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DNA secondary structure is influenced by genetic variation and alters susceptibility to de novo translocation

Author(s): Kato Takema | Inagaki Hidehito | Tong Maoqing | Kogo Hiroshi | Ohye Tamae | Yamada Kouji | Tsutsumi Makiko | Emanuel Beverly | Kurahashi Hiroki

Journal: Molecular Cytogenetics
ISSN 1755-8166

Volume: 4;
Issue: 1;
Start page: 18;
Date: 2011;
Original page

Keywords: Polymorphism | Palindrome | Secondary structure | Hairpin structure | Cruciform structure | Breakpoint | Translocation

Abstract Background Cumulative evidence suggests that DNA secondary structures impact DNA replication, transcription and genomic rearrangements. One of the best studied examples is the recurrent constitutional t(11;22) in humans that is mediated by potentially cruciform-forming sequences at the breakpoints, palindromic AT-rich repeats (PATRRs). We previously demonstrated that polymorphisms of PATRR sequences affect the frequency of de novo t(11;22)s in sperm samples from normal healthy males. These studies were designed to determine whether PATRR polymorphisms affect DNA secondary structure, thus leading to variation in translocation frequency. Methods We studied the potential for DNA cruciform formation for several PATRR11 polymorphic alleles using mobility shift analysis in gel electrophoresis as well as by direct visualization of the DNA by atomic force microscopy. The structural data for various alleles were compared with the frequency of de novo t(11;22)s the allele produced. Results The data indicate that the propensity for DNA cruciform structure of each polymorphic allele correlates with the frequency of de novo t(11;22)s produced (r = 0.77, P = 0.01). Conclusions Although indirect, our results strongly suggest that the PATRR adopts unstable cruciform structures during spermatogenesis that act as translocation hotspots in humans.
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