Chromosomal Abnormalities II Flashcards
Why and how do we get structural abnormalities in DNA?
The double strand of DNA can break.
This occur throughout cell cycle.
It’s generally repaired through DNA repair pathways.
However, it is the mis-repair that leads to structural abnormalities.
What are reciprocal translocations?
It is the exchange of two segments between non-homologous chromosomes.
It is a balanced translocation – there is no net gain or loss of material.
There is usually no deleterious phenotype unless the breakpoint affects regulation of a gene.
The carrier of a balanced translocation at risk of producing unbalanced offspring.
Unbalanced individuals are at significant risk of chromosomal disorder.
The mechanism by which this occurs is called Non-Homologous End Joining (NHEJ).
Describe the mechanism of translocation due to inappropriate NHEJ.
Translocation is where we happen to have two double strands breaks, each on a different chromosome.
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
What is balanced vs unbalanced exchange?
Balanced = when you have the right amount of each chromosome just maybe not in the expected place.
Unbalanced = when you too much or too little of a particular chromosome.
Describe the consequences of reciprocal translocations in mieosis.
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.
In meiosis, you might be lucky in that the way the chromosomes separate is 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 one ‘line’ (horizontal), resulting in one cell having a gain in the first chromosome and a loss of the end of the other chromosome; the other daughter cell has a loss of the end of the other chromosome and gain of the first chromosome.
Alternatively, the chromosomes could separate along a different ‘line’ (vertical).
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.
The exact consequences of inheriting a unbalanced rearrangement depend on the particular chromosomes involved and the size of the translocated material.
What can be the clinical result of an unbalanced reciprocal translocation?
- it many lead to miscarriage (hence why a woman with a high number of unexplained miscarriages should be screened for an unbalanced translocation)
- can cause learning difficulties, and/or physical disabilities
- they tend to be specific to each individual so exact risks and clinical features vary
What happens in a 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.
As a recap, which chromosomes are acrocentric?
The acrocentric chromosomes are 13, 14, 15, 21 and 22.
What are some features of a Robertsonian translocation?
- two acrocentric chromosomes join near centromere with the loss of p arms.
- a balanced carrier ends up with 45 chromosomes
- if 46 chromosomes are present. including the Robertsonian, then it must be unbalanced
- the p arms encode rRNA (there are multiple copies so not it’s 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 outcomes of translocations?
- they are very difficult to predict
- we 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 (developmental, most of the time)
Besides translocations, list and describe some other chromosomal structural changes.
- terminal deletion: a loss of DNA from the end of a chromosome
- interstitial deletion: a loss fo DNA from the middle of the chromosome
- inversion: where there are two breakpoints within the same chromosome and when these are repaired the middle section is “upside down”
- duplication: where you get a region of the chromosome repeated
- ring chromosome: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
Describe deletions.
It occurs in 1:7000 of live births.
The deletion may be terminal or interstitial. Some examples of clinical presentations caused by interstitial deletions are: Prder-Will, DiGeorge Syndrome and Cri-du-chat.
It causes a region of monosomy:
- haploinsufficiency of some genes
- monosomic region has phenotypic consequences
- phenotype is specific for size and place on deletion
Gross deletions can be seen on a metaphase spread on G-banded karyotype.
Describe microdeletions/ microduplications.
With this, many patients have no abnormality visible on a metaphase spread.
However, thanks to technology advancing to give us high resolution banding, FISH and now CGH can now show ‘micro’ deletions.
Only a few genes may be lost or gained – leads to contiguous gene syndrome.
List some examples of syndromes caused by microdeletions.
Velocardiofacial (DiGeorge, Shprintzen): 22q11
Wolf-Hirschhorn: 4p16
Williams: 7q11
Smith-Magenis: 17p11
Angelman: 15q11-13 (mat)
Prader-Willi: 15q11-13 (pat)
These syndromes can also be caused by other mechanisms that cause deletions.
