Open Journal of Genetics, 2013, 3, 8-13 OJGen
http://dx.doi.org/10.4236/ojgen.2013.32A3002 Published Online August 2013 (http://www.scirp.org/journal/ojgen/)
Predominance of constitutional chromosomal
rearrangements in human chromosomal fragile sites
Inês J. Sequeira1, João T. Mexia1, João Santiago2, Rita Mamede2, Elisa Silva2, Jo rge Santos2,
Daniel Faria2, José Rueff2, Aldina Brás2*
1Department of Mathematics and CMA, Faculty of Sciences and Technology, Universidade Nova de Lisboa, Caparica, Portugal
2Department of Genetics and CIGMH, Faculty of Medical Sciences, Universidade Nova de Lisboa, Lisbon, Portugal
Received 21 May 2013; revised 22 June 2013; accepted 8 July 2013
Copyright © 2013 Inês J. Sequeira et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Chromosomal fragile sites (CFSs) are loci or regions
susceptible to spontaneous or induced occurrence of
gaps, breaks and rearrangements. In this work, we
studied the data of 4535 patients stored at DECI-
PHER (Database of Chromosomal Imbalance and
Phenotype in Humans Using Ensembl Resources). We
mapped fragile sites to chromosomal bands and di-
vided the 23 chromosomes i n to fragile and non-fragile
sites. The frequency of rearrangements at the chro-
mosomal location of clones found to be deleted or du-
plicated in the array/CGH analysis, provided by DE-
CIPHER, was compared in Chromosomal Fragile
Sites vs. non-Fragile Sites of the human genome. The
POSSUM Web was used to complement this study.
The results indicated 1) a predominance of rear-
rangements in CFSs, 2) the absence of statistically
significant difference between the frequency of rear-
rangements in common CFSs vs. rare CFSs, 3) a
predominance of deletions over duplications in CFSs.
These results on constitutional chromosomal rear-
rangements are evocative of the findings previously
reported by others relatively to cancer supporting the
current line of evidence and suggesting that a com-
mon mechanism can underlie the generation of con-
stitutional and somatic rearrangements. The combi-
nation of insights obtained from our results and their
interrelationships can indicate strategies by which the
mechanisms can be targeted with preventive medical
interventions.
Keywords: Chromosomal Fragile Sites; Constitutional
Chromosomal Rearrangements; Databases
1. INTRODUCTION
From a mere cytogenetic observation of 40 years ago [1],
fragile sites of human chromosomes became the subject
of important studies in human genetics.
Based on their inheritance patterns and population fre-
quency, chromosomal fragile sites (CFSs) were classified
in two main categories: rare and common. A subsequent
subdivision was made based on the class of chemicals
which may induce these types of CFSs [2]. Recently,
aphidicolin was able to indu ce all types of rare and com-
mon CFSs, suggesting that these breakage-prone regions
are less dependent on specific inducing chemicals than
originally considered [3].
Despite the DNA sequence is substantially different
among the types of fragile sites, the idea that a general
mechanism of failure of replication and fragility at dif-
ferent types of chromosomal fragile sites is emerging [4].
Together the different DNA sequences in fragile sites,
including the CCG/CGG trinucleotide repeats, AT-rich
minisatellite repeats or AT-dinucleotide-rich islands, are
1) prone to form stable DNA secondary structures which
may interfere with DNA replication, 2) h ave been shown
to contain highly flexible DNA sequences that could
prevent the replication fork progression and affect chro-
matin organization, 3) were found to disfavour nucleo-
some assembly [4].
The traditional classification of fragile sites has re-
cently been questioned [3] and the extension of the defi-
nition of CFSs to chromosomal fragile regions has been
proposed, since molecular genetic mapping data indi-
cated that breaks do not occur in a defined sequence of
CFSs, but most likely in regions prone to breakage as
large as 10 Mb [5,6].
Although several lines of evidence indicated that so-
matic rearrangements occurring within CFSs are associ-
ated with cancer development [7], fragile sites have
*Corresponding a uthor.

I. J. Sequeira et al. / Open Journal of Genetics 3 (2013) 8-13 9
rarely drawn attention as genomic structures associated
with constitutional chromosomal rearrangements leading
to birth defects. Chromosome breakage at or near the
rare fragile site FRA11B has been implicated in Jacobsen
syndrome and an aphidicolin-inducible fragile site, FRA
18C, was identified in the father of a patient with an
18q22.2-qter truncation and the Beckwith-Wiedemann
syndrome [8,9].
Given the paucity of data indicating a role for other
fragile sites in the formation of constitutional rearrange-
ments as well as a study reporting on the lack of associa-
tion between fragile sites and constitutio nal chromosome
breakpoints [10], it was thought that the involvement of
CFSs might be minimal in constitutio na l aberrations. The
recently obtained evidence that chromosomal instability
associated with CFSs plays an important role in gross
deletions and duplications in germ cell lines, considered
causal in human diseases [11], led us readdress this old
issue.
Therefore, the main aim of our stud y was to determine
the frequency of constitutional chromosomal rearrange-
ments in CFSs, including common and rare CFSs. Com-
parison of the frequencies of chromosomal aberrations in
these sites will help clarify the molecular events that
might lead to disease.
2. METHODS
2.1. Data
The genomic position of fragile and non-fragile sites was
based on the NCBI Map Viewer (Build 37.2). The con-
sented DECIPHER patient data, including the start and
the end positions of the deleted or duplicated regions,
remapped to GRCh37 (hg1 9), were provided b y DECIP-
HER in 2011. The analysis of a total of 4535 DECI-
PHER patients was performed. The POSSUM Web was
assessed during 2010-2011. On ly rearrangements involv-
ing DNA fragments larger than 1 Kb were considered.
2.2. Study Strategy
The human genome was divided into regions by inspect-
ing their sequential position ing, in line with Laganà et al.
[12]. Two sequential bands associated with fragile sites
are grouped together to form a FR and the region be-
tween two separate FRs is considered a non-Fragile Re-
gion. As such 258 different regions (fragile and non-
fragile) could be considered and were used throughout
this study. We take into account that 1) the fragile sites’
set was recently extended [3], 2) co mmon and r are chro -
mosomal fragile sites share some characteristics [4], 3)
some rare fragile sites span the same genomic regions as
common fragile sites [13], and 4) the CFS do not break
at defined sequences but in breakage-prone regions [5,6].
The Y chromosome was excluded from this study, since
there is only one suggestion that this chromosome might
contain a fragile site [14].
2.3. Statistical Analysis
For each chromosome, the number of deleted and dupli-
cated regions was obtained, including the start and end
positions, as well as the lengths, of fragile lFR and non-
fragile lnon-FR regions. Rearrangements could be grouped
into four classes: N1 (Yes-Yes) as the proportion of rear-
rangements that start and end in FRs, N2 (Yes-Start) as
the proportion of rearrangements that start in FRs and
end in non-FRs, N3 (Yes-End) as the proportion of rear-
rangements that start in non-FRs and end in FRs and N4
(No) as the proportion of rearrangements that start and
end in non-FRs.
We used these values to calculate the rearrangement
intensities given by 11FR
iNl

,

12
22FR non-FR
iNl l

12
33FR non-FR
iNl l and 44 non-FR iNl. As such,
the intensity was defined as the frequency of rearrange-
ments occurring in each class, weighted by the respective
length of the region. Intensity values were plotted, locat-
ing the different chromosomes for each pair of intensi-
ties.
The graphs correspond to the pairs of variables (x,y)
where each chromosome will be represented by a point.
We plotted the straight line y = x to see if we had more
chromo somes w ith y > x or more c hromo somes with y <
x. In order to compare two different intensities the sign
test was used.
Moreover, to position the chromosomes when consid-
ering the four intensities, we carried out a principal
component analysis (PCA). The leading principal com-
ponents are the linear combinations of the initial vari-
ables containing more information. We used the first and
second principal components to get a global representa-
tion of rearrangement occurrence in all chromosomes.
3. RESULTS AND DISCUSSION
3.1. Predominance of Constitutional
Chromosomal Rearrangements in CFSs
Figure 1 indicated that chromosomal rearrangements,
both deletions and duplications, responsible for chromo-
somal imbalance and associated phenotype alterations,
occur predominately in CFSs. This predominance of re-
arrangements in CFSs was also found in the POSSUM
syndromes database (data not shown). This conclusion is
in line with the current evidence, and definitely away
from the finding that there was no particular association
between fragile sites and constitutional chromosome re-
arrangements [10]. The clarification of this point may be
due, at least in part, to advances in cytogenetic tech-
niques from the conventional G banding to the recent

I. J. Sequeira et al. / Open Journal of Genetics 3 (2013) 8-13 10
1
23
4
5
678
9
10
11
12
13
14
15
16
17
18
19
20
X
21
22
0
0.005
0.01
0.015
0.02
0.025
00.005 0.01 0.015 0.02 0.025
Rear range m ents int ensities in non-FRs
Rear r an g e m e n ts in te ns ities in FRs
Figure 1. Representation of the intensity of rearrangement
located in FRs vs. intensity of rearrangement located in non-
FRs. Each chromosome is represented by a point. The coordi-
nates of each point are a pair of intensities of rearrangement
located in FRs and located in non-FRs. The straight line (y = x)
allow us to identify more chromosomes with x > y. To test the
hypothesis of equal intensities against the alternative of higher
intensities for fragile regions we used the sign test, given its
robustness. We obtained a p-value = 0.005 so we can clearly
reject the hypothesis of equal intensities at the 1% level.
array-based techniques.
When the CGH array has been intro duced in the clini-
cal practice, it became increasingly clear that the diag-
nostic potential of this technology was greater than G
banding [15,16]. Reviewing 29 studies of patients with
developmental delay/mental retardation (DD/MR), Ho-
chstenbach et al. [16] showed that a yield of approxi-
mately twice the rate of the classical cytogenetics’ find-
ings would be achieved using array analy s is.
On the other hand, our results indicating predomi-
nance of constitutional chromosomal rearrangements in
CFSs are evocative of the findings previously reported
by others concerning rearrangements in cancer. Namely,
Burrow et al. [17] reported that most of the breakpoints
in pairs of genes involved in cancer-specific recurrent
translocations are located in human chromosomal fragile
sites, supporting a causal role for frag ile sites in the gen-
eration of chromosomal rearrangements in somatic cells.
Using a custom-designed high-density CGH analysis to
study the junction sequences of approximately 500 break-
points in germ cell lines and cancer cell lines involving
PARK2 or DMD, Mitsui et al. [11,18] suggested that a
common mechanism may be involved in the generation
of rearrangements in both types of cell lines. Our results
extend the findings of these authors, adding evidence that
chromosomal fragility associated with CFSs plays a role
in constitutional chromosomal rearrangements as well.
In what concerns the exception of chromosome 22
(Figures 1 and 2), it was reported that the 22q11.2 region,
a hotspot for chromosomal rearrangements, showed in-
stability features of fragile sites [19], however this reg ion
is not yet classified as a CFS and as such not included in
FRs in this study.
3.2. Absence of Significant Statistical Difference
between Rare and Common CFSs Relative
to the Frequency of Chromosomal
Rearrangements
In spite of the useful dichotomy between rare and com-
mon chromosomal fragile sites, studies showed that, fra-
gile sites have actually a broad continuous gradient of
frequency ranging from very rare to very common (for
discussion see [20]). Both types of fragile sites display
common molecular characteristics associated with chro-
mosomal rearrangements, both in vitro and in vivo (for
review see [4]). Supporting this association in vitro is the
fact that following indu ction of the fragile site, a propor-
tion of cells from individuals with rare fragile sites are
found to have various duplications or deletions of mate-
rial distal to the fragile site [21]. This is considered to be
the result of break age at the fragile site followed by non-
disjunction of the distal chromosoma l m at e r i a l [ 2 1 ]. A l so ,
common fragile sites have been shown to display a num-
ber of characteristics of unstable and highly recombino-
genic DNA in vitro, including chromosome rearrange-
ments [22].
In vivo evidence of instability and constitutional chro-
mosomal breakage is given by the chromosomal dele-
tions in a proportion of patients with Jacobsen and Fra-
gile X syndromes [23-25], as well as the association be-
tween common fragile sites and chromosomal deletions
and translocations occuring in human genetic disorders
[20].
1
2
3
4
56
7
89
10
11
12
13
14 15
16
17
18
19
20
X
21
22
Second Principal Component
First Principal Component
Figure 2. First Principal Component (PC1) vs. Second Princi-
pal Component (PC2). The fraction of the total information
contained in PC1 is 79% and by PC2 is 18%. Intuitively, the
first two PCs show that chromosome 22 is isolated. The isola-
tion of chromosome 22 is also evident when we include the
cases in which only the start position or only the end position
of deleted or duplicated regions are located in FRs.

I. J. Sequeira et al. / Open Journal of Genetics 3 (2013) 8-13 11
Since common and rare fragile sites are breakage-
prone regions and recent data suggest that the differences
between mechanisms of instability at common versus
rare fragile sites are not so stringent [3], we compared
the frequency of rearrangements in rare vs. common fra-
gile sites. We could not detect any statistically significant
difference between rare and common fragile sites relative
to the frequency of chromosomal rearrangements (Fig-
ure 3). For this lack of statistical significance between
rare and common fragile sites, we pursued this study
without discriminating between common and rare fragile
sites.
3.3. The Most Frequent Chromosomal
Rearrangements That Occur in CFSs
Are Deletions
A higher number of deletions compared to duplications
in CFSs was found (Figure 4) but not in non-FRs. These
findings can be due to the differences in mechanisms of
generation of these chromosomal rearrangements. The
NAHR mechanism favours deletions over duplications,
because deletions can result from crossovers both in cis
and in trans, whereas duplications can only result from
crossovers in trans [26]. As the majority (66.7%) of the
NAHR-prone regions described by Liu et al. (2012) are
wholly or partially included in CFSs, it is possible that
this mechanism play a role in the rearrangements occur-
ring in CFSs. In the male germline, it has been found th at
deletions occur approximately twice as frequently as du-
plications on autosomes [27]. In spite of the role of se-
lection in the population, it is possible that other factors
are involved in this higher rate of deletions [27].
Among many factors determining the fragility of CFSs,
changes in replication time of DNA seem to play an im-
portant role. The breakpoint-clustering region is repli-
cated later and flanked by the high-flexibility peaks and
the R/G band boundaries [11]. When replication forks
slow, the likelihood that replication is incomplete at the
time of entry into division is increased in the region
without initiating events. This contributes to explain the
high frequency of breaks observed in CFSs [28]. Further-
more, the analysis of nucleotide-sequence content flank-
ing the breakpoints in CFSs demonstrated junctions with
microhomologies to be predominant, favouring the in-
volvement of MMEJ at CFSs [11]. Studying two Com-
mon Fragile-Site-Associated Loci, PARK2 and DMD, in
germ cell and cancer cell lines, these authors also found
that deletions were more frequently observed than dupli-
cations [11]. Our results are consistent with these find-
ings, showing that the higher frequency of deletions ver-
sus duplications generation occurs at the expense of de-
letions at CFSs.
Work is in progress to better clarify these mechanisms
in chromosomal fragile sites.
1
2
34
567
8
910
11
12
13 14
15
16 17 18
19
20
X
21
22
0
0.01
0.02
0.03
0.04
0.05
0.06
00.02 0.04 0.06
Rearr ang e ments intensitie s in rar e FRs
Rearr ang e me nts inte nsitie s in co m mo n F Rs
Figure 3. Representation of the intensity of rearrangement lo-
cated in common FRs vs. intensity of rearrangement located in
rare FRs in each chromosome. We used again the sign test for
comparing the intensities for rare and common fragile regions.
The p-value obtained was 0.202 so we cannot reject the hy-
pothesis of equal intensities.
1
23
45
6
7
8
910
11
12
13
14
15 16
17
18
19
20
X
21
22
0
0.002
0.004
0.006
0.008
0.01
0.012
00.002 0.004 0.0060.0080.010.012
Duplication intensitie s in F Rs
Deletion intensities in FRs
Figure 4. Representation of the intensity of deletions vs. du-
plications located in FRs in each chromosome. Each chromo-
some is represented by a point. The coordinates of each point
are a pair of intensities of deletions and duplications located in
FRs. The straight line y = x allow us to identify more chromo-
somes with the intensity of deletions located in FRs larger than
the intensity of duplications located in FRs. The sign test indi-
cates the rejection, at the 1% level (p-value = 0.008), the hy-
pothesis of equal intensities.
4. ACKNOWLEDGEMENTS
This study makes use of data generated by the DECIPHER Consortium.
A full list of centres that contributed to the generation of the data is
available at http://decipher.sanger.ac.uk and via email at
[e-mail]. Funding for the project was provided by the
Welcome Trust. We declare that those who carried out the original ana-
lysis and collection of the data bear no responsibility for the further

I. J. Sequeira et al. / Open Journal of Genetics 3 (2013) 8-13 12
analysis or interpretation of it. The authors deeply acknowledge the
invaluable help of Manuel Corpas who kindly provided us with the
DECIPHER data. We are also indebted to Professors A. Rodrigues and
M. Kranendonk for the critical reading of this work.
This work was partially supported by CIGMH/FCM/UNL, under the
project PEST-OE/SAU/UI0009/2011 and CMA/FCT/UNL, under the
project PEst-OE/MAT/UI029 7/2011.
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