Chromosomal Abnormalities II

Question 1

Outline structural chromosomal abnormalities

Answer 1

• Translocations
  - Reciprocal
  - Robertsonian
• Inversion
• Deletion
• Duplication
• Rings
• Isochromosomes
• Microdeletions/Microduplications

Question 2

Outline the mechanism of structural changes in chromosomes

Answer 2

1. Double strand DNA breaks
2. Occur throughout cell cycle
3. Generally repaired through DNA repair pathways in G2 phase
4. Mis-repair leads to structural abnormalities

Question 3

What are reciprocal translocations?

Answer 3

chromosomes

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

Question 4

Give an example of non-homologous end joining

Answer 4

1. Plus copy of normal 1 and normal 22
2. Double strand break occurs at chr.1 and chr.22
3. Due to close proximity chr.1 segment joins onto chr.22
   and vice versa forming derivative chromosomes (der)
4. Carrier of balanced translocation = normal copy of both
   chr. 1 and chr.22 present as well as derivatives

Question 5

What are derivative chromosomes?

Answer 5

Derivative chromosomes are a mixture of 2 chromosomes

Question 6

What is meant by a balanced translocation?

Answer 6

No net gain or loss of genetic material - have right amount just in incorrect place

Question 7

What is NHEJ?

Answer 7

The DNA repair mechanism is called “non-homologous end joining”: joins together two ends irrespective of DNA sequence joined together - balanced translocations

Question 8

When does NHEJ occur?

Answer 8

Forms spontaneously during meiosis

Question 9

Give an example of a ‘harmful’ balanced translocation?

Answer 9

Philadelphia chr = abnormal chr22

Leads to Chronic myeloid leukaemia (CML)

Question 10

What loci are involved in the philadelphia gene translocation?

Answer 10

BCR = breakpoint cluster region on Chr.22 (Function of normal protein product not known)

ABL = protooncogene

Question 11

Outline how philadelphia gene leads to CML

Answer 11

Reciprocal translocation occurs and they’re brought together to generate a fusion gene (BCR-ABL)
The BCR activates the ABL to become an oncogene which leads to uncontrolled cell division and cancer

Question 12

When do reciprocal translocations produce deleterious phenotypes?

Answer 12

Usually no deleterious phenotype unless breakpoint affects regulation of a gene

Question 13

What is the consequence of unbalanced translocations?

Answer 13

Carrier of balanced translocation at risk of producing unbalanced offspring

Unbalanced individuals at significant risk of chromosomal disorder

Question 14

How do homologous chromosomes normally create genetic variation during meiosis?

Answer 14

Homologous chromosomes line up during metaphase I in meiosis to form bivalents in order to exchange material

Question 15

How is crossing over affected in derivative chromosomes?

Answer 15

Derivative chromosomes form quadrivalents rather than bivalents

Question 16

How does a reciprocal translocation effect DNA content?

Answer 16

Reciprocal translocation means no material loss / gain ⇒ often little consequence to the cell carrying a reciprocal translocation.
However – that changes during meiosis.

Question 17

Describe how no net gain / loss can occur in reciprocal translocation offspring?

Answer 17

In meiosis, the chromosomes may separate where the correct amount of each chromosome goes into the resultant cell

Question 18

Why is no net gain/loss unlikely to occur in reciprocal translocation offspring?

Answer 18

Before separating, chromosomes line up forming a structure called a pachytene quadrivalent and separate unequally

Question 19

What is the consequence of quadrivalent formation in meiosis?

Answer 19

Results 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.

Question 20

What is the effect of inheriting an unbalanced chromosome?

Answer 20

The exact consequences of inheriting a unbalanced rearrangement depend on the particular chromosomes involved and the size of the translocated material

Question 21

Describe the clinical results of unbalanced reciprocal translocations

Answer 21

• Many lead to miscarriage
  (women with a high no. of unexplained miscarriages should be screened for balanced translocation)
• Learning difficulties, physical disabilities
• Specific to each individual; risks + clinical features vary

Question 22

What are robertsonian translocations?

Answer 22

Loss of satellites due to only the long arms being joined together again after chromosomes break at / near their centromeres

Question 23

Describe no. of chromosomes in a robertsonian carrier

Answer 23

Balanced carrier has 45 chromosomes

If 46 chromosomes present including Robertsonian then must be unbalanced

Question 24

What is the net loss of genetic material in robertsonian translocations?

Answer 24

The only genetic material lost are satellites; p arms encode rRNA (multiple copies so not deleterious to lose some)

Question 25

Which type of chromosomes are affected by robertsonian translocations?

Answer 25

Only affects acrocentric chromosomes – centromere near chromosome tip (Chr. 13, 14, 15, 21 & 22)

Question 26

What are common robertsonian translocations?

Answer 26

Robertsonian translocations 13;14 and 14;21 relatively common. 21;21 translocation leads to 100% risk of Down syndrome in fetus

Question 27

What is a centromere?

Answer 27

Part of chromosome attaching to the spindle during cell division; not always in the middle.

Question 28

What are the 5 acrocentric chromosomes?

Answer 28

Of note is the fact that there are 5 acrocentric chromosomes: 13, 14, 15, 21 and 22.

Question 29

What are the normal outcomes of a robertsonian translocation between chromosomes 14 and 21?

Answer 29

1. Daughter cell end up w/ normal chr. 14 and 21: gamete can form normal child after fertilisation 2. Daughter cell only has translocated chromosome: gamete capable of forming a normal child

Question 30

How does a robertsonian translocation between chromosomes 14 and 21 cause Downs?

Answer 30

1. Chromosomes segregate 2. Daughter cell contains normal chr. 21 and translocated chromosome 3. After fertilisation, these are joined by another chr. 14 and chr. 21 = normal no. of chr. 14, but trisomy of chromosome 21. ⇒ Down’s syndrome

Question 31

How do lethal combinations of robertsonian translocations between Chr. 14 and 21 occur?

Answer 31

Other chromosome segregations will result in monosomy of one of the chromosomes or trisomy 14 – all incompatible with life

Question 32

Explain how robertsonian translocations can lead to msicarriage

Answer 32

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

Question 33

Outline the numerical and structural causes of Trisomy 21 Downs syndrome

Answer 33

Trisomy 21 due to NDJ 3 full copies - numerical abnormality Trisomy 21 due to Robertsonian Translocation Chr.21 also on chr.14 as well as 2 normal copies of chr.21 leading to a trisomy - structural abnormality

Question 34

Outline the outcomes of unbalanced translocations

Answer 34

- Spontaneous abortion of conceptus; so early its not seen as problem - Miscarriage later on and present clinically - Live-born baby with various problems

Question 35

How can we fix a chr. that has lost an end?

Answer 35

If end of a chr. is lost, only way to make it stable is adding a new telomere; without the telomere the cell will die

Question 36

What is duplication?

Answer 36

Duplication - a region of chromosome is repeated e.g. globin gene family

Question 37

What is inversion?

Answer 37

Inversion - 2 breakpoints within the same chromosome and when repaired the middle section is “upside down”

Question 38

What is a ring chromosome?

Answer 38

A ring chromosome - 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 39

What are the effects odf chromosome deletions?

Answer 39

Deletion may be terminal or interstitial Causes a region of monosomy - Haploinsufficiency of genes - Monosomic region has phenotypic consequences - Phenotype specific for size + place on deletion

Question 40

How can we view gross deletions?

Answer 40

Gross deletions seen on metaphase spread on G-banded karyotype

Question 41

How are microdeletions visualised?

Answer 41

Many patients had no abnormality visible on metaphase spread | High resolution banding, FISH and now CGH showed ‘micro’ deletions

Question 42

What are microdeletions / microduplications?

Answer 42

Only a few genes may be lost or gained – contiguous gene syndrome

Question 43

Outline common microdeletion syndromes

Answer 43

``` Velocardiofacial 22q11(DiGeorge, Shprintzen) Wolf-Hirschhorn 4p16 Williams 7q11 Smith-Magenis 17p11 Angelman 15q11-13 (mat) Prader-Willi 15q11-13 (pat) ```

Question 44

What is the effect of non-allelic crossing over?

Answer 44

Non-allelic unequal crossing over occurs causing a loss / gain of loci on resulting gametes 2 are altered while 2 are normal (causing deletions or duplications)

Question 45

What is array cgh?

Answer 45

Microarrays created by deposit and immobilization of probes on a solid support e.g. glass slide, in an ordered fashion.

Question 46

How big are array CGH probes?

Answer 46

Probes vary in size from oligonucleotides;areas of interest (25–85 base pairs) to genomic clones;bacterial artificial chromosomes (80,000–200,000 base pairs)