Palindromic DNA and Genome Stability: Further Studies^a

Abstract

Unusual DNA structures promote genetic instability. One such example is hairpin DNA, which can form from palindromic sequences and triplet repeats, and is also a characteristic intermediate in V(D)J recombination. We previously found that a large 15.3-kb palindrome that was introduced as a transgene into the mouse germline was highly unstable. Although it could be transmitted, the transgene was found to be rearranged in up to 56% of the progeny, and rearrangement events often involved deletion at the center of symmetry. Here, the fine structure of centrally deleted palindromes was sampled by analysis of recombinant junctions isolated from testes DNA, providing further evidence for a model, previously proposed, that accounts for such deletions on the basis of a hairpin-tip nicking activity. In addition to central deletions, gene conversion events were also elevated in the transgenic palindrome. We have now analyzed instability in two mouse sublines in which (as a result of inversion) the transgenic palindrome had been shortened to 4.2 kb. In these sublines, the transgene was still subject to both rearrangement and gene conversion events at a high frequency, similar to the original 15.3-kb palindrome. Recombination was not limited to the sequences constituting the inverted repeat, but was seen to include sequences lying outside the palindrome. As discussed, the salient feature in all of these observations, a high level of genetic change associated with palindromic DNA, underscores the significance of hairpin DNA and hairpin-tip nicking in genome stability.

Does Gene Translocation Accelerate the Evolution of Laterally Transferred Genes?

“…Furthermore, short palindromic sequences (Lewis et al 1999;Tobes and Pareja 2006) or short signature sequences (Robins et al 2005) have been suggested to serve as a source of recombination sites for gene movement. However, detection of recombination sites requires more experimental evidence.…”

Biased Distribution of Inverted and Direct Alus in the Human Genome: Implications for Insertion, Exclusion, and Genome Stability

“…Pairs of large inverted DNA repeats can be unstable, lead to deletions, and stimulate recombination between DNAs surrounding the inverted repeats in yeast (Gordenin et al 1993;Ruskin and Fink 1993;Nag and Kurst 1997;Tran et al 1997;Lobachev et al 1998Lobachev et al , 2000 ) and mammalian cells (Akgun et al 1997;Lewis 1999;Lewis et al 1999). Sequence identity was suggested as a likely factor in the stability of Alu repeats based on results in yeast.…”

“…Observations with yeast and mouse cells suggest that long closely related inverted repeats are unstable and can cause deletions in eukaryotes (Gordenin et al 1993;Ruskin and Fink 1993;Lewis 1999;Lewis et al 1999). Moreover, they are initiators of recombination in yeast (Gordenin et al 1993;Nag and Kurst 1997;Lobachev et al 1998).…”

Biological, cellular, and molecular characteristics of an inducible transgenic skin tumor model: a review

“…Palindromic sequences are known to be unstable and prone to deletion (Leach, 1994;Collick et al, 1996;Lewis et al, 1999). It has been reported that a Tg.AC carcinoma cell line continued to express the transgene despite loss of the promoter palindromes (Humble et al, 2000).…”