Download Chromothripsis: how does such a catastrophic event impact human

Human Reproduction, Vol.29, No.3 pp. 388–393, 2014
Advanced Access publication on January 21, 2014 doi:10.1093/humrep/deu003
OPINION
Chromothripsis: how does such a
catastrophic event impact human
reproduction?
Franck Pellestor 1,2,*
1
Laboratory of Chromosomal Genetics, Arnaud de Villeneuve Hospital, Montpellier CHRU, Montpellier, France 2Inserm Unit ‘Plasticity of the
Genome and Aging’, Institute of Functional Genomics, Montpellier, France
*Correspondence address. E-mail: [email protected]
Submitted on November 1, 2013; resubmitted on December 27, 2013; accepted on January 6, 2014
abstract: The recent discovery of a new kind of massive chromosomal rearrangement, baptized chromothripsis (chromo for chromosomes,
thripsis for shattering into pieces), greatly modifies our understanding of molecular mechanisms implicated in the repair of DNA damage and the
genesis of complex chromosomal rearrangements. Initially described in cancers, and then in constitutional rearrangements, chromothripsis is
characterized by the shattering of one (or a few) chromosome(s) segments followed by a chaotic reassembly of the chromosomal fragments,
occurring during one unique cellular event. The diversity and the high complexity of chromothripsis events raise questions about their origin,
their ties to chromosome instability and their impact in pathology. Several causative mechanisms, involving abortive apoptosis, telomere
erosion, mitotic errors, micronuclei formation and p53 inactivation, have been proposed. The remarkable point is that all these mechanisms
have been identified in the field of human reproduction as causal factors for reproductive failures and chromosomal abnormalities. Consequently,
it seems important to consider this unexpected catastrophic phenomenon in the context of fertilization and early embryonic development in
order to discuss its potential impact on human reproduction.
Key words: chromothripsis / chromosomal rearrangement / genomic instability / fertilization / embryo
Introduction
Chromosomal abnormalities account for the majority of pre- and postimplantation embryo wastages and make a major contribution to pregnancy loss, birth defects and genetic disorders found in humans
(Gardner et al., 2012).
Most of the abnormalities are de novo, resulting from meiotic errors
during gametogenesis in subjects with normal karyotypes or occurring
post-fertilization during early cleavage divisions. Consequently, investigating human gametes and embryos has become an important field contributing to the understanding of the formation, the transmission and the
etiology of chromosomal abnormalities. The introduction of techniques
for in situ chromosomal analysis and rapid genomic investigation has led
to the advent of efficient procedures for cytogenetic examination of
human gametes and the development of preimplantation genetic diagnosis (PGD), which offer an alternative to prenatal diagnosis and pregnancy
termination to carriers of chromosomal abnormalities (for review see
Martin, 2005; Delhanty and Pellestor, 2011).
Among the chromosomal abnormalities, structural aberrations are of
particular interest since they involve a multitude of rearrangements
which can induce a great variety of syndromes. The rearrangements involving at least three chromosomal breakpoints on two or more
chromosomes are named complex chromosomal rearrangements
(CCRs) (Pellestor et al., 2011a). They are usually considered to be the
most complicated form of chromosomal rearrangements. Because of a
high risk for abnormal reproduction, CCRs constitute a difficult challenge
for genetic and reproductive counseling. To date, only a few laboratories
have been successful in performing segregation analysis of these abnormalities and developing PGD procedures for couples with CCRs (Escudero et al., 2008; Lim et al., 2008; Loup et al., 2010; Pellestor et al., 2011b;
Scriven et al., 2013).
The recent discovery of a new type of massive chromosomal rearrangement has radically revisited the view of how de novo structural
rearrangements are generated.
Definition and key features
of chromothripsis
The term ‘chromothripsis’ (from chromo for chromosome and thripsis for
breaking into small pieces) has been chosen to designate this newly
recognized phenomenon, first observed in tumors (Stephens et al.,
2011) and then rapidly described in congenital disorders (Kloosterman
et al., 2011). The hallmark of chromothripsis is the occurrence of tens
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Chromothripsis in human reproduction
Figure 1 Principle of the chromothripsis process: during a one-step catastrophic event, multiple DSBs occur. The breaks are restricted to a simple
chromosomal segment or to a few closed chromosome domains, but lead to the pulverization of chromosomal fragments. Most of them are stitched
back together, resulting in one or more chaotic derivative chromosome(s), whereas some are lost or combined in small circular extra-chromosomes
(double-minute chromosomes) usually harboring oncogenes. DSB, double-strand breaks.
to hundreds of genomic rearrangements confined to one or a few chromosomes, through a unique cataclysmic cellular event, leading to chaotically reassembled chromosomes (Fig. 1). Only the novel technique of
mate-pair sequencing presently allows the identification of chromothripsis and the complete assessment of the complexity of the generated
genomic rearrangements. A recent re-analysis by paired-end sequencing
of 45 reciprocal translocations and 7 inversions previously defined as
balanced has revealed extensive and yet balanced rearrangements due
to chromothripsis in 20% of them (Chiang et al., 2012). These findings
validated the occurrence of chromothripsis in the human germline or
in early embryonic development, and also confirmed its compatibility
with viability and transmission.
Several features common to all chromothripsis rearrangements distinguish this phenomenon from other complex structural aberrations. (i)
Chromothripsis always occurs in a unique catastrophic genomic event.
(ii) This cataclysmic event leads to the generation of tens to hundreds
of rearrangements, locally clustered on one single chromosome or a
few chromosomes rather than scattered throughout the whole
genome. (iii) Multiple copy numbers and structural aberrations resulting
from double-strand breaks (DSB) are found in derivative chromosomes,
including translocations, inversions, insertions, deletions, duplications
and triplications. (iv) Most of the reassembled DNA fragments are randomly joined and they do not display any sequence homology in their
breakpoints or only micro-homology of a few nucleotides. (v) In the reassembled segments, copy-number profiles show oscillating states
between loss and retention of heterozygosity, which would be unlikely
in a scenario of gradually acquired rearrangements. (vi) Finally, congenital
chromothripsis rearrangements are characterized by their low copynumber changes and their relatively balanced status. This does not
signify that unbalanced chromothripsis does not occur in germline or
during post-zygotic divisions, but it strongly emphasizes the effect of
selection as a bias factor in the assessment of congenital chromothripsis,
since only balanced chromothripsis outcomes compatible with life have
been found in individuals to date.
Altogether, these key features define the molecular signature of chromothripsis (Maher and Wilson, 2012; Korbel and Campbell, 2013). The
definition of these features characterizing chromothripsis is an important
step towards our understanding of how and where chromothripsis
arises, and if it arises alone or in association with other cellular mechanisms (Sorzano et al., 2013; Wyatt and Collins, 2013).
Potential causes of
chromothripsis in human
reproduction
Analyses of breakpoint junction sequences have revealed that the reassembly of DNA fragments is driven either by template-independent
double-strand break (DSB) repair mechanisms such as non-homologous
end-joining (NHEJ), or by replicative processes such as fork stalling template switching (FoSTeS) and micro-homology-mediated break-induced
repair (MMBIR). NHEJ mechanism may explain the lack of sequence
homology or micro-homology at breakpoint junctions as well as insertions or deletions of nucleotides, whereas replicative processes offer
an explanation for the generation of duplications and triplications in chromothripsis events (Liu et al., 2011a; Kloosterman et al., 2012).
Although the molecular mechanisms for chromosomal segment
stitching are well understood, the causes of chromothripsis and its mechanistic basis are still under discussion. What exogenous or endogenous
processes can induce such a highly localized chromosomal pulverization
and how can cells manage such a cataclysmic crisis on a short time scale?
A striking noteworthy point is that all the mechanisms which are now
being suggested to trigger chromothripsis were previously identified as
390
potential causal factors for infertility, reproductive failures and aneuploidy induction.
Chromothripsis in germlines
Existing data show that constitutional chromothripsis occurs in the male
germline (Kloosterman et al., 2011; Chiang et al., 2012). This finding is
consistent with the preferential paternal origin of the vast majority of
de novo chromosomal structural aberrations found at term (Pellestor
et al., 2011a). This confirms the great vulnerability of spermatogenesis
to DNA damage and its limited or less efficient DNA repair capacity
when compared with somatic tissue cells.
In the course of spermatogenesis and according to the availability of
DSB repair systems, chromothripsis initiation can occur either during
the pre-meiotic division of diploid spermatogonia through the first
meiotic division involving recombination events, or during the differentiation of round spermatids into spermatozoa (i.e. spermiogenesis).
During each of the three steps, environmental stimuli such as ionizing
radiations or free radicals may act as triggers for chromothripsis.
DNA replication stress can also serve as an endogenous stimulus.
Various factors such as inhibition of DNA polymerase function or defective topoisomerase activity may induce a DNA replication stress
through replication fork collapse and template-switching events,
leading to genomic instability and induction of chromothripsis (Liu
et al., 2012).
The frequent localization of chromothripsis rearrangements on a
unique chromosomal region suggests that pulverization might occur
when chromosomes are condensed, i.e. during mitosis. Since spermatogonia can undergo hundreds of mitotic divisions before entering into
meiotic prophase, these cells seem to be particularly prone to chromothripsis. However, examples involving several chromosomes indicate
that the phenomenon may also occur during interphase when chromosomes are relaxed throughout the nucleus. This notion implies either a
spatial proximity of chromosomes during the chromothripsis, with reference to the well-known spatial organization of chromosomes in nuclear
territories (Bickmore and van Steensel, 2013) and/or the movement of
chromatin within the nucleus which recent studies have correlated with
DSB repair process (Dion and Gasser, 2013).
In this context, various triggers have been suggested for chromothripsis initiation. Tubio and Estivill (2011) proposed that chromothripsis
might be caused by abortive apoptosis. During spermatogenesis, apoptosis is a major mechanism controlled by Sertoli cells for the elimination
of defective germ cells. Among the cells undergoing apoptosis, a few
could undergo a restricted form of apoptosis or escape the process,
and subsequently survive after performing a rapid and chaotic DNA
repair to maintain their genome integrity. This could induce multiple
and complex chromosome rearrangements. Another view is that chromothripsis is caused by the combination of mitotic errors due to various
mechanisms (centrosome overduplication, chromatid cohesion deficiency . . .) and replication stress (Jones and Jallepalli, 2012). This can
occur through alterations of DNA replication checkpoints or deficient
replication mechanisms, generating genomic instability. Since many
examples of chromothripsis rearrangements affect chromosome ends,
telomere attriction could also induce chromothripsis through
end-to-end chromosome fusion and generation of multiple chromosome breaks and reassociations during the resolution of anaphase
bridges (Stephens et al., 2011).
Pellestor
An attractive explanation to link all these causal processes with the
confined nature of the damage created during chromothripsis is that
the damaged chromosome(s) is (are) incorporated into a micronucleus
which can persist in cells over several generations (Crasta et al., 2012). In
micronuclei, chromosomal material can undergo defective and asynchronous DNA replication as well as aberrant chromatin compaction.
Thus, chromosomal pulverization and reassembly are restricted to the
chromosome trapped in the micronuclei. The rearranged chromosome
can be re-integrated into the nucleus of the daughter cell and be stably
maintained through subsequent cell divisions.
During meiosis, the chromatin of germ cells sustains programmed
structural changes (meiotic recombinations) which require the formation and the repair of DSB. Deficiencies in the recombination machinery
linked to exogenous agents or intrinsic causes such as gene mutations
might result in ectopic synapsis and erroneous resolution of physiological
DSB by non-homologous pathways (Hassold and Hunt, 2001; Liu et al.,
2011b). Variations in some repeat sequence arrays, such as PRDM9, can
strongly affect meiotic recombination activity and stimulate intrachromosomal homologous recombinations (Berg et al., 2010). Heavy
loads of DSB probably saturate the error-free repair machinery and
stimulate DSB resolution by error-prone systems such as multiple
NHEJ, leading then to the random chromosome reassembly characteristic of chromothripsis (Gudjonsson et al., 2012). Also, the possibility
of chromothripsis occurrence in female meiosis should not be neglected
since female meiosis is the major source of aneuploidy (Pellestor et al.,
2005; Fragouli et al., 2011) and displays permissive checkpoints (Steuerwald, 2005). Chromosome mal-segregation or premature separation of
sister chromatids occurring during the two female meiotic divisions can
induce genome instability, micronuclei formation and subsequent chromothripsis events. The particular cytokinesis operating in female meiosis
between the large-sized oocyte and the small polar bodies could facilitate
the initiation of chaotic rearrangements.
Finally, during spermiogenesis, round spermatids have a slow and
moderate repair capacity. At this stage, DSB cannot be repaired by homologous recombination since spermatids lack sister chromatids for
homologous repair. Consequently, repair is processed by homologyindependent and error-prone mechanisms such as NHEJ or less welldefined repair pathways (Ahmed et al., 2010). This can also be associated
with the abortive apoptosis process. In late spermiogenesis, maturing
cells also undergo a histone-to-protamine transition. This extensive
chromatin remodeling requires the creation and ligation of DSB. Alterations in this process may lead to DNA fragmentation and unrepaired
DNA breaks that make spermatozoa more susceptible to post-testicular
assaults, especially during transport through epididymis where the generation of reactive oxygen species and exogenous factors might induce
additional sperm DNA breaks (Oliva, 2006).
Chromothripsis in zygotes and
preimplantation embryos
During the fertilization process, the paternal nucleus decondenses and
undergoes extensive chromatin remodeling and DNA replication. This
new modification of chromatin architecture certainly has an impact on
DNA repair mechanisms since modulation of the chromatin structure
itself constitutes a precondition for the recruitment and action of
DNA repair proteins. DNA breaks generated during spermiogenesis
and sperm transport need to be repaired before the first round of
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Chromothripsis in human reproduction
DNA replication in the zygote, since extensive DNA damage is virtually
incompatible with embryonic development. This phase of DNA repair is
entirely dependent on the repair capacities of the oocyte and the zygote.
The ability of human oocytes to repair DNA damage in the fertilizing sperm
nucleus is limited to 8–10% of the haploid genome (Sakkas and Alvarez,
2010), and this is probably highly variable among oocytes according to the
genetic background, the maturity status and the women’s age. Thus,
when confronted with extensive damage, the repair machinery could be inefficient and the zygote could die. However, one can speculate that in good
quality oocytes and zygotes, the cell would be able to rapidly repair chromatid damage localized on one chromosomal segment or on a few closed
chromosome domains in order to maintain a relatively complete and
balanced genome. This kind of repair could be performed through fast
and error-prone repair pathways leading to the chaotic reassembling of
chromatid segments. This repair scenario could be facilitated by relaxed cellcycle checkpoints in oocytes and in early cleavage embryos (Harrison et al.,
2000).
Another phenomenon that may initiate chromothripsis during fertilization is the premature chromosome condensation (PCC) of sperm
nuclei due to the asynchrony between the female nucleus blocked in
the metaphase II stage and the male nucleus in S-phase and the abnormal
activity of persistent mitotic promoting factors. Thus, incompletely replicated male chromosomes can be partially pulverized. In the vast majority
of cases, zygotes with such extensive damage will die through an apoptotic process. However, the induction of PCC might subsequently
corrupt the G2-checkpoint. Thus, the zygote with partially underreplicated and fragmented DNA might prematurely enter into mitosis
(Stevens et al., 2010) and generate the formation of micronuclei in
which fragmented chromosomes can undergo random repair and independent replication before being reincorporated into the nucleus of a
daughter embryonic cell.
All the alterations evoked can also occur during early cleavage divisions. Accumulating data show that human preimplantation embryos
have a high rate of chromosomal abnormalities, including frequent
chromosomal mosaicisms and chaotic chromosomal patterns (Mantzouratou and Delhanty, 2011; Mertzanidou et al., 2013). It has also
been shown that good quality human preimplantation embryos display
a remarkably high incidence of structural abnormalities involving
complex segmental rearrangements (Vanneste et al., 2009) and frequent
chromosomal instability (Voet et al., 2011, Fragouli et al., 2013). Thus, a
high incidence of chromosome defects in rapidly dividing blastomeres
with relaxed cell-cycle and mitotic checkpoints supports the assumption
that chromothripsis events may also arise during early human embryogenesis. It is probable that the combination of chaotic chromosomal rearrangements and gene dosage alterations preferentially lead to non-viable
embryos which are lost around the time of implantation. Only chromothripsis resulting in balanced and stable chromosomal rearrangements
would be viable. According to the embryonic stage where the
catastrophic event occurs, chromothripsis will be confined to extraembryonic tissues or be present as full chromothripsis or mosaic chromothripsis in the embryonic lineage and have pathogenic consequences
(Lebedev, 2011).
When in vitro conceived embryos are morphologically assessed,
blastomere fragmentation, presence of micronuclei or asynchronous
cleavage is often noted (Chavez et al., 2012). These observations may
constitute arguments supporting the assumption of chromothripsis occurrence at early cleavage stages. They also raise questions about the
implication of in vitro manipulations in the initiation of chromothripsis.
Several studies have speculated that the in vitro culture conditions and
handling of gametes and embryos could alter the behavior of cells and
possibly affect the efficiency of checkpoints and the ability to repair
DNA damage (Ledbetter, 2008). This stresses the need to better understand how zygotes and embryos in culture experience changes in the
capacity to manage DNA repair.
Link between chromothripsis and
p53 family proteins in human
reproduction
Finally, the occurrence of chromothripsis has been strongly associated
with dysregulation or loss of the p53 tumor suppressor gene (Rausch
et al., 2012). Known as the guardian of the genome, p53 plays a major
role in maintaining genome stability by mediating cell-cycle arrest, apoptosis and cell senescence in response to DNA damage (Vogelstein et al.,
2000). Alterations to the p53 pathways could support or initiate chromothripsis by disrupting these fundamental mechanisms of cell-cycle control
and then facilitating cell survival after chromosome shattering and
massive rearrangements (Kloosterman and Cuppen, 2013). The p53
family proteins, involving p53, p63 and p73, play important roles in reproduction. p53 is highly expressed in testes, in particular in early spermatocytes where it mediates DNA damage-induced apoptosis (Odorisio
et al., 1998). In p53 null mice, a high incidence of multinucleated cells
and limited apoptosis are observed. Recently, p53 has also emerged as
a fertility regulator controlling embryo implantation (Corbo et al.,
2012). In female meiosis, the p53 homologue p63 is essential for the
process of eliminating damaged oocytes (Suh et al., 2006). Oocytes
without p63 are resistant to DNA damage-induced apoptosis. The
third transcription type p73 is also involved in the regulation of oocyte
quality by interacting with the spindle assembly checkpoint complex.
Oocytes that are deficient in p73 exhibit spindle abnormalities and an increasing rate of chromosomal defects (Hu et al., 2011). All these data
seem to be consistent with the hypothesis of an association between
the occurrence of constitutional chromothripsis and alterations of p53
family proteins. Further understanding of the functions of these proteins
in reproduction may shed light on the molecular mechanisms governing
the process of chromothripsis.
Conclusion
Chromothripsis is an unexpected phenomenon whose discovery has
deeply modified our perception of the genesis of genome rearrangements and their impact on human development and congenital diseases.
Multiple lines of evidence support the concept that chromothripsis
originates through a single catastrophic event. Although the causes of
chromothripsis are still being debated, various procedures have been
proposed. The present short review shows that all the causative mechanisms suggested may occur in germlines or during early embryonic development. Clearly, more work is needed to define the contribution of
chromothripsis to altered human development and congenital disorders.
However, it seems important to take into consideration this new process
for the study of reproductive disorders, and particularly for the investigation of the causes of low success rates in natural and assisted reproduction.
392
Acknowledgements
The author thanks Dr G. Lefort and Dr J. Puechberty for critically reading
the manuscript.
Authors’ roles
F.P. was responsible of the writing of the manuscript, reference search
and figure execution.
Funding
This manuscript did not have any specific funding.
Conflict of interest
The author declares no conflict of interest.
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