Structural Chromosomal Abnormalities Flashcards
List the structural abnormalities.
Translocations - Reciprocal - Robertsonian Inversion Deletion Duplication Rings Isochromosomes
What is translocation?
Exchange of two segments between non-homologous chromosomes
Can be reciprocal or Robertsonian
How does translocation due to inappropriate NHEJ happen?
There are DNA mechanisms within the cell which monitor genome integrity and when they detect a fault, will repair that fault.
However, what happens very occasionally is that instead of joining together the correct two bits, the DNA repair mechanism happens to stitch together the chromosome in incorrect pairs
What we see therefore is most of one chromosome, with the end of another chromosome attached and vice verse in this chromosome
The DNA repair mechanism is called “non-homologous end joining”: end joining because it’s joining together two ends and non-homologous because it’s irrespective of the DNA sequence joined together
These are also known as balanced translocations
It’s thought that they form spontaneously during meiosis
The key characteristic is that there is no net gain or loss of genetic material – it’s all there, just in a different place.
They can involve any chromosome and the fragments can be of any size
They are relatively common – estimates suggest that they occur in 1 in 930 people
Can a balanced translocation have negative effects? Give an example?
Yes
Philadelphia chr = abnormal chr22
Leads to Chronic myeloid leukaemia (CML)
BCR=breakpoint cluster region on chr22 (Function of normal protein product not known)
ABL=proto-oncogene on chromosome 9
Fusion of these two genes now on chromosome 22 leads to an activated oncogene
What are the consequences of reciprocal translocations in meiosis? I promise it makes sense in the lecture
A reciprocal translocation means that there is no loss or gain of material and so there’s often little consequence to the cell of carrying a reciprocal translocation.
However – that changes when we look at what happens to these chromosomes during meiosis.
Here we have a pair of chromosomes, chromosomes 11 and 22 and we have a reciprocal translocation at this point here.
In meiosis, you might be lucky in that the way the chromosomes separate is like this or this – where the correct amount of each chromosome goes into the resultant cell.
However, if we think about how these chromosomes pair up before separating, we find that they form this structure called a pachytene quadrivalent
What can happen is that the chromosomes separate along this horizontal blue line, resulting in one cell having a gain in yellow chromosome and a loss of the end of the purple chromosome; the other daughter cell has a loss of the end of the yellow chromosome and gain of the purple chromosome.
Alternatively, the chromosomes could separate along this vertical blue line.
Again, this will result in an unbalanced arrangement where, in each daughter cell, there is loss of one end of a chromosome and gain of the end of the other chromosome.
The exact consequences of inheriting a unbalanced rearrangement depend on the particular chromosomes involved and the size of the translocated material.
What are the results of unbalanced reciprocal translocation?
Many lead to miscarriage (hence why a woman with a high number of unexplained miscarriages should be screened for a balanced translocation)
Learning difficulties, physical disabilities
Tend to be specific to each individual so exact risks and clinical features vary
What is Robertsonian translocation?
When two acrocentric chromosomes break at or near their centromeres, when the fragments are joined together again it’s possible for just the two sets of long arms to be brought together and there’s loss of the satellites.
This is called a Robertsonian translocation.
These are chromosomes 13, 14, 15, 21 & 22
Most common Robertsonian translocation involves chromosomes 13 and 14, which accounts for approximately 1/3 of all Robertsonian translocations
Results in loss of two short arms and fusion of the two long arms, with either one or two centromeres
The resultant chromosome usually contains the long arms of different chromosomes (unusual to see, for example, the maternal and paternal long arms of chromosome 13 fused together)
What are balanced and unbalanced Robertsonian translocations like?
Two acrocentric chromosomes join near centromere with the loss of p arms
Balanced carrier has 45 chromosomes
If 46 chromosomes present including Robertsonian then must be unbalanced
p arms encode rRNA (multiple copies so not deleterious to lose some)
Robertsonian translocations 13;14 and 14;21 relatively common. 21;21 translocation leads to 100% risk of Down syndrome in fetus
What are the possibilities of combinations of Robertsonian translocation between chromosomes 14 and 21 during meiosis? Again this makes sense with the diagram
It could be that the daughter cell ends up with the normal copy of chromosome 14 and 21 – in which case, this gamete can go on to form a normal child after fertilisation.
Or, perhaps the daughter cell just has the translocated chromosome. Again, this gamete is capable of forming a normal child.
However, it could be that when the chromosomes segregate, the daughter cell ends up containing the normal chromosome 21 plus the translocated chromosome. After fertilisation, these will be joined by another chromosome 14 and a chromosome 21 – resulting in a normal number of chromosomes 14, but triploidy of chromosome 21. As you know, this will result in Down’s syndrome.
There are three other ways in which these chromosomes can segregate but these will either result in monosomy of one or the chromosomes or trisomy 14 – all of which are incompatible with life.
Remember, carriers of Robertsonian translocations can be phenotypically normal and it is possible for them to have a child with a normal chromosomal complement, or even a normal carrier of the same Robertsonian chromosome.
However, couples where one partner is a carrier of a Robertsonian translocation can experience multiple miscarriages because of the way the chromosomes segregate, leading to loss of a chromosome or a trisomy which is incompatible with life
How can a baby be born with Down syndrome from translocation?
However, it becomes a problem in the context of forming gametes, because although there’s the correct amount of genetic material, the chromosomes can’t segregate properly.
If you’re lucky, the gamete will contain the normal chromosomes, or the robertsonian chromosome
If you’re unlucky then the gamete will contain one of these combinations.
Most of them will be lethal
But upon fertilisation with a normal gamete, this cell will have 2 copies of chromosome 14, which is fine, but 3 copies of chromosome 21 – and will therefore be a Down’s baby.
This will be a “normal” Down’s baby in that the phenotype will be similar to a Down’s which is the product of non-disjunction.
Approximately 4% of Down’s patients are because of Robertsonian translocations and 95% are due to non-disjunction.
What are the general outcomes of translocations?
Very difficult to predict
Only have approximate probability of producing possible gametes
Some unbalanced outcomes may lead to spontaneous abortion of conceptus so early that not seen as problem
Some unbalanced outcomes may lead to miscarriage later on and present clinically
Some may result in live-born baby with various problems
What are some other structural changes in chromosomes?
There are some other types of structural changes which are summarised here
The first two are deletions, either from the end of the chromosome (terminal deletion) or from within a chromosome (interstitial deletion)
If the end of the chromosome is lost then the only way the chromosome can be made stable is if a new telomere is added; without the telomere the cell will die
An inversion is where there are two breakpoints within the same chromosome and when these are repaired the middle section is “upside down”
A duplication is where you get a region of the chromosome repeated – you’ll probably be familiar with this in terms of the globin gene family
A ring chromosome is where you get two breaks in the same chromosome and that non-homologous end joining mechanism joins the two ends of the large chunk together, resulting in a ring.
What are chromosomal deletions like?
1:7000 live births
Deletion may be terminal or interstitial
Causes a region of monosomy
Haploinsufficiency of some genes
Contiguous gene syndrome (multiple, unrelated clinical features)
Phenotype is specific for size and place on deletion
Gross deletions seen on metaphase spread on G-banded karyotype
What are microdeletions like?
Many patients had no abnormality visible on metaphase spread
High resolution banding, FISH and now CGH showed ‘micro’ deletions
Only a few genes may be lost or gained
What happens during unequal crossing over?
When you get exchange of genetic material between homologous pairs of chromosomes but they have not aligned properly
Simultaneous deletion and duplication
