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