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The choice in meiosis – defining the factors that
influence crossover or non-crossover formation
Jillian L. Youds and Simon J. Boulton*
DNA Damage Response Laboratory, Cancer Research UK, London Research Institute, Clare Hall, Blanche Lane, South Mimms EN6 3LD, UK
*Author for correspondence (email@example.com)
Journal of Cell Science
Journal of Cell Science 124, 501-513
© 2011. Published by The Company of Biologists Ltd
Meiotic crossovers are essential for ensuring correct chromosome segregation as well as for creating new combinations of alleles for
natural selection to take place. During meiosis, excess meiotic double-strand breaks (DSBs) are generated; a subset of these breaks
are repaired to form crossovers, whereas the remainder are repaired as non-crossovers. What determines where meiotic DSBs are
created and whether a crossover or non-crossover will be formed at any particular DSB remains largely unclear. Nevertheless, several
recent papers have revealed important insights into the factors that control the decision between crossover and non-crossover formation
in meiosis, including DNA elements that determine the positioning of meiotic DSBs, and the generation and processing of recombination
intermediates. In this review, we focus on the factors that influence DSB positioning, the proteins required for the formation of
recombination intermediates and how the processing of these structures generates either a crossover or non-crossover in various
organisms. A discussion of crossover interference, assurance and homeostasis, which influence crossing over on a chromosome-wide
and genome-wide scale – in addition to current models for the generation of interference – is also included. This Commentary aims
to highlight recent advances in our understanding of the factors that promote or prevent meiotic crossing over.
Key words: DSB repair, Meiosis, Crossover control, Homologous recombination
Meiosis is the specialised reductive division that generates haploid
cells. During this process, a single round of replication is followed
by two rounds of chromosome segregation: in the first division
(meiosis I), homologous chromosomes segregate, whereas in the
second division, sister chromatids segregate (meiosis II). A key
step in meiosis I is the recognition of homologous chromosomes,
which then align and pair along the length of the chromosome.
Once homologues have aligned, synapsis can proceed with the
formation of the synaptonemal complex (SC), a protein structure
that supports and maintains homologues in close juxtaposition and
serves as a scaffold for crossover-promoting recombination factors.
Meiotic crossing over involves the generation of meiotic doublestrand breaks (DSBs), which are subsequently repaired either as
crossovers or non-crossovers (Fig. 1). Meiotic recombination is
not only necessary to create new allele combinations that generate
genetic diversity, but is also essential in ensuring accurate
chromosome segregation at the first meiotic division because the
crossover acts as a tether between homologues, which ensures that
each homologue will properly align at the metaphase plate and
thereby correctly attach to the spindle. DSB repair occurs
concurrently with SC formation and is required for normal synapsis
in yeast and mice (Baudat et al., 2000; Roeder, 1997; Romanienko
and Camerini-Otero, 2000), whereas in Caenorhabditis elegans
and Drosophila melanogaster, homologue pairing and SC formation
can occur independently of meiotic recombination (Colaiacovo et
al., 2003; Dernburg et al., 1998; Liu et al., 2002; McKim et al.,
The process of meiotic recombination is initiated when meiotic
DSBs are created by the endonuclease SPO11, in conjunction with
a number of additional proteins (Keeney and Neale, 2006). DSBs
are then resected to generate 3⬘ single-strand DNA (ssDNA)
overhangs that are initially bound by replication protein A (RPA),
which is subsequently displaced by the recombinase radiation
sensitive 51 (RAD51) and/or the meiosis-specific recombinase
dosage suppressor of Mck1 (DMC1) to form nucleoprotein
filaments. These filaments serve to find a complimentary sequence
within a homologous chromosome, at which they instigate singleend strand invasions (Hunter and Kleckner, 2001) to generate socalled displacement loop (D loop) recombination intermediates
(Fig. 1). If the second end of the original DSB binds with the
homologous chromosome, a double Holliday junction is formed,
which can be resolved to generate either a non-crossover or an
interhomologue crossover, the latter of which is hereafter referred
to simply as crossover (Bishop and Zickler, 2004; Schwacha and
Kleckner, 1995). Double Holliday junctions can also be processed
through dissolution, which results in a non-crossover (Fig. 1) (Wu
and Hickson, 2003). Meiotic non-crossovers have also been
proposed to form when strand invasion is transient, and when a
limited amount of DNA synthesis occurs before the invaded strand
dissociates and anneals to its partner strand, as in mitotic synthesisdependent strand annealing (SDSA; see Box 1 and Fig. 1) (Allers
and Lichten, 2001; Bishop and Zickler, 2004). During meiosis in
budding yeast, non-crossover heteroduplex products are found to
form with the same timing as double Holliday junctions, whereas
crossovers occur later (Allers and Lichten, 2001), consistent with
the idea that crossovers and non-crossovers are formed through
distinct pathways. Analysis of ZMM mutants (Zip1, Zip2, Zip3,
Zip4, Mer3, Msh4 and Msh5; further discussed below) in yeast
indicates that the decision between crossover and non-crossover is
made very early, i.e. at or prior to the establishment of a stable
single-end invasion intermediate, when one of the two ends of the
DSB invades its homologous chromatid (Bishop and Zickler, 2004;
Borner et al., 2004; Hunter and Kleckner, 2001). Thus, the
Journal of Cell Science 124 (4)
D loop recombination
Journal of Cell Science
crossover–non-crossover decision is thought to occur around the
time of strand exchange.
This Commentary will discuss the factors that contribute to
crossover or non-crossover formation in meiosis, including the
generation and positioning of meiotic DSBs, formation of the SC
and generation of recombination intermediates. We will also discuss
how interhomologue crossing over is promoted compared with
intersister repair, how recombination intermediates are resolved
into crossovers as well as how anti-recombinases prevent crossing
over. Crossover interference, assurance and homeostasis will also
be discussed (see text box), including a summary of the current
models for how crossover interference is established.
Control of meiotic DSB formation
Meiotic crossovers tend to form at specific sites in the genome of
most organisms (Buard and de Massy, 2007; Mezard, 2006; Pryce
and McFarlane, 2009); these are known as recombination hotspots.
In mammals, hotspots are typically regions of 1–2 kb that occur
every 50–100 kb within the genome (Jeffreys et al., 2001; McVean,
2010; Myers et al., 2008). Human recombination hotspots often
occur relatively close to genes (within 50 kb), but are preferentially
found outside of transcribed regions (Myers et al., 2005). At
hotspots in eukaryotes, meiotic DSBs are generated by the
conserved topoisomerase-like endonuclease Spo11 (Bergerat et al.,
1997; Cao et al., 1990; Keeney et al., 1997). However, insights
into what controls the position of break formation were unknown
Fig. 1. Model for meiotic crossover or non-crossover
formation. Double strand breaks are generated and their
5⬘ ends are resected to generate a 3⬘ overhang. A strand
invasion event then generates a single-end invasion D
loop intermediate. If the second end of the original DSB
also engages with the homologue, a double Holliday
junction is formed (shown on the left). The double
Holliday junction can be resolved to form either a
crossover (interference-dependent) or a non-crossover.
Alternatively, the junction can be dissolved by double
Holliday junction dissolution to form a non-crossover.
Instead of forming a double Holliday junction, the D
loop can be dissociated and the invading strand can
associate with the opposite end of the original break, as
in synthesis-dependent strand annealing (SDSA), to form
a non-crossover. Alternatively, the intermediate can be
acted upon by enzymes such as Mus81 that can form
Several studies have shown that Spo11 access to DNA is one of
the determinants of DSB location, because DSBs are often found
within open chromatin in yeast (Berchowitz et al., 2009; Ohta et
al., 1994; Wu and Lichten, 1994). In C. elegans, the putative
chromatin-modifying protein high incidence of males 17 (HIM17) is required for successful DSB formation and for normal levels
of dimethylation of lysine residue 9 of histone 3 (H3K9Me2)
during meiosis, because mutants display a marked reduction in
H3K9Me2 staining (Reddy and Villeneuve, 2004). Furthermore,
DSB formation in him-17 non-null mutants can be enhanced by
loss of LIN-35, the C. elegans retinoblastoma (Rb) protein
homologue, which is a known component of chromatin modifying
complexes (Reddy and Villeneuve, 2004). Collectively, these data
suggest that the activity of HIM-17 alters the chromatin state,
probably by opening the chromatin to allow access by SPO-11,
and this governs DSB competence. More recently, components of
the C. elegans condensin I complex have been implicated in
regulating both the position and number of DSBs, because mutants
show increased formation of meiotic DSBs and a distribution of
crossovers that differs from the wild type (Mets and Meyer, 2009;
Tsai et al., 2008). Here, it was demonstrated that disruption of the
condensin I complex causes an increase in chromosomal axis
length, which is independent of DSB formation but requires the
axis-associated protein HIM-3 (Mets and Meyer, 2009). Thus, in
C. elegans, it appears that the condensin I complex controls
chromosome structure and the association of chromatin with the
chromosome axis, which in turn might determine its accessibility
Journal of Cell Science
Meiotic crossover and non-crossover control
by SPO-11. This and other evidence suggests that the chromosome
axis has an important role in meiotic DSB formation. Certainly,
proteins associated with the chromosome axis have also been
shown to be important for DSB formation. For example, the C.
elegans HIM-3 paralog – him three paralog 3 (HTP-3) – is a
component of the meiotic chromosome axis that mediates DSB
formation through its interaction with a complex required to
generate DSBs (Goodyer et al., 2008). The conserved mouse
protein meiosis-specific 4 (MEI4), which associates with the axis
of meiotic chromosomes, was also shown to be required for DSB
formation (Kumar et al., 2010). Thus, a functional relationship
appears to exist between the chromosome axis and DSB formation
and might have some bearing on where hotspots arise. For a
detailed discussion and models of the interplay between the
chromosome axis and DSB formation, readers are referred to the
article by Kleckner (Kleckner, 2006).
If DSB hotspots are associated with sites of open chromatin,
then the question arises what exactly determines the chromatin
state at hotspots. Evidence suggests that some recombination
hotspots in humans are associated with specific sequence motifs.
Ten percent of the hotspots identified in a genome-wide survey of
~1.6 million single-nucleotide polymorphisms (SNPs) in three
sample populations were associated with the 7-mer motif
CCTCCCT (Myers et al., 2005). Using more detailed data from
the human ‘haplotype map’ (HapMap) project, work by the
same group identified a degenerate 13-mer sequence
(CCNCCNTNNCCNC) that was present in one or more copies at
40% of all human hotspots (Myers et al., 2008). These data indicate
that there is some correlation between DNA sequence and hotspot
location. However, although humans and chimpanzees have more
than 98% sequence identity, hotspot locations in these two species
are not conserved (Ptak et al., 2005; Winckler et al., 2005). In
addition, there is evidence that recombination rates vary both
between ethnic groups (Evans and Cardon, 2005) and between
individuals (Cheung et al., 2007; Coop et al., 2008). Thus, sequence
alone is clearly not the only factor determining hotspot activity.
Recent studies indicate a role for specific epigenetic
modifications at DSB sites. A recent study in C. elegans identified
the new chromatin factor X-non-disjunction factor 1 (XND-1),
which is required for DSB formation specifically on the X
chromosome, as well as for the distribution of DSB formation (but
not DSB number) on the autosomes (Wagner et al., 2010). Increased
acetylation of histone H2A at lysine 5 (H2AK5Ac) that is likely to
be mediated by the histone acetylation protein Myst family histone
acetyltransferase-like (MYS-1; TIP60 in humans) in xnd-1 mutants
was identified as a chromatin modification associated with the
alteration in autosomal distribution of meiotic DSBs and reduced
DSB formation on the X chromosome (Wagner et al., 2010). This
study suggests that H2AK5Ac is a determinant of DSB distribution
in C. elegans, although the influence of this modification on DSB
formation in other organisms still needs to be shown. Trimethylation
of lysine 4 of histone 3 (H3K4Me3) has been considered as a preexisting marker for sites of DSB formation in S. cerevisiae because
this histone modification is frequently found in regions close to
DSB sites, independently of gene expression levels (Borde et al.,
2009). The same study showed that deletion mutants of the SETdomain-containing 1 (set1) gene, which encodes the only H3K4
methyltransferase in S. cerevisiae, display a dramatic reduction in
DSBs, and that those DSBs that form in the absence of Set1 are
differentially localised (Borde et al., 2009). Specific histone
modifications were also shown to be present at meiotic DSB
Box 1. Terms used to describe meiosis
Anti-recombinase: A protein that acts to prevent or inhibit
Chiasmata: The (cytologically) visible structure that is the
physical manifestation of a crossover between homologous
chromosomes in meiosis.
Crossover assurance: The mechanism that makes certain each
homologous chromosome pair will receive at least one meiotic
Crossover homeostasis: A mechanism that ensures a constant
number of meiotic crossovers, even under conditions where more
or fewer meiotic DSBs are generated. Homeostasis maintains
meiotic crossovers at the expense of non-crossovers. How
homeostasis is maintained is not well understood but it might be
governed by the same mechanism as interference.
Crossover interference: A mechanism that distributes meiotic
DSBs and crossovers such that adjacent crossovers tend to
occur further apart than expected by chance. The basis of
crossover interference is not well understood.
D loop: A recombination intermediate structure wherein one end
of the DSB has invaded into the homologous chromosome and
been extended to form a stable structure. A D loop can be
dissociated to allow non-crossover repair through SDSA, or can
go on to form a double Holliday junction. See Fig. 1.
Double Holliday junction: A recombination intermediate
structure that can be formed following D loop formation if the
second end of the original DSB also associates with the
homologous chromosome. This structure can be processed into
either a crossover or non-crossover. See Fig. 1.
Haplotype map: A map generated to describe common patterns
of human genetic variation using single nucleotide
polymorphisms in various populations. Also known as the
Interference-independent crossovers: Crossovers that do not
exhibit interference. Crossovers in this class are formed by
Mus81 catalyzed recombination intermediate cleavage in many
organisms. Because they do not display interference,
interference-independent crossovers can occur in close proximity.
Interference-independent crossovers contrast with interferencedependent crossovers, which always display interference in terms
of their positioning.
Interhomolog crossover: Also known as a meiotic crossover, a
crossover that has occurred between homologous chromosomes
Intersister repair: Repair of damage or a meiotic DSB (as in this
article) that uses the sister chromatid as a template rather than
the homologous chromosome. Repair between sister chromatids
can be through crossover or non-crossover pathways.
Synthesis-dependent strand annealing (SDSA): A pathway for
non-crossover repair wherein a D loop recombination
intermediate is formed and limited DNA synthesis occurs in the
region of the break, using the homologous chromosome as a
template. The D loop is then dissociated and the invading end of
the DSB that has been extended anneals back with the other end
of the original DSB. DNA synthesis and ligation seals the break.
ZMM proteins: A group of proteins that includes Zip1, Zip2, Zip3,
Zip4, Mer3, Msh4, Msh5 and the recently identified Spo16 in S.
cerevisiae; they are involved in both SC formation and meiotic
initiation sites in mice with H3K4Me3 enriched at active DSB
sites, whereas histone H4 hyperacetylation was found to occur
after DSB formation (Buard et al., 2009). H3K4Me3 is present in
Spo11–/– mice, which lack meiotic DSBs, and thus H3K4Me3 is a
marker for sites of DSB initiation that might contribute to hotspot
Journal of Cell Science
Journal of Cell Science 124 (4)
activity (Buard et al., 2009). HapMap-methylation-associated SNPs,
which are markers of germline methylation, are positively correlated
with regional meiotic recombination rates in humans (Sigurdsson
et al., 2009), providing further evidence that epigenetic
modifications influence hotspot activity in mammals.
It remains unclear exactly how sites of frequent meiotic
recombination are identified and marked as hotspots. However,
recent studies in mice have identified the gene PR-domaincontaining 9 (Prdm9) (Baudat et al., 2010; Parvanov et al., 2010),
which encodes for a protein with histone methyltransferase activity.
Different human alleles of PRDM9 show altered activity of
recombination hotspots (Baudat et al., 2010). Furthermore, in vitro,
the protein product of the human PRDM9 A allele was shown to
bind to the specific 13-mer motif previously associated with
recombination hotspots, suggesting that PRDM9 marks DSB
initiation sites by recognising this motif (Baudat et al., 2010).
Thus, sequence motifs that are modified by certain epigenetic
marks appear to designate some of the known mammalian
recombination hotspots by either signalling to the recombination
machinery or allowing SPO11 to access the DNA. However, it is
not known how these signals integrate with factors that control the
association of chromatin with the chromosome axis. Furthermore,
the H3K4Me3 mark is highly enriched in promoter regions of
actively transcribed genes (Bernstein et al., 2005; Schneider et al.,
2004), but meiotic DSBs do not form in all promoter regions and,
currently, there is no known direct relationship between DSB
formation and transcriptional activity (Hunter, 2006; Kniewel and
Keeney, 2009). Thus, this chromatin modification alone is not
likely to account for all hotspot activity. As the roles of epigenetic
modifications in meiotic DSB formation and crossover control
remain poorly understood, they should be an important focus of
Proteins that influence crossover outcomes
The factors influencing DSB position are not yet well-understood,
but a number of proteins that function downstream of DSB creation,
to either promote or prevent crossover formation, have been
characterised. Although it is not known exactly how the decision
is made to form a crossover or non-crossover, many meiotic
proteins influence whether or not a crossover can take place. Here,
these proteins will be classified as having either pro-crossover or
anti-crossover activities, although at least one of these proteins can
be considered to fit into both categories, depending on the context
of the protein activity or the model system in which it has been
examined. A non-exhaustive list of these genes is presented in
Setting the stage for crossover formation
A number of pro-crossover proteins have roles in pairing or SC
formation that indirectly promote crossovers. SC formation involves
the assembly of several structural elements, specifically a pair of
lateral elements connected by transverse elements and a central
element, which facilitates crossovers by continuously maintaining
homologues in close juxtaposition (Costa and Cooke, 2007; de
Carvalho and Colaiacovo, 2006). Among the proteins that form the
Table 1. A non-exhaustive list of genes with either pro- or anti-crossover activities
DSB end resection
MRE11, RAD50, NBS1
SLX1, SLX4/BTBD12 a
Homologs that exist but have not yet been characterized with respect to the meiotic activity indicated.
Characterized homologs that do not appear to have a role in meiosis.
Atgr1, Arabidopsis thaliana -response gene 1; tos, Drosophila tosca; spnB, Drosophila spindle-B; rck, Arabidopsis rock-n-rollers; mlh3, Mut L homolog 3;
tefu, Drosophila telomere fusion; mms4, methyl methanesulfonate sensitive.
Meiotic crossover and non-crossover control
SC in S. cerevisiae are the Zip proteins (part of the ZMM group of
proteins). Zip1 is a structural protein that makes up the central
regions of the SC (Sym et al., 1993). Zip2, Zip3 and Zip4 are also
required for SC assembly, and have been implicated in
ubiquitylation and/or sumoylation of proteins associated with SC
formation (Agarwal and Roeder, 2000; Borner et al., 2004; Cheng
et al., 2006; Chua and Roeder, 1998; Perry et al., 2005; Tsubouchi
et al., 2006). A common theme among SC proteins is that, although
the sequence homologues of lower-organism SC proteins are not
easily detectible in higher organisms, structural features of the
proteins are conserved (Costa and Cooke, 2007). In mammals, the
SC is made up of multiple proteins including SC proteins 1, 2 and
3 (SYCP1, 2 and 3), SC central element proteins 1 and 2 (SYCE1
and SYCE2) and testis-expressed gene 12 (TEX12) (Costa and
Cooke, 2007), but these will not be discussed further here. A
detailed review of proteins that are involved in homologue pairing
and synapsis, as well as recent insights into meiotic pairing centres
in C. elegans that are beyond the scope of this review can be found
elsewhere (Costa and Cooke, 2007; Ding et al., 2010; Lynn et al.,
2007; Yang and Wang, 2009; Zetka, 2009; Zickler, 2006).
Journal of Cell Science
Generation of the recombination intermediate
In the last few years, considerable progress has been made towards
defining the activities that process DSBs to generate 3⬘ ssDNA
overhangs, which are the substrate for initiating homologous
recombination. Studies of C. elegans completion of meiotic
recombination-1 (com-1) and its homologue in Arabidopsis thaliana,
com1 (homologues of yeast sae2, human CtIP), found a similar
phenotype in these two species, in which mutants failed to load
RAD51 onto meiotic DSBs, suggesting that COM1 acts in DSB
resection (Penkner et al., 2007; Uanschou et al., 2007). More recently,
data from budding yeast and mammalian cells have revealed that
DSB resection is dependent on the cooperative action of multiple
factors, including the Mre11–Rad50–Xrs2 (MRX) complex [Mre11–
Rad50–Nbs1 (MRN) in mammals] SUMO activating enzyme 2
(Sae2; CtIP in mammals), small growth suppressor 1 [Sgs1; Bloom’s
syndrome mutated (BLM) in mammals], exonuclease 1 (Exo1;
EXO1 in mammals) and DNA replication helicase 2 (Dna2; DNA2
in mammals) (Gravel et al., 2008; Mimitou and Symington, 2008;
Zhu et al., 2008) (Fig. 2). These studies have been validated by the
analysis of DSB end processing in vitro using the respective purified
proteins (Nimonkar et al., 2008). This area has been intensively
reviewed and discussed elsewhere and we refer the reader to several
reviews on this topic (Bernstein and Rothstein, 2009; Mimitou and
Symington, 2009). Once the DSB has been processed, Rad51 and/or
the meiosis-specific recombinase Dmc1 bind the 3⬘ ssDNA to
generate a nucleoprotein filament that carries out a homology search
and strand invasion into the homologous chromosome. Both Dmc1
and Rad51 are required for efficient meiotic recombination in yeast
(Schwacha and Kleckner, 1997) and mice (Pittman et al., 1998;
Sharan et al., 2004; Yoshida et al., 1998), but Dmc1 orthologues
have not been identified in C. elegans or D. melanogaster. Human
DMC1 has robust D-loop-forming activity in vitro (Li et al., 1997;
Sehorn et al., 2004), whereas in S. cerevisiae, Rad54 is required
together with Rad51 for D loop formation (Sung et al., 2003). In
vivo, the Dmc1 nucleoprotein filament is more adept at forming D
loops with the homologous chromosome than the Rad51
nucleoprotein filament (Shinohara et al., 2003; Tsubouchi and Roeder,
2003). Co-ordination of RAD51 and DMC1 activities in mammalian
meiosis might be achieved through the breast cancer susceptibility
protein 2 (BRCA2), because BRCA2 binds to both proteins at
distinct sites (Sharan et al., 1997; Thorslund et al., 2007), and is
required for localisation of RAD51 and DMC1 at foci that are
presumed to be meiotic DSBs in mice (Sharan et al., 2004). Similarly,
C. elegans BRCA2 (BRC-2) is essential for meiotic DSB repair, in
which it functions to promote RAD-51 filament nucleation and
stabilisation, and in the stimulation of RAD-51 mediated strand
exchange (Martin et al., 2005; Petalcorin et al., 2007; Petalcorin et
Mismatch repair defective 4 and 5 (Msh4 and Msh5, respectively)
and meiotic recombination 3 (Mer3), i.e. other members of the
ZMMs, also promote crossovers, probably by facilitating the stable
formation of recombination intermediates. msh4 and msh5 mutants
in S. cerevisiae have reduced inter-homologue crossing over
(Hollingsworth et al., 1995; Ross-Macdonald and Roeder, 1994).
Similarly, in C. elegans, MSH-4 and MSH-5 are essential for
crossing over (Kelly et al., 2000). Msh4 and Msh5 are known to
form a heterodimer, and one proposal is that this acts as a clamp to
hold homologous chromosomes together, thereby stabilising the
Holliday junction and facilitating crossing over (Snowden et al.,
2004) (Fig. 2). In Msh4 and Msh5 knockout mice, chromosomes
fail to correctly pair, crossovers are absent and, consequently,
animals are sterile (de Vries et al., 1999; Edelmann et al., 1999;
Kneitz et al., 2000). In mammals, unlike in S. cerevisiae, Msh4 and
Msh5 are required for correct chromosome pairing during meiotic
prophase, and both are clearly associated with recombination
intermediates destined to form both crossovers and noncrossovers
(Kneitz et al., 2000; Santucci-Darmanin et al., 2000). Thus, the
mouse phenotype associated with loss of Msh4 or Msh5 does not
only reflect of a loss of crossovers, but is also more severe than that
of other mutants, such as loss of the mut L homologue 1 (Mlh1;
discussed below) (Edelmann et al., 1996). Interestingly, msh4 and
msh5 are not found in D. melanogaster and in S. pombe. The latter
relies solely on the structure-specific endonuclease complex between
mutagenesis sensitive 81 (Mus81) and essential meiotic
endonuclease 1 (Eme1) for crossover formation (Osman et al.,
2003), whereas in D. melanogaster the clamp function of Msh4 and
Msh5 can potentially be replaced by alternative proteins or an
alternative mechanism might be present (Blanton et al., 2005). In
addition to Msh4 and Msh5, the Mer3 helicase promotes normal
crossover frequencies in yeast (Nakagawa and Ogawa, 1999). Mer3
functions to stimulate heteroduplex extension by Rad51, thereby
stabilising nascent D loop structures to promote capture of the
second free DNA end, double Holliday junction formation and,
ultimately, crossovers (Mazina et al., 2004). In Sordaria, Mer3,
Msh4 and Mlh1 have recently been shown to have roles in
homologous chromosome pairing (Storlazzi et al., 2010).
MLH1 is a well-known marker for sites designated as crossovers
in the mouse (Anderson et al., 1999). MLH1 is required for
crossovers, as germ cells from mice that lack MLH1 do not display
sufficient chiasmata and do not progress beyond the meiotic
pachytene stage, and thus, Mlh1 null mice are infertile (Edelmann
et al., 1996) (Fig. 3). Budding yeast mlh1 deletion mutants have
reduced crossing over (Hunter and Borts, 1997). In vitro, human
MSH4 interacts with MLH1, and in vivo the two proteins colocalise
during early to mid-pachytene, when crossing over takes place
(Santucci-Darmanin et al., 2000). One possible function of MLH1
is that it mediates release of the MSH4 and MSH5 clamp (Snowden
et al., 2004), thereby facilitating crossover completion. mlh-1 has
not been characterised in C. elegans; instead, Zip homologous
protein 3 (ZHP-3), the C. elegans homologue of yeast Zip3, has
been shown to be a marker for meiotic crossovers (Fig. 3). ZHP-3
Journal of Cell Science 124 (4)
Journal of Cell Science
Fig. 2. Biochemical activities that promote crossover and/or non-crossover recombination. Shown are schematic representations of specific recombination
intermediates that are subject to biochemical activities of meiotic enzymes (helicases, nucleases, DNA-binding proteins) that act to promote one of two repair
outcomes: non-crossover or crossover (recombination). Arrows indicate the directionality of the helicase activity; arrows with scissors indicate the position of
cleavage of the nuclease activity; yellow circles indicate the preferred substrate for DNA binding. The human BLM orthologues Sgs1 (S. cerevisiae), Rqh1 (S.
pombe), HIM-6 (C. elegans) and Mus309 (D. melanogaster) are presumed to perform roles in both resection of DSBs and dissolution of double Holliday junctions.
Yen1 is the S. cerevisiae orthologue of human GEN1. Slx4, HIM-18 and Mus312 are the S. cerevisiae, C. elegans and D. melanogaster orthologues of human
has two roles in meiosis: it promotes crossover formation and also
restructures chromosomes at diakinesis, the chromosome
condensation stage, so that appropriate segregation can take place
(Bhalla et al., 2008; Jantsch et al., 2004). Thus, several proteins are
required to generate and maintain a stable recombination
intermediate. In order for appropriate chromosome segregation to
take place, the stable recombination intermediate must have
engaged the homologous duplex and not the sister chromatid,
ultimately resulting in formation of an interhomologue crossover.
Promoting interhomologue crossing over versus intersister
Meiotic crossover formation can be controlled by genes that allow
meiotic DSB repair from only certain templates, i.e. not all. The
proteins that participate in the barrier to sister chromatid repair are
pro-crossover factors because they promote DSB repair that uses
the homologous chromosome, but not the sister chromatid (see text
box). In this way, these factors allow crossovers between
homologues but not between sister chromatids. For example, in
budding yeast, interhomologue recombination is ensured by
phosphorylation of the axial element protein homologue pairing 1
(Hop1) by the serine/theronine protein kinases meiotic checkpoint
1 (Mec1) and telomere length 1 (Tel1), the homologues of
mammalian ataxia telangiectasia and Rad3-related protein (ATR)
and ataxia telangiectasia mutated (ATM), respectively (Carballo et
al., 2008). It has been proposed that Hop1 phosphorylation leads
to dimerisation of the meiotic axial element meiotic kinase 1
(Mek1), which enables it to phosphorylate its target proteins that
prevent the repair of DSBs using the sister chromatid (Niu et al.,
2005). In addition, Mek1 inhibits Rad51 activity by attenuating the
formation of the Rad51–Rad54 complex; with less active Rad51,
the activity of the meiosis-specific strand exchange protein Dmc1
is favoured (Niu et al., 2009). Dmc1 is thought to be more efficient
at promoting interhomologue recombination than Rad51 (Shinohara
et al., 2003; Tsubouchi and Roeder, 2003), thus, the activity of
Mek1 promotes interhomologue recombination over sister
Meiotic crossover and non-crossover control
Mouse crossover sites marked by MLH1
C. elegans crossover sites marked by ZHP-3
DAPI + GFP
Journal of Cell Science
Fig. 3. Examples of crossover interference. (A)Examples of crossovers
marked by staining of MLH1 (green) on mouse chromosomes. The SC is
marked in red by staining of the SC protein 3 (SCP3). When multiple
crossovers occur on the same chromosome, they tend to be spaced far apart,
demonstrating crossover interference. (B)Complete crossover interference in
C. elegans. The images in the top row show the single recombination foci per
chromosome marked by staining of ZHP-3 (six chromosomes, hence six foci)
at meiotic diplotene in a wild type animal. The rtel-1 mutant exhibits defective
complete crossover interference, as illustrated by the increased number of
ZHP-3 foci per meiotic nucleus (bottom images).
chromatid repair. In C. elegans – which do not have Dmc1 – germ
cells, at the onset of meiotic prophase, switch into a specialised
mode of DSB repair that is characterised by the requirement for
RAD-50 in loading RAD-51 onto meiotic DSB ends, a process
that is essential for interhomologue crossover formation (Hayashi
et al., 2007). By mid- to late pachytene, a second developmentally
programmed switch occurs; RAD-50 is no longer required for
RAD-51 association with DSBs, and competence for
interhomologue crossing over is lost (Hayashi et al., 2007). Repair
of any remaining DSBs might then occur through the sister
chromatid, which requires BRCA homologue 1 (BRC-1) that is
dispensable for repair through the homologue (Adamo et al., 2008).
The requirement for RAD-50 in RAD-51 loading at DSBs is
partially dependent on a number of proteins that have roles in
meiosis-specific chromosome axis structure (Hayashi et al., 2007).
Thus, mechanisms exist to ensure that crossing over with the
homologue will occur at the correct time, rather than with the sister
chromatid. Once the stable interhomologue crossover intermediate
has been generated, the activity of a resolution enzyme will
ultimately complete the crossover.
Resolution of the recombination intermediate
Crossover formation is controlled directly by enzymes that act on
recombination intermediates and resolve these either as crossovers
or non-crossovers. Mus81–Eme1 can resolve intermediates into
crossovers (Fig. 2), but also has multiple biochemical abilities,
including a preference for acting on structures that include D
loops, nicked Holliday junctions, replication forks with the lagging
strand at the junction point, and 3⬘ flap structures (Bastin-Shanower
et al., 2003; Fricke et al., 2005; Osman et al., 2003). Yeast Mus81–
Eme1 is also reported to have robust cleavage activity on intact
Holliday junctions, although they are not its preferred substrate in
vitro (Gaskell et al., 2007). Mus81 is responsible for generating
interference-independent crossovers in S. cerevisiae (Argueso et
al., 2004; de los Santos et al., 2003) and in mouse (Holloway et
al., 2008), and also generates the majority of crossovers in S.
pombe, which has only interference-independent crossovers (Boddy
et al., 2001; Osman et al., 2003; Smith et al., 2003). In C. elegans,
MUS-81 is also responsible for a subset of crossovers that occur
when meiotic non-crossover repair through SDSA is blocked by
mutation in the anti-recombinase regulator of telomere length 1
(RTEL-1) (Youds et al., 2010).
A number of DNA processing enzymes have recently been
identified in various organisms that possess the biochemical activity
to resolve Holliday junctions – specifically, the ability to cleave
Holliday junctions symmetrically. These resolvases have the
potential to generate either crossover or non-crossover products,
and other factors, perhaps the MSH4-MSH5 complex, might
influence this decision. The human resolvase XPG-like
endonuclease 1 (GEN1), and its S. cerevisiae orthologue Yen1,
have been independently identified through their ability to
symmetrically cleave Holliday junctions (Ip et al., 2008) (Fig. 2).
Yen1 has functional overlap with Mus81 in budding yeast (Blanco
et al., 2010) and human GEN1 was found to rescue the meiotic
phenotype of mus81 S. pombe mutants (Lorenz et al., 2009),
indicating conserved, functionally similar roles for Mus81 and
Yen1 or GEN1 in yeast and humans, respectively. However, we
have not observed a meiotic phenotype for gen-1 mutants in C.
elegans (J.L.Y. and S.J.B., unpublished data) and, together with the
recently demonstrated role for gen-1 in DNA damage signalling
and repair in the nematode (Bailly et al., 2010), this indicates that
additional enzyme(s) act as the meiotic resolvase in this organism.
In addition to GEN1, concurrent works from several groups
described roles for the orthologous proteins Drosophila Mus312,
C. elegans HIM-18, and mammalian synthetic lethal of unknown
function 4 (SLX4) in resolving Holliday junctions (Andersen et
al., 2009; Fekairi et al., 2009; Munoz et al., 2009; Saito et al.,
2009; Svendsen et al., 2009) (Fig. 2). In mus312 mutants of D.
melanogaster, meiotic crossing over is reduced by ~95%, consistent
with the hypothesis that Mus312 is the key protein required for
Holliday junction resolution in this organism (Andersen et al.,
2009; Yildiz et al., 2002). Gene expression patterns and knockdown
studies suggest that mammalian SLX4 has a meiotic function in
humans that is conserved with that of D. melanogaster Mus312
(Andersen et al., 2009). SLX4 interacts with SLX1, and the SLX4–
SLX1 complex has a robust Holliday junction cleavage activity in
vitro, which probably accounts for its role in meiosis (Fekairi et
al., 2009; Munoz et al., 2009; Svendsen et al., 2009). SLX4 also
binds the structure-specific complex between the endonucleases
Xeroderma Pigmentosum complementation group F and excision
repair cross-complementing 1 (XPF–ERCC1) complex and
MUS81–EME1, among other proteins. Depletion of SLX4 also
Journal of Cell Science 124 (4)
causes sensitivity to a number of DNA damage agents, indicating
that it serves as a platform for different structure-specific
endonucleases that are most likely to act both in meiosis and in
DNA repair (Fekairi et al., 2009; Munoz et al., 2009; Svendsen et
al., 2009). Similarly, the C. elegans SLX4 orthologue HIM-18 is
required for processing meiotic recombination intermediates,
because him-18 mutants display phenotypes that are consistent
with reduced meiotic crossover formation (Saito et al., 2009).
Moreover, HIM-18 physically interacts with the structure-specific
endonucleases SLX-1 and XPF-1, and might serve as a scaffold
that binds certain nucleases to allow cleavage of Holliday junction
intermediates in various cellular contexts (Saito et al., 2009). For
further details on recent advances in the area of resolvases, the
reader is directed elsewhere (Mimitou and Symington, 2009;
Svendsen and Harper, 2010).
Journal of Cell Science
Several proteins are known to inhibit crossover formation by
promoting different pathways for meiotic DSB repair, and these
involve alternative processing of recombination intermediates.
BLM, together with topoisomerase TOPOIII, has double Holliday
junction dissolution activity in vitro, which resolves these junctions
without crossover formation and, thereby, explains the increased
degree of sister chromatid exchange observed in BLM-deficient
cells (Wu and Hickson, 2003) (Figs 1 and 2). The budding yeast
BLM homologue Sgs1 suppresses the formation of multi-chromatid
joint molecules during meiosis and, thereby, prevents aberrant
crossing over (Oh et al., 2007). These anti-crossover activities of
Sgs1 are normally antagonised by the ZMM proteins (Jessop et al.,
2006). Conversely, the fission yeast BLM homologue Rec Q
helicase 1 (Rqh1) might extend hybrid DNA and, thereby, bias the
recombination outcome toward crossover formation (Cromie et al.,
2008). In C. elegans mutants for the BLM orthologue him-6,
meiotic crossovers are decreased compared with those in wild type
(Wicky et al., 2004). Similarly, meiotic recombination is reduced
to about half of the wild type frequency in D. melanogaster with
mutations in the BLM orthologue mus309 (McVey et al., 2007).
Therefore, BLM might have context-dependent effects or differing
roles in different organisms and, thus, could be classified as having
both pro- and anti-crossover activities. It is also possible that the
pro-crossover function of BLM reflects a role in meiotic DSB
resection (Fig. 2).
The C. elegans anti-recombinase RTEL-1 promotes noncrossover repair both in meiosis and mitosis (Barber et al., 2008;
Youds et al., 2010). Analysis of the meiotic phenotypes of rtel-1
mutants revealed that these animals had multiple crossovers per
chromosome, whereas wild type animals usually have only a single
crossover per chromosome (Youds et al., 2010). rtel-1 mutants also
have an increased number of recombination foci, as marked by
ZHP-3 in meiotic nuclei, indicating excess crossovers. RTEL-1
has the ability to disrupt D loop recombination intermediates in
vitro (Barber et al., 2008; Youds et al., 2010) (Fig. 2). Thus, RTEL1 is likely to promote non-crossovers by functioning in meiotic
SDSA, where it probably dissociates the D loop intermediate to
facilitate the association of the invading DNA strand back with the
original duplex DNA, thereby inhibiting a stable strand invasion
event. In addition to its meiotic functions, RTEL1 acts in interstrand
crosslink repair in C. elegans and human cells, and is required for
maintenance of telomere length in mice (Barber et al., 2008; Ding
et al., 2004). Thus, RTEL1 is believed to have important roles as
an anti-recombinase in multiple cellular scenarios. BLM and
RTEL1 are the only examples of meiotic anti-crossover proteins in
the current literature. However, it has been reported that S.
cerevisiae mutator phenotype 1 (Mph1) has biochemical abilities
similar to those of RTEL1 (Prakash et al., 2009) (Fig. 2); therefore,
future experiments should address whether Mph1, like RTEL1, has
a role in meiotic SDSA.
Possible mechanisms for crossover
The proteins discussed thus far all make an individual contribution
to the formation of either a crossover or non-crossover. These roles
must be carefully regulated and work in concert for successful
completion of either crossover or non-crossover repair. However,
the factors described above are not the only factors that control the
decision between crossover and non-crossover; it is also influenced
by crossover interference, assurance and homeostasis on a
chromosome-wide and genome-wide scale.
It is well known that crossovers are distributed non-randomly
along chromosomes. This phenomenon exists because of two
underlying factors: first, DSBs are not formed randomly and, second,
crossover choice is governed by crossover interference. Crossover
interference dictates that adjacent crossovers on the same
chromosome tend to occur at sites that are further apart than
expected if they were randomly positioned. Crossover assurance
makes certain that all chromosomes will obtain at least one
crossover, known as the obligate crossover. The presence of at least
one crossover between homologous chromosomes serves as a
physical linkage between homologues so that they can each attach
to the correct spindle and, subsequently, segregate accurately in
meiosis I. In budding yeast, crossover interference and assurance
are separately regulated by the ZMM proteins (Shinohara et al.,
2008). Mutations in the ZMM genes result in defective SC formation
together with reduced crossovers, but non-crossovers are unaffected
(Borner et al., 2004). Different subcomplexes formed by ZMM
proteins might have different functions. For instance, Mer3 and the
Msh4–Msh5 heterodimer participate in promoting the differentiation
of crossovers, which establishes crossover interference; whereas
the newly identified ZMM protein Spo16 acts in complex with Zip4
to efficiently implement crossovers, which is important for crossover
assurance (Shinohara et al., 2008). However, observations by de
Boer et al. (de Boer et al., 2007) suggest that, in mice, a separate
mechanism for crossover assurance, in addition to that of
interference, is not necessary (de Boer et al., 2007).
C. elegans meiosis presents an extreme case for the control of
crossover formation. Here, meiotic crossover interference is referred
to as ‘complete’ because each chromosome has only a single
crossover, indicating that the number of crossovers per chromosome
is tightly regulated (Hillers and Villeneuve, 2003; Wood, 1988);
<1% of oocyte meioses have a chromosome that lacks a crossover
(Dernburg et al., 1998) and double crossovers are very rare (Lim
et al., 2008). Studies of this system have shown that complete
crossover interference in C. elegans can be altered by either
increasing the number of meiotic DSBs, for example, by mutating
the condensin dumpy 28 (dpy-28), or by changing the balance
between crossover and non-crossover repair of meiotic DSBs (by
mutation in rtel-1). It is, therefore, possible that crossover
interference is regulated on at least two levels in C. elegans: by the
number of DSBs generated and by the pathway through which
they are repaired.
Related to crossover assurance and interference is crossover
homeostasis, a mechanism that regulates the balance between
Journal of Cell Science
Meiotic crossover and non-crossover control
crossovers and non-crossovers. In S. cerevisiae, experiments have
shown that crossover homeostasis exists. Specifically, a set level
of crossovers is always maintained at the expense of noncrossover pathways, such as SDSA, in situations where fewer
meiotic DSBs are generated (Chen et al., 2008; Martini et al.,
2006). In mutants with reduced Spo11 activity, which have
reduced numbers of meiotic breaks, crossover homeostasis is
maintained by shifting the ratio between crossovers and noncrossovers towards fewer non-crossovers (Martini et al., 2006).
Homeostasis also exists in C. elegans when additional breaks are
generated by ionising radiation (IR); when excess DSBs are
induced by IR treatment in wild type animals, little or no increase
in recombination is observed (Youds et al., 2010). However, in
rtel-1 mutants treated with IR, a large, dose-dependent increase
in recombination is observed, indicating that rtel-1 mutants cannot
maintain homeostasis in the presence of additional meiotic DSBs
(Youds et al., 2010). Homeostasis and crossover interference are
potentially regulated by a common mechanism because mutants
defective in interference, such as budding yeast zip2 and zip4
mutants and C. elegans rtel-1 mutants, also show compromised
homeostasis (Chen et al., 2008; Joshi et al., 2009; Youds et al.,
Several models have been proposed over the years to explain
how crossover interference is propagated (Fig. 4). One early
hypothesis in the field is the polymerisation model, in which the
completion of a crossover initiates polymerisation of an inhibitor
of recombination along the chromosome (King and Mortimer,
1990). More recently, the stress model has been proposed, which
posits that mechanical stress along the chromosome results in axis
buckling that places one recombination intermediate into a position
where it commits to becoming a crossover and, subsequently,
tension is released in the area near the crossover so that no other
DSBs nearby will form crossovers (Borner et al., 2004; Kleckner
et al., 2004) (Fig. 4).
Current evidence indicates that the establishment of crossover
interference is linked to chromosome axis structure. In yeast, the
conserved ATPase pachytene checkpoint 2 (Pch2) regulates meiotic
axis morphogenesis by controlling the overall levels and localisation
patterns of the structural protein Hop1 and the association of Zip3
with meiotic chromosome axes (Joshi et al., 2009), but it is not
required for crossover formation (Joshi et al., 2009; Zanders and
Alani, 2009). A proposed model for Pch2 function is that it
reorganises chromosome axes into long-range, one-crossover
modules, in which only a single crossover is assured and additional
crossovers are prevented (Joshi et al., 2009). The authors suggest
that multiple single-crossover modules exist along the length of
each homologous chromosome pair, and that tension release – as
proposed by the stress model (Borner et al., 2004; Kleckner et al.,
2004) – prevents multiple crossovers from occurring within any
one module (Joshi et al., 2009). Therefore, higher-order
chromosome structure appears to have an important role in
crossover interference, at least in yeast.
Data from mouse studies have also provided insights into the
establishment of crossover interference. It has been reported that
MLH1 foci, which mark crossovers in meiotic pachytene in mice,
exhibit strong interference (de Boer et al., 2006). The same group
showed that, prior to pachytene, late zygotene MSH4 foci and RPA
foci – which mark interhomologue interactions that could be
Compression stress on axis exists
Potential crossover sites designated
Axis buckling occurs
Recombination inhibitor localisation
Crossover formation allows local stress release
Recombination inhibitor polymerisation prevents crossover,
allows non-crossover repair
Axis relaxation occurs within the crossover region; other
potential crossovers are repaired as non-crossovers
Fig. 4. Illustration of two proposed mechanisms
of crossover interference. In the polymerisation
model (left), the formation of a crossover (blue X)
leads to the localisation of a recombination
inhibitor (orange oval) at the crossover and its
polymerisation along the vicinity, preventing other
potential sites (blue circle) nearby from forming
crossovers, thereby allowing non-crossover repair
(green region of DNA) instead. In the mechanical
stress model (right), compression stress (red
arrows) along the chromosome axis leads to
buckling of the axis at one of the potential
crossover sites. Buckling at the site changes the
configuration of the recombination intermediate,
committing it to become a crossover. Crossover
formation (blue X) at this site allows local stress
release, preventing other crossovers from forming
close by. Similar to the polymerisation model,
other potential recombination sites nearby are
repaired as non-crossovers (green region of DNA).
Journal of Cell Science
Journal of Cell Science 124 (4)
resolved into either crossovers or non-crossovers – also exhibit
substantial interference (de Boer et al., 2006). These data are
consistent with the idea that interference occurs in at least two
consecutive steps. Furthermore, mice that lack the axial element
protein SYCP3 show structurally abnormal axial elements and
incomplete chromosome synapsis, but have similar levels of
crossover interference when compared with wild type animals,
indicating that axial element structure and full synapsis are not
required for the establishment of normal interference (de Boer et
al., 2007). However, correlations between SC length and
interference in mammals have been reported by other groups (Lynn
et al., 2002; Petkov et al., 2007), so further research will be
required to clarify the exact relationship between the SC, meiotic
chromosome structure and crossover interference.
One further possibility is that epigenetic signals are also involved
in marking the crossover site and preventing other crossovers from
occurring nearby. The above mentioned study that showed that
HapMap methylation-associated SNPs are positively correlated
with regions of meiotic recombination (Sigurdsson et al., 2009)
suggests that either methylation is a marker for DSB sites or,
alternatively, its occurrence after crossover formation inhibits
further crossovers, which serve as the signal for interference.
Further studies will be essential to understand the relationship
between epigenetic marks, chromosome axis morphogenesis and
the crossover–non-crossover decision.
Although recent studies have enhanced our understanding of the
factors that control meiotic crossing over, many questions remain.
Further experiments are needed to clearly define how the
chromosome axis and its association with DNA control the location
of meiotic DSBs. Understanding the timing of epigenetic marks
will also be important in clarifying how these DNA modifications
control DSB initiation. For example, one question is whether there
are different modifications at crossover and non-crossover sites.
Prdm9 has recently been identified as a histone modifying protein
that might mark DSB initiation sites (Baudat et al., 2010), but are
there other proteins that act similarly? Answers to these and other
questions will help to establish the involvement of epigenetic
signals in designating DSB and/or crossover sites.
The activities of a number of pro-crossover proteins are relatively
well understood. However, only a few meiotic non-crossover
proteins have been identified. Given that, in most eukaryotes, far
more meiotic DSBs occur compared with the number of crossovers
that will eventually be formed, meiotic non-crossover proteins
have an extremely important role in preventing excess crossovers.
Thus, additional anti-crossover proteins probably exist but need to
be identified. Synthetic lethal screens in the genetic backgrounds
of anti-crossover mutants, such as rtel-1 or BLM, might identify
additional genes with overlapping functions. Furthermore, any
proteins that can act on D loop recombination intermediates should
be tested for roles in meiotic crossover control. In addition, other
modes of regulating the promotion of non-crossovers should also
be considered, aside from a direct activity on recombination
intermediates. For instance, are there proteins that promote DSB
repair by using the sister chromatid rather than the homologous
chromosome? Or is the activity of certain proteins that aid in the
formation or resolution of stable recombination intermediates
temporally inhibited to favour non-crossovers?
Finally, recent years have seen strides toward a greater
understanding of crossover interference, assurance and homeostasis,
but many questions remain regarding these processes. Further
details are needed to clarify how a higher-order chromosome
structure contributes to crossover interference and whether a role
for the chromosome axis in interference is conserved in higher
organisms. If a common mechanism controls one or several of
these processes, how does this involve the chromosome axis and
other factors? Mutants that display phenotypes in which interference
and homeostasis defects are uncoupled would be highly valuable
to address these questions. Whatever the answers to these questions,
future investigations into the factors that control the crossovernon-crossover decision promise to be intriguing.
We acknowledge Carrie Adelman for images of mouse MLH1 foci,
and thank Jennifer Svendsen and Carrie Adelman for comments on the
manuscript. Research in the lab of S.J.B. is funded by Cancer Research
UK. S.J.B. is a Royal Society Wolfson Research Merit Award holder.
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