Coordinating the events of the meiotic
prophase
Wojciech P. Pawlowski1
and W. Zacheus Cande2
1
Department of Plant Breeding and Genetics, Cornell University, Ithaca, NY 14853, USA
2
Department of Molecular and Cell Biology, University of California, 345 LSA, Berkeley, CA 94720, USA
Meiosis is a specialized type of cell division leading to
the production of gametes. During meiotic prophase I,
homologous chromosomes interact with each other and
form bivalents (pairs of homologous chromosomes).
Three major meiotic processes ­ chromosome pairing,
synapsis and recombination ­ are involved in the
formation of bivalents. Many recent reports have
uncovered complex networks of interactions between
these processes. Chromosome pairing is largely depen-
dent on the initiation and progression of recombination
in fungi, mammals and plants, but not in Caenorhabditis
elegans or Drosophila. Synapsis and recombination are
also tightly linked. Understanding the coordination
between chromosome pairing, synapsis and recombina-
tion lends insight into many poorly explained aspects of
meiosis, such as the nature of chromosome homology
recognition.
Introduction
Upon entry into meiosis, the diploid nucleus contains two
homologous copies of each chromosome, one inherited
from the father and the other from the mother. During
meiotic prophase I (see Glossary), homologous chromo-
somes, previously distributed throughout the nucleus,
identify each other, enter into an intimate contact and
form bivalents (Glossary; Figure 1). At the same time,
double-strand DNA breaks (DSBs) are generated in
chromosomal DNA and repaired, resulting in meiotic
recombination (Glossary). Meiotic prophase I combines
events that are biochemical in nature, such as processing
of meiotic DSBs, with those that also involve the physical
three-dimensional structure of chromosomes, such as co-
alignment or juxtapositioning of homologous chromo-
somes. These events can be categorized as three processes:
(1) chromosome pairing (i.e. an interaction between
homologous chromosomes that results in their juxtaposi-
tioning and formation of bivalents. It includes a step in
which homologs get into physical proximity with each
other and a subsequent step of the identification of
homology between the partners; Glossary), (2) synapsis
(i.e. installation of the proteinaceous synaptonemal
complex (SC) structure between the two chromosomes in
a bivalent that stabilizes the initial pairing interaction;
Glossary), and (3) meiotic recombination (which spans
the period from the formation of meiotic DSBs to the
completion of their repair, including reciprocal chromo-
some arm exchange). These processes show high complex-
ity, yet, at the same time, they require error-free
completion. Errors in meiosis are costly; in humans, they
lead to infertility, miscarriage during pregnancy and
severe birth defects.
Many individual components involved in chromosome
pairing, synapsis and recombination have been identified
Glossary
Bivalents: pairs of chromosomes that form as a result of chromosome pairing
and synapsis interactions. They form during zygotene and persist until
metaphase I.
Crossover: a reciprocal exchange of chromosome arms and one of the
alternative outcomes of meiotic recombination. In late meiotic prophase I,
crossovers are sites of chiasmata, cytological structures that link non-sister
chromatids of homologous chromosomes and hold bivalents together until
metaphase I.
Meiotic prophase I: the longest and most complex stage of meiosis.
Subdivided into five substages (Figure 1) based on the changes in chromosome
morphology and the progression of pairing and synapsis. In leptotene, the
decondensed chromatin is organized into chromosomes by the assembly of a
proteinaceous core (the axial element). Meiotic recombination is initiated at this
step by DNA double-strand breaks (DSBs) that are formed on chromosomes.
During zygotene, homologous chromosomes pair and synapse, when the
central region of the synaptonemal complex (SC) is installed between the
paired homologous chromosomes. In pachytene, SC formation is complete and
meiotic recombination between homologs is resolved. In diplotene, the SC
disassembles and chiasmata, which are responsible for holding the homologs
together, are visible. Finally, in diakinesis, the chromosomes undergo a final
stage of condensation.Figure 1
Meiotic recombination: the process of formation of DSBs in chromosomal DNA
in early meiotic prophase I and their subsequent repair. Meiotic recombination
results in formation of crossover and non-crossover products.
Pairing: interactions between HOMOLOGOUS_ chromosomes that result in
their juxtaposition. The mechanism of chromosome pairing is not known.
However, pairing must include a step in which homologs get into physical
proximity with each other and a subsequent step involving the identification of
homology between the partners (homology search). By definition, only
interactions between homologous chromosomes are designated as `pairing'.
Chromosome pairing is followed by synapsis and leads to the formation of
bivalents, i.e., stable pairs of homologous chromosomes.
Synapsis: the process of installation of the proteinaceous synaptonemal
complex (SC) structure between the two homologous chromosomes in a
bivalent that stabilizes the initial pairing interaction. The presence and
progression of synapsis are usually inferred experimentally with electron
microscopy or immunolocalization of SC component proteins. Synapsis
follows chromosome pairing and usually occurs between homologous
chromosomes. However, in certain situations (e.g. in haploid cells or in
mutants defective in homologous chromosome pairing) synapsis can take
place between non-homologous chromosomes.
Synaptonemal complex (SC): a tripartite proteinaceous structure installed
between two chromosomes in the process of synapsis. SCs consist of two
lateral elements connected by a central region. The lateral elements form as
axial elements (AEs, also called the chromosome axis) in leptotene. The central
region assembles following chromosome pairing during zygotene. The Zip1
protein forms the central region of the SC in S. cerevisiae.
Corresponding author: Pawlowski, W.P. (wp45@cornell.edu).
Available online 27 October 2005
Review TRENDS in Cell Biology Vol.15 No.12 December 2005
www.sciencedirect.com 0962-8924/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tcb.2005.10.005
in the past two decades. However, it is only recently that
we have begun to understand the mechanisms responsible
for coordination of these processes. Here, we review recent
reports that seek to explain how the different meiotic
processes are indeed coordinated with each other.
Interaction between homologous chromosome pairing
and meiotic recombination
Homologous chromosome pairing includes a step in which
the homologs overcome spatial separation within the
nucleus and get into close physical proximity with each
other and a step in which sequence homology is compared
between the interacting partners. The mechanism of
chromosome pairing is one of the least-understood aspects
of meiosis. It is likely that several different processes
contribute to homolog pairing, including associations of
homologous chromosomes that exist before meiosis [1,2].
Among the various mechanisms proposed to explain
chromosome pairing, a link between meiotic recombina-
tion and pairing has been suggested to play a major role.
In Saccharomyces cerevisiae and in the mouse, chromo-
some homology search and pairing have been shown to
require proteins involved in initiation and progression
through the early steps of meiotic recombination [3­6].
A similar situation has been suggested to exist in plants
[7­9], although this has not yet been demonstrated
directly. By contrast, pairing is independent from
recombination in C. elegans and in Drosophila females,
where chromosomes pair normally in mutants that do not
initiate meiotic recombination [10,11]. In fact, in wild-type
female Drosophila, chromosome pairing precedes the
initiation of meiotic recombination [12].
DSB formation and repair
Meiotic recombination is universally initiated by the
introduction of DSBs into chromosomal DNA by the
recombination protein Spo11 [13] (Box 1). The DSBs are
then resected from 50
to 30
by a complex of recombination
proteins containing Rad50, Mre11 and others [14]. Single-
stranded DNA ends created in this way subsequently
invade homologous double-stranded DNA. This process is
facilitated by another complex of recombination proteins
containing two RecA homologs ­ Rad51 and its meiosis-
specific cousin Dmc1 (described below). Later, DSB repair
is channeled through two or more [15] alternative path-
ways that lead to formation of either crossover (Glossary)
or non-crossover products [16­18]. The presence of
separate pathways leading to crossovers and non-cross-
overs was first detected in S. cerevisiae [16,17], but a
similar situation might also exist in Arabidopsis [19].
Initial experiments to define these two pathways
suggested that they branch no later than the single-
strand invasion step [17,18].
Although chromosome pairing in many species is linked
to proteins involved in the initiation of meiotic recombina-
tion, the nature of this interaction has not been fully
elucidated. In Saccharomyces cerevisiae and Coprinus
cinereus, chromosome pairing, as measured with fluor-
escent in situ hybridization (FISH) probes to specific
chromosomal loci, requires the presence of the Spo11
protein but does not require the formation of DSBs [20,21].
However, when pairing was measured with a site-specific
recombination system in living S. cerevisiae cells [3,4], the
presence of DSBs was required for pairing. It is not
entirely clear why the two approaches for measuring
homologous chromosome pairing in yeast gave contra-
dictory results, although different genetic backgrounds of
the mutant strains have been suggested as the reason [4].
Role of the Rad51­Dmc1 protein complex in pairing
Several recombination proteins acting downstream from
Spo11 are also involved in chromosome pairing. An
involvement for Rad51 and Dmc1 in pairing has been
proposed in S. cerevisiae, mouse and maize, based on
analyses of rad51- and dmc1-defective mutants and
analyses of dynamic changes in distribution of Rad51
foci during meiosis [2,7,9,22,23]. In addition, the claim of
Rad51 and Dmc1 involvement in chromosome pairing is
supported by biochemical data, which indicate that Rad51
and Dmc1 can promote efficient homologous interactions
between kilobase-long DNA substrates [24,25]. This
ability might provide the basis of the proposed involve-
ment of these proteins in chromosome pairing.
Rad51 and Dmc1 form protein complexes [26], which
appear on chromosomes in early meiotic prophase I. These
complexes interact with other proteins, such as Hop2
[27­32]. In yeast, absence of Hop2 allows non-homologous
chromosome interactions that partially replace homolo-
gous pairing and lead to non-homologous synapsis [33],
suggesting that this protein is required for the fidelity of
chromosome pairing. Hop2 binds to double-stranded DNA
and does this before the Rad51­Dmc1 complex is loaded
onto chromosomes, suggesting that, during single-strand
invasion, it acts on the donor DNA strand, which does not
contain DSBs [27,33]. Hop2 also interacts with Mnd1,
which requires Hop2 for loading onto chromosomes
[32,34]. Tsubouchi and Roeder [30], based on results
from S. cerevisiae, recently proposed a model in which
Rad51 and Dmc1 perform the homology search by acting
in two parallel pathways. One of these pathways relies
solely on Rad51. In the second pathway, Rad51 is first
loaded on chromosomes and then recruits Dmc1, which
requires additional factors, including Hop2 and Mnd1, for
efficient homology recognition [26,30]. C. elegans and
Drosophila do not have Dmc1 and also lack Hop2 and
Mnd1, implying that the entire Dmc1-based pathway has
been lost in these species and suggesting that they must
rely on a different mechanism to perform the homology
search. These mechanisms are unlikely to involve
recombination proteins as chromosome pairing in
C. elegans and Drosophila precedes recombination.
Zierhut et al. [35] proposed an alternative model of
Mnd1­Hop2 function in which these two proteins primar-
ily act on chromatin structure rather than directly at the
strand invasion site. These authors discovered that a
prophase arrest in yeast Mnd1 knockouts can be
alleviated by deleting Red1 and Hop1, which both encode
components of the chromosome axis [35]. They also
observed that Mnd1 does not localize directly to the sites
of DSBs. Consequently, they suggested that Hop2­Mnd1
might act globally, for example, by making chromatin
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more accessible to proteins involved in chromosome
pairing and recombination.
Recently, another RecA homolog in addition to Rad51
and Dmc1, Rad51C, has been shown in Arabidopsis to act
in chromosome pairing, in addition to its role in meiotic
recombination [36]. Rad51C is closely related to Rad51
but, interestingly, its function in chromosome pairing is
not identical with the function of Rad51. A Rad51C
homolog also has been shown to play a role in Drosophila
female meiosis, although it is unknown whether it is
involved also in pairing [37].
Other recombination proteins
Other recombination enzymes might also be involved in
pairing of homologs, but the nature of these interactions is
not fully understood. For example, in S. cerevisiae,
mre11S, a mutation in the Mre11 protein involved in
DNA strand resection, results in a significant frequency of
non-homologous chromosome synapsis [38].
In contrast to genes regulating early recombination
steps, mutations in genes encoding recombination pro-
teins involved in the formation of crossovers, such as msh4
or msh5, do not affect chromosome pairing [3,4]. This
observation suggests that the commitment to pairing is
already made at the time when crossovers are formed or
that pairing depends mostly on the non-crossover
pathway.
Interaction between synapsis and recombination
The relationship between synapsis and meiotic recombi-
nation varies among species. In species that require
recombination for pairing, such as S. cerevisiae, Sordaria,
Coprinus, mouse and Arabidopsis, synapsis, which nor-
mally follows pairing, also requires DSB formation and
TRENDS in Cell Biology
Premeiotic
interphase
Diplotene DiakinesisPachytene
DSB formation
Most DSBs repaired
into non-crossovers;
pairing; synapsisDSB repair
SC disappears
MeiosisITwo homologous
chromosomes
Axial elements (AE)
Synaptonemal complex (SC)
Anaphase I
Metaphase II TetradsProphase II Anaphase II Telophase II
MeiosisII
DyadsMetaphase I
Early nodules
Late nodules
Prophase I
Prophase I
ZygoteneLeptotene
Crossover
formation
Telophase I
Figure 1. Diagram showing the stages and main events in meiosis. Only one pair of chromosomes is shown, and each homolog is depicted in a different color. Early and late
recombination nodules are depicted as dots of different size. The two upper panels show the extended meiotic prophase I. Major events during prophase I are depicted,
including DNA double-strand break (DSB) formation and repair, crossover formation, homologous chromosome pairing and synapsis. Interactions between homologous
chromosomes during prophase I lead to formation of homolog pairs (bivalents) and reciprocal exchanges of chromatid arms, as a result of crossing-over. Homologous
chromosomes segregate in anaphase I. During the second division of meiosis (meiosis II), the chromatids segregate, much like during a normal mitotic division.
Review TRENDS in Cell Biology Vol.15 No.12 December 2005676
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progression through early stages of the recombination
pathway [2,5,6,20,22,23,38­45]. The situation is obviously
different in C. elegans and Drosophila, in which the
chromosomes pair and synapse in the absence of DSBs
[10,11]. However, even in the latter two species, synapsis
and recombination are not completely independent. For
instance, proper assembly of the SC is required in
C. elegans and Drosophila for the completion of recombi-
nation [46,47].
Temporal coordination
The link between synapsis and recombination is not well
understood mechanistically, but most likely lies in the
process of the initiation of synapsis. In S. cerevisiae,
synapsis initiates at distinct sites along each chromosome
pair. By contrast, in many plants, synapsis starts
primarily at telomeres [48]. Initiation of synapsis is linked
to the presence of recombination nodules, which are
cytological structures detectable by transmission electron
microscopy and implicated in recombination processes
[49,50]. Two types of recombination nodules have been
observed: early and late nodules. Both types are known to
contain recombination enzymes (Figure 2). Early nodules
are more numerous, contain Rad51 and Dmc1, and are
thought to be the sites of initial single-strand invasions
[51]. Late nodules might form from a subset of early
nodules or might arise de novo later in meiosis [52]. They
are few in number, contain recombination enzymes such
as Mlh1 and Msh4 instead of Rad51 and Dmc1, and mark
the sites of crossovers [52­54]. Several lines of evidence
suggest that late recombination nodules also mark the
sites of SC initiation [53,55]. In plants, late nodules are
located primarily near telomeres, where synapsis is
initiated [48]. In yeast, the Zip3 protein is the key
component of SC initiation sites. It promotes synapsis by
recruiting other SC proteins, such as Zip1 and Zip2 [53].
Zip3 interacts with Msh4 and Msh5, which localize to late
recombination nodules. Interestingly, Zip3 also interacts
with Rad51, which is a component of early nodules [53].
This and other evidence suggests that Zip3 might define
the fraction of early nodules that subsequently become
late nodules ­ that is, sites that correspond to early
Box 1. Key recombination proteins
Spo11: a meiosis-specific recombination protein belonging to the
topoisomerase family and responsible for creating DNA double-
strand breaks (DSBs) in chromosomal DNA in meiotic prophase I.
Rad50 and Mre11: recombination proteins that form a complex
acting downstream of Spo11 in the meiotic recombination pathway.
Involved in 50
to 30
resection of the meiotic DSBs generated by
Spo11.
Rad51 and Dmc1: RecA homologs involved in repair of meiotic DSBs.
Rad51 and Dmc1 act downstream from Rad50­Mre11 and Spo11.
The proteins cover single-stranded DNA ends created by the Rad50­
Mre11 complex, forming a nucleoprotein filament. The nucleopro-
tein filament invades the corresponding region in the homologous
double helix in a process called single-strand invasion. Rad51 and
Dmc1 form foci on meiotic chromosomes at the sites of meiotic
DSBs (see Figure 2) and are components of early recombination
nodules. Rad51 is also involved in the repair of somatic DNA breaks.
Dmc1 is specific to meiosis.
Hop2 and Mnd1: recombination proteins interacting with Rad51 and
Dmc1. Hop2 and Mnd1 are required for homologous chromosome
pairing (the hop2 mutant in yeast shows a high frequency of
associations between non-homologous chromosomes) and meiotic
recombination. They most likely act during the single-strand
invasion step of recombination on the DNA donor strand, which
does not contain DSBs.
(a)
(c) (d)
(e) (f)
(b)
Figure 2. Recombination in the context of the synaptonemal complex (SC) and the
chromosomes. (a,b) SC spreads of tomato showing recombination nodules. Stained
are the lateral elements of the SC. (a). Early nodules in zygotene. Arrows indicate
several nodules. (b) A late nodule in pachytene indicated by an arrow. Bar, 5 mm.
Images courtesy of L. Anderson and S. Stack, Colorado State University, USA. (c­f)
Meiotic chromosomes of maize with foci of the Rad51 recombination protein, a
component of early recombination nodules. (c) Leptotene. (d) Zygotene. (e) Early
pachytene. (f) Late pachytene. Rad51 foci appear on maize chromosomes in early
zygoteneandtheirnumberreachesapeakofw500focipernucleus in midzygotene. In
late pachytene, the number of Rad51 foci drops to w20 per nucleus, roughly
corresponding to the average numberof crossoversin maize. DAPI-stained chromatin
is shown in red; Rad51 is shown in green. Images are flat projections from several
consecutive optical sections through three-dimensional nuclei. Bars, 5 mm.
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recombination events destined to become crossovers
[48,53,55,56]. Not surprisingly, increasing the number of
crossovers in yeast leads to a higher number of SC
initiation sites [56] and decreasing the number of
crossovers leads to a lower number of SC initiation sites
[55]. These observations suggest a role for the recombi-
nation pathway leading to crossovers in the initiation of
synapsis.
In species that require the initiation of recombination
for synapsis, the timing of synapsis is also tightly linked to
the progression of meiotic recombination. In mutants that
exhibit stalled or delayed DSB repair (and non-homolo-
gous chromosome associations in place of homologous
pairing), such as hop2 in yeast [33] and phs1 in maize [8],
completion of synapsis is delayed. Conversely, in the sgs1
mutant in S. cerevisiae, which shows increased rates of
crossing-over, the completion of synapsis is accelerated in
comparison with that of wild-type cells [56].
Spatial coordination
A key feature of meiotic recombination, as compared with
somatic recombination, is that DSB repair preferentially
uses homologous chromosomes rather than sister chro-
matids as templates. While crossovers between sister
chromatids are not completely inhibited, in S. cerevisiae
they are w10-fold less frequent than recombination
between homologous chromosomes [57]. This phenomenon
is crucial for the formation of chiasmata, which are
cytological representations of crossovers, necessary to
hold homologous chromosomes together as bivalents in
later stages of meiotic prophase I following disassembly of
the SCs. Generating the recombination bias towards the
homologous chromosome appears to be one of the
functions of the lateral element of the SC.
Three axial and lateral element proteins in
S. cerevisiae, Hop1, Red1 and Mek1, have been proposed
to interact with recombination proteins to ensure that
crossovers occur between homologous chromosomes
rather than sister chromatids [58]. Red1 and Hop1 are
required for activation of Mek1. Mek1, in turn, acts to
prevent the use of sister chromatids for DSB repair and
enables the Dmc1-mediated DSB repair, which employs
the homologous chromosome as a template [58­60].
Recently, proteins with similar functions have also been
identified in Drosophila and C. elegans, suggesting that
these species might have analogous mechanisms to ensure
the homologous chromosome recombination bias, even
though they lack Dmc1. In Drosophila, the ORD protein,
which has been proposed to act in meiotic sister-chromatid
cohesion and SC formation, was found to be involved in
maintaining the homolog bias by stimulating inter-
homolog crossovers [61]. In C. elegans, a similar role is
played by Him-3 [62]. Him-3, an axial/lateral element
component, also appears to be involved in the spatial
reorganization of chromosomes in the nucleus during
early meiotic prophase I and in the initial alignment of
homologous chromosomes [62]. This suggests that the
homolog bias might be achieved through spatial con-
straints that make homologous chromosomes more acces-
sible than sister chromatids for reciprocal interactions.
These specific spatial constraints might, for example,
result from local destabilization of the chromosome axis
after the introduction of DSBs [63].
Crossover interference
The crossover pathway eventually leads to the formation
of chiasmata, which are essential for proper segregation of
chromosomes at anaphase I. Not surprisingly, the number
of crossovers per chromosome is tightly regulated. Most
eukaryotes, regardless of their genome size or chromo-
some length, form only one crossover per chromosome or
chromosome arm, and the presence of a crossover
discourages additional crossovers in its vicinity. This
phenomenon is known as crossover interference. The
mechanism of crossover interference is not completely
understood. However, it appears that interference might
be yet another manifestation of coordination between
meiotic recombination and synapsis. It is not our intention
to discuss the mechanisms of interference in this review.
We will instead focus on the aspects of chromosome
interference that might involve coordination between
meiotic processes.
Crossover interference has long been linked to the
presence of SCs [64,65]. However, recent results suggest
that interference precedes synapsis. Fung et al. [66]
studied the Zip2-containing SC initiation sites (that may
be marked by late recombination nodules, see the
`Temporal coordination' section) in yeast and found that
they already exhibit an uneven distribution and inter-
ference, even though they precede synapsis. Studies of
recombination intermediates also suggest that, at least in
yeast, synapsis requires interference, and not the other
way around [18]. Results of theoretical predictions of the
mechanical properties of chromosomes and empirical
observations of meiotic protein distribution in different
chromatin domains along chromosomes indicate that
internal physical forces play a major role in chromosome
function [67,68]. These analyses also suggest that the
internal mechanical forces might be responsible for
creating crossover interference. This conclusion, based
mostly on studies in S. cerevisiae, is also supported by
results of a study of chromosome fusions in C. elegans by
Hillers and Villeneuve [69]. C. elegans normally has only
one crossover per chromosome. The fusion products
consist of two or three whole chromosomes. Yet, they
behave as single chromosomes and mostly exhibit a single
crossover per bivalent. Analyses of different types of
chromosome fusions suggested that crossover interference
in C. elegans relies on the presence of a continuous
chromosome axis [69].
Synapsis and pairing
Both chromosome pairing and synapsis involve intimate
associations between chromosomes. However, they are
two very different processes. Pairing is an interaction
between homologous chromosomes, which is based on
homology recognition. Synapsis is a process of cementing
an association of two chromosomes by installation of the
SCs. In normal meiosis, synapsis follows pairing and binds
homologous chromosomes together. However, in mutants
and other abnormal situations, such as meiosis in haploid
cells, synapsis can be uncoupled from pairing. Extensive
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synapsis has been documented in haploid yeast and
plants, which obviously lack homologous chromosome
pairs [70,71]. Specific proteins, whose absence results in
a high frequency of non-homologous synapsis, have also
been identified. In hop2 knockouts in yeast, w60% of all
synapsis is between non-homologous chromosome seg-
ments [33]. In maize, a mutant in the phs1 gene has an
even more extreme phenotype, showing w95% non-
homologous synapsis [8]. Hop2 and PHS1 are not SC
components but both appear to play a role in linking
chromosome pairing and recombination. Hop2 homologs
so far have been found in mouse [28], plants [29] and in
Schizosaccharomyces pombe [72], which lacks SCs, and
have been found to perform similar functions in these
species. In hop2 and phs1 mutants, synapsis is delayed.
This suggests that synapsis might be based only on
proximity, while sequence homology between the synap-
sing partners is irrelevant. As a result, synapsis might
stabilize any type of intimate chromosome association if
homologous pairing is not established in time, as is the
case in the hop2 and phs1 mutants. It is likely that there
are mechanisms in normal meiosis that prevent pre-
mature synapsis of any closely positioned chromosome
fragments. However, Hop2 and PHS1 are probably not
elements of such mechanisms as, if they were, one would
expect to see earlier rather than delayed synapsis in the
hop2 and phs1 mutants. Contrary to the data suggesting
independence of synapsis from homologous pairing, a
study by Crackower et al. [73] described synapsis between
nonhomologous chromosome segments that was caused by
a mutation in the SC protein Fkbp6 in the mouse. This
indicates that perhaps some aspects of synapsis might still
depend on homology.
In yeast, independence of pairing from synapsis is also
evident from the fact that chromosomes pair in the
absence of Zip1, a component of the central region of SCs
[4,64]. By contrast, in C. elegans, synapsis-dependent
mechanisms do contribute to chromosome pairing, and the
central SC element is required to stabilize pairing along
the entire lengths of chromosomes [74]. This observation
might be another indication that the chromosome pairing
mechanisms operating in C. elegans are different from the
ones in yeast.
Concluding remarks
Chromosome interactions during meiotic prophase I occur
in the form of pairing, synapsis and recombination. These
three processes are not separate from each other but show
tight coordination. An extensive amount of data suggests
that meiotic recombination is linked to chromosome
pairing and to synapsis. Improving understanding of
these interactions is of major importance as they lie at
the heart of several poorly understood aspects of meiosis,
such as the mechanisms of homologous chromosome
recognition and crossover interference.
Several meiotic recombination proteins have been
postulated to affect chromosome pairing. However, in
most cases, understanding of this interaction at the
mechanistic level is lacking. It is not entirely clear
whether the link between recombination and pairing is
mediated by dual-function proteins (i.e. proteins that act
in both pairing and recombination), as has been proposed
for Spo11, or through the recombination pathway DNA
intermediates that act in the chromosome homology
search, or both. The best genetic and biochemical evidence
exists so far for the case of the involvement of Rad51,
Dmc1 and proteins that interact with them, such as Hop2
and Mnd2, in chromosome pairing.
It is still unknown to what extent recombination affects
homologous chromosome pairing. It is conceivable that
other mechanisms, in addition to the recombination-
dependent homology search, are necessary for efficient
pairing, especially in species with large and complex
genomes that contain large fractions of repetitive DNA.
However, regardless of how this question is resolved, the
current data point to the existence of a continuous
coordination between the progression of meiotic recombi-
nation and the progression of chromosome pairing.
Similarly to recombination and pairing, a strong link
exists between recombination and synapsis/the synapto-
nemal complex. Recombination nodules, the sites of
meiotic recombination, are likely involved in the initiation
of synapsis, while the lateral elements are involved in
generating the recombination bias towards the sister
chromatid. Crossover interference, a phenomenon that
limits the number of crossovers per chromosome, links
recombination with synapsis and the chromosome axis.
Nevertheless, synapsis is largely independent from
pairing and sometimes proceeds regardless of whether
proper pairing is established.
The observations of strong links between recombina-
tion and pairing, and between recombination and
synapsis, suggest that recombination plays a key role in
unifying meiotic processes. In yeast, plants and mammals,
meiotic recombination starts in early leptotene [8,75,76]
and proceeds during most of the meiotic prophase I
through a series of distinct steps. Coordinating other
meiotic processes, such as pairing and synapsis, to the
progression of recombination might be a way to accurately
time their initiation, progression and completion. Under-
standing the intricate interactions between meiotic
processes will certainly be one of the hallmarks of meiosis
research in the next few years.
Acknowledgements
We thank Lorrie Anderson, Lisa Harper, Olivier Hamant, and Teresa
Pawlowska for helpful comments on this manuscript.
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