Mechanism of TGG repeat-induced deletion. (a) Schematic representation of the 14q32.2 deletion (blue lines) and proximal and distal breakpoint sequences (red boxes A and B, respectively). Nucleotide sequences of A and B TGG repeat tracts are shown. Green indicates interruptions; pure repeat tracts (of at least 8 repeat units) are underlined. (b) Potential mechanisms that can explain the formation of TGG repeat-mediated deletion. NAHR requires homology between breakpoint sequences, NHEJ relies on joining dsDNA breaks induced by DNA structures at breakpoints, and FoSTeS depends on replication stalling and switching of the lagging strand to another replication fork. Both replication stalling and disengagement of the lagging strand can be facilitated by structures formed by template or synthesized DNA strands. (c) Frequency of different TNRs in the human genome. Blue bars indicate the number of pure TNR tracts with at least eight repeat units according to  (this is the length required for stable G-quadruplex formation); red bars indicate the number of interrupted TNR tracts with at least 100 units (the minimal sequence length required for catalyzing NAHR is 300 bp) according to Simple Repeat track, available on the UCSC Browser (hg18) (our unpublished data). (d) G-quadruplex structure formed by eight GGA DNA repeats (GGA)8 . The most 5' and 3' nucleotides are shown and arrows indicate direction of DNA strand from 5' to 3' end. A similar structure can be expected for TGG repeats based on the results of an RNA study .