Structural chromosomal abnormalities Flashcards
Structural abnormalities
· Translocations
>reciprocal
>robertsonian
· Inversion · Deletion · Duplication · Ring chromosome · Isochromosomes · Micro-deletions/duplications
What is a reciprocal translocation?
Exchange of genetic material between non-homologous chromosomes (non-homologous end joining- NHEJ)
e.g. double strand break of chromosome 11 and chromosome 15, and segments are exchanged between the chromosomes.
What are the chromosomes produced from reciprocal translocation (NHEJ) called?
Derivative chromosomes
Balanced reciprocal translocation
equal exchange of chromosome segments between non-homologous chromosomes
-no net gain/loss of genetic material
Unbalanced reciprocal translocation
unequal exchange of chromosome segments between non-homologous chromosomes
-net gain/loss of genetic material
What causes CML (chronic myeloid leukaemia)?
Balanced reciprocal translocation between:
- chromosome 9 (ABL= proto-oncogene)
- chromosome 22 (BCR= breakpoint cluster region)
Philadelphia chromosome produced, and fusion of ABL and BCR leads to an activated oncogene causing cancer
Consequence of balanced reciprocal translocation
Most carriers of balanced translocation usually don’t have a deleterious phenotype unless breakpoint affects regulation of a gene.
However, carrier of balanced translocation is at risk of producing unbalanced offspring. Unbalanced individuals at significant risk of chromosomal disorder.
How are balanced individuals produced?
Reciprocal Translocation in Meiosis:
- derivative chromosomes in metaphase I align in BIVALENT, producing either normal gametes or balanced reciprocal translocations when they split
- UPON FERTILISATION, you can either end up as normally diploid or a balanced carrier (usually not deleterious)
How are unbalanced individuals produced?
Reciprocal Translocation in Meiosis:
-derivative chromosomes in metaphase I align by forming a PACHYTENE QUADRIVALENT structure
- all 4 pieces of genetic material are involved in the alignment
- chromosomes can separate along horizontal or vertical line, resulting in a net loss or gain of genetic material either way →unbalanced
- UPON FERTILISATION, you can end up with partial trisomy or partial monosomy in the zygote (some will miscarry, others go to term resulting in developmental disorders)
Clinical result of unbalanced reciprocal translocation
Upon fertilisation, you can end up with partial trisomy or partial monosomy in the zygote
Many lead to miscarriage
Learning difficulties, physical disabilities
Tend to be specific to each individual so exact risks and clinical features vary
What is a Robertsonian translocation?
the exchange of genetic material between two acrocentric chromosomes resulting in the loss of the p arms (satellites) and the bringing together of the two q arms around a single centromere
-chromosomes 13,13,15,21&22
Consequence of a Robertsonian translocation
Results in 45 chromosomes
However, because the only genetic material lost are the satellites, the cell can still function normally without them
Why are Robertsonian translocations not deleterious?
because p arms only encode multiple copies of rRNA meaning it is not deleterious to lose them
Most common Robertsonian translocation
13-14 and 14,21
Link between Robertsonian Translocation and Downs syndrome
21;21 translocation leads to 100% risk of Down syndrome in foetus
Consequences of Robertsonian Translocation in Meiosis: 14q21q
During meiosis, chromosomes align in metaphase I by forming a TRIVALENT STRUCTURE
Daughter cell could end up with the normal copy of chromosome 14 and 21- in which case, the gamete can go on to form a normal child after fertilisation. Or, perhaps the daughter cell just has the translocated chromosome (carrier). Again, this gamete is capable of forming a normal child.
However, it could be that when the chromosomes segregate in meiosis I, the daughter cell ends up with 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. This results in Down’s syndrome.
There are three other ways in which these chromosomes can segregate but these will either result in monosomy of one of the chromosomes or trisomy 14- all which are incompatible with life.
Chromosomal inversion
An inversion is where there are two breakpoints within the same chromosome and when these are repaired the middle section is “upside down”.
Chromosomal duplication
A duplication is where you get a region of the chromosome repeated e.g. globin gene family.
Ring chromosome
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.
Chromosomal deletions
Deletions occur either from the end of the chromosome (terminal) or from within the end of the chromosome (interstitial).
-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
What do chromosomal deletions cause?
A region of monosomy
>Haploinsufficiency of some genes
>Monosomic region has phenotypic consequences
>Phenotype is specific for size and place on deletion
How are gross deletions seen?
on a metaphase spread on G-banded karyotype
Microdeletions/duplications
· 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
How do microdeletions/duplications arise?
- deletions and duplications arise after the homologous chromosomes don’t align exactly next to one another (misalignment) in meiosis I,
- resulting in unequal crossing over (non-allelic recombination).
- it results in a loss and gain of particular loci/genes on the resulting gametes. Two chromatids, therefore, remain the same and two are altered.
What technique is used to detect microdeletions/duplications?
FISH can’t detect any deletions smaller than 5Mb.
Array CGH on the other hand can detect much smaller deletion events (kilobases).
