Origin of Trisomy (Diagnostics L6)


Rarely see loss of a full chromosome. Smaller loss can have a bigger effect than a bigger gain. Autosome changes have a bigger impact on development.

1st trisomy discovered in Drosophila in 1916 Calvin Bridges. It provided evidence that chromosomes carried inheritable material.

Frequency of aneuploidy

  • Yeast 1:10,000 cell divisions
  • Drosophila 1:6,000 offspring
  • Mouse 1-2% of fertilised oocytes
  • Humans
    • over 30% of human oocytes show numerical chromosome errors (been seen for every chromosome but most lethal)
    • 5% of clinically recognised pregnancies are aneuploid
    • A major cause of spontaneous abortion (many aneuploidies lost very early and few reach term)
    • A major cause of congenital birth defects and mental retardation

Human Aneuploidy

  • 1959 - Lejune identified Trisomy 21 in blood sample from a Down's syndrome patient
  • 1960 - Patau identified Trisomy 13
  • 1960 - Edwards identified Trisomy 18

The Mechanism of Non-disjunction

  • Nomal Meiosis I
    • The separation of homologous chromosomes
      • Recombination
      • Physical connection - synaptonemal complex/chiasmata
      • Sister chromatids attach to same spindle fibre
      • Sister chromatids drawn to same pole
    • If homologous chromosomes do not separate = aneuploidy and results in half gametes disomic and half nullisomic when should all be haploid
  • Normal Meiosis II
    • The separation of sister chromatids
      • Sister chromatids attach to different spindle fibres
      • Sister chromatids drawn to opposite poles
    • If sister chromaatids do not separate = aneuploidy and results in half normal gametes, a quater nullisomic and a quarter disomic
  •  MI cohesion between sister chromatids must be released at MII

Molecular marker enable identification of the origin of the meiotic error. Maternal Meiosis I errors predominate.

Alternative Theory of Trisomy

  • Premature separation of sister chromatids in meiosis I
  • Rosyln R. Angell 1991
  • Premature separation and malsegregation of chromatids would lead to extra chromatids rather than extra chromosomes) present at MII
  • FISH analysis of an MII oocyte showed an extra chromatid 16  Mahmood et al. 2000 - shouldn't be possible with traditional non-disjunction
  • Another analysis showed 2 cells about to divide and 2 of the chromatids were not at the pole and so depending on where the cell divides the chromatids could both end up in one cell and not the other or end up 1 in each
  • Presence of extra chromosomes at MII has been observed, above observation provide evidence of an alternative theory for trisomy
  • Errors from premature chromatid separation or achiasmate non-disjunction can mimic MI and MII errors
  • Can use FISH analysis using REC8 which is a subunit of the Cohesin protein responsible for binding chromatids and CREST identies kinetochores - results have showed premature separation of the sister chromatids 

The Maternal Age Effect

  • Incidence of aneuploidy in clinically recognised pregnancies
    • 2-3% (maternal age 20 – 30)
    • 35% (maternal age 40-45)
  • 1970-80s prenatal testing for trisomy offered to mothers over 35 years of age
  • Downs syndrome children are usually the last child
  • Why?
    • Accumulation of environmental threats/insults - longer stuck at MI the more environmental affect…


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