31. Chromosomal Abnormalities II

Question 1

Why and how do we get structural abnormalities in DNA?

Answer 1

Double strand DNA breaks

Occur throughout cell cycle

Generally repaired through DNA repair pathways

Mis-repair leads to structural abnormalities

Question 2

What are reciprocal translocations?

Answer 2

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.

So mechanism is called Non-Homologous End Joining (NHEJ)

Question 3

Describe the mechanism of translocation due to inappropriate NHEJ.

Answer 3

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

Question 4

What is balanced vs unbalanced exchange?

Answer 4

Balanced = have the right amount of each chromosome just maybe not in the expected place!

Unbalanced = too much or too little of a particular chromosome

Question 5

Describe the consequences of reciprocal translocations in meiosis?

Answer 5

• 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 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 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.

Question 6

What can be the clinical result of an unbalanced reciprocal translocation?

Answer 6

• 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

Question 7

What happens in a Robertsonian translocation?

Answer 7

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.

Question 8

RECAP: Which chromosomes are acrocentric?

Answer 8

The acrocentric chromosomes 13, 14, 15, 21 & 22

Question 9

What are some features of a Robertsonian translocation?

Answer 9

• 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 foetus

Question 10

What are the outcomes of translocations?

Answer 10

• 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 (developmental, most of the time)

Question 11

Besides translocations, list and describe some other chromosomal structural changes

Answer 11

1. Terminal deletion: a loss of DNA from the end of a chromosome
2. Interstitial deletion: a loss of DNA from the middle of the chromosome
3. Inversion: where there are two breakpoints within the same chromosome and when these are repaired the middle section is “upside down”
4. Duplication: where you get a region of the chromosome repeated
5. 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

Question 12

Describe deletions

Answer 12

1:7000 live births

Deletion may be terminal or interstitial

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 seen on metaphase spread on G-banded karyotype

Question 13

Describe microdeletions/microduplications

Answer 13

With this, 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 – contiguous gene syndrome