Review
Chromosomal speciation revisited:
rearranging theory with pieces of
evidence
Rui Faria1,2 and Arcadi Navarro1,3
1
IBE, Institute of Evolutionary Biology (UPF-CSIC), Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra,
PRBB, Av. Doctor Aiguader, 88, 08003 Barcelona, Spain
2
CIBIO, Centro de Investigação em Biodiversidade e Recursos Genéticos, Universidade do Porto, Campus Agrário de Vairão,
4485-661 Vairão, Portugal
3
Institució Catalana de Recerca i Estudis Avançats (ICREA) and Universitat Pompeu Fabra, Av. Doctor Aiguader, 88, 08003
Barcelona, Spain
The suggestion that chromosomal rearrangements play
a role in speciation resulted from the observation that
heterokaryotypes are often infertile. However, the first
chromosomal speciation models were unsatisfactory
and data available to test them was scarce. Recently,
large amounts of data have become available and new
theoretical models have been developed explaining how
rearrangements facilitate speciation in the face of gene
flow. Here, we re-examine theoretical predictions and
revisit different sources of data. Although rearrange-
ments are often associated with increased levels of
divergence, unequivocal demonstration that their role
in suppressing recombination results in speciation is
often lacking. Finally, we question some previous pre-
dictions and suggest new empirical and theoretical
approaches to understanding the relevance of rearran-
gements in the origin of species.
Chromosomal rearrangements and speciation
A considerable amount of indirect evidence [1,6] prompted
the classical idea that chromosomal rearrangements (CRs)
play a role in speciation. However, most researchers
remained unconvinced. One of the reasons for the general
lack of acceptance of chromosomal speciation was that the
abundant verbal models (e.g. [6]) were not accompanied by
a formal theoretical framework. In addition, the prevalent
view of speciation was that reproductive isolation is mostly
completed without gene flow (allopatry) [7]. The theoretical
basis of the allopatric view was provided by Dobzhansky [8]
and Muller [9], partially preceded by Bateson [3,7,10], who
independently solved Darwin’s paradox about how a taxon
with a genotype ‘aa’ could be derived from an ancestor ‘AA’,
without a sterile or inviable genotype ‘Aa’ being formed
first [7,8]. They proposed that hybrid sterility and invia-
bility are caused by incompatible alleles alternatively fixed
in two previously isolated populations (BDM model). If
individuals from the two populations meet and are still
able to mate, these alleles will generate unfit or unviable
hybrids and, thus, originate reproductive isolation. The
BDM model is so straightforward that it became the null
Corresponding authors: Faria, R. (rui.faria@upf.edu); Navarro, A.
(arcadi.navarro@upf.edu).
660 0169-5347/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tree.2010.07.008 Trends in Ecology and Evolution, November 2010, Vol. 25, No. 11
model of speciation [7] and except for a few strong propo-
nents (notably [1,2]) chromosomal speciation was largely
neglected.
The theoretical basis of chromosomal speciation
According to the BDM model, speciation is the expected
outcome when there is no gene flow [11]. In parapatry or
sympatry, either strong divergent natural selection or
some other mechanism must counteract gene flow. The
two main extant classes of chromosomal speciation models
try to explain, precisely, how CRs preclude gene flow [12].
Hybrid-sterility models
The first chromosomal speciation models were hybrid-
sterility models in which individuals heterozygous for
CRs (heterokaryotypes) are partially or totally infertile,
either due to segregation problems or to their recombinant
products originating unbalanced gametes. According to
these models, CRs are underdominant and thus can act
as genetic barriers to gene flow between populations
with fixed CR differences [6,13,14 and referencs therein].
Glossary
Allelic homologous recombination: the process by which chromosomes are
broken and reconnected to the homologous chromosome during meiosis. This
results in the exchange of some portion of genetic material between
chromosomes and along with segregation leads to offspring having different
combinations of genes from their parents.
Bateson–Dobzhansky–Muller (BDM) incompatibilities: genetic incompatibil-
ities that appear in hybrids lowering their fitness, as a result of interaction
between alleles at different loci.
Breakpoint: location where chromosomes break delimiting chromosomal
rearrangements. They can appear through various mechanisms, such as
breakage and repair of DNA or non-allelic homologous recombination.
Collinear region: syntenic genomic regions that have not been rearranged, i.e.
present the same distribution and order of DNA elements along chromosomes,
between individuals, populations or species.
Meiotic drive: distortion in the transmission ratio of a particular gene,
chromosomal fragment or chromosome at meiosis.
Muller’s Ratchet: a process by which asexual organisms and/or non-
recombining genomes irreversibly accumulate deleterious mutations.
Non-allelic homologous recombination: also known as ectopic recombination
refers to incorrect meiotic pairing of homologous, but not allelic, regions of the
genome followed by recombination. It generates chromosomal rearrange-
ments and potentially deleterious unbalanced gametes carrying duplications
and deletions.
Review
Box 1. Recombination and speciation
Recombination explains part of the evolutionary success of
eukaryotes and of sexual reproduction. Its main role is to shuffle
genetic material, providing a multiplicity of genetic combinations
upon which natural selection can act. Recombination rates are not
uniformly distributed within and among chromosomes and are, to
some degree, related to nucleotide-composition (GC content and
CpG islands), chromatin condensation and the nuclear distribution
of chromosomes, e.g. [80]. A trend towards lower recombination
near centromeres has been observed in some species (e.g. [97]), as
well as within or close to CRs [13]. However, many of these
observations must be interpreted with caution since recombination
rate was not directly quantified but inferred from studies of
introgression in natural populations. Variation in recombination
rates is affected by population-level processes like natural selection,
sexual selection, genetic drift, admixture and non additive fitness
interactions among loci (see [98] and references therein).
In population genetic terms, while recombination breaks down
linkage across loci, the evolution of reproductive isolation is more
likely given the existence of linkage between alleles at different loci.
The suggestion that the absence of recombination facilitates
speciation has been supported on both theoretical, as well as
empirical grounds [7,78]. For instance, when recombination breaks
down the association between genes responsible for mate choice
and adaptation, it is difficult for speciation to be completed [85,99]. It
is not surprising that definitions of speciation exist that are centred
on recombination, like the one suggested by Butlin [87]: ‘‘the
evolution of restrictions on the freedom of genetic recombination’’.
From this we can infer that any factor or mechanism inhibiting
recombination between chromosomes of two populations con-
nected by gene flow, such as CRs, are strong candidates to play a
role in speciation.
However, hybrid-sterility models were problematic. First,
evidence for strong underdominance was not as common as
initially thought [15–18]. Second, these models are incon-
sistent. On one hand, it is unlikely that strongly under-
dominant CRs get fixed [4,17,19,20]. On the other hand, if
underdominance is weak enough for CRs to fix, they will not
constitute strong barriers to gene flow and, consequently,
are unlikely to cause speciation [4–6,21]. Some more com-
plex hybrid-sterility models, such as cascade [1] or mono-
brachial models (see [6] for a review) tried to avoid this
paradox by postulating the sequential accumulation of
several neutral or weak-effect CRs in independent subpo-
Box 2. The role of CRs in speciation
CRs are known to suppress recombination in heterokaryotypes in two
ways: (i) mechanical pairing problems within CRs which inhibit
crossover during meiosis [14,37,100]; and (ii) unbalanced gametes
produced by crossover events within the rearranged regions of
heterokaryotypes (see Ref. [4] and references therein). The main
outcome of these two mechanisms is that the shuffling of genetic
material passed on to future generations is restricted within regions
affected by CRs but not outside them.
But what is so special about CRs when compared with other regions
of low recombination such as centromeres? Centromeres are
surrounded by regions of low gene density. Therefore the number
of genes that can take part in reproductive isolation is probably higher
within medium to large CRs (although this can be compensated for if
centromeres are involved in segregation distortion [101]). Moreover,
in contrast to other regions of low recombination, CRs have the
crucial effect of reducing recombination only in heterokaryotypes,
avoiding the accumulation of deleterious mutations due to Muller’s
Ratchet.
When compared with centromeres, CRs have at least three
additional effects. First, higher gene-expression divergence is
Trends in Ecology and Evolution Vol.25 No.11
pulations. However, these complex models have limited
applications and their plausibility is difficult to evaluate.
Suppressed-recombination models
A decade ago, new empirical evidence [6,22] inspired a new
framework for chromosomal speciation that went beyond
conventional views: the suppressed-recombination models.
These models propose that the reduction of recombination
between chromosomes carrying different rearrangements
is the factor determining their role in speciation (Box 1).
That is, CRs allow genes located in these regions to differ-
entiate, in contrast to genes in freely recombining collinear
regions (Box 2). The extra divergence time this generates
provides sufficient opportunity for the accumulation of
incompatibilities, thus causing further reduction of intro-
gression, until speciation is completed [5,6,22,23].
One of the first suppressed-recombination models was
presented by Coluzzi to explain multiple speciation events
within the mosquito species complex Anopheles gambiae
[12,23]. Inspired by Dobzhansky’s co-adaptation concept
[24], Coluzzi proposed that the adaptive allele combina-
tions arising in marginal populations are protected from
recombination by CRs [23]. Later Trickett and Butlin [25]
showed how recombination suppressors such as CRs can
favour speciation by sexual selection and reinforcement.
Another model proposed by Rieseberg [6], based on studies
in sunflowers (Helianthus), suggested that CRs act syner-
gistically with incompatibilities to delay gene flow between
populations. Almost simultaneously, Noor et al. [22] pro-
posed that lack of recombination between chromosomes
that differ by rearrangements can provide additional time
for incipient Drosophila species to persist without complete
admixture. This generates an opportunity for natural se-
lection to decrease hybridisation by reinforcement.
Although promising, these models lacked theoretical for-
malisation, which was later provided by Navarro and
Barton [5]. As we explain below, this model established
a link between chromosomal speciation and BDM incom-
patibilities. However, any chromosomal speciation model
begs a question: how do CRs get established within popu-
lations in the first place?
expected near the breakpoints or within CRs, when compared with
collinear regions. This can happen due to the direct effects of CRs by
disrupting genes located in their breakpoints or by changing their
positions relative to regulatory regions. Second, CRs (duplications)
play a role in facilitating the evolution of lineage-specific genes (sub-
or neo-functionalisation). Third, CRs can promote changes in patterns
of mutation, and consequently of divergence, that are not related to
recombination suppression. This can happen if genes located within
certain CRs change their position relative to replication origins (and
between strands), thus changing their mutational bias context.
Recently, Homolka and collaborators [76] provided further evidence
for the role of CRs in speciation by showing that male sterility in mice
occurs though interference of a CR with meiotic inactivation of sexual
chromosomes.
Although centromere repositioning can be associated with hybrid
sterility [102], the relevance of centromeres as recombination
suppressors relative to CRs needs to be investigated in more detail.
In particular, since they are often included in inversions, under-
standing their synergy with CRs in facilitating speciation constitutes a
promising research avenue.
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Box 3. Fixation of CRs
The probability that a CR gets fixed in a population depends on
several factors linked to its underdominance: the type of CR, its
genetic background, and the species and sex of the individuals in
which it occurs [4]. According to Spirito [4], the establishment of fixed
CR differences occurs through two main steps: first, the appearance
and establishment of the CR at a stable high frequency in the deme it
appeared; and second, the spread and fixation in many demes within
the entire region ([4] and references therein). The first step is the most
stringent [103] since under strict underdominance, the probability that
a CR gets fixed is lower than in the case of strict neutrality (<<1/2N)
[17,26]. In contrast, when meiotic drive is strong and a CR is
advantageous (capturing alleles under selection or through positive
epistasis), both first and second steps are more probable than under
neutrality [4]. Thus, if there is neither selection nor meiotic drive,
demes must be small and semi-isolated for a CR to get fixed [4].
CR fixation due to advantage of the CR homozygote was for a long
time neglected because when CRs first appear they do so in
heterokaryotypes. If strongly underdominant, the homozygote for
the CR will almost never be generated and/or will be vulnerable to
The fixation of CRs in populations connected by gene
flow
Previous attempts to model the establishment of high-fre-
quency CRs have been based on drift [4,17,26], selective
advantage of homokaryotypes [27], meiotic drive [1] or
epistatic interactions between genes trapped by a neutral
rearrangement [28] (Box 3). However, most of these models
consider a single population in a constant environment,
ignoring an important aspect of the natural world: spatial
variation of selective pressures [29]. This was recently taken
into account by Kirkpatrick and Barton [30]. Their analysis
shows that selection can favour inversions that decrease
recombination between alleles involved in local adaptation
which, in turn, favours the fixation of alternative CRs in
different subpopulations connected by gene flow. These CRs
can become strong genetic barriers and lead to speciation by,
for example, trapping more locally adapted genes (Figure 1).
The accumulation of incompatibilities in populations
connected by gene flow
The genetic incompatibilities postulated by the BDM mod-
el are unlikely to fix in panmictic populations. However,
under the divergent selection regime proposed by Kirkpa-
trick and Barton, incompatible alleles might fix in different
subpopulations aided by previously established CRs. In
addition, under uniform rather than divergent selection,
the accumulation of incompatibilities between positively
selected alleles is possible if their spread to the whole
species range is delayed for long enough for advantageous
but incompatible alleles to appear elsewhere [5,31].
According to Navarro and Barton [5], CRs can provide
such delay. Their model considers two parapatric popula-
tions connected by gene flow and with a fixed inversion
difference. In this scenario suppressed-recombination is
equivalent to reduced gene flow in the genomic region
delimited by a rearrangement, so CRs can delay the fixa-
tion of favourable alleles and allow the accumulation of
incompatibilities (Figure 2).
A bridge between models
The selective regimes assumed by the two models might
seem contradictory, but they are in fact complementary.
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Trends in Ecology and Evolution Vol.25 No.11
loss unless it reaches high frequency (>50%), [4] and references
therein. When the CR is not underdominant and carries a positively
selected allele, the fixation of CRs due to advantage of the CR
homozygote is expected. Interestingly, a model recently proposed by
Kirkpatrick and Barton [30] provides an alternative model for the
establishment of CRs in the face of gene flow, even when the
chromosome carrying the CR initially has no selective advantage
relative to the collinear chromosome (Figure 1).
Because many CRs segregate normally, the idea that meiotic drive
might contribute to the fixation of CRs was initially discarded [104].
Moreover, some of the segregation distorters examined to date
prevent the fixation of the rearranged driving chromosome due to the
accumulation of deleterious mutations, which preclude the formation
homokaryotypes [89]. However, it is still possible that some strong
distorters increase the CR frequency above 50% so rapidly that
deleterious mutations do not have time to accumulate. Despite this
controversy, recent findings have resurrected interest in the putative
role of meiotic drive in speciation (e.g. [90,105,106]), which should not
be ignored in future research on chromosomal speciation.
Although the Navarro–Barton model proposed a mecha-
nism by which CRs contribute to speciation, it did not
tackle the fundamental step of how CRs themselves get
alternatively fixed in different populations in the presence
of gene flow. The Kirkpatrick–Barton model explains this
step, setting up the starting conditions for the Navarro–
Barton model. Moreover, the genetic incompatibilities pos-
tulated by the Navarro–Barton model would be easier to
accumulate under divergent selection. Finally, not all
parts of the genome are involved in local adaptation and
a mechanism that extends the reduction of gene flow might
be needed to complete speciation under the Kirkpatrick–
Barton model. The Navarro–Barton model provides such a
mechanism.
The predictions of chromosomal speciation models
Models of chromosomal speciation, particularly sup-
pressed-recombination models, make qualitative predic-
tions that can, in principle, be tested. The scope of these
predictions ranges from biogeography, with expectations
about the distribution of CRs in sister taxa, to molecular
evolution, with predictions about contrasting patterns of
divergence within and outside CRs (Box 4). As we shall see,
considerable effort has been devoted to search for the
signature of chromosomal speciation in nature. However,
this signature is often elusive, since some of the empirical
observations that are predicted by chromosomal specia-
tion are similar to those expected under other scenarios
[32].
Chromosomal rearrangements and speciation: pieces of
evidence
If chromosomal speciation via suppressed recombination
happens in nature, at least three main conditions must be
met. First, CRs must suppress recombination. Second, the
suppression of gene flow within CRs must have played a
pivotal role in reproductive isolation. Finally, there must
be CR differences between sister taxa. While the compara-
tive genomics revolution has shown that CR differences are
more abundant than previously thought [33–35], the other
two classes of evidence are more difficult to obtain and
interpret.
(Figure_1)TD$IG][ Review
Figure 1. The fixation of CRs: the Kirkpatrick–Barton model. The model proposed
by Kirkpatrick and Barton [30] explains how, under divergent selection, alternative
CRs can get fixed in two parapatric populations. The starting point consists of two
populations, 1 and 2, that separated recently and, thus, present no significant
differentiation (a). Over time (b), mutations occur at a minimum of two loci in
population 1 (green asterisks) that are favourable under local environmental
conditions but that are disadvantageous in population 2. The two loci are not
tightly linked, otherwise they would work as a single gene and the model would
not apply [30]. The two alleles will spread and get fixed only within population 1.
During this period, a neutral or weakly underdominant CR (e.g. pericentric
inversion, in yellow) might occur within population 2 (b). The inversion carriers
have similar fitness to the carriers of the collinear chromosomes in population 2.
However, in contrast to what happens with collinear chromosomes, the rearranged
region will recombine less (or not at all) with chromosomes arriving from
Trends in Ecology and Evolution Vol.25 No.11
Suppressed recombination within CRs
Direct evidence for recombination suppression in hetero-
karyotypes, especially around inversion breakpoints,
comes from the analysis of gametes and/or offspring of
several species [14,36,37 and references therein]. Indirect
evidence comes from comparisons of rates of genic diver-
gence between rearranged and collinear regions. Among
plants, early studies on sunflowers (Helianthus spp.)
showed that the rate of introgression is lower within rear-
ranged chromosomes [38,39]. Recent studies of the same
species only detected this pattern close to the breakpoints
[40–42], which is consistent with suppressed-recombina-
tion models since these regions experience the strongest
reduction in recombination. Similar patterns of divergence
have also been observed between two species of Solanaceae
[42 and references therein].
In animals, studies in Drosophila consistently detect
higher genetic differentiation within and close to inversions,
especially around the breakpoints [43–46]. Gene expression
data also support this tendency. For example, in populations
of Drosophila subobscura that diverged repeatedly in their
inversion frequencies in response to thermal selection
regimes, genes with different expression levels are more
commonly found within inversions [47]. In mosquitoes,
higher sequence divergence between Anopheles gambiae
and Anopheles arabiensis was found within an inversion
that differentiates the X-chromosome of the two species [48].
However, these results should be interpreted with caution,
since recent molecular studies on Anopheles gambiae have
questioned the role of some ‘‘speciation islands’’ on the
diversification of these mosquitoe species [49,50]. Higher
divergence between chromosomal forms was also observed
in Anopheles funestus [51] and between Rhagoletis pomo-
nella host races [52,53], near or inside inversions.
Among mammals, shrews and mice present high karyo-
typic diversity and rates of chromosomal change [54,55].
Analysis of two hybrid zones of the common shrew group
(Sorex araneus) detected stronger genetic structure and
lower gene flow in loci located within rearranged chromo-
somes [56,57]. Restricted gene flow was observed near cen-
tromeres of fused chromosomes in a hybrid zone between
chromosomal races of the house mouse Mus musculus
domesticus [58]. A genome-wide comparison between the
mouse and human detected an association between CRs and
nucleotide substitution rates [59], and similar results were
obtained comparing the mouse and rat genomes [60].
Primates have also been studied but, in contrast to the
previous examples, results are quite inconsistent. The first
test of chromosomal speciation in primates [61] found that
rates of protein evolution between humans and chimpan-
zees were higher within rearranged chromosomes than in
the rest of the genome. However, subsequent studies found
population 1 and, therefore, the alleles that the inversion carries will never suffer
the ‘‘Achilles’ heel’’ of being found on the same chromosome with the ‘immigrant’
disadvantageous alleles at the other locus. The chromosomes with the inversion
will thus carry a combination of alleles at two loci that present higher fitness in the
environmental conditions of population 2 than the recombining chromosomes (r)
that tend to be eliminated (red cross). The chromosome with the inversions will
therefore increase in frequency (c). This scenario results in two populations with a
set of alleles that are locally adapted but with almost fixed alternative
arrangements (d). The authors predict that if the two populations are distributed
along an environmental gradient, the inversion will establish a cline.
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664
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Box 4. The main predictions of models of chromosomal speciation

According to verbal and formal models, if chromosomal speciation happened, the following signatures might be detectable (especially close to
breakpoints). Most of these predictions were made in the context of suppressed-recombination models, but some might also be met in a hybrid-
sterility scenario. We include a view of up to which point these predictions have been validated empirically and references for some examples.

Prediction Empirical support Refs

(i) Higher differentiation and/or lower gene flow and recombination within CRs, U [6,38,39, (but see 40,41);
specially near the breakpoints 22,52,53,56–58]
(ii) Signature of selection within CRs when adaptation drives the process U [52,53]
(such as the Kirkpatrick–Barton and Navarro–Barton models) [5,61,30]
(iii) Longer extension of genealogical concordance within and near CRs Doubtful [6] but see [40,41]
than near QTLs involved in isolation [6] (indirectly tested)
(iv) Higher sequence and gene expression divergence within CRs [5,66] Ambiguous [63,66,67]
(v) Loci associated with assortative mating, sexual selection or other traits U [22]
that are good candidates to host genetic incompatibilities should map
within or closer to CRs [22]
(vi) Higher speciation rates should correlate more with CRs that can suppress Not formally tested
recombination (e.g. inversions) than with CRs that have a smaller effect on
recombination (e.g. fusions) [6]
(vii) More karyotypic differences between sympatric sister than between U [22,43,73]
allopatric ones [22,43]
(viii) Younger species are expected to have a higher proportion of CRs relative to U [22,43,73]
molecular divergence when compared with species that originated long ago [22,43]
(ix) Central and marginal populations within a species range are more prone to U [107]
show a large number of different CRs [30]

either no striking difference [62,63], or even the opposite
trend [64,65]. The picture is made even more puzzling by
patterns of divergence in gene expression levels. The first
study analysing expression divergence between humans
and chimpanzees did not find any association [66]. A
subsequent study found that, for brain cortex tissue, gene
expression divergence was higher within rearranged than
within collinear chromosomes [67], a result confirmed by
an independent study [68]. Just as in the case of sequence
divergence, expression differences are largest around the
inversion breakpoints [67].
Nonetheless, evidence based on sequence or gene ex-
pression divergence needs to be re-examined in the light of
the recent simulations by Feder and Nosil [69], who stud-
ied the effects of CRs on gene flow after secondary contact.
They show that even low levels of recombination within
inverted regions, due to double crossing-over or gene con-
version (e.g. [13] and references therein), might result in
loss of divergence. These results raise doubts about chro-
mosomal speciation, but they must be interpreted with
caution. First, alleles involved in reproductive isolation can
accumulate near the rearrangements’ breakpoints, where
double crossovers are scarce [13]. Second, as stressed by
the authors, their scenario was not dynamic: they only
considered a limited number of fixed incompatibilities and
did not allow for additional differences to accumulate.
CRs and the establishment of reproductive isolation
Evidence that CRs can induce reproductive isolation main-
ly conforms to hybrid-sterility models. One of the most
simple and convincing results was obtained by crosses
between two yeast species, Saccharomyces cerevisiae and
Saccharomyces mikatae. The resulting hybrids show
markedly reduced fertility due to reciprocal translocations.
Fertility, however, was partially recovered when collinear-
ity was artificially re-established [70]. A more recent
study showed that a single translocation is the basis for
reproductive isolation between certain Drosophila mela-
nogaster and Drosophila simulans hybrid strains [71].
In plants, the fact that genomic regions associated with
hybrid sterility are often localised within CRs [42] is
consistent with both hybrid-sterility and suppressed-re-
combination models. The role of CRs in plant speciation is
supported by the over-representation of chromosomal dif-
ferences in some sympatric species (e.g. orchids) [72].
Indeed, it has been suggested that speciation fuelled by

Figure 2. The accumulation of incompatibilities between two populations connected by gene flow: the Navarro–Barton model of chromosomal speciation. The Navarro–
Barton model [5] was conceived to test the efficiency of CRs in delaying gene flow of alleles that are advantageous in the two populations (uniform selection).The starting
point of this model is precisely the end of the Kirkpatrick–Barton model (Figure 1): i.e. fixed CR differences between parapatric populations. For contrasting purposes here
we present two scenarios: (i) no initial fixed CRs differences between populations (a1); and (ii) at least one fixed CRs difference between populations, a pericentric inversion,
represented in yellow (a2).
An advantageous mutation that occurs in collinear regions in any population (black asterisk) will spread, first within its population of origin (in this example population 2)
and, afterwards, all over the species range (b1), unless it is trapped by an inversion and cannot easily recombine (b2). Under these circumstances, its spread to population 1
will be delayed relative to alleles outside the rearrangement or relative to alleles from other chromosomes without CRs (b2). The delay in the spread of the black mutation
into population 1 can be enough for new mutations to occur (red square – c2) that can be incompatible with the black allele. If this is the case, this advantageous red
mutation will become fixed in population 1, but when it arrives at the hybrid zone, where it meets for the first time an incompatible allele (black asterisk), it will not be able to
spread into population 2 (c2). In contrast, in scenario c1, when the red square mutation appears in population 1, it will be immediately eliminated (red cross) because it is
incompatible with the black allele. Other advantageous alleles that subsequently appear but are not involved in incompatibilities with existing alleles (white square – c1 and
c2) can either spread and get fixed in both populations (d1), or get fixed only within its population of origin if trapped within a CR (d2). In a scenario with fixed CRs, the white
square allele that appears in population 2 (c2) will get fixed in this same population but will not spread to population 1 because it is located within a CR (c2). At this stage, the
genetic barrier caused by incompatible alleles comprises two fixed alleles (represented by the red square and black asterisk), but the probability that new incompatible
alleles will arise and get established will keep increasing. With the establishment of new incompatible alleles, the barrier gains more and more strength, triggering the so
called ‘snowball effect’ ([5] and references therein).

665
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CRs is common in plants due to their lower pleiotropy, open
development, frequent fluctuations in population size, self-
fertilisation, and the absence of degenerated sex chromo-
somes [7,42].
In Drosophila [22,43] and some butterflies [73], sympat-
ric species show more marked CRs differences than allo-
patric taxa, suggesting that inversions facilitate the
persistence of closely related species. In addition, genes
contributing to hybrid male sterility, male mating success,
female mating preferences and hybrid inviability have
been mapped to inverted regions [22]. Inversions that
contain alleles associated with reproductive isolation have
also been identified in host races of Rhagoletis pomomella
[52]; see also [74]. In this case, the inversions harbour
genes affecting adaptation to host fruiting cycle and, thus,
can be involved in prezygotic, as well as postzygotic isola-
tion. It has also been suggested that A. gambiae inversions
located in chromosome 2R play a role in ongoing speciation
among different chromosomal forms [75]. More recently,
studies on Drosophila hybrid inviability [76] and on Mus
sterility [77] have suggested alternative mechanisms by
which CRs might play a role in speciation (Box 2).
In summary, it has been shown that CRs can participate
in the establishment of sterility and the building up of
locally adapted complexes, giving greater opportunity for
natural selection to decrease hybridisation [78]. In addi-
tion, the evidence for an adaptive role of CRs is strong [74]
and there are clear examples even in humans, where an
inversion appears to be advantageous at least in some
populations [79]. However, it remains to be clearly seen
how often CRs contribute to or facilitate speciation and
what their role is in the process.
Revised theoretical predictions
Under the light of evidence, some of the initial predictions
of suppressed-recombination models of chromosomal spe-
ciation need to be revisited. For example, Noor and Ben-
nett [32] draw attention to problems associated with using
certain divergence or differentiation measures that are
prone to confounding biases. The authors propose methods
that can be applied to correct such problems and defend
approaches based on multiple lines of evidence. Here, we
want to discuss a few more concerns.
A particularly important problem is that, even in cases
in which an increase in substitution rates within CRs has
been detected, it is difficult to distinguish if this is related
to speciation. It might be due to other processes that acted
long before or after speciation [32]. The inverse problem is
also important; the fact that increased rates of substitution
are not detected within a given rearrangement does not
necessarily discard chromosomal speciation. No model
predicts that every single CR separating two species must
have played a role in speciation. In spite of that, predic-
tions have been over interpreted and in many studies all
rearrangements are just pooled together (e.g. [63]) thus
blurring any potential signal.
Choice of taxa has also been problematic. Even if cases
where speciation has been due to CRs, if it was completed
long ago, patterns of divergence will be dominated by post-
speciation evolution within taxa. This issue complicates
the interpretation of abundant evidence showing higher
666
Trends in Ecology and Evolution Vol.25 No.11
divergence in rearranged regions between distant species,
such as humans and mice [59], which separated millions of
years ago and have undergone many speciation events in
the meantime. Why would old CRs show increased diver-
gence? The potential explanations range from biases, such
as recurrent rearrangements or high substitution rates
being linked to a third factor like nucleotide composition
[80]; to a general increase of substitution rates around
speciation time [81]. Of course, in that respect, the main
problem is that no chromosomal speciation model makes
precise predictions, either about the time window during
which differential divergence can build up, or about how
long after speciation such increased divergence can be
detected. Chromosomal speciation models are not even
able to precisely predict the kind of divergence (e.g. synon-
ymous or non-synonymous substitutions) that is more
likely to arise or be detected.
Finally, a potential source of confusion relates to the
underdominant status of rearrangements and the fact that
speciation processes will be dynamic and not instanta-
neous. Currently, underdominant rearrangements are
not strong candidates to have played a role in speciation,
e.g. [17]. However, it is possible that they played a role in
the establishment of reproductive isolation by recombina-
tion suppression and only after speciation was completed
did they become underdominant.
Future perspectives
In terms of theoretical developments, there is a pressing
need for explicit quantification of the predictions of chro-
mosomal speciation models. A feasible way forward would
be to complement analytical work with large-scale simula-
tion studies designed to evaluate under which circum-
stances speciation can be achieved and its signature
detected. An extension of the simulations performed by
Feder and Nosil [69], to incorporate dynamic models that
allow for the appearance of new adaptive and/or incompat-
ible mutations, for example, would provide important
quantitative information.
Modelling the effect of CRs in sex chromosomes would
also be important. Sex chromosomes are known to have
major effects in speciation in relation to Haldane’s [82] rule
or the large X-effect [83]. In addition, a good number of the
CRs that have been suggested to play a role in speciation
are located on sex chromosomes; and ‘gene movement’ of X-
autosomes has been associated with male sterility [84].
Another useful focus would be to extend models beyond
post-zygotic isolation. An increasing number of studies
suggest that many species differentiated primarily due
to pre-zygotic and behaviour isolation, through ecological
or sexual selection mechanisms [7], some suggesting the
participation of CRs (notably [52,53]). Classical work by
Felsenstein [85] and Kirkpatrick [86] shows that recombi-
nation can break down the association between, for in-
stance, genes responsible for mate choice, behaviour and
adaptation. Thus, CRs could foster speciation by suppres-
sing recombination between these genes [25,87]. The study
of the role of CRs in hybrid speciation is also a promising
research line in evolutionary genetics [7,88].
A complete chromosomal speciation theory should also
consider meiotic drive. The benefits of the interaction
Review
between segregation distorters and CRs can be mutual.
Linkage among drivers and responders provided by CRs
might facilitate their initial evolution which, in turn, might
allow CRs to spread and fix. Indeed, segregation distorters
are often found within CRs (e.g. [89]) and it has been
suggested that genetic conflict might be an important
and underappreciated ingredient in speciation [90]. In
addition, recent findings on Prdm9 (PR domain containing
9) [91–93], a gene implicated in male sterility in mice [94],
show that it is associated with the delimitation of recom-
bination hotspots. If the evolution of Prdm9, which in mice
is located inside an inversion, has been driven by segrega-
tion distortion, as hypothesised by Myers and collaborators
[92], it would imply that many speciation factors (recom-
bination modifiers, CRs, segregation distorters and incom-
patibilities) are co-localised in the same genomic regions.
However, there are serious difficulties with this possibility
(Box 3) and we need more empirical and theoretical studies
to understand the interconnection between CRs, segrega-
tion distorters and speciation.
In empirical terms, proper inference of the history of
rearrangements can help solving many problematic issues
mentioned above. Dating the origin of CRs, probably by a
combination of cytogenetics and molecular data, would
allow researchers to exclude from analysis CRs that could
not possibly have participated in speciation. Additionally,
as explained by Noor and Bennett [32], the comparison of
divergence estimates across multiple CRs provides infor-
mation about the geographic context and timescale over
which an inversion was fixed. The phylogeographic distri-
bution of inversions can be very informative by itself, as
shown in studies that found more inversions separating
sympatric than allopatric sister species of Drosophila
[22,43]. Given that no process other than chromosomal
speciation mediated by suppressed-recombination predicts
such an observation, extending this kind of study to other
taxa could provide data about the frequency of chromosom-
al speciation processes.
Furthermore with respect to data, the increasing avail-
ability of full genomes will allow the selection of more
adequate taxa for analysis. Work focusing on closely relat-
ed species or on populations with on-going gene flow,
particularly if based on genomic data [95], is more likely
to produce clearer results than studies of phylogenetically
distant taxa where many processes have influenced sub-
stitution rates. In addition, multi-species comparisons are
necessary to find and date potential correlations between
rates of CRs and molecular divergence.
Finally, we believe that experimental studies are also
required to push the field forward. For instance, it is possible
to use either extant or artificial CRs in populations of
adequate model species in order to observe if they result
in recombination suppression and ultimately reproductive
isolation [78]. If such experiments are successful, they might
even allow the identification of incompatibilities and the
measurement of their effects on reproductive isolation.
Final remarks
Since the emergence of genomics we have learned that
structural variation is a prevalent property of many spe-
cies, highlighting the relevance of CRs in evolution [96].
Trends in Ecology and Evolution Vol.25 No.11
The question then is, are CRs an important component of
speciation? When considering all the data presented above,
the emerging picture is that evidence for chromosomal
speciation varies between lineages. For example, it is
strong for Drosophila, but much weaker or absent in
primates. The observation that appears most consistently
in many species is an increased level of divergence near
rearrangement breakpoints. According to suppressed-re-
combination models, these regions constitute strong can-
didate regions to accumulate alleles involved in
reproductive isolation.
Evolutionary research has been characterised by ex-
haustive discussions about alternative views (e.g. drift
versus natural selection, gradualism versus punctuated
equilibrium and many others). These discussions are a
fundamental step for validating ideas or theories, but it
usually turns out that many of these alternative models or
ideas are compatible with each other. New models of
chromosomal speciation incorporate both genic (BDM
incompatibilities) and non-genic factors (CRs) into the
same framework. Therefore, the term ‘chromosomal speci-
ation’ should not be interpreted with a strong or exclusive
meaning, but rather should be viewed as the convenient
label of a set of evolutionary processes in which CRs play a
role. Speciation in the face of gene flow is fertile ground
where CRs can contribute to the establishment of repro-
ductive isolation.
Acknowledgements
We thank S. Baird, N. Barton, M. Noor, M. Carneiro, D. Ayala, M.
Kirkpatrick, S. Rocha, C. Pinho, A. Sá-Pinto and G. Sotelo for their
comments and suggestions on a previous version of this manuscript. We
also thank three anonymous referees for suggestions on this final version.
We thank T. Lage for her contribution to improving the figures. RF is also
grateful to O. Fernando for contributing to his initial motivation on this
topic. We are both deeply indebted to D. Comas for mediating our
discussions. Financial support for was provided by the Spanish Ministry
of Science and Innovation (Ref. BFU2009-13409-C02-02), FEDER and the
Fundação para a Ciência e a Tecnologia (FCT-Portugal), through the post-
doc fellowship (SFRH/BPD/26384/2006) to RF.
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