large structural rearrangements Flashcards
why are rearrangements usually transmitted through maternal line?
spermatogenesis is inhibited by large structural rearrangements
what is a robertsonian translocation
an unbalanced rearrangement between two acrocentric chromosomes
what is a non-homologus robertsonian translocation?
q arm of one chromome fused to q arm of another- 10 possible combinations
what is a homologus robertsonian translocation
2 q arms of the same chromosome fuse- only 5 possible translocations
why is the loss of chromsosome part tolerated?
p arm of acrocentrics contains lots of repteitive sequences
what is the distribution of non-homologous robertsonian translocations?
non-random. 76% are 13;14, 10% 14;21 and the rest are evenly distributed throughout the remaining 8 translocations
what do nuclear organiser regions on p12 do?
allow all acrocentric chromosomes to come together at nucleolous
why is it likely that the ds breaks will occur in the nucleolous?
high level of free radicals, transcription and replication
where are the majority of breakpoints in robertsonian translocations?
proximal to the NOR
how are 13;14 and 14;21 translocations formed?
fusion site for 13;14 and 14;21 are basically homogenous so most likely get homologous recombination between repetitive sequences in opposite direction
how is the orientation of p11.2 satellites important?
there are 4 microsatellites, if they are inverted then will get a dicentric chromosome formed. one centromere is deactivated
what are the 3 possible products from a robertsonian translocation segragation in meiosis I?
- 2 normal, 2 balanced robertsonians 14;21
- 2 disomic 21 and 2 nullisomic 21
- 2 disomic 14, 2 nullisomic 14
what can affect the risk of a child being abnormal for downs?
robertsonian translocations have increased meiotic NDJ likleyhood, also need to account for trisomy and monosomy rescue events, advanced maternal age, adormalities of other chromosomes could also result in NDJ, issues regarding UPD
what is Uni parental isodisomy?
2 copies of the same chromosome from one parent
how does UPD occur?
trisomy rescue or gamete complementation
how does UPID occur?
monosomic rescue, gamete complementation
what are robertsonian translocation carriers at higher risk of?
UPD pregnancies, as predisposed to aneuploid gamete formation
how do UPD and UPID result in disease?
LOH- loses the gene in a chromosome so results in recessive disease. or if chromosomes imprinted
how can structural rearrangements be transmitted?
errors in meiosis late in spermatogeneis can result in a translocation that is mosaic
if neither parent carries the abnormality how many the translocation have arisen?
de novo from mitotic NDJ
what is a recurrent translcoation?
where translocations appear in individuals in the population that are not related
what is the most common recurrent translocation? what are the breakpoints?
(11;22)(q23;q11) AT rich palindromic repeat breakpoints
what does this recurrent translocation increase the risk of what disease?
Emanuel
what is emanuel syndrome caused by?
3:1 malsegregation of chromosome 22 and the supernumary inheritance of this derivative chromosome. 2 normal chromosome 11 and 22 and derivative one fromed from a translocation between 11 and 22
what are the symptoms of emanuels
mental retardation, morphological features eg cleft lip pallete, small head, genital defects. kidney and heart abnormalities
what are 30% of oligo and azoospermia due to?
AZFa, AZFb and AZFc genes on Y chromosome. deletion of these genes occurs due to homolgous recombination
what can make translocations more likley? (3)
repetitive sequences, longer length of homology between repetitive sequences and shorter distance between the repetitive sequences
what is a pachytene cross?
where the 4 chromosomes pair together in meiosis I
what gametes are made in alternate segregation?
alternate centromere segreagate together- 2 normal and 2 with balanced translocations
what gametes are made in adjacent I segregation?
non-homologous adjacent centromere segregate toegther- unbalanced gametes
what gametes are made in adjacent II segregation?
adjacent homologous centromere segreagte together- v unbalanced gametes made
how do PATRRs cause instability in the genome?
suspetible to mispairing leading to formation of secondaruy structures which cause instability
how are 11;22 translocations thought to happen?
colocalisation of PATRR11 and PATRR22 during late spermatogenesis then get DSB and subequent repir by NHEJ
