What are the 3 main balanced chromosomal rearrangements?
- Inversion
- Insertion
- Translocation
What causes the formation of gross structural abnormalities in the genome? (3)
- Recombination events between homologous sequences in an illegitimate manner
- DNA damage are usually repaired using homologous sequences located in equivalent positions in the sister chromatid (mitosis) and the homolog (meiosis)
- Illegitimate recombination describes events where the template and repair sites are at non-allelic genomic positions
What are the 2 types of inversion?
- Pericentric
- Paracentric
What is pericentric inversion? (2)
- 2 breaks occur in the same chromosome on different arms so the DNA fragment between the breaks includes the centromere
- Causes a change to the G banding structure and obvious change to chromosome morphology
What is the most common inversion seen in humans? (3)
- Inversions of chromosome 9
- Carriers are often not identified until adulthood because the inversions don’t disrupt gene function/expression as the regions proximal to the centromere of 9 tend to be heterochromatin
- However inversions create abnormal chromosome structures during meiosis which can be disruptive to spermatogenesis
What is paracentric inversion? (2)
- When the chromosome breakpoints don’t flank the centromere
- Disrupt the G banding structure of chromosomes but not morphology so more difficult to spot in a karyotype
Why are insertions rarer than inversions?
Insertions require more events to take place in the same time frame (2 breakpoints in the same chromosome and 1 in another) than inversions (2 breakpoints in the same chromosome)
What do all carriers of structural rearrangements have in common?
Homologous chromosomes form highly abnormal pairing structures when paired in prophase and metaphase I
Why are male carriers of structural rearrangements more likely to be infertile than females? (2)
- Spermatogenesis is highly susceptible to abnormal pairing structures in MI so males are often unable to form mature spermatids resulting in oligospermia or azoospermia
- Oogenesis is more robust
What is oligospermia?
Low sperm count
What is azoospermia?
Lack of sperm in the semen
What happens to chromosomes with inversions and insertions in meiosis I? (2)
- The chromosomes generate abnormal looped structures in meiosis I which can be sufficient to disrupt spermatogenesis
- If a crossover occurs within the inverted region then unbalanced gametes may form which leads to karyotypically abnormal conceptions that are likely to spontaneously abort or lead to serious health complications if brought to term
What is the most common balanced chromosomal rearrangement? (2)
- Balanced translocations
- Roughly 1 in 1000 are carriers
What are the 2 types of balanced translocation in the population?
- Unique/familial translocations
- Recurrent translocations
How do balanced translocations arise?
Illegitimate recombination during spermatogenesis (in contrast to aneuploidy which is largely attributed to maternal meiotic errors)
How is the identity of a chromosome determined?
The origin of the centromeric region
What happens to chromosomes with balanced translocations during MI? (2)
- Chromosomes pair up to form a pachytene cross
- The pachytene cross is susceptible to errors in chromosome segregation
What are all the ways in which pachytene crosses can segregate? (4)
- Alternate segregation
- Adjacent I segregation
- Adjacent II segregation
- 3:1 mal-segregation
What is alternate segregation? (4)
- Anaphase of meiosis I: alternate centromeres are segregated to the same pole of the cell (both normals go together, both translocated go together)
- Sister chromatids are then segregated at anaphase of meiosis II into 4 viable gametes
- Shows that a carrier of a translocation can generate a viable balanced pregnancy
- If the foetus inherits the translocation they may suffer reduced fertility in later life (especially if male)
What is adjacent I segregation? (3)
- Adjacent centromeres are co-segregated either side of the longest synaptic axis (a normal and a translocated go together)
- Generates 4 unbalanced gametes because fertilisation of all 4 would result in trisomy/monosomy of something
- Shows that genetically unbalanced pregnancies are possible/more likely for carriers of large structural rearrangements
What is adjacent II segregation? (2)
- Adjacent centromeres are co-segregated either side of the shortest synaptic axis (a normal and a translocated go together)
- Generates 4 unbalanced gametes like in adjacent I segregation
What is 3:1 mal-segregation? (4)
- Segregation results in gametes containing 3 or 1 of the chromosomes in the pachytene cross
- Those with only 1 would not be viable because the imbalance is too massive (monosomy is lethal)
- Those with 3 would not be affected by monosomy but partial trisomy so may come to term
- If the baby was born it would be have serious health complications
How many clinically recognised pregnancies miscarry?
15%
What proportion of miscarriages have an abnormal complement of chromosomes?
Between 30-50%
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Module induction39
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PND aneuploidy40
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PND structural abnormalities40
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Rare disease genetic testing19
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DNA variant analysis19
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Osteogenesis imperfecta31
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DMD related disorders35
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Cystic fibrosis29
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Microarrays in genomics35
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Hallmarks of cancer47
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Haematological malignancies53
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Chronic Myeloid Leukaemia33
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Hallmarks of CML25
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Extra reading35
