TICB 1284 No.

of Pages 14

Review

Mechanisms of Aneuploidy in
Human Eggs
Alexandre Webster1 and Melina Schuh1,*
Eggs and sperm develop through a specialized cell division called meiosis.
During meiosis, the number of chromosomes is reduced by two sequential
divisions in preparation for fertilization. In human female meiosis, chromosomes
frequently segregate incorrectly, resulting in eggs with an abnormal number of
chromosomes. When fertilized, these eggs give rise to aneuploid embryos that
usually fail to develop. As women become older, errors in meiosis occur more
frequently, resulting in increased risks of infertility, miscarriage, and congenital
syndromes, such as Down's syndrome. Here, we review recent studies that
identify the mechanisms causing aneuploidy in female meiosis, with a particular
emphasis on studies in humans.
Aneuploidy in Human Oocytes: A Topic of Growing Relevance in Society
Over the past century, greater medical knowledge and technological advances have improved
the quality and duration of human lives. By contrast, the span of female fertility remains
unchanged. A limited reserve of oocytes (see Glossary) is formed before birth, but gradually
declines in quality with age, resulting in reduced fertility and an age-related increase in eggs with
an abnormal number of chromosomes, termed aneuploidy. Despite this concern, women more
frequently delay having their rst child until later in life [1]. In 2013, nearly 43% of live births in
the USA were delivered to mothers 30 years of age or older [2]. Consequently, women in their
late 30s and 40s experience more miscarriages and pregnancies with fetuses [6_TD$IF]that have severe
congenital abnormalities.

Trends
Fertility steadily decreases as women
age and, by mid-life, women fail to
produce healthy eggs. Meiotic chromosomes experience age-related
structural changes that may contribute
to increasing rates of chromosome
segregation errors.
Novel error-causing pathways are
reported in human oocytes that might
explain how a previously undetected
alternative segregation pattern arises.
Emerging studies provide a better
understanding of why oocytes are frequently defective and lead to agerelated infertility.
Recent studies have found that meiosis
in mammalian females is intrinsically
error prone, causing high rates of aneuploidy and infertility. Cellular mechanisms responsible for segregating
chromosomes are inefcient, affecting
females of all ages.

Errors in chromosome segregation during meiosis occur frequently in human eggs and cause
aneuploidy in embryos (Box 1). These errors increase dramatically in the eggs of older women.
Here, we review recent work that has shed light on how the progressive deterioration of
chromosome structures contributes to age-related aneuploidy. In addition, we examine several
cellular pathways that cause aneuploidy in the oocytes of women of all ages. Evidence from
mouse and human oocytes is discussed, with an emphasis on studies focusing on humans.

Meiosis in Human Oocytes

Meiosis involves two successive[7_TD$IF] cell divisions, in which rst homologous chromosomes (meiosis I)
and then sister chromatids (meiosis II) separate. The segregation of homologous chromosomes
during the rst meiotic division requires that the homologous chromosomes become linked with
each other. These links are established in the early stages of oocyte development during growth of
the female fetus in a process called homologous recombination [3] (Figure 1). The maternal and
paternal chromosomes are rst zipped together by the synaptonemal complex and then undergo
crossover (Figure 1A). After crossover, new sister chromatids are formed that comprise contiguous segments of maternal and paternal sister chromatids. The cohesin complexes that previously
linked the sister chromatids of each homologous chromosome now link homologous chromosomes (Figure 1B) [46]: cohesin distal to crossover sites (distal cohesin) binds homologs
together, while cohesin between crossover sites and centromeres (proximal cohesin) continues

Trends in Cell Biology, Month Year, Vol. xx, No. yy

1
Department of Meiosis, Max Planck
Institute for Biophysical Chemistry, Am
Fassberg 11, D-37077, Gttingen,
Germany

*Correspondence:
melina.schuh@mpibpc.mpg.de
(M. Schuh).

http://dx.doi.org/10.1016/j.tcb.2016.09.002
2016 Elsevier Ltd. All rights reserved.

TICB 1284 No. of Pages 14

Box 1. What Happens If [4_TD$IF]an Aneuploid Egg Is Fertilized?

A healthy human embryo contains a maternal and paternal copy for each of the 22 autosomal (nonsex) chromosomes, in
addition to a sex chromosome from each parent for a set of 46 chromosomes (females acquire two X chromosomes,
while males inherit one X and one Y chromosome). Errors during chromosome segregation in meiosis lead to aneuploid
eggs that carry an incorrect number of chromosomes [90]. If these eggs are fertilized, they give rise to aneuploid embryos.
The frequency of chromosome segregation errors during meiosis increases as women age, so that older women more
frequently conceive embryos with an incorrect number of chromosomes [96]. Most aneuploidies lead to severe cellular
dysfunction since each chromosome encodes[5_TD$IF] up to thousands of genes. Consequently, aneuploid embryos often fail to
develop into functional blastocysts and, thus, never implant [97]. In this case, pregnancy is never detected, since
pregnancy tests screen for hormones produced only upon implantation. In less severe cases of aneuploidy, a functional
blastocyst may form and implant [98]. However, aneuploidies of most chromosomes cause early embryonic lethality, and
pregnancy usually terminates within the rst trimester [41]. Only a few aneuploidies are viable. Trisomic embryos with
three copies of chromosome 13, 18, or 21 can survive full-term pregnancies, although aficted individuals typically suffer
severe developmental syndromes. Down's syndrome caused by trisomy 21 is the most common fetal trisomy occurring
in approximately 1 in 500 of pregnancies [99]. Several sex chromosome aneuploidies are also viable but cause
developmental disorders, such as Turner's (XO) and Klinefelter's (XXY) syndromes. Females with X trisomy or XYY
males are also born with less severe symptoms and often remain undiagnosed [100,101]. New methods are currently
emerging to better study the early development of human embryos [102].
The recent introduction of non-invasive prenatal testing (NIPT) technology allows fetal aneuploidy to be routinely detected
early in gestation [103105]. Unlike amniocenteses or chorionic villus sampling, NIPT is a non-invasive technique that only
requires a blood sample of the pregnant woman. The fetal DNA released into the maternal plasma can be used to
determine the cytogenetics of a fetus. However, when parents learn that their fetus is aficted with severe congenital
disorders due to trisomy, a decision can be extremely difcult [106,107].

to link sister chromatids. The resulting chromosome conguration in which two homologous
chromosomes are linked is called a bivalent (Figure 1C).
During meiosis I, bivalents need to orient on the spindle so that the two sister chromatids of
each homologous chromosome face towards the same spindle pole. The kinetochores of
sister chromatids need to function as a single kinetochore. Coupling sister kinetochores into a
functional unit is thought to facilitate this function [7]. Coupling has been suggested to involve
different mechanisms in different species: the monopolin complex in budding yeast [8,9]; Moa1
in combination with cohesin in ssion yeast [10]; and Meikin in conjunction with cohesin in mice
(Figure 1D) [11]. There is a homolog of Meikin in humans, but it is unknown whether its function is
conserved in human oocytes [11].
The oocytes then enter a state of cellular quiescence termed dictyate arrest, which may last
several decades in humans. The functional unit of oocyte and somatic cells in the ovary is called
the follicle. In their storage state, oocytes remain small and are surrounded by a single epithelial
layer of at somatic cells in a so-called primordial follicle. Periodically, some primordial follicles
start to grow. Somatic cells feed the oocyte with macromolecular precursors via gap junctions
and the oocyte volume increases dramatically. This enrichment of nutrients prepares the oocyte
to mature into an egg that can give rise to an embryo after fertilization [12,13].
Oocytes exit from dictyate arrest after puberty. During the middle of the menstrual cycle, a surge
of luteinizing hormone from the pituitary gland causes an oocyte to resume meiosis and mature
into a fertilizable egg. First, the nucleus breaks down and a meiotic spindle assembles that aligns
the chromosomes in metaphase of meiosis I (Figure 2A). The spindle migrates to the oocyte
cortex, where it segregates homologous chromosomes. One set of homologous chromosomes
remains in the oocyte, while the other is extruded into the rst polar body (Figure 2B). At a
molecular level, the segregation of chromosomes during meiosis I is triggered by cleavage of
Rec8, a meiosis-specic subunit of the cohesin complex [6]. Rec8 is cleaved by Separase, which
is activated during anaphase (Figure 1B) [14]. Only cohesin in the arm region is cleaved during
anaphase I, so that the chromosomes can segregate from each other. Cohesin in centromeric

Trends in Cell Biology, Month Year, Vol. xx, No. yy

Glossary
Anaphase: the stage of cell division
when the spindle segregates
chromosomes by pulling them to
opposite spindle poles.
Blastocyst: a stage in early embryo
development that forms before
implantation into the uterus.
Centromere: the region of a
chromosome where the kinetochore is
assembled and microtubules attach.
Homologous recombination: an
event specic to meiosis where DNA
of homologous chromosomes is
covalently exchanged to produce
chromosomes with new allele
combinations and that links
homologous chromosomes with each
other to form a bivalent.
Kinetochore: a proteinaceous
structure assembled on the
centromeres of chromosomes that
binds spindle microtubules
responsible for pulling chromosomes
apart during segregation.
Merotelic attachment: a single
kinetochore incorrectly bound to
microtubules originating from
opposite spindle poles.
Metaphase: the stage of cell division
when spindle microtubules align
chromosomes at the metaphase plate
between spindle poles before
anaphase.
Oocyte: a female germ cell that
becomes a fertilizable egg after
meiosis.
Polar body: the product of
asymmetric cell division during female
meiosis containing discarded genetic
material from the oocyte.
Premature separation of sister
chromatids (PSSC): a chromosome
segregation error where cohesion
between sister chromatids is lost,
permitting them to randomly
segregate during meiosis.
Sister chromatids: two identical
copies of a chromosome replicated
during the S phase of the cell cycle.
Sperm: a male germ cell produced
by meiosis that can fertilize an oocyte.
Spindle: a cytoskeletal network
comprising microtubules formed
between two spindle poles that
segregates chromosomes during cell
division.
Univalent: a type of chromosome
comprising a pair of sister chromatids
that forms abnormally in meiosis I.
Univalents can form by the premature
splitting of a bivalent before
anaphase I, or if chromosomes fail to
undergo homologous recombination.

TICB 1284 No. of Pages 14

(A)

(B)

Sister chromads

Homologous
chromosomes

Cohesin
Crossover

Cohesin
Sgo

Rec8

Homologous
recombinaon

Kinetochore

Separase

Crossover

Sister
chromads

(C)

Homologous
chromosomes

The bivalent
Distal
cohesin

Sister
centromeres

Proximal
cohesin
Kinetochore
Shugoshin

Cohesin

(D)
Sgo

Sgo

Sgo

Sgo

Sgo

Sgo

Sgo

Sgo

Sgo

Sgo

Sgo

Sgo kinetochores

Sgo

Sgo

Sgo

Sgo

Meikin

Sister

Proximal
cohesin
Distal
cohesin

Figure 1. Bivalent Chromosomes Are Formed after Homologous Recombination. (A) During fetal development,
DNA replication produces two identical sister chromatids for both maternal and paternal homologous chromosomes in
primary oocytes. Cohesin complexes are installed along the lengths of sister chromatids, binding them together. Homologous recombination between homologous chromatids covalently exchanges DNA strands to generate chromosomes
with reshufed allele combinations. Crossover sites appear where chromosomes have undergone homologous recombination. (B) Cohesin is a three-subunit protein complex that binds two strands of chromosomal DNA together. During
anaphase, Separase cleaves the cohesin subunit, Rec8, allowing chromosomes to segregate. Shugoshin (Sgo) proteins
prevent Separase from cleaving Rec8 in pericentromeric regions. (C) The bivalent is formed after homologous recombination. Exchange of DNA between homologous chromosomes causes cohesin distal to crossover sites (distal cohesin) to link
homologous chromosomes together. Cohesin between centromeres and crossover sites (proximal cohesin) binds sister
chromatids to tightly associate the kinetochores of sister chromatids. Sgo proteins localize to pericentromeric regions and
protect proximal cohesin from Separase cleavage. (D) The centromeric regions of sister chromatids in meiosis I. In mouse,
cohesin and the meiosis-specic kinetochore protein, Meikin, tightly associate kinetochores. Cohesin complexes are
protected from removal by Sgo proteins. In meiosis II, the spindle recongures chromosomes, such that Sgo proteins no
longer protect cohesin from Separase cleavage, allowing sister chromatids to segregate.

regions is protected from cleavage by Shugoshin proteins (Sgo), so that sister chromatids
remain together during anaphase I (Figure 2A) [1517].
In meiosis II, the second meiotic spindle is assembled. The now mature egg arrests in
metaphase II and is transported to the oviduct during ovulation. The egg only completes the
second meiotic division upon fertilization by sperm [18]. During the second meiotic division, Sgo
proteins relocate to kinetochores, permitting cleavage of centromeric cohesin in anaphase II

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(A)

Meiosis I
Metaphase I

Oocyte

Anaphase I

Nuclear envelope
breakdown

Dictyate arrest

Spindle assembly

Spindle migrates

First polar body

extrusion

Homologous chromosomes
segregate in anaphase I

Bivalents align

Sgo

(B)

(C)

Meiosis II
Metaphase II

PB1

Embryogenesis

Anaphase II

Mitosis

Ovulaon

Egg

PB1

Metaphase II
arrest

Ferlizaon

Second polar body

extrusion

Sgo
PB2

Sister chromads
align

Sister chromads
segregate

Blastocyst

Zygote

PB2

Formaon of
pronuclei
Maternal
chromad

Paternal
chromad

Figure 2. Two Cell Divisions in Meiosis Prepare Oocytes for Fertilization. (A) Oocytes generated during fetal development remain quiescent for decades in dictyate
arrest within ovarian follicles. Only after puberty can they be reactivated to complete meiosis. During the menstrual cycle, hormonal signals release the oocyte from dictyate
arrest to resume meiosis. Condensed chromosomes (purple) are released into the cytoplasm after nuclear envelope breakdown. Microtubules (green bers) assemble the
meiotic spindle and align bivalents in metaphase I. The spindle migrates to the oocyte cortex. Homologous chromosomes segregate at the onset of anaphase I. Meiosis I is
completed when one set of homologous chromosomes is extruded into the rst polar body (PB1), while the other remains in the oocyte. Sister chromatids remain bound by
cohesin proximal to centromeres, which is protected from removal by Shugoshin (Sgo) proteins. This ensures that sister chromatids remain linked during meiosis II. (B) In
meiosis II, a second meiotic spindle aligns sister chromatids and the oocyte arrests in metaphase II. Sgo proteins no longer protect cohesin from cleavage. At this stage, the
oocyte is a mature egg and is released from the ovary during ovulation to be fertilized by a sperm.[3_TD$IF] (C) Fertilization triggers anaphase II, where sister chromatids are segregated
into the egg and second polar body (PB2).[1_TD$IF] In the zygote, pronuclear envelopes form around the maternal chromosomes of the egg and paternal chromosomes contributed
by the sperm. Pronuclei migrate towards each other to unite as the genome of the embryo. The embryo transitions from meiosis to mitosis and divides many times over
several days to nally become a blastocyst.

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TICB 1284 No. of Pages 14

[16,17,19]. Sister chromatids of the remaining chromosomes segregate into the egg and the
second polar body to complete meiosis (Figure 2B). Chromosomes from the egg and sperm
become enclosed in pronuclear envelopes, which then coalesce in preparation for the rst
mitotic division of the embryo (Figure 2C) [18,20]. The embryo then divides into a multicellular
blastocyst and implants into the uterus to develop further [18].

Types of Aneuploidy in Human Oocytes

Recent technological developments have increased the ability to detect aneuploidy in eggs or
during the early stages of embryonic development (See Outstanding Questions). During preimplantation genetic diagnostics, cells of an embryo can sometimes be biopsied and screened
for genetic abnormalities to select healthy embryos for implantation [21]. Testing of oocytes can
be helpful and may minimize the need to test embryos. In particular, polar bodies can be used to
determine the cytology of an oocyte without causing it harm [22]. The use of polar bodies to
diagnose aneuploidy for in vitro fertilization (IVF) treatments also improves embryo selection
before implantation [23,24]. Analysis of both polar body genomes can correctly diagnose
aneuploidy in mature eggs, because all but one set of chromosomal copies are extruded into
polar bodies [2527]. For example, a gain of an extra chromosome in the rst polar body
indicates a reciprocal loss of that chromosome in the oocyte after meiosis I, while an incorrect
chromosome count in the second polar body implies a chromosome segregation error in
meiosis II. However, the second polar body is extruded only after the egg is fertilized.
Chromosomes from biopsied polar bodies were previously best analyzed by uorescence in situ
hybridization (FISH). Although still widely in use for embryo selection, clinical implementations of
FISH only detect a subset of chromosomes and diagnosis is often inaccurate [28]. Newer, more
sensitive methods, such as array Comparative Genome Hybridization (aCGH) [23,24,27,2931]
and next-generation sequencing (NGS) platforms [26,32,33], provide improved statistics for the
prevalence of aneuploidy and better characterization of segregation errors. These ndings have
enhanced our understanding of how chromosome segregation errors arise in meiosis (Box 2).
Two classical pathways that have been suggested to account for chromosome segregation
errors in meiosis are nondisjunction (NDJ) and premature separation of sister chromatids
(PSSC). For NDJ, homologous chromosomes or sister chromatids fail to segregate in meiosis I
or meiosis II, respectively (Figure 3A). However, several studies have reported that many
aneuploidies in meiosis I comprise gains or losses of single chromatids, but not pairs of
chromatids that would instead indicate NDJ [3436]. This nding helped establish PSSC as
a model where sister chromatid pairs split from one another to independently (and often
incorrectly) segregate during anaphase I (Figure 3A). Indeed, recent cytogenetic analyses of
polar bodies suggest that errors caused by PSSC are more common than those caused by NDJ
[27,37,38].
Segregation errors occur at similar rates between meiosis I and II, although meiosis II error rates
are sometimes reported to be higher [27,38,39]. This could be explained by a fraction of meiosis I
errors only appearing in meiosis II, since prematurely separated sister chromatids might
segregate correctly in meiosis I, but experience errors later in meiosis II. Interestingly, PSSC
errors in meiosis I can be rescued by a balancing error in meiosis II: if both the rst and second
polar bodies share reciprocal errors (e.g., a loss in the rst polar body followed by gain in the
second polar body; or vice versa) the resulting oocyte will have a correct chromosome count
[27,40]. Chromosomes 15, 16, 21, and 22 are among the most common contributors to human
aneuploidy, although data on the contributions of individual chromosomes vary between
studies, which may be due to limited statistics for each type of aneuploidy [27,30,37,41].
Frequently, an oocyte will experience simultaneous errors involving multiple chromosomes,
suggesting that some oocytes are susceptible to global dysfunction [27,38]. This effect is also

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Box 2. How Can Scientists Study Meiosis in Human Oocytes?

Human oocytes normally mature within the body where they cannot be accessed. However, human oocytes are routinely
obtained and fertilized in vitro for assisted reproduction. To obtain these oocytes, women are most often treated with
hormones that promote the growth of follicles and maturation of eggs. The oocytes are then collected from the ovaries by
follicle aspiration. Oocytes that are obtained for in vitro fertilization are in different stages of meiosis. Typically, only those
oocytes that have completed the second meiotic division with a metaphase II spindle, which are considered mature eggs,
are used for IVF treatment. Oocytes that are immature are not suitable for fertilization because they still contain a full set of
unsegregated chromosomes. Instead, they can be used to study how meiosis progresses in human oocytes and to
investigate the causes of aneuploidy.
There may be concerns that oocytes obtained from couples experiencing difculty to conceive are more likely to be
defective. However, this potential problem can be circumvented by focusing studies on oocytes that were obtained for
treatment of male factor-related infertility. The quality of oocytes should not be affected for these couples. It is also difcult
to assess how similar eggs obtained after hormonal stimulation are to eggs that have matured in vivo during a natural
cycle [108]. Are the error rates in natural cycles different from the error rates in super-ovulated eggs? Studies in mouse
oocytes have established that oocytes matured in vivo and in vitro are similar, but also reveal a few differences [109]. The
large number of babies that are born from these eggs illustrates that they are capable of giving rise to viable embryos
[110]. However, a detailed comparison for human oocytes is hindered by the fact that in vivo matured human oocytes are
difcult to obtain since they are typically used for IVF treatments, and because oocytes cannot yet be studied as they
mature within ovaries.
For these reasons, oocytes obtained by hormonal stimulation for assisted reproduction are currently the best cells to
study to learn more about aneuploidy in human eggs and the causes of the maternal age effect.

apparent in embryos, where up to 42% of detected aneuploidies involve multiple chromosomes

[42,43]. However, the etiology of embryonic aneuploidy is more complex, since errors may also
be derived from sperm [4446] or during the rapid mitotic divisions in embryogenesis [47,48].
Recent advances in single-cell whole-genome amplication (WGA) allow for unprecedented
characterization of genomic content within polar bodies [26,49]. Genome analyses of polar
body-oocyte and polar body-embryo trios (i.e., an oocyte or embryo biopsy combined with rst
and second polar bodies) revealed an alternative segregation mechanism termed reverse
segregation (Figure 3A) [29]. Initially proposed more than 30 years ago as balanced predivision
of sister chromatids [50], reverse segregation had, until recently, remained undetected.
Reverse segregation occurs when sister chromatids, but not homologous chromosome,
segregate in meiosis I. While reverse segregation leads to a correct number of chromosomal
copies inherited by the oocyte and rst polar body, chromatid pairs have different parental
origins and are heterozygous at their centromeres. They remain unlinked after meiosis I and
may experience problems aligning to the spindle during metaphase II. In one study, reverse
segregation was detected in less than 10% of analyzed trios, although it was the most
represented error observed [29]. Interestingly, of the donors that participated in this study,
all produced at least one oocyte or embryo that experienced reverse segregation [29]. Indeed,
the oocytes included in this study were obtained from women between 33 and 41 years of age.
A similar study examining oocytes of younger donors between 25 and 35 years of age did not
report reverse segregation [26].

Age-Related Causes of Aneuploidy

Women experience a gradual loss in the ability to become pregnant as they become older.
Infertility is often reached from the age of 35 to about 10 years later. Meiotic chromosome
segregation errors increase sharply in this age window. A comprehensive cytogenetic analysis
examining more than 20 000 human oocytes by FISH reported that aneuploidy occurs in 20% of
oocytes from 35-year-old women and increases to nearly 60% of oocytes from women over
43 years of age [39]. Recent studies utilizing aCGH conrmed that the rates of aneuploidy
dramatically increase in oocytes from older women [23,27,30,37,38]. What are the pathways
that might cause this age-related decline in female fertility?

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TICB 1284 No. of Pages 14

(A)

Normal segregaon

Oocyte

PB1

Oocyte

Premature separaon of
sister chromads (PSSC)

Oocyte

(C)

Amphitelic bivalent

PB1

Merotelic bivalent

Reverse segregaon

PB1

Oocyte

Mulpolar intermediate

PB1

Merotelic bivalent forms

Chromosome lag anaphase I

(B)

Nondisjuncon (NDJ)

+
+

Figure 3. Chromosome Segregation Errors in Meiosis. (A) Three main classes of segregation error. In meiosis I,
homologous chromosomes are normally segregated into the oocyte and rst polar body (PB1). Nondisjunction (NDJ) errors
occur when chromosome segregation fails. Premature separation of sister chromatids (PSSC) results in sister chromatids
incorrectly segregating into the oocyte and PB1. The newly identied reverse segregation pattern occurs when sister chromatids
(but not homologous chromosomes) are segregated in meiosis I. Note that a correct number of chromosome copies are
inherited by the oocyte but are of different parental origins. However, the chromatids are no longer linked, which may hinder
correct alignment and segregation in meiosis II. (B) The kinetochores of meiotic chromosomes can sometimes be incorrectly
attached to spindle microtubules (green bers). For correct alignment, amphitelic attachments are formed when a kinetochore
binds spindle microtubules from a single spindle pole. Chromosomes to be segregated bind spindle microtubules from opposite
poles. Incorrect merotelic attachments occur when a kinetochore binds microtubules from opposing spindle poles. (C) Meiotic
spindles in human oocytes sometimes form multipolar intermediates that may lead to error-prone merotelic attachments. A
kinetochore can become attached to opposing spindle poles (purple bers), when the multipolar intermediate reforms into a
bipolar spindle. Chromosomes with merotelic attachments fail to segregate correctly since they tend to lag behind while being
pulled to both poles in anaphase. This may cause them to become trapped in the wrong cell after division. Vice versa, the
separation of sister kinetochores in human oocytes may also facilitate the formation of merotelic attachments. This may
contribute to spindle reorganization and instability, reecting attempts of the spindle to correctly attach the chromosomes.

The integrity of bivalents is crucial for accurate chromosome segregation. However, recent work
in human oocytes reveals that the structure of bivalents tends to be disintegrated in the oocytes
of older women [5154]. In both mice and humans, bivalents experience two major structural
defects with age (Figure 4A). First, sister kinetochores separate by large distances, which
correlate with the discordant and often incorrect attachment of sister kinetochores to the
meiotic spindle. Second, bivalents from aged oocytes more frequently split into individual
chromosomes, called univalents. Pairs of univalents can segregate in an uncoordinated
manner and may also contribute to aneuploidy. Interestingly, it is possible for both defects
to result in a reverse segregation pattern, as we discuss below.
Sister Kinetochore Separation Promotes Incorrect Alignment to the Meiotic Spindle
Sister chromatids in mouse and human oocytes lose cohesion with age, which may lead to
incorrect alignment of bivalents in meiosis I [5157]. The kinetochores of sister chromatids within

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TICB 1284 No. of Pages 14

(A)

Young bivalent

Aged bivalent
Loss of distal cohesin

Cohesin
Cohesin

Kinetochores
orient together

Shugoshin

Loss of
proximal
cohesin
Sister kinetochore
separaon
Sister kinetochore
separaon

Kinetochores
orient together

(B) Correct alignment

Premature
bivalent spling

Cohesin

Cohesin

Normal segregaon

Oocyte

(C)

Twisng

PB1

Half-inverted

(D) Weak distal cohesion

Oocyte

Fully inverted

PB1

Reverse segregaon

Bivalent spling
Oocyte

(E)

Univalents

PB1

Reverse segregaon

Oocyte

PB1

Figure 4. Structural Changes and Alternative Alignments of Meiotic Chromosomes. (A) A model for the agerelated structural changes bivalent chromosomes in mammalian oocytes might experience. Left panel: a bivalent from the
oocyte of a young female. Distal cohesin binds homologous chromosomes together and proximal cohesin associates the
kinetochores of sister chromatids to orient together. Shugoshin (Sgo) proteins localize to both pericentromeric regions of
sister chromatids and protect proximal cohesin from removal in anaphase I. Right panel: a bivalent in the oocyte of older
females. Distal cohesin is lost and homologous chromosomes separate. Proximal cohesin deteriorates and sister
kinetochores separate by large distances. Sgo is less able to protect cohesin in pericentromeric regions. (B) Bivalents
take on unusual alignments in the meiotic spindle. For correctly aligned bivalents, each pair of sister chromatids align to the
same spindle pole. Half-inverted bivalents form when one pair of sister chromatids is attached to microtubules from
opposing spindle poles, leading to unbalanced segregation patterns. In fully inverted bivalents, both pairs of sister
chromatids are bound to opposite spindle poles and may lead to a reverse segregation pattern. (C) Twisting of homologous
chromosomes in the bivalent might strain cohesion between chromosomes. (D) In some bivalents, homologous chromosomes are separated by large gaps. This might indicate weak cohesion between homologous chromosomes. In extreme
cases, bivalents can split into two univalents. (E) Univalents form when bivalents prematurely split into pairs of homologous
chromosomes. Univalents in human oocytes often align on the meiotic spindle where sister chromatids bind microtubules
from opposite spindle poles, which might lead to reverse segregation.

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bivalents separate by a mean distance of 0.20.4 mm in oocytes of young mice, and this distance
can double in aged mice [54,56,58]. Recent observations found that, in women of all ages, sister
kinetochores of bivalents can separate by as much as 2.0 mm, and the frequency of separated
sister kinetochores greatly increases with maternal age [5153]. Sister chromatids that are
loosely associated may no longer function correctly when aligning on the meiotic spindle. In
human oocytes, sister kinetochores that segregate tend to form more merotelic attachments
to spindle microtubules (Figure 3B) [52]. In addition, other age-related pathways might promote
defective kinetochoremicrotubule attachments [59].
The extreme separation of sister kinetochores in human oocytes allows bivalents to take on
unexpected alignments in the meiotic spindle. In a newly identied conguration of bivalents
termed inverted bivalents [52], the bivalents are rotated to the spindle axis: the sister
chromatids of a homologous chromosome incorrectly orient as in mitosis, binding microtubules from opposing spindle poles instead of orienting towards the same spindle pole
(Figure 4B). Both half- and fully inverted bivalents are observed. Only one pair of sister
chromatids bind opposite spindle poles in half-inverted bivalents, while both pairs are bound
to opposing poles in the fully inverted bivalents. Inverted bivalents are more frequently
observed in oocytes from older women and correlate with increased distances between
sister kinetochores [52]. Fully inverted bivalents could lead to a reverse segregation pattern,
because the sister chromatids are oriented apart on the spindle, similar to mitosis (Figure 4B)
[29,52]. Bivalents also sometimes appear twisted along their axis because homologous
chromosomes rotate with respect to each other, which might exert further strain on already
weakened cohesion (Figure 4C) [52].
Bivalents with Decreased Distal Cohesion Can Prematurely Split into Univalents
Age-related cohesion loss within bivalents is not restricted to pericentromeric regions surrounding kinetochores. Cohesion linking homologous chromosomes is also compromised. Homologous chromosomes within bivalents are frequently separated by large gaps in the oocytes of
older mouse and human females [52,54,60]. These structural defects indicate weak cohesion
between homologous chromosomes in the bivalent. In more extreme cases, bivalents sometimes prematurely split into two individual chromosomes (univalents) before anaphase I
(Figure 4D) [52,54,60]. The prevalence of univalents increases dramatically with age, occurring
in 40% of oocytes from women older than 35 compared with 10% of oocytes from women
3035 years of age [52]. In mouse oocytes, problems aligning univalents may contribute to
chromosome segregation errors [60]. Univalents in mouse and human oocytes can also align on
the rst meiotic spindle with both sister kinetochores facing towards opposite spindle poles, in a
similar manner to mitotic chromosomes (Figure 4E) [52,54,6163]. This could lead to a segregation pattern similar to mitosis and result in reverse segregation: equal segregation of both
univalents into sister chromatids will result in a correct number of chromosomes acquired by the
oocyte and rst polar body, but the chromatids will be of different parental origins (Figure 4E)
[29,52,54]. However, the sister chromatids are already split and cannot align correctly to the
spindle in metaphase II.
The molecular mechanisms that might cause these dramatic age-related changes to chromosome architecture in human oocytes are still unknown (see Outstanding Questions).
Studies in mice identied cohesin loss as a major contributor to age-related aneuploidy
(Figure 4A) [56,6466]. Rec8-containing cohesin complexes in mouse oocytes are already
present during DNA replication in the early stages of meiosis. It is thought that they are only
replenished after fertilization, when DNA is replicated again in the embryo [6769]. Therefore,
cohesin complexes must remain in place throughout the protracted period of dictyate arrest
to ensure correct chromosome segregation in meiosis. The levels of Rec8 are markedly
decreased on the bivalents of oocytes from naturally aged mice [55,56]. Oocytes experience a

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TICB 1284 No. of Pages 14

drastic increase in segregation errors when levels of Rec8 on bivalents become nearly
undetectable by microscopy [56]. Pericentromeric Sgo2 is also decreased on the bivalents
of oocytes from older female mice [55]. This might indicate that proximal cohesins are
unprotected from Separase cleavage in meiosis I [60]. While many of the molecular details
regarding human meiotic chromosomes are unknown [57], these chromosomes experience
similar age-related structural changes to those observed in mouse [5154]. It will be vital to
understand how cohesin is depleted from chromosomes to prevent these mechanisms from
acting (see Outstanding Questions) [70].

Age-Independent Causes of Aneuploidy

Aneuploidy affects not only eggs from older women, but also those from younger women since
eggs produced by young women in the prime years of reproductive potential are still frequently
defective. Eggs donated by young women for IVF often produce embryos with aneuploidy
[43,71] and many individuals with Down's syndrome are born to mothers under the age of 35
[72,73]. Depending on the study, 361% of oocytes from women younger than 30 years of age
are affected by aneuploidy [7476], suggesting that oocytes are intrinsically more prone to errors
than are mitotic cells [77] or spermatocytes [45,46] (see Outstanding Questions). What primes
human oocytes for aneuploidy?
Spindle Assembly Checkpoint[2_TD$IF] in Oocytes Is Less Stringent than in Mitosis
Accurate chromosome segregation depends on the correct attachment of spindle microtubules
to kinetochores. In metaphase I, bivalent chromosomes align between the two spindle poles
(Figure 2A). Each pair of sister kinetochores of a bivalent must be attached to the same spindle
pole, while homologous chromosomes must be attached to opposing spindle poles. Kinetochores may form incorrect microtubule attachments, which are destabilized to allow for correct
attachments to form [78]. During this process, kinetochores that are unattached to spindle
microtubules are sensed by the spindle assembly checkpoint (SAC), which only licenses cells to
progress into anaphase if all kinetochores are attached to spindle microtubules [79]. However,
mammalian oocytes can proceed through meiosis despite misaligned chromosomes (see
Outstanding Questions) [80]. In mouse oocytes, misaligned chromosomes merely delay the
progression of meiosis [63,8183], while correct spindle attachments are sometimes incorrectly
destabilized [82,84]. Human oocytes with misaligned chromosomes also progress efciently into
anaphase [52].
Why is the SAC pathway permissive to misaligned chromosomes in mammalian oocytes? The
alignment of chromosomes on the metaphase spindle takes several hours in mammalian
oocytes. Evidence from mouse oocytes suggests that increasing activity of CDK1 in complex
with Cyclin B stabilizes microtubule attachments and deactivates SAC arrest [82,84]. This may
explain why oocytes are allowed to progress into anaphase despite chromosome alignment
errors.
Spindle Instability and Transient Multipolar Spindle Stages Impede Chromosome
Microtubule Attachments
Recent work revealed that the spindle in human oocytes is frequently unstable, forming transient
multipolar intermediates that correlate with segregation errors [85]. Somatic cells undergoing
mitosis nucleate spindle microtubules from two centriole-containing centrosomes. Through a
related mechanism, spindles assemble from acentriolar microtubule organizing centers
(aMTOC) in mouse oocytes [86]. Human oocytes are devoid of prominent microtubule organizing centers and instead nucleate microtubules from chromosomes and kinetochores [85].
Microtubules project outward from chromosomes and undergo extensive reorganization as
they assemble into a spindle (see Outstanding Questions). Spindles are often unstable and tend
to fragment into multiple poles [85]. Interestingly, multipolar spindles have been implicated in the

10

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TICB 1284 No. of Pages 14

aneuploidy of cancer cells [87,88]. Transient multipolar stages are suggested to promote
merotelic attachments, which occur when kinetochores bind to spindle microtubules from
multiple spindle poles (Figure 3B). Indeed, merotelically attached chromosomes are common
in human oocytes, and might form during the reorganization of transient multipolar spindles
(Figure 3C) [85]. Spindle instability and merotelic attachments may also be favored by the
specialized organization of sister kinetochores in human oocytes, which are often separated by
large gaps instead of being closely associated, even in oocytes from young women [5154].
Compared with bivalents in which each pair of sister kinetochores form single microtubule
attachment sites, extensive error correction and spindle reorganization may be required to
correctly align bivalents with four sister kinetochores interacting independently to spindle microtubules. Therefore, separated sister kinetochores may increase the probability of abnormal
kinetochore microtubule attachments.
Homologous Recombination Inuences Chromosome Cohesion in the Bivalent
Suboptimal positioning of crossover sites may cause weak association of chromosomes
within the bivalent, making them prone to segregation errors [3,89,90]. The placement of
crossover sites varies between species and genders. In human females, chromosomes tend
to have more crossover sites than in males, and longer chromosomes form more crossovers
than shorter ones [26,29,91]. When crossover sites form close to telomeres, reduced
amounts of cohesin may link homologous chromosomes, while crossover sites within
centromeres may compromise sister chromatid cohesion, or prevent the removal of cohesins, causing NDJ errors [9295]. Two crossover sites that form in close proximity might
also lead to weak cohesion between homologous chromosomes. However, crossover
interference was reported in several studies where two crossover sites tended to form
further away than what would be expected by chance [26,29,91]. This mechanism may help
to decrease the probability that homologous chromosomes are only weakly associated
during meiosis I.

Outstanding Questions
What are the evolutionary pressures
that have shaped mammalian meiosis
to be intrinsically prone to chromosome mis-segregation?
What are the mechanisms controlling
the gradual deterioration of chromosome structures?
What are the similarities and differences in the molecular changes observed
in bivalents of oocytes from aged mice
compared with those from aged
humans?
Why is the spindle assembly checkpoint less stringent in mammalian
oocytes?
Why are spindles in mammalian
oocytes assembled by different mechanisms compared with mitotic cells?
How will new technologies shape
human reproduction in the near future?

Concluding Remarks
Human oocytes frequently experience chromosome segregation errors in meiosis that result in
aneuploidy. As women [8_TD$IF]become older, their oocytes lose the potential to give rise to viable
embryos. Several pathways contribute to errors in meiosis. Age-related changes to the structure
of chromosomes in oocytes promote incorrect attachments of chromosomes to the meiotic
spindle and the premature splitting of bivalents before cell division. What is the cause of these
age-related structural changes? In mice, cohesin complexes deteriorate from the chromosomes
of oocytes during aging. Whether this is also the case for human oocytes remains to be
conrmed. Nevertheless, is the age-related loss of [9_TD$IF]cohesin complexes sufcient to explain
the dramatic increase in segregation errors that occurs in oocytes of older women? Indeed,
several age-independent pathways also promote errors in meiosis, and insensitivity to meiotic
checkpoint activation, instability of the meiotic spindle, in addition to defects in homologous
recombination likely compound the risk of chromosome segregation errors in oocytes and
aneuploidy in embryos. A greater understanding of aneuploidy in humans may provide opportunities to therapeutically counteract the age-related deterioration of chromosome structures in
human oocytes. However, until a treatment is developed, biology obligates women to conceive
before fertility is lost.
Acknowledgments
It was the authors intention to write an article accessible to a wide audience while also including as many new and exciting
studies as possible. We would like to apologize for any omissions, because these were unintentional or due to space
limitations imposed by the journal. We thank Agata Zielinska and other members of the Schuh lab for critical review of this
article. M.S. and A.W. have received nancial support from the Max Planck Society, the European Research Council under
grant agreement no. 337415, and the Lister Institute for Preventive Medicine.

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