Lecture 3

Question 1

Structural Chromosome Variation

Answer 1

• Contributes to normal genetic diversity
• Etiology of genetic diseases
• Sizes range from single nucleotide to entire chromosome arm
• Population data: rare to common polymorphisms

Question 2

What are the mechanisms that mediate structural chromosome variation?

Answer 2

• Improper repair of double strand breaks
• Nonallelic homologous recombination (NAHR)
• Malsegregation of rearranged chromosomes

Question 3

Kinds of Double Strand Breaks (DSB)

Answer 3

Programmed DSB

Pathological DSB

Breakage of both strands of double helix

Question 4

Programmed DSB

Answer 4

• Meiosis is required for synapsis

- Physiological DSB (VDJ recombination)

Question 5

Pathological DSB

Answer 5

• Common
• Multiple causes
• 2 types of causes: Endogenous & Exogenous

Question 6

What are the two types of causes for Pathological DSB

Answer 6

-Endogenous:
Improperly repaired single nucleotide breaks
Unrepaired single strand breaks
Reactive oxygen species

-Exogenous:
Ionizing radiation
Chemical mutagens

Question 7

Breakage of both strands of double helix

Answer 7

• Breaks may or may not be in same place on both strands
• Lack of repair leads to complex or large, potentially lethal chromosome aberrations
• Error prone repair also leads to structural abnormalities

Question 8

Examples of DSB repair pathways

Answer 8

-Homologous recombination
Error free
Homologous chromosome or sister chromatid used for template
Occurs between S and M phases of cell cycle

-Non-homologous end joining (NHEJ)
Error prone
Does not utilize complementary base pairs 
Can occur at any stage of cell cycle
Occurs between any broken ends
Same break
Different breaks

Question 9

Nonhomologous End-joining (NHEJ)

Answer 9

• 3’ overhangs promote formation of tandem duplications
• Break produces “jagged” edges
• Proteins bridge gap and modify broken ends to allow for ligation
• Ligation occurs

-May result in deleted base pairs
Initial break
Processing for ligation

Question 10

Nonallelic Homologous Recombination (NAHR)

Answer 10

• Misalignment of LCRs during bivalent formation of meiosis
• Misalignment can also occur in mitosis
• Crossover within the misaligned LCRs results in deletions and duplications

Question 11

A Common Mechanism of Generating Recurrent Deletions and Duplications

Answer 11

-Nonallelic homologous recombination between LCRs

-Low copy repeats (LCR)
Regions of high sequence similarity – at least 95% homology
Usually range in size from 10 to 300 kb

-Occur more commonly in some regions of genome
8p
17p
22q