structural chromosomal abnormalities

Question 1

What is a normal human karyotype?

Answer 1

• consists of 22 pairs of autosomes and two sex chromosomes
• similar size and striped chromosome pairs
• arranged from largest to smallest.

Question 2

What are different types of structural abnormalities?

Answer 2

1. translocations
   -Reciprocal
   -Robertsonian
2. inversion
3. Deletion
   4 Duplication
4. rings
5. isochromosomes

Question 3

What is translocation

Answer 3

• exchange of two segments between non- homologous chromosomes
  => Eg. Reciprocal or Roberstsonian

Question 4

Why does translocation occur?

Answer 4

• translocation occurs due to inappropriate non-homologous end joining (NHEJ).
• NHEJ is a type of DNA repair mechanism, when a double strand breaks in DNA, separating chromosome this NHEJ mechanism stick them together repairing it BUT if there is inappropriate NHEJ, chunk of one chromosome gets attached to free end of another forming a new chromosome called ‘derivative chromosome’
• the ‘derivative chromosome’ has one copy of normal chr1 and one copy of normal chr22 so you are a carrier of balanced translocation.
• no net gain or loss in genetic material.

Question 5

Philadelphia chromosome (derivative chr22)

Answer 5

• generated due to translocation between chr9 and chr22
  -ABL proto oncogene found in chr9, it is not oncogenic (cancer causing) when on chr9 but when it translocates to chr22 which contains the BCR gene, the fusion between ABL and BCR in this derivative chr 22 triggers oncogenic potential of ABL.
  -derivative chr 9 is fine.
  => Karyotype : G- banding, derivative chr9 longer than normal and philadelphia chr22 much shorter than it should be.

Question 6

How are unbalanced individuals produced?

Answer 6

• translocation isnt always bad if it is balanced the total is the same just in different places but in unbalanced individuals too much or too little of a chromosome leads to complication

Question 7

What is the consequences of reciprocal translocation in meiosis?

Answer 7

• normal meiosis chromosomes form bivalent but in reciprocal translocation meiosis chromosomes form tetravalent (4)
• mixture of monosomy and trisomy
• monosomy = diploid chromosome complement in which chromosome lacks its homologous partner
• trisomy = extra copy of a chromosome is present causing developmental abnormalities

Question 8

What is the result of unbalanced reciprocal translocation?

Answer 8

• many lead to miscarriage (hence why woman with 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 risk and clinical features vary.

Question 9

Robertsonian translocation.

Answer 9

• type of translocation which involves only acrocentric chromosomes (vey short P arm and normal q arms) because the p arm is so short it is not deleterious if it breaks off bc q arm can cover it but the problem is the two q arms can join together forming Robertsonian chromosome (made up of two arms of q)

Question 10

3 types of chromosomes

Answer 10

1. metacentric = equal p and q arm lenght
2. submetacentric = short p arm and long q arm
3. acrocentric = normal long arm and very small p arm (satellites)

Question 11

What are the 5 acrocentric chromosomes?

Answer 11

-13, 14, 15, 21, 22

Question 12

What is the result of robertsonian translocations?

Answer 12

• two acrocentric chromosomes join near centromere with the loss of p arms
• balanced carrier has 45 chromosomes (not 46 like other translocations) so if there is 46 chromosomes in Robertsonian translocation then it 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% down syndrome in fetus.

Question 13

Trisomy 21

Answer 13

1. non disjunction (NDJ) = 3 full copies of chr21
2. Robertsonian translocation = mixture of chr14 and 21
   => different karyotypes but both results to down syndrome

Question 14

What is the outcomes of translocations?

Answer 14

• 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

Question 15

Other structural changes : deletion

Answer 15

1. Terminal deletion: loss of telomere, new telomere added continues as normal .
2. Interstitial:
   loss of a chunk of chromosome from the middle as oppose to end, the telomere re attaches but a chunk is lost leading to abnormalities like : Prader - willi , DiGeorge syndrome, Cri du chat
   -larger the deletion, easier to detect.

=>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
=>micro deletion: few genes lost or gained, not visible on metaphase spread

Question 16

How do duplications occur?

Answer 16

• unequal crossing over, exchange of material between homologous chromosome but have not aligned properly