Summary
Summary chromosomal abnormalities
- Module
- Medicine
- Institution
- Cambridge University (CAM)
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Discuss the causes and consequences of numerical and structural chromosomalabnormalities. (40 minutes)
Chromosomal aberrations refer to a mutation involving a large portion of the
chromosome, of which there are two types: numerical and structural. They can affect
somatic and germ cells. This essay seeks to discuss the causes and consequences of
numerical and structural chromosomal aberrations/ abnormalities including the clinical
conditions which each can give rise to.
Cells which may be affected
If chromosomal aberrations (structural or numerical) arise as a somatic mutation, then
this will only affect a proportion of the foetal cells. This is referred to as mosaicism.
During development, this may occur in the placenta and result in the embryo having a
perfectly normal chromosome constitution but will result in the placenta having a
different genotype to the foetus – this is called confined placental mosaicism. However if
the mutation arises in the germ cell, all the cells of the foetus (which inherits this) will be
affected.
Numerial aberrations: overview
A somatic cell is said to have a numerical aberration if it has an abnormal number of
chromosomes – this can be polyploidy (i.e. has a chromosomal number which is an exact
multiple of the haploid number) or aneuploidy (i.e. chromosomal number is not an exact
multiple of the haploid number). One consequence of both aneuploidy and polyploidy is
that the cell that is recognised as having an abnormal chromosomal number can result in
spontaneous miscarriage. 95% of spontaneous miscarriages are thought to be due to
numerical aberrations – 60% of this is due to trisomies, 20% due to 45,X (Turner’s
syndrome) and 15% due to polyploidy, especially triploidy (see later).
Causes and consequences of polyploidy
Two examples of polyploidy are triploidy and tetraploidy. Triploidy may be caused by
dispermy (i.e. two sperm trying to enter one ovum) which occurs in 66% of triploid cases.
Another cause whole genome non-disjunction during meiosis i.e. due to a diploid sperm
(24% of cases) or diploid ovum (10% of cases). Tetraploidy is very rare and always lethal
– it is caused by failure to undergo the first zygotic division, yet the cell still undergoes
cell replication thus resulting in a 4n chromosome number. This affects males most
severely and most of affected males die.
Females however are less severely affected due to X chromosome inactivation
(silencing)/dosage compensation where one X chromosome is silenced to prevent
overexpression of genes found on the X chromosome. The X chromosome to be silenced
expresses a RNA Xist gene which triggers a hierarchy of epigenetic events resulting in
,chromatin modifications to condense the X chromosome thereby inactivating it. Lyon’s
hypothesis states that a condensed X chromosome is always inactive, whether this
silenced X chromsome is from the mother/father is random and there is a stable
inheritance of this silenced X chromosome to the daughter cell (i.e. memory). Some
genes however escape inactivation e.g. PAR1 and PAR2 genes found between the tips of
X and Y chromsomes, as well as 20% of all X chromosomal genes found in humans. They
escape and behave like autosomal genes.
Causes and consequences of aneuploidy
Aneuploidy is when genes have an abnormal chromosomal number which is not a
multiple of the haploid number. The ultimate cause of aneuploidy is meiotic
non-disjunction i.e. the failure of chromosomal segregation during meiosis. This can
occur in meiosis I (primary non-disjunction) or meiosis II (secondary non-disjunction).
This is illustrated below:
The image on the left shows primary non-disjunction i.e. failure to separate
chromosomes in meiosis I. Secondary non disjunction i.e. failure to separate
chromosomes in meiosis II.
One type of aneuploidy is trisomy i.e. when there are three sets of a chromosome
(instead of two). The most common aneuploidy that is compatible with life is Trisomy21
otherwise known as Downs’ Syndrome. This is characterised by an extra set of
chromosomes on chromosome 21 – in 90% of cases this is due to maternal inheritance
(likelihood of maternal inheritance increases with maternal age), in 4% of cases it is due
to paternal inheritance and the rest of the time it occurs post fertilisation. Affected
individuals often have memory and learning difficulties, characteristic craniofacial
alterations, epilepsy, congenital heart malformations and more.
Other common aneuplodies are Turner’s Syndrome, Klinefelter’s syndrome and XYY
syndrome. Turner’s syndrome (45,X or 45,XO) affects females where they are missing an
X chromosome and tend to have a short stature, webbed neck and are infertile.
Klinefelter’s syndrome affects males who have an XXY genotype and may have
gynecomastia, often tall and thin and are also infertile. Males having an XYY genotype is
an aneuploidy where affected males may have an increased velocity of growth but have
normal fertility and testosterone levels – it doesn’t cause any (significant) clinical
problems but is merely an abnormality.
STRUCTURAL ABERRATIONS
Causes
There are many subtypes of structural aberrations which will be discussed: 1)
translocations 2) duplications/deletions 3) inversions.
,Translocations is the transfer of genetic material between chromsomes due to breakage
of both chromosomes either during repair or accidental recombination during meiosis.
They can be balanced, unbalanced, reciprocal or Robertsonian. Balanced translocations
cause no significant loss/gain of DNA – it simply causes the fusion of genetic material
which is normally unlinked. It has no clinical problems but may cause unbalanced
gametes in future offspring. However unbalanced translocations do cause a significant
gain/loss in DNA. Robertsonian translocations are due to two breaks in an acrocentric
chromosome just above the centromere. This can result in dicentric chromosomes or
acocentric chromosomes (which have no centromere therefore cannot undergo mitosis).
This creates no clinical problems but does mean that future offspring are at risk of
unbalanced gametes. Reciprocal translocations are usually an exchange of genetic
material between two non-homologous chromosomes – they are usually harmless too
and often discovered through pre-natal testing.
Duplications are when there is an extra copy of a segment on a chromosome which
usually arises from unequal crossing over. Its reciprocal product is a deletion and it can
result in copy number variables.
Inversions are when there are two breaks in a chromosome and a 180 degree rotation of
the segment. This may be paracentric i.e. chromosomal breaks occur in one arm above
the centromere, or pericentric i.e. chromosomal breaks occur on either side of the
centromere. It may change the gene order but poses no clinical problems – with the
exception of a risk of unbalanced gametes in future offspring.
Consequences of structural aberrations
One consequence of unbalanced translocations can result in partial trisomy 21 however
this is different from Downs syndrome in the sense that it is not associated with maternal
age. A consequence of reciprocal translocation in the Philadelphia chromosome is the
exchange of genetic material between chromosomes 9 and 22. 95% of patients with
chronic myeloid leukaemia have this translocation. The ABL on 9q being juxtaposed on
the 22q in BCR creates a BCR-ABL hybrid gene which encodes a novel chimaeric protein
in chromosomal cells. Its persistent activity is responsible for neoplastic
transformations.
A consequence of deletion is the 22q11.2 microdeletion syndrome (i.e. the most common
microdeletion syndrome) which occurs in 1:4000 births. It can result in schizophrenia,
hypoparathyroidism as well cardiac and craniofacial abnormalities. The syndrome can
be mediated by LCRs (low copy repeats – highly homologous sequence repeats,
otherwise known as segmental duplications).
To conclude, there are two types of numerical aberrations – polyploidy (e.g.
triploidy/tetraploidy) and aneuploidy. Aneuploidies are caused by meiosis
non-disjunction. This can result in clinical conditions such as Trisomy 21, Turner’s
, syndrome, Klinefelter’s syndrome and XYY syndrome. There are several types of
structural aberrations e.g. translocations, duplications, deletions and inversions. They
can result in clinical conditions such as 22q11.2 microdeletion syndrome and partial
trisomy 21. Some aberrations do not have any clinical consequences but can give rise to
unbalanced gametes in future offspring.
Discuss the causes and consequences of numerical and structural chromosomal
abnormalities. (40 minutes)
Chromosomal aberrations refer to a mutation involving a large portion of the
chromosome, of which there are two types: numerical and structural. They can affect
somatic and germ cells. This essay seeks to discuss the causes and consequences of
numerical and structural chromosomal aberrations/ abnormalities including the clinical
conditions which each can give rise to.
Cells which may be affected
If chromosomal aberrations (structural or numerical) arise as a somatic mutation, then
this will only affect a proportion of the foetal cells. This is referred to as mosaicism.
During development, this may occur in the placenta and result in the embryo having a
perfectly normal chromosome constitution but will result in the placenta having a
different genotype to the foetus – this is called confined placental mosaicism. However if
the mutation arises in the germ cell, all the cells of the foetus (which inherits this) will be
affected.
Numerial aberrations: overview
A somatic cell is said to have a numerical aberration if it has an abnormal number of
chromosomes – this can be polyploidy (i.e. has a chromosomal number which is an exact
multiple of the haploid number) or aneuploidy (i.e. chromosomal number is not an exact
multiple of the haploid number). One consequence of both aneuploidy and polyploidy is
that the cell that is recognised as having an abnormal chromosomal number can result in
spontaneous miscarriage. 95% of spontaneous miscarriages are thought to be due to
numerical aberrations – 60% of this is due to trisomies, 20% due to 45,X (Turner’s
syndrome) and 15% due to polyploidy, especially triploidy (see later).
Causes and consequences of polyploidy
Two examples of polyploidy are triploidy and tetraploidy. Triploidy may be caused by
dispermy (i.e. two sperm trying to enter one ovum) which occurs in 66% of triploid cases.
Another cause whole genome non-disjunction during meiosis i.e. due to a diploid sperm
(24% of cases) or diploid ovum (10% of cases). Tetraploidy is very rare and always lethal
– it is caused by failure to undergo the first zygotic division, yet the cell still undergoes
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