Origins Of Aneuploidy & UPD Flashcards
What causes most occurrences of aneuploidy?
Meiotic non-disjunction.
In females which stage of meiosis do aneuploidies usually occur? Why?
Meiosis I.
Meiosis is paused here from early fetal development and does not resume until ovulation, this may be 15-45 years later.
What is thought to cause non-disjunction?
Altered genetic recombination - reduced recombination between chromosomes or an alteration in the location and number of chiasmata.
How do we know which stage of meiosis an aneuploidy is likely to have occurred?
Meiosis I - homologues fail to separate and therefore chromosomes resulting from this type of error will be heterozygous.
Meiosis II - sister chromatids fail to separate and so an error here will result in chromosomes which are homozygous.
What are the 3 main mechanisms behind non-disjunction?
- True non-disjunction - failure of chiasmata so homologues don’t separate
- Achiasmate - absence of chiasmata between pairs
- PSSC - premature separation of sister chromatids.
What is PSSC or premature separation of sister chromatids?
- Rather than being joined together, sister chromatids are separate and act independently. It has been linked to increased maternal age!
- It occurs when homologues fail to pair in meiosis I. Univalent’s are then prone to separating.
- because the result can be aneuploidy with homozygous chromosomes, it can look like a meiosis II error when in actual fact the error occurred at meiosis I with PSSC.
What is the outcome if non-disjunction occurs after the 1st meiosis e.g. 2nd onwards?
Possibly 3 cell lines - normal, trisomy and monosomy.
The later it occurs, the higher the % of normal cells.
The monosomy cell line would likely die off due to the affected chromosome not having anything to pair up with. It would replicate slowly and eventually die off.
How can mosaicism occur?
Mitotic non-disjunction
A rescue event in an initially aneuploid fetus.
Give an example of how trisomy rescue could occur? What could be clinically important about this?
Anaphase lag.
The 3rd chromosome lags behind either as the chromosomes are connecting to the spindle or it lags behind as they are segregating to poles. The lagging chromosome is not included when the new nuclear membrane forms. It is then lost.
This would be clinically relevant if the chromosomes that remain both originated from the same parent! E.g. UPD
How clinically significant is mosaicism?
Depends on the level and distribution amongst tissues.
If mosaicism is very low level, does this mean it is not clinically relevant? Why?
No. It could be in very low levels but if it is present in a key tissue it can be clinically important e.g. in the brain of a patient with learning difficulties or an abnormal cell line confined to the gonad.
What would raise suspicion of gonadal mosaicism?
Two siblings with the same ‘de novo’ abnormality.
Give an example of a tissue specific mosaic.
Tetrasomy 12p - mosaic isochromosome 12p.
Pallister Killian syndrome.
Abnormal cell line seen in AF, BM and fibroblast but exceptionally rare in lymphocytes.
What is UPD? What are the subtypes?
Uniparental disomy - both copies of a particular chromosome are inherited from the same parent.
Uniparental Isodisomy - 2 copies of the SAME homologue e.g. genetically identical (SNP arran can detect)
Uniparental heterodisomy - 2 copies are from same parent but they are heterozygous chromosomes e.g. genetically different (most common)
What mechanisms mainly generate UPD?
What are the more obscure ones?
Main:
- gamete complementation (almost never!)
- trisomy rescue (most ‘common’)
- monosomy rescue
- mitotic error
Rare:
- correction of interchange monosomy or trisomy
- isochromosome formation
- correction of imbalance due to additional marker chromosome
