Download Genetics of mammalian meiosis: regulation, dynamics and impact

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Genetics of mammalian meiosis:
regulation, dynamics and impact
on fertility
Mary Ann Handel* and John C. Schimenti‡
Abstract | Meiosis is an essential stage in gamete formation in all sexually reproducing
organisms. Studies of mutations in model organisms and of human haplotype patterns are
leading to a clearer understanding of how meiosis has adapted from yeast to humans, the
genes that control the dynamics of chromosomes during meiosis, and how meiosis is tied to
gametic success. Genetic disruptions and meiotic errors have important roles in infertility
and the aetiology of developmental defects, especially aneuploidy. An understanding of the
regulation of meiosis, coupled with advances in genomics, may ultimately allow us to
diagnose the causes of meiosis-based infertilities, more wisely apply assisted reproductive
technologies, and derive functional germ cells.
Disjunction
The separation of
chromosomes or chromatids
during anaphase of mitosis
or meiosis. The failure of
chromosomes to separate
at anaphase is called
non-disjunction.
Aneuploidy
The presence of an abnormal
number of chromosomes,
either more or less than the
diploid number. It is associated
with cell and organismal
inviability, birth defects
and cancer.
*The Jackson Laboratory,
600 Main Street, Bar Harbor,
Maine 04609, USA.
‡
Cornell University, College of
Veterinary Medicine, Ithaca,
New York 14853, USA.
e-mails: maryann.handel@
jax.org; [email protected]
doi:10.1038/nrg2723
Published online
6 January 2010
Meiotic recombination generates diversity within a
population but, equally importantly, it creates the con­
nections between homologous chromosomes — chias­
mata — that hold them in opposition on the meiotic
spindle and ensure their accurate segregation. Correct
execution of meiosis is essential for fertility, for main­
taining the integrity of the genome and for ensuring
the normal development of offspring. In most organ­
isms, crossover (CO) recombination in meiosis is
required to ensure accurate segregation of homologous
chromosomes at the first meiotic division. The absence
of crossing over can result in random disjunction and
aneuploidy, which leads to embryonic death or develop­
mental abnormalities. Indeed, gametic aneuploidy is a
major cause of birth defects in humans1. Most gametic
aneuploidy originates during oogenesis, particularly
during the first meiotic division, and the frequency of
such errors increases with female age. Therefore, aside
from the fundamental importance of meiosis to the
eukaryotic life cycle and the evolution of diversity,
the process of meiosis is of paramount relevance to
successful human reproduction.
Our understanding of the genetic control of meiosis
and meiotic recombination in mammals has depended
heavily on studies of tractable model organisms, such as
yeast, as well as directed approaches in mice. Although
there are clear differences among organisms 2, the
most salient features of meiosis are conserved. Indeed,
many of the fundamental genes and proteins that are
involved in conserved structures and processes related
to recombination and chromosome behaviour have rec­
ognizable orthologues from fungi to mammals. Mouse
models with null mutations in many of the orthologous
yeast genes have been generated. Often (but not always)
they have phenotypes that are similar to yeast. However,
it is also clear that many meiotic proteins show little
sequence conservation and that mammals have many
genes required for meiosis that do not have orthologues
in yeast, and vice versa. Because most of the genetic ‘low­
hanging fruit’ — that is, the mammalian orthologues of
meiosis genes from other organisms — have already
been ‘picked’ through the generation of mouse mutants,
the challenge now becomes one of identifying the other
genes that are required for mammalian meiosis and that
potentially affect human fertility. Methods such as tran­
scriptional profiling have helped to identify genes for
targeted mutagenesis. Alternatively, unbiased mutagen­
esis and phenotype screening for infertility have led to
the discovery of novel and/or previously unsuspected
meiotic genes3–5. These genetic approaches and other
increasingly powerful genomic technologies are likely
to result in new discoveries in the genetics of human and
mammalian meiosis.
Here, after a brief overview of meiotic events, we focus
on the essential features of meiosis. For each of the most
important steps in meiosis we consider what is known
about genetic regulation in mammals and how this com­
pares to yeast, in addition to the implications of meiotic
errors and mutations for human fertility. We consider
how understanding the regulation of meiosis can affect
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S phase
Prophase I
Metaphase I
Two chromatids
Two chromatids
Anaphase I
Chiasma
Haploid
gametes
Telophase I
Anaphase II
Metaphase II
(Ovulation)
Fertilization
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Figure 1 | Mammalian meiosis and gametogenesis. The beige cells in the central portion of the
figure
depict
the
events of meiosis. Spermatocytes and oocytes differ markedly in their development. The distinctions are highlighted
at key stages by diagrams of the male (blue) and female (pink) germ cells in brackets outside the central diagram.
Meiosis is preceded by DNA replication in a pre-meiotic S phase that is frequently longer than the usual mitotic S
phase. It results in cells with 4C DNA content. S phase is followed by the long meiosis I prophase, during which
homologous chromosomes pair and undergo recombination in a series of events that define the substages of meiosis I
prophase (FIGS 2,3). These events are accompanied by synapsis of the chromosomes in a specialized meiotic structure,
the synaptonemal complex (SC, shown in green in the prophase I gonocyte). At metaphase of the first meiotic division
(metaphase I), chiasmata (one chiasma is shown) maintain homologous chromosomes in a bipolar orientation. The
first, reductional meiotic division separates the homologues (anaphase I and telophase I). The result is two cells (or, in
females, one cell with a polar body, shown as a small yellow sphere). These are the secondary gametocytes: each has
haploid chromosome content, but each chromosome is still comprised of two chromatids. The second meiotic division
is an equational one: in male germ cells the chromatids are separated to form immature spermatids, each of which
contains the haploid 1N chromosome number and 1C DNA content; in female germ cells the second meiotic division
occurs after fertilization, so that the fertilized egg contains two haploid pronuclei, one paternal (blue) and the other
maternal (pink), as well as three polar bodies.
Chromatid
An identical copy of a
chromosome that is created
through DNA replication. The
two sister chromatids of a
chromosome each become
a chromosome when their
centromeres are separated in
mitosis or in the second
meiotic division.
recent applications of assisted reproductive technologies
(ArTs) and efforts to derive gametes in vitro. Although
neither the frequency of meiotic mutations nor the rate
of infertility due to such mutations in the human popula­
tion is known, the incidence of human aneuploidy due
to meiotic error is quite high — approximately 5% of all
conceptuses exhibit monosomy or trisomy 1. Therefore,
we draw attention to particular features of mammalian
meiosis, including sexual dimorphism, and how these
affect human fertility and the well­being of offspring.
Meiosis and gametogenesis: an overview
Meiosis, which is intimately tied to gametogenesis in
higher eukaryotes, is characterized by an extended
prophase, followed by two divisions that produce gam­
etes (FIG. 1). The pre­meiotic DNA replication generates
primary gametocytes in which each chromosome is com­
prised of two chromatids (4C DNA content). In females,
the entire oogonial population initiates meiosis synchro­
nously in fetal ovaries. Meiotic prophase is arrested before
birth and resumed in small subsets of the oocyte popula­
tion at periodic intervals after puberty. By contrast, male
mammals are born with a population of spermatogonial
stem cells; meiosis is initiated in maturing cohorts of
spermatogonia, resulting in the continuous production
of sperm throughout the reproductive lifespan.
During the meiosis I prophase, homologous chro­
mosomes pair and synapse, a process that is mediated
by a unique meiotic scaffold, the synaptonemal complex
(SC). The substages of meiosis I prophase are defined
by chromosome configurations and structure: pairing,
which occurs during the leptotene and zygotene stages;
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Synapsis
The intimate apposition
that occurs after pairing of
homologous chromosomes
along their length during
prophase I of meiosis;
synapsis is mediated by a
proteinaceous structure, the
synaptonemal complex.
Double-strand break
A serious form of DNA
damage that is created
enzymatically during
meiosis and that stimulates
repair by crossover or
non-crossover recombination.
Induced pluripotent stem
cells
These are derived from
somatic cells by
‘reprogramming’ or
de-differentiation triggered
by the transfection of
pluripotency genes, which
alters the somatic cells to
a state that is similar to that
of embryonic stem cells.
synapsis, which is completed at the onset of the pachytene
stage; and desynapsis, which occurs during the diplotene
stage (FIG. 2). This intricate chromosomal choreography
accompanies the events of recombination, which is
initiated by DNA double-strand breaks (DSBs); during
recombination, these breaks are repaired by either CO
or non­CO (NCO) processes (see below). Patterns of
recombination in meiotic prophase differ between sexes
(see below). The first meiotic division is reductional
and separates homologous chromosomes, producing
secondary gametocytes (FIG. 1). This division is sexually
dimorphic: in males it results in two secondary sperma­
tocytes and in females it results in one secondary oocyte
and a polar body. The second meiotic division — an
equational division that separates sister chromatids —
is also sexually dimorphic, both in its timing and in the
products formed. In males it occurs immediately after
the first division and produces four haploid sperma­
tids. In females, the timing of the second meiotic divi­
sion is coordinated with ovulation and fertilization, and
Leptonema
SPO11
DMC1
RAD51
γH2AX
yields a haploid oocyte and another polar body. In both
cases, the products are gamete cells with the haploid 1N
chromosome number and 1C DNA content.
The fact that meiosis is always a sub­program of
gametogenesis in higher eukaryotes (FIG. 1) raises several
important considerations. First, mammalian germ cells
are surrounded by specialized somatic cells (Sertoli cells in
males and granulosa cells in females) that influence
their homeostasis and meiotic status. For these reasons,
it has not yet been possible to successfully sustain ini­
tiation and continuous execution of all steps of meiosis
in vitro. This is relevant to attempts to derive germ cells
from embryonic stem cells or induced pluripotent stem
cells (iPS cells). The key features of meiosis (FIGS 1,2) are
the essential hallmarks that must be met for a convinc­
ing demonstration of meiosis in vitro and in mamma­
lian germ cells derived from precursor stem cells. Our
inability to promote all of the meiotic stages of male
germ cells in vitro is also important to consider in the
context of ArTs that involve the injection of immature
Pachynema
Sister
chromatids
MLH1
MLH3
Zygonema
Diplonema
Centromere
Cohesins
Central
zone
γH2AX
DMC1
RAD51
SYCP1
SYCP2
SYCP3
Chiasma
AE
Figure 2 | Meiotic chromatin substages. The substages of meiosis I prophase in mammals; similar substages occur in
yeast and many other organisms (here mammalian protein symbols are indicated). During leptonema,
homologous
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chromosomes begin to align but are not yet paired. A chromosomal scaffold begins to form through the assembly of
axial elements (AEs) from cohesin proteins (for example, REC8 and structural maintenance of chromosomes 1B
(SMC1B)) and synaptonemal complex (SC)-specific proteins, such as SYCP3 and SYCP2. The chromatids experience
genetically programmed double-strand DNA breaks (induced by SPO11), which provide the substrate for
recombination (the two chromatids of the upper homologue are depicted by a turquoise line, and the two chromatids
of the lower homologue are depicted by a gold line). The breaks are recognized by homologous recombination repair
machinery (including phosphorylation of H2AX to form γH2AX by ataxia telangiectasia mutated (ATM)) and resected,
which triggers binding by the recombinase A (RECA)-related proteins DMC1 and RAD51, among other proteins, which
colocalize to electron-dense structures called recombination nodules (RNs) along the developing AEs. By zygonema, it
is obvious that homologous chromosomes have found each other; pairing extends and synapsis is initiated, forming the
SC, and the AEs begin to ‘zip’. Through this process the AEs become the lateral elements (LEs) of the SC. Pachynema is
defined by completion of synapsis, at which point the central zone of the SC is apparent; it is comprised of proteins
such as SYCP1, synaptonemal complex central element protein 1 (SYCE1) and SYCE2. The pachytene stage is lengthy
and includes maturation of a subset of meiotic recombination sites (<10%) into crossovers marked by the mismatch
repair proteins MutL protein homologue 1 (MLH1) and MLH3, which also colocalize to RNs. After recombination is
completed, chromosomes undergo desynapsis and condense in the final diplotene substage. At this stage, the
homologues are held together by the recombination sites (crossovers), which are seen in cytological preparations as
chiasmata. Figure is modified, with permission, from REF. 127  (2005) Society for Reproduction and Fertility.
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male germ cells into oocytes; research shows that some
events of meiosis may not be properly recapitulated
outside the testis6.
Initiation and regulation of the meiotic program
Yeast. Control over entry into meiosis is best under­
stood in Saccharomyces cerevisiae, in which genetic and
molecular studies have led to a relatively comprehen­
sive understanding of the transcriptional regulation of
genes involved in meiosis 7. The ‘master regulator’
of yeast meiosis is meiosis­inducing protein 1 (Ime1),
which, by interacting with the DNA­binding protein
ume6, activates transcription of ‘early’ meiosis genes.
Ime1 expression is affected by nutritional signals and is
dependent upon respiration8,9. The early genes, which
encode proteins that are required for pre­meiotic DNA
synthesis and subsequent meiosis­specific chromosomal
events, such as recombination and synapsis, enable entry
into the meiotic cell cycle. Among the genes activated in
this first wave are NDT80 (which encodes a transcrip­
tion factor) and IME2 (which encodes a kinase that acti­
vates Ndt80). These in turn stimulate the transcription
of ‘middle’ genes that are required for meiocyte divisions
and spore formation, followed by ‘late’ genes that are
involved in spore maturation. The application of gene
expression profiling technology to meiotically synchro­
nized budding 10 and fission11 yeast cultures aided in the
characterization of transcriptional regulatory cascades.
Cohesins
Multi-protein complexes that
maintain tight association
(cohesion) of sister chromatids.
Resection
In the context of
recombination, strand-biased
enzymatic removal of
nucleotides at the site of a
double-strand break. In most
recombination models,
resection occurs in the 5′ to
3′ direction.
Mammals. In mammals, meiotic entry requires exit
from a mitotic program — for example, the mitotic
population of oogonia or spermatogonial stem cells
and differentiated spermatogonia. Meiotic prophase is
marked by a prolonged pre­meiotic S phase. Mammals
have no clear orthologues of the key meiotic transcrip­
tional regulatory genes NDT80 and IME2. A germ­
cell­specific gene encoding a protein with sequence
similarity to Ime2, male­germ­cell­associated kinase
(Mak), is not essential for fertility in mice12. Several
studies have characterized the transcriptome during
male meiosis in mice13,14, but regulators of the mam­
malian meiotic program remain largely unidentified.
A major advance was the discovery that the onset of
meiosis in mice is regulated by retinoic acid (rA) and
mediated by the product of stimulated by retinoic acid 8
(Stra8), which is conserved throughout amniotes15–17.
The effect of rA on Stra8 induction and initiation of
meiosis is sexually dimorphic in timing. In fetal ova­
ries, rA emanating from the mesonephroi induces
Stra8 expression and causes germ cells to enter meiosis,
which can be detected by waves of expression of meiotic
markers, such as disrupted meiotic cDNA 1 homologue
(Dmc1) and synaptonemal complex protein 3 (Sycp3)
(see below). In fetal testes, which are also exposed to rA
from the mesonephroi, Stra8 expression is not induced
because a retinoid­degrading enzyme, CyP26B1 (a
member of the cytochrome P450 family), is expressed
in Sertoli cells (but not in fetal ovaries). Consequently,
male germ cells do not enter meiosis at this time; the
entry of germ cells into meiosis in the adult testis
may be controlled, at least in part, by stage­specific
expression of CyP26B1. The role of STrA8 and rA in
regulating meiotic initiation in both spermatogenesis
and oogenesis was confirmed by genetic analysis18. The
regulation of meiotic initiation by rA could involve
germ­cell­intrinsic factors, such as the rNA­binding
protein deleted in azoospermia­like (DAZl), which
may act upstream of Stra8 in the pathway of meiotic
induction19. The lack of obvious mechanistic conserva­
tion between yeast and mice in regulating meiotic entry
sets a challenge for future gene and pathway discovery.
It is currently unclear whether meiotic entry failure
underlies any cases of human infertility.
Recombination: the crux of meiosis
Crossing over is crucial for the proper segregation of
homologous chromosomes at the first meiotic division
of most organisms. The chiasmata formed by CO events,
minimally one per chromosome in humans20, physically
tether chromosome homologues to keep them attached
during the end of prophase, when inter­homologue
cohesins are removed. Failure of a chromosome pair to
undergo at least one CO can result in both homologues
segregating to the same daughter cell at the reductional
division, leading to aneuploidy.
Meiotic recombination involves several steps (FIG. 3),
including formation of DSBs, exonucleolytic resection of
5′ ends at the breaks and strand invasion into a chroma­
tid of the homologous chromosome. After this point,
there is a divergence in subsequent steps between two
major, distinct pathways — CO and NCO recombina­
tion (also known as the ‘modified Szostak model of
double­strand break repair’ and the ‘synthesis­dependent
strand annealing’ pathways, respectively 21). The molec­
ular components of the steps after DSB formation
— such as the recombinase A (recA) homologues
DMC1 and rAD51, which are involved in homolo­
gous recombination repair (Hrr) of DSBs — comprise
the most conserved group of meiotic recombination
proteins. This is consistent with Hrr being essential
in mitosis as well as meiosis; in mitosis it is a crucial
pathway for DNA damage repair in all organisms.
Recombination initiation. Initiation of recombination
by the genetically programmed formation of DSBs is
an essential event that leads to both recombination and
synapsis in mammals and yeast (FIG. 3). In S. cerevisiae,
DSB formation occurs after pre­meiotic DNA replica­
tion and is catalysed by the SPO11 transesterase and at
least nine other proteins22,23 (FIG. 3). Whereas SPO11 is
highly conserved and is also required for meiotic DSB
induction in mice24–26 (FIG. 4), only two of the other pro­
teins have defined mammalian homologues. These two
are rAD50 and Mre11, which are part of a mitotic DSB
repair complex, but no role has been found for them in
meiotic DSB formation in mammals. It is likely that, as
in yeast, several more mammalian proteins exist that
are required for recombination initiation and the early
steps of DSB processing. More sensitive methods for
functional orthologue detection might identify these.
Indeed, mouse orthologues of Mei4 and rec114 have
recently been identified (r. Kumar, H. M. Bourbon and
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DSB formation
SPO11, MEI1, RAD50?
(Locations influenced by:
H3K4Me3, RNF212, DSBC1/RCR1)
5′ end resection
3′ end invasion
D-loop formation
DMC1, RAD51, MSH4,
MSH5, HORMADs?
dHJ formation
Branch migration
SDSA
MLH1, MLH3, EXO1
dHJ resolution
Reannealing
Mismatch repair
Crossovers
Chiasmata
Non-crossover
Gene conversion
Figure 3 | Overview of major meiotic recombination pathways. The horizontal red and blue lines
represent
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DNA strands. At the top, two homologous unpaired acrocentric chromosomes (which have centromeres at one end, as is
the case in mice) are depicted. The remainder of the figure (except for the recombinant chromosomes on the bottom left)
focuses on a small region (indicated by yellow boxes) of two homologous sister chromatids. Recombination is initiated by
double-strand breaks (DSBs), and subsequent steps of recombination are thought to help establish inter-homologue
interactions, including pairing, as indicated at the strand invasion step. Proteins that are known or thought (‘?’) to
contribute to the various indicated steps are named on the left in bold. The two major recombination pathways are
shown: on the left is the crossover (CO) pathway (the canonical Szostak model with double Holliday junctions (dHJs)),
which leads to CO products that are visualized at metaphase I as chiasmata, and on the right is the non-crossover (NCO)
pathway (also known as synthesis dependent strand annealing (SDSA)), which does not produce chiasmata but may
result in a phenomenon called gene conversion, which has the appearance of a double CO within a small interval. The
CO pathway is subject to the phenomenon of interference, but there is also evidence for a less prevalent, interferenceindependent pathway in mice, as has been observed in yeast128. Note that small regions of gene conversion can also
occur in association with COs (bottom left). Recombination regulator 1 (RCR1) and double strand break control 1
(DSBC1) are the putative products of loci (or a single locus) on chromosome 17 that have been shown to influence
recombination hotspot activity. EXO1, exonuclease 1; H3K4Me3, histone H3 lysine 4 trimethylation; HORMAD, HORMA
domain-containing; MLH, MutL protein homologue; MSH, MutS protein homologue; RNF212, RING finger protein 212.
B. de Massy, personal communication). Other yeast
recombination initiation proteins may not have ortho­
logues outside vertebrates. This underscores the need
for alternative discovery methods. One such method
is forward genetic mutation screening in mice, which
identified the only other mammalian gene known to be
required for DSB formation, Mei1 (which encodes a pro­
tein of unknown activity)27 (FIG. 4). Other clues to genes
involved in DSB formation are emerging from genetic
studies that are aimed at revealing how the locations of
crossing over are determined, as described below.
Distribution of recombination events. The distribution
of recombination events (both CO and NCO) through­
out the genome is not entirely random. rather, there
are preferential locations, called hot spots, and other
locations that rarely have recombination events, called
cold spots. evidence is accumulating that hot spots are
locations of more frequent DSB formation and that their
locations are influenced by chromatin structure28,29. In
yeast, in which genome size and other features make
the detection of Spo11­induced DSBs relatively sim­
ple, single DSB sites can be detected by Southern blot
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SYCP3
RAD51
SYCP3
γH2AX
SYCP3
MLH3
SYCP3
WT
γH2AX
Dmc1
Trip13
Ccnb1ip1
Genes
Causes
Mutant phenotype
Mutant
Spo11
Leptonema
Zygonema/pachynema
Pachynema
Pachynema/diplonema
• Asynapsis in zygonema
• Absence or diminished
γH2AX phosphorylation
• No RAD51 foci
• Extensive asynapsis
• Excessive RAD51 foci
and γH2AX
• No/abnormal XY body
in pachynema
• Minor asynapsis
• Persistent RAD51 foci
• γH2AX on autosomes
• No/abnormal XY body
• Abnormal chromosome
condensation or cohesion
• Premature separation
of homologues
• No chiasmata
• Metaphase I univalents
• Lagging anaphase
chromosomes
• Failure to initiate
recombination (no DSBs)
• Failure to signal presence
of or to process DSBs
• Failure to repair DSBs
• SC defects
• Cell cycle defects
• Minor DSB repair defect
• SC defects
• Cell cycle defects
• Cohesion defects
• Faulty meiotic sex
chromosome inactivation
• No crossing over
• Faulty kinetochore cohesion
• Cell cycle defects
• Mismatch repair defects
• Incomplete recombination
repair
• Mei1; Spo11
• Cdk2; Dmc1; Fkbp6;
Psmc3ip (Hop2); Msh4;
Msh5; Piwil2; Prdm9;
Rec8; Syce1; Syce2;
Sycp1; Sycp2; Sycp3
• Cpeb; H2afx; Smc1b;
Tex11; Trip13
• Ccna1; Ccnb1ip1 (Hei10);
Dmrtc2 (Dmrt7); Exo1;
Hspa2; Mlh1; Mlh3
Reviews
Figure 4 | Mouse meiotic mutant phenotypes. Numerous mouse meiotic mutants have been Nature
generated,
and| Genetics
their
underlying molecular defects can be deduced by probing surface-spread meiotic chromosomes with antibodies
that are diagnostic for double-strand break (DSB) repair, synapsis or other chromatin features. Coupled with
histopathological analysis, this provides a good assessment of processes that are disrupted. The figure gives
examples of mutations that act at different stages of meiotic prophase I, as characterized by immunolabelling of
surface-spread spermatocyte nuclei with the synaptonemal complex (SC) axial element synaptonemal complex
protein 3 (SYCP3; in red) and γH2AX (a marker of DSBs), RAD51 (a marker of sites at which DSB repair by
homologous recombination has begun) or MutL protein homologue 3 (MLH3; a marker of reciprocal
recombinations). In leptonema, DSBs are induced by SPO11, which leads to phosphorylation of histone H2AX (to
form γH2AX). γH2AX is absent in Spo11 mutants, but persists in some other mutants, such as thyroid hormone
receptor interactor 13 (Trip13). In zygonema, synapsis between homologues is ongoing as DSBs are repaired by
recombination. In the recombination-defective disrupted meiotic cDNA 1 homologue (Dmc1) mutant, there are
persistent RAD51 foci and failed synapsis, which prevents entry into pachynema. Chromosomes are fully synapsed in
pachynema and crossover sites contain MLH3; these sites are mostly absent in a cyclin B1 interacting protein 1
(Ccnb1ip1) mutant. Synapsed chromosomes separate prematurely in the mutant, which leads to activation of the
spindle checkpoint at metaphase I. Other meiotic mutants and phenotypes that are typically observed are listed
below these specific examples. The same analyses can be performed on germ cells from sterile human males who
display maturation arrest, thereby allowing one to form a list of candidate genes (based on the mouse mutant
phenotypes) that potentially underlie the phenotype. The images on the top row, second from right, and bottom row,
second from right are from REF. 59. The image on the top right is from REF. 116. Ccna1, cyclin A1; Cdk2, cyclin
dependent kinase 2; Dmrtc2, doublesex and mab-3 related transcription factor-like family C2; Exo1, exonuclease 1;
Fkbp6, FK506 binding protein 6; Hspa2, heat shock-related 70 kDa protein 2; Msh5, MutS protein homologue; Piwil2,
piwi-like 2; Prdm9, PR domain-containing 9; Psmc3ip, proteasome (prosome, macropain) 26S subunit, ATPase 3,
interacting protein; Smc1b, structural maintenance of chromosomes 1B; Syce, synaptonemal complex central
element; Sycp, synaptonemal complex protein; Tex11, testis-expressed sequence 11.
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Gene conversion
Originally coined to describe
non-Mendelian segregation of
alleles obtained from a single
meiosis, this typically (but
not always) refers to
a non-reciprocal form of
non-crossover recombination
that results in the alteration of
the sequence of a gene (or
DNA sequence) to that of its
homologue. In ectopic gene
conversion, the donor and
recipient DNA strands are not
allelic copies of the same locus.
Checkpoint
A mechanism that monitors the
fidelity of cellular events and
triggers cell cycle arrest
and possibly apoptosis when
errors are not corrected. In
meiosis, unrepaired DNA
damage and synapsis failure
trigger checkpoints that can
halt meiotic progression.
analysis. With microarray technology, high­resolution
mapping of all recombination events in single yeast mei­
osis is possible30,31. This is a powerful way to analyse the
effects of mutation or genetic variation on the distribu­
tion of DSBs. recently, Borde and colleagues32 found
that recombination initiation sites in yeast are marked
— before DSB formation — by histone H3 lysine 4
trimethylation (H3K4me3), which indicates that the
selection of hot spots has an epigenetic component. This
epigenetic mark of DSB sites is also a feature of mouse
hot spots33. Notably, H3K4me3 modification is a fea­
ture of transcriptional promoters, which have long been
recognized as sites of preferential DSB formation34.
Hot spot analysis in mammals presents far greater
technical difficulties, the two most serious of which are
the larger genome size and the inability to recover all
four products of meiosis. Nevertheless, it has been clear
for a long time that COs are unequally distributed and
that some hot spots in mice are strain dependent 35,36.
Although detection of hot spots and their timing is
more difficult than in yeast, single­molecule­based
PCr strategies have allowed high­resolution analy­
ses of recombination events37,38. One important ques­
tion regarding the selection of recombination sites in
hybrid strains is whether selection is driven by DNA
sequences or by key proteins, or by a combination of
the two. A subset of yeast hot spots have cis­acting
determinants, such as transcription factor­binding
sites near promoters. However, there are clearly trans­
acting loci in both yeast and humans that influence hot
spot site selection39,40. In mice, two remarkable genetic
studies revealed a trans­acting locus or loci on chro­
mosome 17 that affects strain­specific hot spots41,42.
Interestingly, this region contains the Pr domain­
containing 9 (Prdm9) H3K4 trimethyltransferase
‘speciation gene’, which is essential for both male and
female meiosis in mice43,44 (FIG. 4). H3K4me3 marks
yeast SPO11 break sites, as noted above. It is clear
from high­resolution haplotype analysis that the
bulk of recombination in humans occurs at hot spots,
although there is differential usage of particular hot
spots between the sexes45. An analysis of recombina­
tion patterns in human families has implicated rING
finger protein 212 (rNF212), a homologue of the yeast
SC protein Zip3, as a determinant of sex­specific,
genome­wide human recombination rates46. A separate
study also implicated this and other loci47. Therefore, in
addition to forward genetics, classical genetic studies
can be a powerful way of identifying genes that influence
recombination patterns.
Repair of double-strand breaks by recombination.
SPO11­induced DSBs trigger the meiotic equivalent
of a DNA­damage response, which involves sensing of
breaks, recruitment of Hrr proteins, and processing
of recombination intermediates (FIG. 3). This general
process is similar among organisms. Because DSB repair
is a fundamental process in both somatic and meiotic
cells and many of the proteins are highly conserved, we
have more knowledge about this step than any other in
meiosis. repair of a DSB by homologous recombination
is eventually resolved either by an NCO event (poten­
tially resulting in gene conversion) or by a reciprocal CO
event (which can also be associated with gene conver­
sion). Work in S. cerevisiae revealed that CO and NCO
pathways are distinct 48; they have different recombina­
tion intermediates and are dependent upon different
proteins21. Mice also seem to have independent CO and
NCO pathways38. The number of recombination events
per mouse meiosis can be estimated by the number of
immunocytologically detected ‘foci’ of the recA­related
rAD51/DMC1 proteins in leptonema49; these proteins
catalyse homologous strand invasion in recombina­
tion. Of the >200 events estimated per meiosis, the vast
majority are resolved as NCO events, compared with
~23 COs. This large amount of NCO recombination
contributes to homologous chromosome pairing, but
its contribution to haplotype structure is unclear.
A major gap in our knowledge relates to the regula­
tion of recombination partner choice in mammals. In
mitotic cells that have replicated their DNA (the S and
G2 stages), spontaneous or environmentally induced
DSBs are preferentially repaired using the identical
sister chromatid as a template, because proximity and
cohesion of sister chromatids predisposes to this out­
come. As the ‘purpose’ of meiotic DSBs is to stimulate
recombination between homologous chromosomes,
ultimately ensuring proper disjunction at the first mei­
otic division, mechanisms have evolved to prevent DSB
repair through sister chromatid recombination — the
so­called ‘barrier to sister chromatid repair’ (BSCr),
which has been well­studied in yeast 50,51. Whether or not
mammals have this bias has not been shown formally;
however, it must exist because without it homologues
would not be joined and aneuploidy would result. In
S. cerevisiae, the two key regulators of homologue bias
are the small SC axial element (Ae) phosphoproteins
red1 and Hop1. Potential mammalian orthologues
of Hop1 — known as HOrMA domain­containing 1
(HOrMAD1) and HOrMAD2 — also localize to chro­
mosome axes52,53. Obtaining functional evidence that a
particular protein is involved in recombination partner
bias presents a challenge; it will be difficult in mam­
mals to identify inter­sister recombination products
that would be characteristic of a mutation disrupting
the hypothetical BSCr.
Checkpoints and quality control in meiosis. Defects in
recombination can preclude homologous chromosome
pairing and leave unrepaired chromosome breaks. To
avoid such deleterious outcomes, surveillance systems
(‘checkpoints’) exist to sense meiotic errors and elimi­
nate meiocytes that contain unresolved defects. In many
organisms, including S. cerevisiae, Drosophila melanogaster and Caenorhabditis elegans 54–56, meiocytes
with defects in recombination and/or chromosome
synapsis trigger delay or arrest in the pachytene stage of
prophase I. This response to meiotic defects is referred
to as the ‘pachytene checkpoint’57. The pachytene check­
point monitors two aspects of meiotic chromosome
metabolism in S. cerevisiae and C. elegans: DSB repair
and chromosome synapsis55,58.
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Despite the extensive work in yeast, mammalian
meiotic checkpoint genes have yet to be identified
unequivocally. The mouse orthologues (ataxia
telangiectasia mutated (Atm) and thyroid hormone
receptor interactor 13 (Trip13)) of two yeast checkpoint
genes (TEL1 and PCH2) do not exhibit meiotic check­
point activity; rather, mutations in each cause severe
recombination defects leading to meiotic arrest and
infertility. Known mitotic DNA­damage checkpoint pro­
teins probably have a role in mammalian meiosis, but for
those that are essential for viability, it is difficult to prove
a meiotic function. Nevertheless, in mouse spermato­
cytes, as in S. cerevisiae, the DNA­damage and synapsis
checkpoints are distinct 59,60. The molecular basis of the
synapsis checkpoint, which is either more sensitive in
males or different between the sexes61,62, also remains
unknown. Immunocytological data support the idea that
ataxia telangiectasia and rAD3­related (ATr; the S. cerevisiae orthologue is Mec1), which is a key serine/threo­
nine kinase checkpoint protein that responds primarily
to DNA damage arising during DNA replication, has a
role in the mammalian meiotic pachytene checkpoint.
In particular, it is thought to trigger meiotic silencing
of unsynapsed chromatin (MSuC)63–65. However, direct
evidence for a meiotic role has been precluded by the fact
that Atr nullizygosity is lethal.
In spite of their obvious importance in avoidance of
gametic aneuploidy, the identification of the components
of mammalian meiotic checkpoints faces major chal­
lenges. Features of a meiotic checkpoint gene would be
that a mutation would not block meiosis but would
allow the bypass of a particular defect, such as failed
DSB repair or asynapsis. Forward genetic screens for
such mutants are routine in S. cerevisiae, but sensi­
tized meiotic screens are not practical in mice. Possible
strategies might be to use proteomics approaches (mass
spectrometry) to identify signalling cascades that occur
in response to defects66, or to genetically map alleles that
are associated with elevated aneuploidy rates in mice
or humans.
Piwi-interacting RNAs
Small germ-cell RNAs that
interact with PIWI proteins.
They are thought to be
involved in the repression of
retrotransposon expression
during gametogenesis.
Chromosome dynamics: pairing to segregation
Fidelity of recombination and chromosome segregation
and avoidance of aneuploidy are dependent upon the
dynamics of chromosome pairing and synapsis during
meiotic prophase. Much is known about the roster of
proteins that contribute to formation of the chromo­
somal axes and the SC (FIG. 2), but little is known in any
organism about exactly how the separable events of pair­
ing and synapsis come about. It is frequently assumed
that the single­strand overhangs at DSBs mediate the
search by which homologous chromosomes find each
other. Although this may well be true for the final stages
of homologous synapsis, it is unlikely that small single­
stranded regions of DNA could be effective for early
stages of the homology search, in which long lengths
of longitudinally compacted DNA (that is, metres of
DNA packaged into nuclei micrometres in diameter)
must recognize homology and pair. Furthermore, DNA
participating in the homology search is not naked,
but is intimately associated with histones and other
chromosomal proteins. Therefore, supra­chromosomal
features are likely to be important facilitators of the
homology search. The two most well studied of these
features in mammalian germ cells are the clustering of
telomeres and the assembly of chromosomal Aes to form
the SC; both processes are required for meiotic success
and fertility in mammals and are discussed below.
Telomere bouquets. A striking and highly conserved
feature of early meiotic prophase cells is attachment and
clustering of telomeres at the nuclear envelope (Ne).
They form of a chromosomal ‘bouquet’67,68 that might
facilitate homologous alignment along the length of
chromosomes. In C. elegans, the cytoskeleton and the
Ne protein SuN­1 have been implicated as participating
in chromosome pairing 69–71. In mammalian germ cells,
telomere clustering involves uNC84A (also known as
SuN1), which is an inner nuclear membrane protein
that is required for anchoring Ne­interacting proteins
to the Ne. In spermatocytes, uNC84A colocalizes with
telomeres. Unc84a deletion disrupts both bouquet for­
mation and homologous chromosome synapsis, result­
ing in male and female infertility 72. However, because
altered expression of reproductive genes and piwiinteracting RNAs (pirNAs) also occurs, the exact causes
of the phenotypic defects are uncertain73. In addition
to telomere clustering in early meiotic prophase, the
telomeric sequences themselves might have a role
in recombination, as there is a relatively high rate of
recombination in sub­telomeric sequences, particu­
larly in the male germline74. In an examination of the
effect of telomere erosion in telomerase­deficient mice,
shortened telomeres were observed to correlate with
lack of perinuclear distribution of telomeres, impaired
homologous synapsis and decreased recombination75.
Therefore, telomeres are structural and functional com­
ponents of chromosomes that are required for meiosis
and fertility in mammals.
The synaptonemal complex: structure and function.
The most obvious supra­chromosomal scaffold element
associated with pairing and synapsis is the SC (FIG. 2).
Although its role is not well understood, the SC is a
feature of meiosis in nearly all eukaryotes, and its func­
tion (although not its specific proteins) must be evolu­
tionarily conserved because mutational disruption of
the SC structure impairs meiosis in a wide variety
of organisms. The SC is assembled from the precursor
chromosomal Aes that align to form the lateral elements
(les), which are separated in the mature SC by a central
region (FIG. 2). Several excellent reviews of the mamma­
lian SC have appeared recently 76–78, and therefore aspects
of its assembly will be only briefly covered here. The Aes
along each pair of sister chromatids form initially from
a chromosomal core of cohesin proteins 79. In mam­
mals, these include meiosis­specific variants of cohesin
proteins, structural maintenance of chromosomes
1B (SMC1B), reC8 (which is related to rAD21) and
STAG3 (which is related to STAG1). In mice, null alleles
of SMC1B80 and reC8 (REFS 81,82) cause both male
and female infertility with meiotic disruption (FIG. 4).
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Interference
A phenomenon in which
the occurrence of a crossover
recombination at one position
on a chromosome suppresses
the frequency of additional,
nearby crossovers;
inhibition decreases with
physical distance.
Bivalent
Two paired or synapsed
homologous chromosomes,
each formed of two
sister chromatids.
Dictyate
A ‘resting’ stage at the end of
the first meiotic prophase. It is
at the end of diplonema but
before the resumption
of meiosis and the onset of
progress to metaphase of the
first meiotic division.
Anastral spindle
A spindle formed without
centrosomes (microtubuleorganizing centres) or the astral
microtubules that usually
surround the centrioles at
spindle poles.
Moreover, the axes of meiotic chromosomes that lack
SMC1B or reC8 are notably shorter than normal and
the chromatin loops that surround the Aes are longer
than normal, which provides evidence for a role of
Aes in longitudinal differentiation of meiotic chroma­
tin. Two SC­specific proteins, SyCP2 and SyCP3, are
recruited to the chromosomal cores to form the mei­
otic Aes. In mice, the null allele of Sycp3 causes male
infertility with failure of synapsis and reduced female
fertility with elevated rate of oocyte aneuploidy 83,84
(FIG. 4). A similar phenotype is caused by a deletion of
the coiled­coil domain of SyCP2, which is required for
binding to SyCP3 (REF. 85) (FIG. 4), highlighting the essen­
tial nature of protein–protein interactions within the
Aes and les. The sexually dimorphic phenotype of
the Sycp3 and Sycp2 mutations suggests the possibility
of different roles for the Aes in spermatocytes versus
oocytes, or different kinds of checkpoints that moni­
tor meiotic progress. All of the proteins that have been
identified so far that localize to the central region —
including SyCP1 (REF. 86), synaptonemal complex cen­
tral element protein 1 (SyCe1)87, SyCe2 (REF. 88) and
testis­expressed sequence 12 (TeX12)89 — seem to be
essential for both male and female fertility (FIG. 4). These
proteins, although not evolutionarily conserved at the
amino acid­sequence level, seem to have conserved
functions and are required for the formation of COs
that are subject to interference76.
exactly what does the SC do? In spite of more than
50 years of study of the SC, the answer to this question
is still not known for the well­studied yeast model nor
for mammalian germ cells. At the simplest level, it might
serve solely to keep long loops of chromatin out of the
way of the recombination machinery. It is more likely,
however, that it has active, functional roles in homo­
logy searching, synapsis and recombination. By form­
ing a chromosomal scaffold and thereby partitioning the
genome into ‘attached’ and ‘unattached’ sequences,
the Aes might limit the homology search by a mecha­
nism that is dependent on the sequence specificity of
attachment of genomic DNA to the SC scaffold. recently,
Dernburg and colleagues90 identified repeat sequence
motifs in the pairing centres of C. elegans chromosomes;
these bind to several zinc finger­containing proteins that
interact with inner and outer Ne proteins. Although
there is little knowledge of specific sequences that associ­
ate with the mammalian SC, two studies have suggested
that such sequences might be enriched for long inter­
spersed elements (lINes) and short interspersed ele­
ments (SINes)91,92. The SC might also function through
interactions of le scaffold proteins with proteins of
the central region to bring about synapsis, mediated by
protein–protein interactions rather than DNA–protein
interactions. Specialized structures in the central region
might provide the solid surface for the assembly of
recombination complexes. Clearly, future genomic and
proteomic analyses of chromatin modifications, DNA­
binding proteins and protein–protein interactions in the
meiotic chromosomal scaffold are required to resolve
these gaps in our understanding of the most fundamental
chromosomal mechanics of meiosis.
Segregating chromosomes. Although the roots of chro­
mosome segregation lie in the formation of chiasma
during prophase, the dynamics of the division phase
are also important for the production of chromosoma­
lly normal gametes. First, germ cells must ‘know’ that
meiotic recombination is completed (for example, com­
pletion of recombination is linked to checkpoint mecha­
nisms) and then disassemble the SC to allow homologue
separation at the first meiotic division. In budding yeast,
several components of the meiotic exit signalling path­
way are known. A polo­like kinase, Cdc5, is required for
both CO resolution and SC disassembly, although the
precise mechanisms by which it acts are not known93.
Additionally, the kinase activity of an aurora B kinase
promotes SC disassembly 94.
In mammals, the exit from meiotic prophase shows
significant sexual dimorphism. Spermatocytes, like
budding yeast, proceed directly from pachynema into
diplonema (FIG. 1). Desynapsis, the first and key step of
prophase exit, requires the spermatocyte­specific chap­
erone heat shock­related 70 kDa protein 2 (HSPA2)95,96.
The formation of highly condensed metaphase I bivalents
and the disassembly of SCs are regulated by cyclin­
dependent kinases and aurora kinases97. HSPA2 also is
required for CDC2 kinase–cyclin B1 complex formation
and activation of the CDC2 kinase98. In oocytes, meiotic
prophase is arrested in a diplotene­like dictyate stage; the
arrest can last for months (in laboratory mice) or decades
(in humans). resumption of meiotic progress and entry
into the meiotic division phase is controlled by somatic
cells and in vivo is hormonally prompted99.
In the first meiotic division, non­sister kinetochores
must orient to opposite poles without premature separa­
tion of sister chromatids. Precise control of the timing
of degradation of the cohesin connections between
sister chromatid arms compared with connections at
the centromere ensures bi­orientation of homologues
at metaphase I100,101. Additionally, a spindle assembly
checkpoint (SAC) inhibits the dissolution of cohesion,
which ensures that the reductional division does not
occur until all bivalents are correctly attached; much is
now known about the timing and mechanisms by which
SAC proteins act 101,102. In the second meiotic division,
sister chromatids are accurately segregated to spindle
poles. Human oocyte aneuploidy rates are much higher
than in sperm (25% compared with ~2%)103. Why are
human oocytes, especially those from older women, so
much more prone than spermatocytes to generate aneu­
ploidy? This is the key human health issue that must be
resolved in future studies of meiosis.
There is sexual dimorphism in the number, place­
ment and resolution of COs, in the assembly and func­
tion of the apparatus for the first meiotic division, and
in checkpoint proteins, all of which might affect the
fidelity of chromosome segregation62,101,102,104. The barrel­
shaped anastral spindle of the oocyte is asymmetrically
positioned close to the egg surface, and in each of the
two meiotic divisions chromosomes segregate either to
a small polar body or to the oocyte; this is unlike the
symmetric division of spermatocytes. evidence suggests
that the ‘egg’ pole of the spindle could be a dominant
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pole, which attracts a univalent X chromosome105, or
acrocentric chromosomes rather than a bi­armed chro­
mosome106,107, providing a potential mechanism for
non­random segregation and biased chromosome con­
tent. Furthermore, oocytes have a long resting period,
so the temporal stability of chromosome interactions
might have implications for the rate of gametic aneu­
ploidy in human females compared with males108. For
example, there might be age­related failure of cohesin
proteins to maintain sister­chromatid cohesion in the
first meiotic division109 or deficiencies in checkpoint pro­
teins that lead to age­related deterioration of checkpoint
mechanisms110. However, a study of a naturally ageing
mouse model suggests that these explanations may be
simplistic111. Therefore, determining the mechanisms
in the aetiology of non­random chromosome segrega­
tion begs the resolution of our poor understanding of
the function of the oocyte spindle. This is likely to come
not only from the unbiased discovery of gene functions
in meiosis (for example, the discovery of the genes that
encode proteins involved in cohesion, kinetochores and
motor functions) but also from high­resolution, real­
time, three­dimensional imaging of chromosome inter­
actions with the spindle in oocytes and spermatocytes.
Box 1 | A scenario for identifying and curing meiotic infertility mutations
Advances in next-generation DNA sequencing technology, germline stem cell culture and assisted reproductive
technologies have allowed us to envision a scenario for correcting meiosis-based infertility in the future. As outlined in the
figure, the approach would permit the identification of potentially causative mutations, the functional evaluation of
candidate mutations, and gene transfer to create viable sperm that are not genetically altered.
In this scenario, a patient with meiotic arrest would have his genome sequenced, and computationally predicted
deleterious mutations in known or presumed meiotic genes would be identified (such as ‘gene X’). The ‘meiotic’ genes
could be informed from knowledge accumulated in model organisms, such as mice (for example, the mouse mutations
shown in FIG. 4). An expression construct bearing a fully functional copy of gene X would be built (and possibly tagged
with a reporter such as GFP, denoted in green in the figure) and transfected into spermatogonia cultured from the
patient — these would be available because stem cells are still present in testes that have meiotic arrest. After culturing
under conditions such as those developed in recent years126, transformed spermatogonia could be either re-introduced
into the patient’s testes or induced to undergo meiosis in culture; the latter option assumes the development of methods
that support accurate meiosis (for example, Sertoli cell co-cultures in the presence of differentiation-inducing factors).
The rescue of meiosis, especially using an in vitro system, would prove that the mutation was indeed causative of the
arrest phenotype.
The resulting spermatozoa (or round spermatids) from the testis could be used for in vitro fertilization (IVF), and the
spermatozoa from the culture system could be used for IVF, intracytoplasmic sperm injection (ICSI) or round spermatid
nucleus injection (ROSNI). Note that although only half of the sperm would carry the rescuing transgene (shown as an
orange bar), even non-transgenic sperm would be rescued owing to syncytial development during spermatogenesis
(FIG. 1) and consequent sharing of meiotic products (all meiotic products are shown in green as they share the GFP tag).
However, after fertilization only embryos that lack the transgene (that is, that do not contain any altered DNA) would be
chosen for transfer to the patient’s partner. Notably, in the event that a meiotic defect is caused by a genetic situation
other than homozygosity for a recessive allele — such as heterozygosity for a haploinsufficient or semidominant mutation
— transgene overexpression could rescue meiosis. Therefore, the infertility specialist could select embryos that lack both
the transgene and mutant allele so that infertility alleles would not be propagated.
Testis
ATTAGCCA
Gene X
DNA from
sterile patient
Sequence
genome
Identify mutation
in meiotic gene X
Spermatogonial stem cells
IVF
Gene X
Univalent
An unpaired chromosome
at metaphase I: usually one
that has failed to synapse or
recombine with its homologue.
Acrocentric chromosome
A chromosome with a
centromere near to one end so
that one arm is very short.
IVF
ICSI
ROSNI
Culture system for meiosis
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Isodicentric chromosome
A cytogenetically anomalous
chromosome characterized
by the presence of two
centromeres, with additional,
identical copies of DNA
segments joined end to end.
1.
2.
3.
4.
5.
6.
Perspectives and challenges for fertility and ARTs
As emphasized throughout this review, the penalties of
mutations that cause meiotic error are either germ­cell
arrest (hence, infertility) or the generation of aneuploid
or mutation­containing gametes (FIG. 4). However, the
astute reader may have noticed that there has been no
discussion of human infertility caused by meiotic muta­
tions in the preceding sections, which is because we really
have no unequivocal evidence for causality. There have
been a number of candidate gene re­sequencing studies
on humans who have ‘maturation arrest’ — a common
male infertility phenotype that resembles some of the
mouse meiotic mutants shown in FIG. 4 — and putative
mutations have been identified in SC and recombina­
tion genes112–115. However, causality is difficult to estab­
lish for individual human patients. Furthermore, all of
the reported mutations have been heterozygous, which
means that they would most likely have to be dominant
to be causative; proof in principle for dominant meiotic
mutations has been presented for only one key recom­
bination gene in mice, Dmc1 (REF. 116). Furthermore, the
use of ArT poses the risk of passing such mutations to
offspring. The advent of personal genome sequencing
and further targeted re­sequencing of candidate genes
in infertile individuals will facilitate the identification
of more potentially causative mutations that underlie
maturation arrest. The major issues then become vali­
dating the causality of the mutations and developing safe
assisted reproduction methods to correct or overcome a
validated mutation. In BOX 1, we present a hypothetical
scenario that addresses both issues.
What is the impact of meiotic recombination itself
on the health of offspring and future generations, aside
from issues of infertility and aneuploidy? unequal cross­
ing over between regions with closely related sequences
and repeats can give rise to sequence copy­number
variants and deletions or duplications. Such structural
changes are implicated in some of the human ‘genomic’
disorders, including some hereditary neuropathies,
Prader–Willi syndrome and Angelman syndrome117.
The frequency of such events might be affected by cer­
tain alleles of mismatch repair proteins that normally
prevent recombination of partially divergent sequences
(‘homeologous’ recombination), or might increase in
environmental or genetic situations in which there is
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aneuploidy: where we have been, where we are going.
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increased DNA damage. These examples underscore
the need for better understanding of how chromatin is
attached to the SC, which normally allows precise pair­
ing of non­sister chromatids. Additionally, in spite of the
obligatory homologue bias of meiotic recombination,
sister­chromatid recombination does occur on human
y chromosomes, where gene conversion maintains long
stretches of palindromes118. One consequence of this
mechanism for maintaining the y chromosome is occa­
sional unequal exchange, which can result in an unstable
isodicentric chromosome. When inherited, an isodicentric
y chromosome can lead to disorders that include infer­
tility, aberrations in sex determination mechanisms and
Turner syndrome118.
Finally, much attention has been devoted recently
to the generation of functional gametes from embry­
onic stem cells or iPS cells. In any attempt to generate
mammalian gametes in vitro, it will be challenging to
mimic the roles of the somatic cells that act in both
instructive and permissive roles to support meiosis and
gametogenesis. Any use of in vitro­derived mammalian
gametes (for example, for the controlled reproduction
of domestic food animals) must be predicated on rigor­
ous proof of the execution of key steps in meiosis and
the fidelity of chromosome segregation. The features
expected of a population of cells in meiosis are: that a
significant fraction of the cells have 4C DNA content and
a small fraction of the population has 1C DNA content;
that the 1C population of putative gametes must exhibit
appropriate chromosomal content (1N) and segregation
of alleles; that homologous chromosomes are compacted
with a clearly defined tripartite SC; and that condensed
metaphase chromosomes exhibit chiasmata. These are
crucial criteria for measuring the success of in vitro deri­
vation of mammalian meiotic cells, and they have not yet
been met in full by studies that report the derivation of
germ cells from stem cells119–125.
ultimately, the identification of genetic risk factors
that have an impact on the generation of gametic aneu­
ploidy is an imperative for ArTs and human health.
This review has highlighted the criteria that must be
assessed, the potential for error and the consequences
of meiosis going wrong, all of which have profound
implications for human reproduction and for assisted
reproduction endeavours.
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Acknowledgements
The authors thank P. Cohen, J. Eppig, K. Paigen and
L. Reinholdt for comments on the manuscript. We apologize
to authors whose papers could not be cited owing to
space limitations.
Competing interests statement
The authors declare no competing financial interests.
DATABASES
Entrez Gene: http://www.ncbi.nlm.nih.gov/gene
IME2 | NDT80 | Prdm9 | Stra8
OMIM: http://www.ncbi.nlm.nih.gov/omim
Angelman syndrome | Prader–Willi syndrome
UniProtKB: http://www.uniprot.org
DMC1 | HSPA2 | Ime1 | RAD51 | RNF212 | SPO11 | SYCE1 |
SYCP2 | Ume6
FURTHER INFORMATION
Mary Ann Handel’s homepage:
http://research.jax.org/faculty/mary_ann_handel.html
John C. Schimenti’s homepage:
http://www.vet.cornell.edu/BioSci/Faculty/Schimenti
All links Are Active in the Online pdf
www.nature.com/reviews/genetics
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