copy integrants [108,109]. The multicopy integrants displayed various modes of instability attributable not to minisatellites but instead to palindromic DNA created during integration [110].…”

Section: Modelling Minisatellite Instabilitymentioning

confidence: 99%

Minisatellite instability and germline mutation

Bois

Jeffreys

1999

Cellular and Molecular Life Sciences (CMLS)

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Tandem-repeat DNA actively turns over in the genome by a variety of poorly understood dynamic mechanisms. Minisatellites, a class of tandem repeats, have been shown to cause disease by influencing gene expression, modifying coding sequences within genes or generating fragile sites. There has been recent rapid progress towards understanding molecular turnover processes at human minisatellites. Instability at GC-rich minisatellites appears to involve distinct mutation processes operating in somatic and germline cells. In the germline, complex conversion-like events occur, probably during meiosis. Repeat turnover appears to be controlled by intense recombinational activity in DNA flanking the repeat array, suggesting that minisatellites might evolve as by-products of localised meiotic recombination in the human genome. In contrast, AT-rich minisatellites appear to evolve by intra-allelic processes such as replication slippage. Curiously, minisatellites in other organisms appear to be more stable than their human counterparts, suggesting species-specific differences in turnover processes. Some yeast models display human-like minisatellite turnover processes at meiosis. However, all attempts to transfer human germline instability to transgenic mice have failed. Finally, tandem repeat instability in various species appears to be extremely sensitive to environmental agents such as radiation via a mechanism which remains enigmatic.

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“…Nevertheless, current data suggest that the mouse is not a good animal model for the analysis of instability processes at unstable human minisatellites. This could explain our previous failure to transfer human germline minisatellite instability to transgenic mice (Collick et al, 1994;Bois et al, 1997). In contrast, large STRs in the mouse genome have been shown to display high levels of germline instability both at Ms6-hm and at Hm-2 (Kelly et al, 1989;Gibbs et al, 1993) and more recently in a family of STRs generated by expansions from within B1 elements (Bois et al, 1998).…”

Section: Discussionmentioning

confidence: 97%

“…Further analysis of minisatellite instability, including the precise determination of the timing of mutation events during meiosis, the functional dissection of cis-acting regulators of germline instability, and the exploration of mutation processes in the female germline, would be greatly facilitated by an animal model. So far, attempts to transfer human minisatellite germline instability to transgenic mice have failed (Collick et al, 1994;. These experiments have highlighted our ignorance of tandem repeat turnover processes in other species and emphasized the need to study endogenous mouse minisatellites.…”

Section: Introductionmentioning

confidence: 99%