Origins of Human Aneuploidy

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Origins of Human
Aneuploidy
Joy DA Delhanty, Institute for Women’s Health, University College London, Lon-
don, UK
Based in part on the previous version of this eLS article ‘Origins of
Human Aneuploidy’ (2010) by Joy DA Delhanty.
Advanced article
Article Contents
• Introduction
• Population Data
• Structural Anomalies Leading to Partial
Aneuploidy
• Developmental Stage of Origin
• Why Do Human Embryos Have Such High Levels
of Chromosome Abnormality?
• Relative Parental Risks – Age, Translocations,
Inversions, Gonadal and Germinal Mosaics
Online posting date: 13th July 2018
At birth, at least 1% of humans have a clinically sig-
nificant chromosomal abnormality. However, this
represents a small fraction of those originally con-
ceived as by the time of birth, natural selection has
eliminated the vast majority of abnormal embryos
and foetuses.
There are three stages in development when ane-
uploidy may arise: during gamete formation, at
fertilisation or during the early stages of embryo
development. Gamete formation differs signifi-
cantly between males and females, affecting the
incidence of aneuploid gametes, which is fourfold
higher in females than in males. Molecular cytoge-
netic techniques have revealed the extent of full
and mosaic aneuploidy in embryos created by in
vitro fertilisation (IVF), explaining the high level
of arrested development affecting these embryos.
Maternal age is the most significant factor affect-
ing the incidence of aneuploidy, but genetic
anomalies in the parents are also important.
Introduction
At birth, approximately 2% of humans have a genetic defect.
Half of these defects involve chromosome imbalance, known as
aneuploidy. Aneuploidy means loss or gain of one or more chro-
mosomes from the usual diploid set. Each somatic cell has 23
pairs of chromosomes, 22 autosomes (nonsex chromosomes) and
a pair of sex chromosomes, XX in females and XY in males.
Aneuploidy can affect any one of these chromosomes; an extra
chromosome is known as trisomy, while one missing is known
as monosomy. Most commonly at birth, aneuploidy involves the
eLS subject area: Genetics & Disease
How to cite:
Delhanty, Joy DA (July 2018) Origins of Human Aneuploidy. In:
eLS. John Wiley & Sons, Ltd: Chichester.
DOI: 10.1002/9780470015902.a0021444.pub2
whole chromosome, but partial aneuploidy also occurs quite fre-
quently due to chromosome breakage and rearrangement. These
cases of full or partial aneuploidy are clinically very significant
and have a huge impact economically and socially. However, they
represent a small fraction of those present in early developmen-
tal stages. By the time of birth, natural selection has eliminated
the vast majority of abnormal embryos and foetuses. At concep-
tion, aneuploidy may affect any chromosome, but only trisomies
of the sex chromosomes or of autosomes 13, 18 or 21, or mono-
somy of the X, are to some extent compatible with survival to
the end of pregnancy, the remainder having been eliminated by
natural selection. Some indication of the high levels of repro-
ductive failure in humans is given by the observation that the
fecundity rate (probability of achieving a clinically recognised
pregnancy within a monthly cycle) is only approximately 25%
(Wilcox et al., 1988). This figure was derived from studying a
group of 220 women, 95% of whom were under 35 years of age
and fertile, who were attempting to conceive. In this group of rel-
atively young women, the rate of identified pregnancy loss, based
on hormonal measurements, was over 30%.
Population Data
For all age groups, clinically recognised pregnancy loss is usu-
ally quoted as 15–20%. It is this fraction of failed pregnancies that
has been extensively studied cytogenetically and in which a chro-
mosome anomaly rate of at least 50% has been found (Hassold,
1986; Popescu et al., 2018). This contrasts with a figure of 5% in
stillbirths, illustrating clearly the selection process that eliminates
95% of chromosomally unbalanced conceptions.
Combining data from cytogenetic studies of spontaneous abor-
tions with those obtained from preimplantation embryos suggests
that chromosomal anomalies are present in 25% of human con-
ceptions, 10-fold higher than is found in other species such as the
mouse (Hassold and Jacobs, 1984; Jamieson et al., 1994; Fragouli
et al., 2013). As examples of full autosomal monosomy are very
rarely found in spontaneous miscarriages, embryos with these
anomalies are thought to fail to implant in the uterus. In addition,
interphase fluorescent in situ hybridisation (FISH) analysis of
3-day-old human embryos created by in vitro fertilisation (IVF)
first showed that up to 50% are chromosomally mosaic, with
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Origins of Human Aneuploidy
Table 1 Incidence of different trisomies at various stages of development
Trisomy Spontaneous abortions (%) Still births (%) Live births (%) Live born (%)
4088 624 56 952
1–12 5.8 0.2 0 0
13 1.1 0.3 0.005 2.8
14 1.0 0 0 0
15 1.7 0 0 0
16 7.5 0 0 0
17 0.1 0 0 0
18 1.1 1.1 0.01 5.4
19 0 0 0 0
20 0.6 0 0 0
21 2.3 1.3 0.13 23.8
22 2.7 0.2 0 0
XXY 0.1 0.2 0.05 53.0
XXX 0.1 0.2 0.05 94.4
XYY 0 0 0.05 100
Mosaics 1.1 0.5 0.02 9.0
Reproduced from Human Cytogenetics, in Embryos, Genes and Birth Defects. eds Ferretti, Copp, Tickle and Moore, 2nd edn., Wiley, 2006.
aneuploid cell lines due to postzygotic errors (Delhanty et al.,
1997; Munné et al., 1998a), further increasing the chance of pre-
and postimplantation failure. A detailed study of very early foetal
losses revealed that mosaic monosomy is a frequent cause of loss
at this stage (Lebedev et al., 2004).
It is interesting to compare the incidence of the various types
of anomalies at different stages, comparing data on spontaneous
abortions (miscarriages), stillbirths and live births (Table 1).
These data are based on large numbers of observations, over
56 000 in the case of live born infants. From these figures a
surviving fraction of those that are live born can be calculated
(Table 1). Half of all chromosomally abnormal miscarriages are
due to trisomy – the presence of an extra chromosome. Triploidy,
the presence of a whole extra set of haploid chromosomes, occurs
in 5–10% of early miscarriages and is almost totally lethal, being
very rare at birth. X monosomy is thought to occur in 1% of
conceptions, but the incidence at birth is reduced to around 1
in 5000. There are clear chromosome-specific variations in inci-
dence (Table 1). The larger autosomes (numbers 1–12) are under-
represented; the one that stands out as most frequently involved
is chromosome 16, followed by chromosomes 22, 21 and 15. Sex
chromosome trisomies do not appear frequently in spontaneous
abortion data, although almost half of the conceptions with a 47,
XXY, karyotype do in fact miscarry, for reasons that are not well
understood. This compares with X-chromosome trisomy with a
survival rate of 94% and 47, XYY, with 100% survival. For the
autosomes, conceptions with trisomies of chromosomes 13, 18
and 21 are the only ones to survive to birth, to varying degrees.
At birth, trisomy 21, leading to Down syndrome, has an incidence
of 1.3/1000, trisomy 13 (Patau syndrome) occurs in 0.05/1000
and trisomy 18 (Edward syndrome) in 0.1/1000. Even for Down
syndrome, the survivors represent less than a quarter of those con-
ceived, and for Patau and Edward’s cases, a mere 3% and 6%,
respectively, are survivors. Mosaic trisomies (embryos or foe-
tuses with more than one chromosomally distinct cell line) are
detected quite infrequently (1.1% of abortions, 0.02% of live born
infants). This probably reflects that fact that analyses are carried
out on small tissue samples in the case of miscarried products and
very few cells in the case of live born infants; they are certainly
underestimates.
Structural Anomalies Leading
to Partial Aneuploidy
Structural anomalies of the chromosomes are also common in the
human population. These are caused by chromosome breakage
andrejoining, either following exchange of segments between
different chromosomes (reciprocal translocations) or after two or
more breaks within one chromosome that can lead to a shift in the
position or reversal of the order (inversions) of the freed segment
of chromosome. Robertsonian translocations are of a particular
type that involves chromosomes 13–15 and 21–22, the so-called
acrocentric chromosomes. In these groups the centromere (pri-
mary constriction where the chromosome attaches to the spindle
during mitosis or meiosis) is close to the end of the chromosome.
The very short segments above the centromere carry little unique
genetic information; breakage at the centromeres of any of these
chromosomes and fusion of the long arms with loss of the short
arms is thus possible without genetic effect. The net outcome is
reduction of the chromosome number by one, but with no pheno-
typic effect on people that are carriers of the balanced form of the
translocation (Figure 1). However, being a carrier of this type of
fusion puts the person at increased risk of producing gametes with
extra or missing copies of the chromosomes that are involved.
As chromosome 21 is commonly one of the chromosomes tak-
ing part in the fusion, the main extra risk in the live born is for
Down syndrome (trisomy 21) (Figure 1). Trisomies of the other
participating chromosomes, numbers 13 and 14 or 15, lead to mis-
carriage.
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Origins of Human Aneuploidy
Robertsonian translocation family pedigree
Robertsonian translocation
der(13;21)(q10;q10)
Miscarriage
Chromosome 13
Chromosome 21
Key
Male Female
Normal
Normal
Carrier
Normal Carrier
Down syndrome Carrier Down syndrome Normal
Figure 1 Robertsonian translocation between chromosomes 13 and 21 leading to a derivative chromosome, der(13;21), with loss of the short arms from
both chromosomes. The derivative chromosome is present in three generations, but the birth of infants with Down syndrome is seen only in the third
generation. Reproduced from Human Cytogenetics, in Embryos, Genes and Birth Defects. eds Ferretti, Copp, Tickle and Moore, 2nd edn., Wiley, 2006.
Reciprocal translocations are carried by about 1 in 500 peo-
ple; Robertsonian translocations as a group are less common
at approximately 1/1000, mostly affecting chromosomes 13 and
14 or 14 and 21. Chromosomal inversions are more rare; exact
incidences are difficult to determine as many remain unde-
tected. Overall, the genetic effect of structural rearrangements is
caused by the increased risk of the production of chromosomally
unbalanced gametes after segregation of paired chromosomes at
anaphase of the first meiotic division. The unbalanced gametes
will lead to the conception of embryos with partial aneuploidy,
either missing certain segments of chromosomes or with extra
pieces, or both. Naturally, such events have deleterious effects on
development and may lead to miscarriage or the birth of infants
with congenital anomalies. The exact risk for a parent is diffi-
cult to quantify as it is frequently unique to the family, but as a
rule of thumb at least half the gametes of a carrier of a structural
rearrangement are likely to be abnormal. See also: Monosomies
Developmental Stage of Origin
There are basically three developmental stages when chromoso-
mal defects that will affect the whole body (constitutional) may
arise: during gamete formation, at fertilisation or in the embryo
before implantation.
The process of gamete formation in humans varies consider-
ably between the two sexes. In males, each cell that enters meiosis
produces four sperm, the process is continuous, taking 64 days
in all. New spermatogonia are constantly being produced so that
once past puberty, the male remains fertile into old age. In con-
trast, the human female is born with a complete set of oogonia;
no more develop after birth. The initial stages of the first meiotic
division take place early in foetal life, but after chromosome pair-
ing and recombination each cell enters a period of arrest until after
puberty. One egg then matures in each monthly cycle. Two very
small cells (the polar bodies, that degenerate) are formed after
each meiotic division so that each oogonium produces a single
mature oocyte. Ovulation occurs when the oocyte is at metaphase
II of meiosis, and completion of the second division only occurs
at fertilisation. Although several million oogonia have developed
by 5 months of pregnancy, most are lost before birth, and only a
few hundred ever mature. Once the egg store is depleted below
a certain level, the menopause begins, and the woman becomes
infertile. These biological differences between male and female
gamete formation are reflected in the varying origins of aneu-
ploidy. The fact that towards the end of her reproductive life the
female is releasing eggs cells that have not been renewed for
decades has an effect on spindle formation and the efficiency with
which the final part of the meiotic process (separation of paired
chromosomes at anaphase I and II) is carried out.
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Origins of Human Aneuploidy
Errors arising during meiosis
The complex behaviour of chromosomes during the two meiotic
divisions provides ample opportunity for errors to arise. Chromo-
some breakage and recombination between nonsister chromatids
during prophase I has two functions – to recombine the genetic
material and to ensure that synapsis between paired chromosomes
persists long enough to allow proper alignment of the bivalent
(paired chromosomes) on the metaphase spindle. In addition,
cohesion needs to be maintained at the centromere of each homol-
ogous chromosome until the second meiotic anaphase, to prevent
early separation of the two chromatids.
Molecular studies of the origin of trisomy using deoxyribonu-
cleic acid (DNA) markers were described for over 1000 con-
ceptions (Koehler et al., 1996). Generally, errors at meiosis I
of oogenesis in the female are the most common, but there are
notable exceptions. Among males with 47, XXY chromosomes
(that causes Klinefelter syndrome), the origin of the extra chro-
mosome is divided almost equally between male and female
parents. In contrast, over 80% of 45, X females (with Turner syn-
drome) lack a paternal sex chromosome (Hassold et al., 1992).
For the autosomes, a paternal origin is evident for a significant
number of trisomies affecting the larger chromosomes, whereas
for trisomy 18, maternal meiosis II errors predominate (Hassold
et al., 1996; Hassold and Hunt, 2001; Table 2). The molecu-
lar studies also provide data on genetic recombination for the
different trisomies. It is clear that unusual recombination pat-
terns are important in the origins of human trisomy, but only a
minority of cases are associated with complete absence of recom-
bination between the chromosomes. Reduced recombination is
associated with all autosomal trisomies that originate from the
mother, as is advanced maternal age. Recent independent studies
also clearly link aneuploidy in oocytes with reduced recombina-
tion (Hou et al., 2013; Ottolini et al., 2015).
Studies on human gametes: the male
gamete
FISH studies on human sperm have taken over from the far
more labour-intensive method of fusing individual sperm with
hamster eggs to allow visualisation of the chromosome set. The
use of multicolour FISH to assess the copy number of two or
three chromosomes at once has enabled chromosome-specific
aneuploidy frequencies of 0.03–0.12% to be obtained for most
chromosomes with the exception of chromosomes 21, 22 and
the sex chromosomes that show higher frequencies (Templado
et al., 2005). The total sperm disomy (extra chromosome present)
is estimated to be 2.2% meaning that 4.5% of sperm would be
expected to have missing or additional chromosomes, as each
disomy isexpected to have a reciprocal nullisomy that is more
difficult to score accurately.
Female gamete
Access to human oocytes is mainly limited to those that fail to
develop following exposure to sperm during IVF after ovarian
stimulation or those that are immature when collected. These
women are usually from a selected population group, couples
with fertility problems, although not necessarily affecting the
female. One advantage of oocytes is that they are at metaphase
of meiosis II when obtained, allowing direct study of the chro-
mosomal complement; this has allowed the accumulation of data
from routine cytogenetic analysis. However, the disadvantage of
this approach is the risk of loss of chromosomes when spread-
ing chromosomes from a single cell on a slide. More recent data
has been obtained using a molecular approach – that of compara-
tive genomic hybridisation (CGH). CGH involves comparing the
DNA of a test sample (in this case the oocyte) with that from
normal female cells to find out whether extra or missing chromo-
somes are present in the test sample. The DNA from each has
first to be amplified many times to allow analysis. CGH anal-
ysis of 100 unfertilised oocytes indicated an aneuploidy rate of
22% (Fragouli et al., 2006), fourfold higher than that of the male.
Interestingly, there was a clear bias towards aneuploidy involving
the smaller autosomes and the X-chromosome, the latter affect-
ing particular patients. The smaller autosomes will have fewer
points of crossing over and therefore may be more suscepti-
ble to premature separation of paired chromosomes, increasing
the chance of nondisjunction. The particularly high frequency of
X-chromosome anomalies in the oocytes of some women may
reflect a genetic difference. See also: Monosomies
Table 2 The parental origin of human trisomies determined by molecular analysis
Trisomy No. of cases Paternal meiosis (%) Maternal meiosis (%) Mitotic (%)
I II I II
2 18 28 – 54 13 6
7 14 – – 17 26 57
15 34 – 15 76 9 –
16 104 – – 100 – –
18 143 – – 33 56 11
21 642 3 5 65 23 3
22 38 3 – 94 3 –
XXY 142 46 – 38 14 3
XXX 50 – 6 60 16 18
Reproduced from Human Cytogenetics, in Embryos, Genes and Birth Defects. eds Ferretti, Copp, Tickle and Moore, 2nd edn., Wiley, 2006.
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Origins of Human Aneuploidy
Mechanisms of maternal aneuploidy
Classically, aneuploidy of meiosis I origin was assumed to arise
from the failure of (paired) homologous chromosomes to sepa-
rate at anaphase I (nondisjunction). An alternative hypothesis was
proposed by Angell, based on cytogenetic analysis of oocytes
(Angell, 1991). From her observation that oocytes contained
additional or missing chromatids (half chromosomes) rather than
whole chromosomes, Angell proposed that early separation of
chromatids before anaphase I, with subsequent random assort-
ment to the oocyte and first polar body, is the main mechanism
of aneuploidy induction in the human female (Figure 2). Sub-
sequent molecular and cytogenetic analysis of IVF oocytes has
shown that nondisjunction of whole chromosomes as well as that
of chromatids does also occur frequently, but chromatid anoma-
lies are particularly prevalent in women of advanced maternal age
(Handyside et al., 2012). This has been associated with gradual
loss of the cohesin protein that holds sister chromatids together
with ageing of the oocytes (Lister et al., 2010). An additional
chromatid or chromosome in the oocyte has genetically indistin-
guishable effects, but as an extra chromatid can pass either to the
mature oocyte or to the polar bodies, the chromatid nondisjunc-
tion will only lead to aneuploidy 50% of the time (Figure 2). The
presence of unpaired, univalent, chromosomes has been shown
to be a factor predisposing to aneuploidy in the mouse (Hunt
et al., 1995). Such chromosomes can either pass intact, and ran-
domly, to the spindle poles or can divide into their component
sister chromatids, which can then undergo normal separation or
nondisjunction (Figure 2). Univalent chromosomes may exist at
metaphase I because of pairing or recombination anomalies in a
normal (disomic) oogonium, but they may also occur with greater
frequency if the cell is originally trisomic. Fully trisomic individ-
uals that reproduce are very rare, but gonadal mosaicism for a
trisomic cell line in an otherwise normal individual may be more
frequent than has been realised. The ability to use molecular cyto-
genetic (FISH) techniques for specific chromosomal analysis of
the oocyte and the corresponding first polar body has for the first
time provided cytological evidence of gonadal mosaicism for tri-
somy 13 and 21, leading to multiple conceptions with trisomy 21
in one case (Cozzi et al., 1999; Mahmood et al., 2000). Gonadal
mosaicism would lead to an increased risk of an aneuploid con-
ception irrespective of maternal age.
Overall, meiosis in the female is obviously more error prone
than in the male; this could result from looser checkpoint con-
trol at the metaphase/anaphase transition in female mammals, a
suggestion for which some experimental evidence exists in the
mouse (LeMaire-Adkins et al., 1997).
Fertilisation
Triploidy is frequent in humans, estimated to occur in 1% of con-
ceptions (Hassold, 1986). Almost all triploid conceptions end in
miscarriage during the first trimester of pregnancy, but a propor-
tion of those where the additional haploid set is of maternal origin
have a longer survival. About two-thirds of triploids are due to
dispermy, the remainder are caused by failure to extrude the first
or, more usually, the second polar body (Zaragoza et al., 2000).
The 45, X anomaly that causes Turner syndrome in live born sur-
vivors is also present in approximately 1% of conceptions; again
almost all miscarry. As stated previously, 80% lack the paternally
contributed sex chromosome. However, the exact cause of the
Precocious division of chromatids
Diakinesis I Anaphase I
Metaphase II
or
Figure 2 Diagram of female meiosis to illustrate premature separation of chromatids. Two pairs of homologous chromosomes are shown, but one pair
is not closely paired during prophase I of meiosis; this predisposes to early separation of the constituent chromatids of one of the unpaired chromosomes
before the first anaphase. The separated chromatids can then migrate at random to the primary oocyte or first polar body, causing aneuploidy in the mature
gamete. Reproduced from Human Cytogenetics, in Embryos, Genes and Birth Defects. eds Ferretti, Copp, Tickle and Moore, 2nd edn., Wiley, 2006.
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Origins of Human Aneuploidy
anomaly is not fully understood and may well frequently involve
a fault at the time of, or soon after, fertilisation.
Embryogenesis
Almost all data on chromosome anomalies in early human
embryos come from analysis of those created by IVF. After fer-
tilisation, the embryo undergoes successive cleavage divisions,
to consist of 6–10 cells by day 3 and maybe over a 100 by
day 5 when blastocyst formation occurs, with separation of the
inner cell mass and the trophectoderm. This is the stage when
implantation should occur. The embryo proper is derived from
the inner cell mass, the placenta from the trophectoderm. Unlike
mouse embryos, most human fertilised eggs in culture do not
become blastocysts, but arrest in development at an earlier stage.
Advances in analysis of the chromosomes were driven by the
need to develop preimplantation genetic diagnosis (PGD). It
became possible to remove one or two cells from the embryo
by day 3 of development and use these for diagnosis (Handy-
side, 1991). Metaphase preparation was not technically possi-
ble, but the application of FISH analysis to interphase nuclei
rapidly became the method of choice when sexing the embryo to
avoid X-linked disease or detecting chromosome anomalies.Flu-
orescently labelled chromosome-specific DNA probes allowed
the copy number of individual chromosomes to be determined
for each cell. It quickly became apparent that chromosomal
mosaicism, as well as aneuploidy, was rife in the day 3 embryo
(Delhanty et al., 1993; Munné et al., 1994). The embryos could be
divided into different classes: completely diploid for the chromo-
somes examined, uniformly aneuploid and mosaic. The mosaics
could be further subdivided into those which were originally
diploid but developed an aneuploid line by mitotic nondisjunc-
tion or chromosome loss, those that were originally aneuploid and
similarly became mosaic and a third group that were designated
‘chaotic’ because the chromosome content varied randomly from
cell to cell with no discernible mechanism (Harper et al., 1995).
With the aim of screening for several aneuploidies simultane-
ously in older women undergoing routine IVF, interphase FISH
employing up to eight chromosome-specific probes was devel-
oped (Munné et al., 1998a). Mosaicism levels greater than 50%
were then detected, raising the question, were there any human
embryos created by IVF that had completely normal chromo-
somes by day 3 of development? The answer could only be
obtained by finding a way to determine the chromosome consti-
tution of every cell from a series of good quality human embryos
at the cleavage stage (up to day 3).
The approach developed was that of CGH applied to individual
cells (blastomeres) from day 3 embryos, after first amplifying the
whole genome of each cell. Twelve good-quality day 3 human
embryos were then separated into single cells, and the combi-
nation of amplification and CGH was then applied to obtain a
complete picture of the chromosome constitution of each individ-
ual cell. The results were remarkable (Wells and Delhanty, 2000).
Most notable was that 3 of the 12 embryos were completely
euploid and had no chromosome imbalance. One was uniformly
double aneuploid (trisomy 21 and X monosomy), one had 3 of
the 4 cells with chromosome one monosomy. Overall, eight were
mosaic, of which two showed a ‘chaotic’ pattern. It seemed likely
Table 3 Results of chromosome analysis by single-cell CGH in
two series of human cleavage stage embryos
London,
UKa
Melbourne,
Australiab
Normal 3 3
Aneuploid throughout 2c 3c
Mosaic at least 50% abnormal 3c 2c
Mosaic less than 50% abnormal 2 3
Chaotic 2c 1c
Meiotic anomaly 4 3
Total mosaic 8 8
Total embryos 12 12
aWells and Delhanty (2000).
bVoullaire et al. (2000).
cLikely to be lethal.
Reproduced from Human Cytogenetics, in Embryos, Genes and Birth
Defects. eds Ferretti, Copp, Tickle and Moore, 2nd edn., Wiley, 2006.
that of the seven containing all or a majority of cells with abnor-
mal chromosomes, four had a meiotic origin. All these types of
abnormalities had been detected by interphase FISH analysis, but
an unexpected finding was evidence for chromosome breakage
in two embryos, with reciprocal products in sister cells in one
case. In the same year, a parallel study was carried out in Mel-
bourne, producing remarkably similar results (Voullaire et al.,
2000; Table 3). These results, and more recent analyses (Fragouli
et al., 2013), have confirmed all the earlier FISH data and pro-
vided an answer as to why so many embryos created by IVF fail
to develop beyond the cleavage stage. We cannot determine how
far a similar situation applies to embryos conceived by natural
means, but the poor fecundity in humans suggests that a some-
what similar scenario may apply.
Why Do Human Embryos Have
Such High Levels of Chromosome
Abnormality?
The frequency and type of postzygotic errors leading to
mosaicism that has been consistently observed in human
cleavage stage embryos is totally unlike any observed in cul-
tured somatic cells, suggesting that the mechanisms operating
are peculiar to this stage of development. The fact that these
embryonic cells resemble tumour cells in terms of chromosome
instability led to the suggestion that the normal cell cycle check-
points are not operating during early cleavage divisions of the
embryo (Delhanty and Handyside, 1995). Cell cycle checkpoints,
first identified in yeast, would normally be expected to protect
cells from genetic damage by ensuring that successive phases
of the cell cycle and of mitosis are completed before the next is
initiated (Hartwell and Weinert, 1989; Murray, 1992). In cancer
cells or those transformed in culture, these checkpoints are often
defective, allowing the accumulation of secondary chromosomal
and other genetic defects. The human embryo largely relies on
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Origins of Human Aneuploidy
transcripts from the oocyte until global activation of the embry-
onic genome at the 6–8 cell stage on day 3 (Braude et al., 1988),
whereas in the mouse, this takes place earlier, at the two-cell
stage, possibly explaining the relative lack of such widespread
mosaicism in that species.
Relative Parental Risks – Age,
Translocations, Inversions, Gonadal
and Germinal Mosaics
In the population as a whole, the most important risk factor for a
chromosomally abnormal conception is advanced maternal age.
Among recognised pregnancies, the main association is with tri-
somy; there is no increased risk with age for triploidy or mono-
somy X. When estimates of maternal-age-specific rates of tri-
somy were calculated, the outcome suggested that in women aged
40 or more, the majority of oocytes may be aneuploid (Hassold
and Chiu, 1985). The causes of age-related aneuploidy have been
much debated, and various hypotheses have been proposed, but
although some experimental evidence has been obtained, a clear
understanding of the problem remains elusive. Evidence obtained
from studying recombination patterns of chromosome 21 in tri-
somic foetuses from younger and older women suggest that the
types of susceptible patterns are similar in both age groups. This
observation has led to the proposal for a ‘two-hit’ hypothesis,
relevant at least for certain of the common trisomies (Hassold
and Hunt, 2001). The first ‘hit’ is a recombination pattern of the
type that is associated with an increased risk of nondisjunction,
whereas the second ‘hit’ involves failure to resolve the difficulties
created by the susceptible recombination, in some way related to
the increased age of the meiotic cell.
Couples at specifically increased risks of a chromosomal
anomaly are those where one partner carries a chromoso-
mal rearrangement such as a translocation or an inversion, as
described earlier. These couples require genetic counselling,
and in most cases appropriate prenatal diagnosis can be offered
ensuring that an ongoing pregnancy is chromosomally balanced.
However, a minority of such couples experience repeated early
miscarriages or primary infertility; for this subgroup, preimplan-
tation diagnosis with selective transfer of embryos is appropriate
(Conn et al., 1998, 1999; Munné et al., 1998b).
A second group of couples at high risk of conceiving a chromo-
somally abnormal child are those where one partner is a gonadal
or germinal mosaic for a trisomic cell line. For example, if 30%
of the primary oocytes (or spermatocytes) are trisomic, then 15%
of gametes formed would be expected to have an extra copy of
the chromosome, as there is inevitable ‘nondisjunction’ in a tri-
somic cell. Couples with several conceptions involving the same
trisomy provide clear evidence for gonadal mosaicism for a tri-
somic cell line affecting the primordial germ cells (Cozzi et al.,
1999), but informative studies on oocytes show that germinal
mosaicism is not an uncommon finding (Obradors et al., 2010;
Ghevaria et al., 2014). Much of this is thought to arise during the
extensive mitotic divisions of the oogonia in early embryonic life,
and so may finally affect only a single oocyte. See also: Chro-
mosomal Numerical Aberrations; Trisomy
Glossary
Aneuploidy The presence or absence of a single chromosome
in a cell.
EmbryogenesisThe early development of an embryo
immediately after fertilisation, characterised by mitotic
division.
Monosomy The absence of one member of a chromosome pair
in a cell.
Mosaicism The presence of cells with more than one genetic
lineage in a population of cells.
Trisomy The presence of an additional member of chromosome
pair in a cell.
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Further Reading
Delhanty JDA (2001) Preimplantation genetics: an explanation for
poor human fertility? Annals of Human Genetics 65: 331–338.
Delhanty JDA (2007) Mechanisms of aneuploidy induction in ooge-
nesis and early embryogenesis. Fetal & Maternal Medicine Review
18 (2): 85–101.
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errors. In: Jorde LB, Little PFR, Dunn MJ and Subramaniam S
(eds) Encyclopedia of Genetics, Proteomics and Bioinformatics,
online edn. Chichester, UK: Wiley.
Hunt PA and Hassold TJ (2008) Human female meiosis: what makes
a good egg go bad? Trends in Genetics 24 (2): 86–93.
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