Lecture 3

Learning outcomes

  1. Understand the approaches used to analyze chromosome abnormalities and the relative advantages and disadvantages of each approach

    • Karyotype

      • Arrest cells in metaphase, stain, and look at through a microscope.

      • Typically used when looking at whole chromosomes and haploid genomes.

      • Resolution of 108 through 109 base pairs

    • Fluorescence in situ hybridization (FISH)

      • Useful to see a submicroscopic region using a probe

      • Resolution of 104 to 105 bp

    • Microarray

      • Can represent an entire genome

      • Have to use both DNA from a patient and reference DNA, then hybridize. The resulting color indicates a gain or loss in a chromosome

      • You don’t get any information about the location or arrangement of the change.

      • High resolution

    • Whole genome analysis

      • Gives information about aneuploidy, duplications, deletions, single base pair changes, translocations, and inversions.

      • Not useful if you’re looking for a mutation in one gene because it’s hard to interpret.

      • Highest resolution

  2. Be able to describe conditions that motivate screening for chromosome abnormalities

    • Family history

    • Fertility problems

    • Stillbirth or neonatal death

    • Early growth/development problems

    • Cancer

    • Pregnancy

  3. Understand the clinical implications of aneuploidy and be able to explain how defects in meiosis lead to errors in chromosome number

    • Trisomy or monosomy

    • Usually causes spontaneous abortion

    • Developmental abnormalities due to altered gene dosage

    • Usually due to meiotic nondisjunction

  4. Understand the difference between balanced and unbalanced chromosome rearrangements and their clinical implications

    • Balanced rearrangements: do not change relative gene dosage

      • includes many inversions and translocations

    • Unbalanced rearrangements: Too many or too few copies of some genes

      • Most deleterious

  5. Be able to describe common chromosome abnormalities

    • Robertsonian translocations

      • Most common structural chromosome abnormality in humans

      • 1/1000 live births

      • Involves 2 acrocentric chromosomes

      • Carriers have a normal phenotype but may have a high rate of miscarriages, difficulty conceiving, or stillbirths.

  6. Understand how balanced chromosome rearrangements can lead to the production of aneuploid gametes

    • Balanced chromosomes can’t line up normally during meiosis because they aren’t real homologues.

    • The chromosomes form a quadrivalent

    • Has the chance of creating normal/balanced offspring, but higher chance of unbalanced, leading to abortion.

  7. Should have a general understanding of the frequencies of chromosome abnormalities and their consequences

Key terms

Aneuploidy

  • Extra or missing chromosomes

Structural abnormalities

  • Includes deficiencies, duplications, translocations, inversions, and other complex rearrangements

Chromosome abnormalities

  • Often alter relative gene dosage

  • Occur in 1% of live births

  • 2% of all pregnancies in women over 35

  • Cause 50% of spontaneous abortions in women

Trisomy

Monosomy

Fluorescence in situ hybridization

Chromosomal microarray

Whole genome sequencing

Meiotic nondisjunction

Balanced rearrangement

Unbalanced rearrangement

Interstitial deletion

  • A deletion in the middle of a chromosome

Terminal deletion

  • A deletion of the end of a chromosome

Isochromosome

  • When the arms of the chromosome are mirror images of each other

Ring chromosome

Robertsonian translocation

Reciprocal translocation

Paracentric inversion

  • Centromere does not lie in inversion

Pericentric inversion

  • Centromere does lie in inversion

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