Minisatellite instability and germline mutation

Abstract

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.

Minisatellites: Mutability and Genome Architecture

“…In brief, minisatellites are thought to contribute to genome function in one of three ways: (1) Some are part of an open reading frame, which may or may not display polymorphism in the human population (for review, see Bois and Jeffreys 1999). (2) Some bind proteins with a variety of functional consequences, strongly suspected or still very hypothetical.…”

Comparative Analyses of Human Single- and Multilocus Tandem Repeats

“…Since homologous recombination is central to the creation and degradation of tandem repeats (Bois and Jeffreys 1999), it has been suggested that the concentrations of tandem repeats at chromosome ends might reflect these locally higher rates of recombination. Colocalization of a human hypermutable minisatellite with a nearby recombination ''hotspot'' has been reported (Jeffreys et al 1998;Jeffreys and Neumann 2005), but it is unclear how prevalent this relationship is.…”

“…The intimate role for recombination in the generation of these tandem repeats and its higher frequency near chromosome ends suggest that it could account for the nonrandom distribution of tandem repeats as noted by reports of colocalization ( Jeffreys et al 1998;Jeffreys and Neumann 2005); however, we were unable to confirm a general colocalization of tandem repeats and recombination hotspots in the human genome, which is consistent with other observations. Recombination is more frequent near chromosome ends in many organisms, yet mouse chromosomes do not exhibit a similarly higher frequency of tandem repeats near their ends (Bois and Jeffreys 1999). If higher recombination frequency is critical to creation of concentrations of tandem repeats, then the concentrations of pericentric satellite repeats are problematic to reconcile with their locations in regions with greatly suppressed recombination.…”

Minisatellite DNA Markers in Population Studies

“…Some models have been proposed to explain the mechanisms of this migration. The transfer of a doublestranded break results in the accumulation of mutations within the minisatellite cluster, but not in other regions of genomic DNA, which explains the hypervariability of minisatellites (Bois & Jeffreys, 1999, Bois, 2003. Fig.…”