Fig. 3. Genomic shards seal complex fusion breakpoints. (A) yp T23 and (B) yp T46
fusion breakpoints. The gray box shows the position of a 1.8-kb locus from which
the genomic shards originated. (C) Model of synthesis-based duplication for yp T46.
points are referred to as genomic shards or junctional sequences (19, 21). This molecular signature
was apparent from sequence analysis for one
telomeric recombination event that was initiated by template-switching events, yp T27 (Fig.
2C and fig. S8), and for three additional fusion
events, yp T23, yp T46, and yp T49 (Fig. 3 and
Large-scale duplication of interstitial segments
of the human genome can result in genomic
disorders. These aberrations display hallmarks
that we observed in 82% of end-to-end fusions
(n = 38): duplications interrupted by triplications
and nonduplicated sequences, likely generated
by template-switching, as well as breakpoints that
are sealed by microhomology (22), which suggested a conserved process that may be relevant
to metazoan genome evolution. Models where a
stalled replication fork or double-strand break
induces promiscuous DNA synthesis—termed
fork stalling and template switching (FoSTeS) or
microhomology-mediated BIR (mmBIR)—have
been proposed to explain the origin of such large
spontaneous mitotic duplications (Fig. 2, C and
D, 3 and fig. S13) (23, 24). Transposon excision
in C. elegans can lead to duplications that may
result from template switching (25), consistent
with a role for replication-based repair in nonterminal segments of nematode genomes.
Although DNA bridges during mitosis are
observed in cells with critically shortened telo-
meres, even in C. elegans (5), we propose that
critically shortened telomeres commonly trig-
ger synthesis events primed by microhomol-
ogy or limited homology to create large-scale,
interrupted subtelomeric duplications, in the
absence of BFB cycles (Figs. 1; 2, C and D;
and 3; and figs. S8 and S13). These inter-
rupted duplications resemble interstitial mam-
malian genome aberrations attributed to FoSTeS
or mmBIR, and they can be resolved by end-
joining with a second dysfunctional chromo-
some end. BFB may function independently
to promote duplication at uncapped telomeres
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Supporting Online Material
Materials and Methods
Figs. S1 to S13
Tables S1 to S6
13 October 2010; accepted 18 March 2011