8. Aneuploidy and non-disjunction Flashcards
What causes random segregation of homologous chromosomes in meiosis?
Homologous chromosomes can randomly segregate if:
1) If chromosomes didn’t recombine - no chiasmata
2) If chiasmata are lost after recombination before segregation
In random segregation: 50% chance that segregate normally, 50% chance of mis-segregation
What causes random segregation of sister chromatids in meiosis?
Sister chromatids segregate randomly if:
all cohesin is degraded prematurely - no cohesin left at centromeres after meiosis I
In random segregation: 50% chance will segregate normally, 50% chance will mis-segregate
Define aneuploidy
Aneuploidy: abnormality in number of chromosomes due to loss/duplication
In gametes n -> 2n/0 is aneuploidy
What are the different types of aneuploidies in humans?
Normal chromosome number 2n, so common aneuploidies:
- n - monosomy (-n chromosome loss)
- 3n - trisomy (+n chromosome gain)
What are the most common aneuploidy syndromes in humans?
Most common aneuploidy syndromes:
Why is aneuploidy is badly tolerated?
Aneuploidy is badly tolerated due to gene dosage:
- some genes sensitive to quantity - aneuploidies of big chromosomes lethal (spontaneous abortion) - higher chance to get sensitive genes on large chromosome where many genes are held
- majority genes not sensitive to dosage - aneuploidies in small chromosomes more viable - 21st/Y chromosomes small -> aneuploidy can be tolerated but with abnormal development
Is the natural rate of aneuploidy in gametes higher in men or women?
In women eggs rate of aneuploidy is higher than men’s sperm
Is natural rate of aneuploidy in gametes high in humans compared to other organisms?
Yes, in humans relatively very high rate of aneuploidy
What is an important factor affecting aneuploidy in women’s eggs?
Maternal age - biggest aneuploidy factor
Why is maternal age a factor in aneuploidy?
Due to female gametogenesis:
- all oocyte meiosis I occurs before birth - arrested in diplotene phase of prophase - further meiosis I + meiosis II after puberty - chromosomes don’t segregate until ovulation (that specific period)
- arrest = maternal age - long arrest - segregation only after arrest => cause not known yet but Cohesin ‘fatigue’ hypothesis
Why is paternal age not a factor of aneuploidy?
Because male gametogenesis is different:
- no meiotic arrest as in women - mitotic arrest
- mitosis + meiosis (chromosome segregation) constant throughout life until olf age - no arrest of specific sperm that would influence segregation quality
=> maternal arrest in oogenesis - the cause of aneuploidy in offspring
Explain what is the Cohesin ‘fatigue’ hypothesis
Cohesin ‘fatigue’ hypothesis - hypothesis to explain why maternal age has an inlfuence on chromosome missegregation - why long oocyte arrest leads to chromosome mis-segregation:
cohesin between sister chromatids established in S phase (established before birth) - majority of cohesin destroyed only left at centromeres - chromosome segregation only occurs at ovulation - arrest for x (maternal age) years => same cohesin molecule has ot remain stable for decades - cohesin might be unstable after many years of existing
How can the source (mother/father) of aneuploidy be studied in laboratory?
Edited chromosomes - molecular markers for maternal and paternal chromosomes - see which missing/extra chromosome copy in offspring responsible for aneuploidy
On a diagram how to figure out in which round of meiosis chromosome mis-segregation occurred?
Compare centromeres:
- if same -> homologous mis-segregated -> meiosis I failure
- if different -> sister chromatids mis-segregated -> meiosis II failure
In statistics, which meiosis is more common cause in which aneuploidies in humans?
Trisomy 16: maternal MI
Trisomy 18: maternal MII
Trisomy 21: maternal MI
Trisomy XXY: maternal MI / paternal MI