Structural Abnormalities Flashcards
Give examples of Structural chromosomal abnormalities
o Translocations
- Reciprocal
- Robertsonian o Inversion o Deletion o Duplication o Rings o Isochromosomes o Microdeletions/Microduplications
What is a reciprocal translocation?
What mechanism does it occur by?
o Exchange of two segments between non-homologous chromosomes
o A physical exchange of a chunk of chromosomes of non-homologous chromosomes
o So mechanism is called Non-Homologous End Joining (NHEJ)
What causes reciprocal translocations?
When do these occur?
Is there a net gain of genetic material?
o Translocation is where we happen to have two double strands breaks, each on a different chromosome.
o There are DNA mechanisms within the cell which monitor genome integrity and when they detect a fault, will repair that fault.
o 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
o What we see therefore is most of one chromosome, with the end of another chromosome attached and vice verse in this chromosome
o The “der” here stands for derivative, meaning “the result”
o The DNA repair mechanism is called “non-homologous end joining”: end joining because it’s joining together two ends and non-homologous beca use it’s irrespective of the DNA sequence joined together
o These are also known as balanced translocations
o It’s thought that they form spontaneously during meiosis
o The key characteristic is that there is no net gain or loss of genetic material – it’s all there, just in a different place.
o They can involve any chromosome and the fragments can be of any size
o They are relatively common – estimates suggest that they occur in 1 in 930 people
o A DNA repair mechanism going wrong
o Copy shown here of chromosome 1 and 22 both undergo a double strand break
o Should be repaired correctly but it isn’t and they get physically exchanged leading to derivative chromosomes.
o So this person is a carrier of a balance translocation without any clinical effect.
o But overall there is no loss or gain of chromosome material
What are balanced and unbalanced chromosomes?
o Balanced = have the right amount of each chromosome just maybe not in the expected place! like the previous slide
o Unbalanced = too much or too little of a particular chromosome potentially a problem
What translocation can occur on the Philadelphia chromosome and what does it cause?
o Philadelphia chr = abnormal chr22
o Leads to Chronic myeloid leukaemia (CML)
o BCR=breakpoint cluster region (Function of normal protein product not known)
o ABL=protooncogene
o Fusion of genes leads to an activated oncogene
o Causes CML
o ABL at the end of chromosome 9 is a protooncogene and so is not causing a problem
o BCR region on chromosome 22 has a tendency to have double stranded DNA breaks
o When you get double stranded breaks so that there is an exchange of material between 9 and 22, it brings the BCR and ABL together in an effusion gene
o That leads to the expression of the ABL gene oncogenic causes cancer
o You can see this on G-staining
What are the results of reciprocal translocations?
o Usually no deleterious phenotype unless breakpoint affects regulation of a gene
o Carrier of balanced translocation at risk of producing unbalanced offspring
o Unbalanced individuals at significant risk of chromosomal disorder
o Offspring are generally at risk
o How are unbalanced individuals produced?
o Balanced carrier to unbalanced zygote
o Meiosis - Consequences of reciprocal translocations
in meiosis
o Robertsonian Translocations
When do unbalanced translocation tend to occur?
What does it cause?
o The problem occurs if a gamete has an intact chromosome and a derivative chromosome
o Then you start to get unbalanced regions
o They will have partial trisomy and partial monosomy
What are the Consequences of reciprocal translocations in meiosis
o 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.
o However – that changes when we look at what happens to these chromosomes during meiosis.
o Here we have a pair of chromosomes, chromosomes 11 and 22 and we have a reciprocal translocation at this point here.
o 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.
o However, if we think about how these chromosomes pair up before separating, we find that they form this structure called a pachytene quadrivalent
o 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.
o Alternatively, the chromosomes could separate along this vertical blue line.
o Again, this will result in an unbalance arrangement where, in each daughter cell, there is loss of one end of a chromosome and gain of the end of the other chromosome.
o The exact consequences of inheriting a unbalanced rearrangement depend on the particular chromosomes involved and the size of the translocated material.
o A and D are the intact copies
o B and C are the derivatives
o They are balanced and it is fine
o But in the production of gametes rather than a bivalence being formed you get a quadrivalent structure where they are looking for their partners
o Then in all depends on how they pull apart the dotted lines show how they can pull apart.
o UNDERSTAND THIS SLIDE
What are the clinical results of unbalanced reciprocal translocation?
o Many lead to miscarriage (hence why a woman with a high number of unexplained miscarriages should be screened for a balanced translocation)
o Learning difficulties, physical disabilities
o Tend to be specific to each individual so exact risks and clinical features vary
o If a women has lots of miscarriages, they will often be a balanced carrier
What’s the centromere?
What do you notice about the position of the centromere?
It’s the part of the chromosome which attaches to the spindle during cell division.
It’s not always in the middle.
o There are terms given to chromosomes depending on where the centromere is: metacentric if it’s in the middle, submetacentric if it’s displaced from the middle and acrocentric if it’s essentially at the end of the chromosome, such that the p arm is just this little stubby satellite structure.
o Of note is the fact that there are 5 acrocentric chromosomes: 13, 14, 15, 21 and 22.
What are Robertsonian Translocations?
If this happens in a cell, how many chromosomes will be have?
What genetic material is lost?
What do P arms encode?
o 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.
45
o The only genetic material we’ve lost are these satellites and the cell can do without those and so this isn’t a problem for the cell.
o Two acrocentric chromosomes join near centromere with the loss of p arms
o Balanced carrier has 45 chromosomes
o If 46 chromosomes present including Robertsonian then must be unbalanced
o p arms encode rRNA (multiple copies so not deleterious to lose some)
o Robertsonian translocations 13;14 and 14;21 relatively common. 21;21 translocation leads to 100% risk of Down syndrome in fetus
What are Consequences of Robertsonian translocations
o In this example, we’re looking at a robertsonian translocation between chromosomes 14 and 21.
o Again, let’s consider what happens to these chromosomes during meiosis
o 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.
o Or, perhaps the daughter cell just has the translocated chromosome. Again, this gamete is capable of forming a normal child.
o 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.
o 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.
o 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.
o 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
o Robertsonian translocation leads to trivalent as there are three chromosomes looking for their partner
o They will then pull apart during anaphase to produce the daughter cells
Robertsonian Translocation & Trisomy 21
When does this cause a problem?
o 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.
o If you’re lucky, the gamete will contain the normal chromosomes, or the robertsonian chromosome
o If you’re unlucky then the gamete will contain one of these combinations.
o Most of them will be lethal
o 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.
o 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.
o Approximately 4% of Down’s patients are because of Robertsonian translocations and 95% are due to non-disjunction.
o There are 3 chromosomes so the daughter cells will get 1 or 2 chromosomes totally random
What are the outcomes of translocations?
o Very difficult to predict
- Only have approximate probability of producing possible gametes
o Some unbalanced outcomes may lead to spontaneous abortion of conceptus so early that not seen as problem
o Some unbalanced outcomes may lead to miscarriage later on and present clinically
o Some may result in live-born baby with various problems
What other structural changes can occur?
o The first two are deletions, either from the end of the chromosome or from within a chromosome
o 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
o There are many examples of disorders caused by loss of chromosomal regions and I’ve listed a few here; you’ll learn more about those next year.
o Inversions and duplications are literally as they’re described:
o An inversion is where there are two breakpoints within the same chromosome and when these are repaired the middle section is “upside down”
o 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
o 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.
o These are due to double stranded breaks not being repaired properly
What are Cri-du-chat?
o 5p minus syndrome
o ID, developmental delay, microcephaly
o Cry of the cat
o Terminal deletion of chromosome 5
o RHS FISH probe designed to anneal to the region of the chromosome that is lost in cri-du-chat it doesn’t fluoresce in the right chromosome as that chromosome has lost that specific region.
o These individuals are haploinsufficient for that region as they are monosomic for those genes
o FISH showing deletion on chromosome 22
o Red probe is specific for the region that is deleted if it is not present then it doesn’t not anneal and so will not fluoresce
o Green probe will show a control
How can we detect Microdeletions/Microduplications?
o Many patients had no abnormality visible on metaphase spread
o High resolution banding, FISH and now CGH showed ‘micro’ deletions
o Only a few genes may be lost or gained – contiguous gene syndrome
o Micro cannot be detected very well with traditional approaches
