Robertsonian Translocations Flashcards
What two types of balanced rearrangements are there?
Those unqiue to individual/family if inherited onwards.
Those observed in popultion.
Collectively 1/1000
What type of recurrent genetic abnormality
Robersonian Transloations.
Present in 1/1000
What are robersonian translocations?
Unbalanced translocations between acrocentric chromosomes.
(13, 14, 15, 21 and 22)
How can robertsonian translocations arise?
Repetative sequences located in the acrocentric P arms of those chromosomes and those repetative sequences mediate illegitimate recombination events that can repair DNA damage and they can result in fusion of one acrocentric chromosome to another because those repeated sequences have an inverted orientation.
So what does robersonian translocation result in? and what do the vast majority of robertsonian translocation occur between?
The rearrangement fuses 2 acrocentric long arms together.
Only one centromere is active. The other is deactivated.
Acentric fragment - repetitive DNA and the rDNA genes is lost.
Non-homologous chromosomes. i.e 13 fused to 14 or 13 fused to 15.
But also get homologous - 21q fused to another 21q.
Why are robersonian translocation considered unbalanced?
As a small acentric fragment consisting of satellited parm material is lost.
What is on the robersonian fragment?
Microsattilite DNA and rDNA genes - you can do without them
Male carriers of robersonian translocations
Will form abnormal structures in meiosis 1 - disruptive to spermatogenesis.
Grow up normal, but when it come times to establish family, likely to not establish clinically recognised pregnancy.
usually failure to establsh pregnancy from male robersonian carriers is due to the structure in meiosis one disrupting spermatogenesis which leads to reduced sperm count in semen and occasially no sperm.
Which are the two robersonians which are common?
Fusion between chromosome 14 and 21. - second most common (10% of all carriers of robertsonian translocations).
Fusion between chromosome 13 and 14 - most common
both count for 80-85% for all robersonian translocations.
Why are these two fusions the most common?
Theres a special mechanism that governs how these are formed.
Thought to be a similar distinct mechanism responsible for the others.
To do with micro-homology repeats.
How would the 14;21 be formed?
Satellites (tandem repeated DNA sequences) present in p11 of acrocentric ch’s
I, II, III, and IV.
β-satellite
Formation of the nucleolus brings above sequences together
Mal segregation leads to genomic imbalance
Get
Getting microhomology. Micro satillited mediated DNA damage repair illegitimately (refers to not repairing damage from a homolog - using nonhomologous chromosom).
What do rDNA genes do?
Come together to form the nucleolus at a specific point in the cell cycle.
Efficient way of transcribing a cluster of genes really efficiently and quickly.
rDNA genes alll colocalise for form the nucleolus, as they are doing that theyre dragging the chromosomes along with them.
Explain why Robertsonian Translocations are most common genetic rearrangement in humans?
This is why all of these repetitive sequences end up in the same point in 3D space, at the same time. Combination of that lolocalisation, repetitive DNA, damage being formed, inverted repeats which means robertsonian translocations are most common (as a class) genetic rearrangement in humans. Why present at such high frequency (1:1000).
Describe Mal segregation
WHen pachytene cross is formed, that pachytene cross those chromosomes want to segregate along the longest axis where the chromosomes are paired. in certain reaggremented like 11;22 rearragment. If you get 3:1 mal segregation of that structure you are at significant risk of developing specific genetic disease (Emanuel syndrome)
Mal segenreation of Robertsonian and how is it different?
Difference - only have 3 functional centromere with Robertsonian translocation whereas for balanced rearrangements you have 4. Massively scews towards mal segregation events for these rearragements.
Is trisomy 15 viable?
No
WHen you form a trisomic conceptus what will the zygote go through?
A lot of mitotic cell divisions. Stuff can still go wrong which can have an impact.
What error can drive formation of aneuploid gamete formation?
Chromosome non-disjunction - which can resue an imbalance.
Mitotic non-disjunction (NDJ) post fertilisation.
Can correct monosomic and trisomic abnormalities.
Describe how a robertsonian translocation can become viable?
A female is carrier of 14;15 Robertsonian translocation.
The three way pairing structure is liable to 2:1 mal segregation, and this can lead to trisomy of 14 or 15 – both inviable. But lets say the segregation occurs either side of this axis, resulting in this gamete after MII.
After fertilisation, a zygote is forms, that has 2 copies of chromosome 14 (one copy in the robertsonian chromosome, the other from the male gamete) and three copies of chromosome 15 (2 from mum, and 1 from dad).
It’s possible for a mitotic non-disjunction event to correct this genomic imbalance in one cell line. For example if both sister chromatids of the paternal chromosome 15 co-segregated to remove this genetic content from 1 daughter cell, then this daughter cell would have a balanced complement of chromosomes.. The cell line would have 2 copes of 14q and 2 copies of 15q..
But – both copies of chromosome 15 are derived from the mother!
WHich chromosome is a classic imprinted chromosome
Chromosome 15.
Whats one way Pradawillis and angelmann syndrome be caused?
By mitotic NDJ rescue events of robersonian translocations (chromosome 15?)
What are the three things to consider for carriers of Robersinian translocations
- Only three centromere, massively at risk of NDJ events in meiosis - form unbalanced gametes. Those unbalanced gamete lead to trisomic conceptions some of which pose a risk to live born with severe genetic disorders.
- Mitotic NDJ events after fertilisation. Can have impact on foetus because, depending on when mitotic NDJ event occurs you can create mosaicism in either placenta or foetus or both. Certain trisomys start to become viable such as 21. If downsyndrome present in all cells viable, if mosiac severity of disease significantly diminished.
- Imprinted regions of genome.
Which diseases are caused by uniparental disomy?
Ch14 UPD (mat/pat: Temple Syndrome)
Ch15 UPD (mat:PWS pat:AS)
Ch7 UPD (mat: Silver-Russell Syndrome)
Ch11 UPD (pat: BWS)
Ch16 Special case (+16 affects 1.5% of all
pregnancies!): UPD or CPM! Reading
However, these diseases can also arise from other abnormalities in the genome.
