Recombination at Disease Associated DNA Repeats Can Lead to Deletions and Expansions

Genetic recombination between two repeat tracts occurring either as crossing over, with exchange of flanking markers, or as gene conversion can generate

Fig. 6 Recombination associated with expansion or deletion. Recombination (gene conversion) within repeats can lead to expansion (left) or deletion (right) depending on the position within the repeat tract the strand exchange occurs. Expansion (left). Following a break within a DNA repeat (step A), strand invasion of the 3' ends at the 3' side of the complementary strands of a second chromosome (step B) would lead to expansion following DNA synthesis (step C). Reannealing of the complementary strands of the second duplex will displace the nascent strands, whereupon the 3' ends of the newly synthesized strands could anneal (step D). Additional synthesis could lead to more than a doubling of the length of the repeat (step E). Deletion (right). If a break occurs to one side of the repeat and the strand invasion occurs near the opposite end of the repeat in the second chromosome (step B), following synthesis, strand displacement, and ligation, a deletion will occur in one chromosome (steps C-E)

Fig. 6 Recombination associated with expansion or deletion. Recombination (gene conversion) within repeats can lead to expansion (left) or deletion (right) depending on the position within the repeat tract the strand exchange occurs. Expansion (left). Following a break within a DNA repeat (step A), strand invasion of the 3' ends at the 3' side of the complementary strands of a second chromosome (step B) would lead to expansion following DNA synthesis (step C). Reannealing of the complementary strands of the second duplex will displace the nascent strands, whereupon the 3' ends of the newly synthesized strands could anneal (step D). Additional synthesis could lead to more than a doubling of the length of the repeat (step E). Deletion (right). If a break occurs to one side of the repeat and the strand invasion occurs near the opposite end of the repeat in the second chromosome (step B), following synthesis, strand displacement, and ligation, a deletion will occur in one chromosome (steps C-E)

variation in the lengths of repeats depending on where the invading strand of one DNA molecule pairs along the length of the second duplex (Fig. 6). As with simple replication slippage during synthesis of a repeat tract, recombination would be expected to generate expansions of less than a factor of 2 or 3.

A large body of evidence has been presented to show that recombination occurs at high rates at disease-associated repeats cloned into bacterial plasmids and that, as expected, this will generate variation in repeat lengths following recombination (Jakupciak and Wells 1999, 2000a,b; Plucien-nik et al. 2002; Napierala et al. 2002, 2004; Vetcher and Wells 2004). The DM1 d(CAG) ■ d(CTG) repeats and the Friedreich ataxia d(GAA) ■ d(TTC) repeats stimulate either intramolecular recombination between two repeat tracts in the same plasmid or intermolecular recombination between two repeat tracts in different plasmids in the same cell. In contrast, some reports indicate that recombination does not appear to be stimulated by d(CTG) ■ d(CAG) repeats in yeast (Miret et al. 1997), while other reports suggest that recombination-related instability can occur in yeast (Jankowski et al. 2000; Jankowski and Nag 2002; Nag et al. 2004). d(CAG) ■ d(CTG) repeats have been shown to promote deletions and rearrangements when cloned into the APRT gene in Chinese hamster ovary cells (Meservy et al. 2003). Genetic recombination in the classic sense of gene conversion or crossing over, however, does not seem to be a major source of repeat expansion in humans, although rare instances associated with recombination have been reported (Brunner et al. 1993; van den Ouweland et al. 1994; Krahe et al. 1995; Brown et al. 1996; Losekoot et al. 1997). Recombination is an integral part of restart of paused replication forks and will be discussed in the next section in this context with respect to repeat instability.

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