# Chromoanagenesis: a piece of the macroevolution scenario

Franck Pellestor, Vincent Gatinois

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Franck Pellestor, Vincent Gatinois. Chromoanagenesis: a piece of the macroevolution scenario. Molecular Cytogenetics, 2020, 13 (1), pp.3. 10.1186/s13039-020-0470-0. hal-03507391

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# Chromoanagenesis: a piece of the macroevolution scenario

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Franck Pellestor<fnref n="1" />,<fnref n="2" />* and Vincent Gatinois<fnref n="1" />,<fnref n="2" />

## Abstract

Over the last decade, new types of massive and complex chromosomal rearrangements based on the chaotic shattering and restructuring of chromosomes have been identified in cancer cells as well as in patients with congenital diseases and healthy individuals. These unanticipated phenomena are named chromothripsis, chromoanasynthesis and chromoplexy, and are grouped under the term of chromoanagenesis. As mechanisms for rapid and profound genome modifications in germlines and early development, these processes can be regarded as credible pathways for genomic evolution and speciation process. Their discovery confirms the importance of genome-centric investigations to fully understand organismal evolution.

Because they oppose the model of progressive acquisition of driver mutations or rearrangements, these phenomena conceptually give support to the concept of macroevolution, known through the models of "Hopeful Monsters" and the "Punctuated Equilibrium". In this review, we summarize mechanisms underlying chromoanagenesis processes and we show that numerous cases of chromosomal speciation and short-term adaptation could be correlated to chromoanagenesis-related mechanisms.

In the frame of a modern and integrative analysis of eukaryote evolutionary processes, it seems important to consider the unexpected chromoanagenesis phenomena.

**Keywords:** Chromoanagenesis, Chromothripsis, Chromoanasynthesis, Chromoplexy, Macroevolution, Complex chromosome rearrangements, Saltational evolution, Speciation

## Background

The last decade has seen the emergence of new concepts in the field of the chromosomal mechanics and genetics, with the identification of a novel class of complex chromosome rearrangements (CCRs) arising during single cellular events and leading to massive and chaotic genomic rearrangements confined to one or a few chromosomes. The unanticipated catastrophic phenomena are named chromothripsis, chromoanasynthesis and chromoplexy, and the term "chromoanagenesis" (for chromosome rebirth) has been proposed to encompass these new types of rearrangements [1]. Although original and surprising in their formation and their complexity, these phenomena take into account previous cytogenetic

data having demonstrated the respective role of recurrent and non-recurrent chromosomal abnormalities in the evolution of cancers [2]. While non-recurring abnormalities were considered as non-significant background, these studies demonstrated their link with genomic instability and karyotype evolution [3, 4].

The prevalence of theories based on gene-centric concepts has dismissed evolution scenarios based on genomic-centric concept changes [5] that the discovery of chromoanagenesis phenomena brings to light. The concept of chromoanagenesis deeply upset our designs concerning the genesis and the etiology of complex chromosomal rearrangements. It also provides new insight into the plasticity and the instability of the genome as well as on the mechanisms underlying the maintenance and the modification of chromosome structure. Accumulating data indicate that chromoanagenesis-related phenomena may occur in germlines or during early embryonic development [6] and they can lead to the formation of stable and heritable rearranged

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<footnote>* Correspondence: fpellestor@yahoo.fr</footnote>

<footnote n="1">¹Unit of Chromosomal Genetics, Department of Medical Genetics, Arnaud de Villeneuve Hospital, Montpellier CHRU, 371 avenue du Doyen Gaston Giraud, 34295 Montpellier Cedex 5, France</footnote>

<footnote n="2">²INSERM 1183 «Genome and Stem Cell Plasticity in Development and Aging », Institute of Regenerative Medicine and Biotherapies, St Eloi Hospital, Montpellier, France</footnote>
genomic constitutions [7]. Thus, as mechanism for the fast restructuring of genome, chromoanagenesis might be evolutionary relevant process. In this review, we summarize the characteristics of the 3 distinct forms of chromoanagenesis-related phenomena and we discuss their potential implications in evolutionary biology.

## All-in-one

For each phenomenon, several specific features have been described, allowing each mechanism to be distinguished from each other (Fig. 1).

Chromothripsis (for breaking into small pieces) was the first of these chaotic processes, described in 2011 [8]. Chromothripsis results from a single cellular event in which one or several chromosome segments are broken in pieces and reassembled in random order and orientation to form complex derivative chromosomes [9]. First observed in tumors, the phenomenon was rapidly identified in patients with congenital malformations, developmental disorders or carrying apparently balanced rearrangements [10, 11]. In the same way, chromothripsis-like events were described in phenotypically normal subjects as well as in prenatal diagnosis [12, 13].

The key-features, common to all chromothripsis events are the occurrence of numerous clustered chromosomal breakpoints, the low DNA copy number changes and the preservation of heterozygosity in the rearranged segments [14, 15]. Several mechanisms involving telomere attrition, mitotic errors, abortive apoptosis, premature chromosome condensation, p53 defect, or viral integration were identified as cellular processes driving chromothripsis [16–20]. An attractive mechanistic explanation to link all these causal processes with the confined nature of genomic alterations generated by chromothripsis, is that the implicated chromosome(s) can be sequestrated into a micronucleus in which chromothripsis-related damages will occur [21, 22]. Micronuclei formation can result from chromosome segregation failure but also can be caused by a wide variety of stresses occurring during any stages of the cell cycle [23, 24]. Micronuclei may persist in daughter cells over several cell cycles before being eliminated or reincorporated into the regular nucleus. Consequently, micronuclei must be regarded as an important source of genetic variations [25]. Experimental models have been developed making it enable to reproduce in vitro chromothripsis-like events and thus validate its existence.

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In particular, elegant models to specifically induce the se-
questration of chromosomes Y into micronuclei and ana-
lyse their subsequent chaotic alterations have been
described [19].

Chromoanasynthesis (for synthesis of new chromosomes)
is a distinct form of “one-step” chaotic chromosomal re-
arrangement described by Liu et al. [26]. Based on DNA
replication defects, chromoanasynthesis involves multiple
template-switching events driven by microhomology-
mediated break-induced replication (MMBIR) or fork
stalling and template switching (FoSTeS) mechanisms. Dis-
engagement of the lagging strand and annealing at a nearby
replication fork site might serially occur and thus cause
complex and multiple rearrangements of different scales
Chromoanasynthesis can lead to the creation of complex
rearranged chromosomal segments with frequent DNA
copy-number changes, particularly region-focused duplica-
tions and triplications and short stretches of micro-
homologies at the breakpoint junctions [27, 28].

By blocking replicative fork progression, various en-
dogenous and exogenous factors might cause replication
stress and induce genomic instability which can lead to
chromoanasynthesis events [29]. Like for chromothrip-
sis, the incorporation of lagging chromosome or chro-
matid fragments within micronuclei offers an appealing
mechanistic explanation for chromoanasynthesis. After
the cell enters S phase, DNA replication can occur in
the micronuclei. However, micronuclei show significant
reduction in the recruitment of components for both
DNA replication and repair machinery [23]. The DNA
replication in micronuclei is asynchronous and defective
compared to the primary nucleus and the rupture of the
micronuclear envelope alters active replication fork pro-
gression by diluting the material components of micro-
nuclei into the cytoplasm [24].

Although the mechanism differs from that of chromo-
thripsis, the biological consequences of chromoana-
synthesis are similar, with the formation of highly
rearranged chromosomes. As with chromothripsis, de-
velopmental delay, autism spectrum disorders, and dys-
morphic facial features are the main disorders observed
in patients with chromoanasynthesis. Chromoanasynth-
esis has also been observed in phenotypically unaffected
individuals [30, 31].

In addition, a third type of “all-at-once” mechanism
for massive chromosomal rearrangement has been evi-
denced in prostate cancer, and then in lung cancer and
melanoma. Termed chromoplexy (for chromosome re-
structuring), this phenomenon is characterized by the
interdependent occurrence of multiple inter- and intra-
chromosomal translocations and deletions [32]. These
chains of rearrangements, numbering from 3 to over 40,
can involve up to 8 chromosomes in a single chain. All
the translocated segments originate from DNA double-

strand breaks and the derivative rearranged chromo-
somes present little or no copy number alterations [33].
Although chromoplexy includes multiple chromosomes,
it is possible that such chain of translocations was pro-
moted by physical clustering of the breakpoints in the
nucleus, in relation with the colocalization of DNA repli-
cation or transcription factories. Since multiple chromo-
somes can be encapsulated in micronuclei, it is also
conceivable that a micronucleus-based model could me-
diate the process of chromoplexy [24].

Some chromoanagenesis events arise de novo, but ac-
cumulating data on familial chromoanagenesis-mediated
rearrangements have validated the notion of the herit-
ability of chromoanagenesis-mediated genomic alter-
ations [12, 34]. Recent reports have provided evidence
that chromoanagenesis can operate in human germline
cells and during early embryonic development [35–37],
strongly suggesting that chromoanagenesis could be
more common than anticipated in gametes and preim-
plantation embryos.

Chromoanagenesis and saltational evolution

To date, numerous studies have confirmed the biological
reality of chromoanagenesis events. In cancer, the dis-
covery of these phenomena has challenged the dogma
that genomic alterations in tumoral cells occur through
progressive accumulation of mutational events [38]. The
chromoanagenesis model offers additional routes to-
wards tumorigenesis that the gradual route. In the field
of constitutional genetics, recent reports have demon-
strated that complex chromoanagenesis-related rear-
rangements can be viable and transmissible [39]. In the
light of this data emerges a new perception of how the
genome can be rapidly reworked and how chaotic rear-
rangements could be credible mechanisms for genome
evolution while maintaining its stability. Because all
chromoanagenesis-related processes are fast mechanisms
occurring from a single cellular event, and they oppose
the model of progressive acquisition of driver mutations,
the concept of chromoanagenesis supports the evolution
models that purpose long periods of relative stability
punctuated by sudden and rapid periods of radical
modifications.

The implication of large and rapid genetic alterations
in speciation was first proposed by the geneticist R.
Goldschmidt (1878–1958) who advanced a model of
saltational evolution known as the “Hopeful Monster”
model [40]. Goldschmidt raised no objection to the
standard neo-Darwinian view of gradual accumulation of
small mutations (micro-evolution) but he suggested that
the large differences between species required macro-
mutations, a source of significant genetic changes
(macro-evolution). According to Goldschmidt’s hypoth-
esis, “one-step” macromutations in “controlling” genes
might modify early development and cause profound
and abrupt changes in the adult phenotypes of organ-
isms that then acquire the potential to establish a new
evolutionary lineage [41]. Obviously, the vast majority of
macromutations could only be disastrous and evolution
could proceed by the rare success of such hopeful mon-
sters and not by the gradual accumulation of small
changes within populations [42]. At the same time, C.H.
Waddington (1905–1975) was trying to identify develop-
mental mechanisms to produce such new species. To ex-
plain certain aspects of morphological evolution, he
formulated the notion of transfer of competence, bap-
tized the genetic assimilation, a process by which a
phenotype originally induced in response to particular
environmental conditions becomes encoded in the gen-
ome by natural selection or artificial selection [43]. Al-
though controversial, the Waddington's theory of
genetic assimilation prefigured the notion of genome
plasticity. In 1972, paleontologists N. Eldredge and S.J.
Gould [44] provided a new perspective for the macro-
evolution model when they proposed the punctuated
equilibrium theory as a complement to phyletic gradual-
ism. This model proposed that biological evolution and
the emergence of new species take place through abrupt
and profound changes, occurring between long periods
of stasis in which few variations occur in established spe-
cies [45]. The punctuated changes might involve spor-
adic genetic mutations with large effects or chromosome
rearrangements affecting gene expression. Punctuated
equilibrium applies to sexually reproducing organisms
and morphological evolutionary changes are regarded as
largely correlated with speciation events [46]. The dis-
covery of homeobox genes first in *Drosophila* and then
in vertebrates has given rise to renewed interest in the
concept of discontinuous evolution and macroevolution
[47]. Phylogenetic studies of the vertebrate *Hox* cluster
and linked genes have suggested that the homeobox
genes organization in malleable gene clusters occurred
through processes of large-scale chromosomal rear-
rangements that reshape gene organization over evolu-
tionary time [48, 49].

Many evolutionary events involve changes in the struc-
ture of chromosomes (fusion, translocation, inversion, in-
sertion, ...) as evidenced by karyotype differences observed
between mammalian species [50]. Heng [5] introduced the
genome-centric concept in order to highlight the essential
contribution of genome alterations (versus gene modifica-
tions) in the evolutionary adaptation and speciation. The
genome-centric concept refers to the notion of macro-
evolution proposed by Goldschmidt [42], and it allows to
define tangible relationships between the biological self-
organization and the natural selection [51]. One of the
keys of the genome-centric evolutionary concept is the
importance of the genome topology and karyotype, in

connection with environment interactions, which can de-
fine an alternative conceptual framework, named the
karyotype coding, for understanding genome beyond
genes and fully appreciating evolutionary process [52, 53].

During the last years, experimental evidence has shown
that genomic changes can confer a large adaptive value
are not rare, and when competing with small-effect muta-
tions, they tend to win [54, 55]. A growing number of
studies has documented punctuated equilibrium and
hopeful monsters in various species. For instance, Fraz-
zetta [56] described a subfamily of monotypic snake, the
*Bolyerinae*, distinct from all monotypic snakes in that they
display a movable joint of the maxillary bone that consti-
tutes a mechanical characteristic adaptive for feeding.
Such a modification that arose suddenly, was in good
agreement with the concept of the “Hopeful Monster”.
Another example of discontinuous evolution concerns
desert rodents. In 2 families of granivorous rodents (Geo-
myidae and *Heteromyidae*), Long [57] demonstrated that
the formation of external check pouches conferring an
adaptive benefit because they prevent salivary water loss
to seeds, was not linked to a series of pre-adaptive possi-
bilities but to a discontinuous transition. A striking ex-
ample of such a short-term evolution was the fast
adaptative changes of the lizard *Podarcis sicula* who, after
36 years of experimental introduction into a novel envir-
onment, displayed significant changes in morphology and
performance (head morphology, bite strength) and a re-
markable evolution of digestive tract structure [58]. In hu-
man, the neurobiological study of 2 subjects with six
anatomically fully developed fingers on the two hands
demonstrated the perfect cortical representation and con-
trol of supernumerary fingers and their augmented ma-
nipulation ability [59]. More anecdotal, the recent
discovery of a python with a third functioning eye on its
forehead could also be related to the macroevolution
process (https://www.livescience.com/65382-three-eyed-
snake.html). Similar ectopic induction of functional eyes
has been genetically induced in scarab beetles [60]. The
rapid emergence and integration of novel complex organs
such as a eye or an extra finger provide remarkable exam-
ples of the ability of developmental systems to channel
massive perturbations toward orderly and functional out-
comes, highlighting the extraordinary plasticity of genome
and the buffering capacity of developmental systems.

In 1999, Rieseberg et al. [61] introduced the notion of “transgressive segregations” for the generation and the rapid fixation of new genotypes in population. Based on genetic recombination in hybrids, this mechanism can rapidly produce novel phenotypes by recombining multiple loci simultaneously. If transgressive hybrids have higher fitness in environments, this increases the likelihood of divergence from the parental populations and of fixation in a population [62].
The phenomena of chromoanagenesis, by their sudden occurrence and the chaotic alterations of the genome that they generate, appear to be a mechanism consistent with these macroevolution concepts and the notion of punctuated change. Thus, genome chaos plays an essential role in the evolution of most cancers [63]. One-step catastrophic genomic events may generate multiple chromosomal rearrangements and significantly accelerate the tumor evolution [64–66]. In pancreatic cancer, the observation of a high prevalence of chromothripsis (> 65%) in tumors supports the punctuated equilibrium model as the principal process for tumorigenesis [67]. Among constitutional chromoanagenesis-related rearrangements, studies have evidenced that chromothripsis and chromoanasyntesis could generate massive but balanced genomic rearrangements, compatible with life and contributing or not to developmental diseases but also able to restore a normal function [68, 69]. To date, the existence of chaotic genomic alterations is not restricted to human but there are also documented in other mammalians [70], in plants [71, 72], in nematode *Caenorhabditis elegans* [73], in *Saccharomyces cerevisiae* [74] and plankton [75] emphasizing the notion that the cellular pathways responsible for generating such complex patterns of chromosomal rearrangements are highly conserved.

## Macro-evolutionary implications of chromoanagenesis

Undoubtedly, chromoanagenesis phenomena are among the most unexpected biological discoveries made in the last years. The investigation of this new class of genomic alterations has provided new insights on the mechanisms connecting their occurrence with cellular stress and genomic stability and integrity [76, 77]. A fundamental question is whether chromoanagenesis is a biological process that can promote the emergence of selective benefits in individuals that can be stably transmitted.

The hypothesis of such massive and abrupt changes doesn't fundamentally discredit Darwinism and its general principle of microevolution. Indeed, macro-mutations could result from selection-driven responses to sudden environmental changes. They may serve as "key" adaption to shift its carrier toward a new mode of life. Sheldon [78] suggested that a punctuated equilibrium could prevail in unstable environments and gradualism in stable regimes. Theoretical models support the hypothesis that chromosomal rearrangements do play a key role in speciation in the face of gene flow. Chromosomal rearrangements could reduce gene flow through their suppressive effects on recombination rather than their effect on fitness [79, 80]. Chromoanagenesis-related rearrangements may promote rapid modifications in patterns of genes that are not related to recombination suppression, for instance by modifying gene position relative to replication origins, thus changing the mutational bias context. They also may lead

to the generation of new gene linkage blocks or new chimeric genes as well as the disruption of the cis-regulatory machinery of gene expression [69]. The role of meiotic drive in the fixation of chromosomal rearrangements within the genome has also been demonstrated [81, 82].

The direct impact of chromosomal rearrangements on nuclear topology and gene expression is now studied directly through the analysis of regional genomic interactions by chromosome conformation capture techniques and the formation of topologically associating domains (TADs). These new approaches have made it possible to demonstrate in several pathologies how chromosomal rearrangements can disrupt TADS and affect the expression of the genes they contain by modifying or eliminating the interactions between promoters and enhancers [83–85]. An additional level of genomic regulation has been recently proposed with the description of a complex 3D network of well-delimited cis regulatory domains (CRDs) consistent with the chromatin organization into TADS, and in which 3D functional link and coordinated gene activity occurs along chromosomes [86].

The occurrence of genomic alterations and their impact are echoed in the notion of genome stability and the function of sexual reproduction as a filter to eliminate deleterious genomic changes, in maintaining the genome of a species [29, 52]. In this context, chromoanagenesis processes and the complex alterations which characterize them, could represent an important pathway for genome reorganization, and therefore for the emergence of new stable karyotypes, able to survive during evolution. Under high level of cellular stress, genome chaos and the subsequent occurrence of chromoanagenesis-mediated genome re-organization may constitute an effective survival strategy, by increasing karyotypic heterogeneity or/and creating new network in a given genome [53, 63]. The genome evolution process appears to be mainly based on the genome reshuffling rather than the accumulation of useful genes [52].

Accumulation of macromutations linked to chromoanagenesis events in gametogenesis or during early embryonic development could lead to profound differences among adults. Interestingly, de novo germline chromoanagenesis rearrangements predominantly occur on paternally derived chromosomes [7, 87]. Regardless of the beneficial or deleterious effect of complex chromosomal rearrangement, there is the question of its long-term fixation in a population. It is recognized that heterozygous carriers of chromosomal rearrangements can produce chromosomally unbalanced gametes in highly variable proportions, which can cause sterility and thus contribute to a form of reproductive isolation. As Gorelick and Heng [88] argued, sexual reproduction as a constraint on eukaryotic evolution, maintains ploidy and genome identity. However, over generations and on a large scale, this state of heterozygosity can turn into a state of homozygosity. Various models of
chromosomal speciation refer to the existence of a gametic
barrier resulting from the progressive fixation of one or
more chromosomal rearrangements in a population [89,
90]. Such structural rearrangements that allow a genetic dis-
tinction between species are considered to be evolutionary
rearrangements, and genome sequencing analyzes indicated
that these evolutionary rearrangements were much more
numerous than initially estimated [89]. For example, it was
estimated in 1980 that the human and chimpanzee genomes
differed only in 9 chromosomal inversions and one fusion
[91]. In 2005, Newman et al. [92] identified 93 supplemen-
tary evolutionary rearrangements, ranging from 12 kb to 1
Mb. More than 245 large rearrangements including translo-
cations, inversions, fusions, deletions, have been identified in
the discriminative path between the mouse and humans
[93], and numerous segmental duplications involved in hu-
man specific adaptive traits have been recently characterized
by sequencing human and non-human primate genome
[94]. Chromoanagenesis and genome instability may have
given rise to rapid evolution in some mammalian species
[95]. Crombach and Hogeweg [96] postulated that genome
restructuring mediated by massive chromosomal rearrange-
ments could be a beneficial operator for short-term adapta-
tions to a new environment. They provide an efficient
model that shows the evolution in gene ordering and clus-
tering as a consequence of retrotransposon-mediated
chromosome rearrangements. Transposable elements are
recognized as significant contributors to chromosome evo-
lution and speciation. Active and inactive transposable ele-
ments can serve as drivers in the formation of germline
chromoanagenesis by compromising the genomic stability
and facilitating chromatin conformation changes and DNA
breaks [97]. They may promote adaptability of a population
by generating changes in gene expression or promoting
rapid chromosome restructuring [98, 99]. For instance, in
the gibbon genome, the insertion of the retro-transposon
LAVA in genes implicated in cell cycle progression and
chromosome segregation appears to be at the origin of a
high rate of chromothripsis-related rearrangements leading
to the accelerated evolution of the gibbon karyotype and the
emergence of different gibbon lineages, with highly rear-
ranged chromosomes [70, 100]. Another example of speci-
ation driven by massive chromosome rearrangements is the
extensive chromosome reshuffling experienced by the mar-
supial family *Macropodidae*, with numerous interchromo-
somal rearrangements and diploid karyotype number
ranging from 2n = 10 to 2n = 24 [101]. A great karyotypic
variability is also observed in the *Arvicolinae* rodent family
characterized by a high rate of complex intrachromosomal
rearrangements and an important level of karyotypic evolu-
tion [102]. Finally, a parallel could be drawn between
marker chromosomes generated by chromoanagenesis
events and the supernumerary chromosomes, named B
chromosomes, found in many eukaryotic karyotypes. It has

been established that these supernumerary chromosomes
represent multichromosomal mosaics arising in taxa that
experienced rapid genome changes [103], like the domestic
dog which has one of the most rearranged karyotypes in
mammals [104, 105].

Finally, a fascinating emerging model, consistent with
chromoanagenesis-related mechanisms, could be the
punctuated occurrence of genomic rearrangements lead-
ing to the creation of new genes subsequently fixed by
natural selection and contributing to diversity. The for-
mation of functional and transmissible de novo genes
from non-coding DNA has thus been described in vari-
ous eukaryote lineages [106], clearly indicating the po-
tential role of this phenomenon in adaptive evolution.

Concluding perspective: towards a gradual acceptance of macroevolution

The identification of the catastrophic chromoanagenesis
phenomena has modified our perception of the genesis
and the aetiology of complex genomic rearrangements,
but also on the extreme plasticity of genomes [107]. In-
tegrity and stability of the genome are essential cellular
objectives that chromoan synthesis-related events can
paradoxically contribute to maintain in case of cellular
crisis, by the chaotic but sporadic reworkings of the gen-
ome that they can generate. As mechanism of rapid gen-
ome reorganization, chromoanagenesis plays an essential
role in promoting macroevolution of genome and there-
fore might be regarded as a credible process for
eukaryotic genome adaptation and speciation and the
creation of new genetic networks during evolution.

With the development of new sequencing technologies,
bioinformatics tools, genomic approaches and experimental
evolutionary modelling, it becomes possible to explore ge-
nomes of various organisms, predict the evolution of repro-
ducible patterns and to reconcile gradual and saltational
evolutionary concepts [54, 108]. Even if gradual changes
represent the common mode of evolution, punctuated and
massive modifications have the potential to establish pro-
found novelties sometimes facilitating adaptation. The im-
pact of genome-level events emphasizes the need to
establish new conceptual framework integrating the gen-
ome organization-based information [52, 53].

The integrative approach, called paleogenomics and
combining cytogenetic maps, whole genome sequencing
and genome studies, provides a new way to trace the evo-
lutionary history of karyotypes, integrate the genome and
genes relationships, and redefine the role of chromosome
rearrangements in evolutionary processes [109].

The slow changes in the perception of the alternative
phenomena of saltational evolution in the world of evo-
lutionary biology show that the acceptance of the macro-
evolution remains a gradual process.
**Abbreviations**

CCR: Complex chromosome rearrangement; DSB: Double-strand breaks; FoSTeS: Fork stalling and template switching; MMBIR: Microhomology-mediated break-induced replication; NHEJ: Non-homologous end-joining; TAD: Topologically associated domain

**Acknowledgements**

The authors thank Professor Henry H. Heng for his interesting and useful comments to improve our reflection on evolution and genome theory.

**Authors' contributions**

FP and VG conceptualized this review and analyzed the data from the literature. FP and VG both contributed to the writing of the manuscript, and approved the final version.

**Funding**

Work in the unit of Chromosomal Genetics is supported by the CHU research platform CHROMOSTEM (http://www.chu-montpellier.fr/fr/chercheurs/plateformes/les-plateformes-recherche/chromostem/).

**Availability of data and materials**

The datasets used and analysed in this review are available from the corresponding author on reasonable request.

**Ethics approval and consent to participate**

Not applicable.

**Consent for publication**

Not applicable.

**Competing interests**

The authors declare that they have no competing interests.

Received: 31 October 2019 Accepted: 5 January 2020

Published online: 28 January 2020

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