Chromosome Rearrangements Notes

Announcements and Reminders

• Pat back quiz is due on Sunday.
• Recombination quizzes grades (three-point mapping) will be available today.
• Canvas Resources for Three-Point Mapping:
  • Canvas pages contain videos and exercises for three-point mapping.
  • Focus on understanding interference and its calculation.
• First day back after spring break will be a review day.

Chromosome Rearrangements

• Focus: Types of rearrangements and their effects on genetic information.
• Key Questions:
  • Are they adding or removing genetic information (balanced vs. imbalanced)?
  • What happens to gametes during meiosis (viable vs. lethal)?
  • Can we make a viable gamete? Do we have a lethal gamete?

Basic Requirements

• Require double-stranded DNA breaks.
• Repair mechanisms:
  • Non-homologous end joining (using DNA ligase).
  • Homologous recombination (using the rad51 complex).
• Recoverable genetic information requires a centromere; otherwise, it is lost.
• Maintain gene balance.

Balanced vs. Imbalanced Rearrangements

• Balanced: No loss or gain of genetic information.
  • Inversions
  • Translocations
• Imbalanced: Loss or gain of genetic information.

Inversions

• Chromosome flips.
• A chromosome that should read $a b c d$ reads $a c b d$.
• Reading DNA:
  • Double-stranded DNA can be read on either strand.
  • Flipping does not necessarily change the ability to read genes.
  • Inversion can be almost silent
• Gene disruption:
  • Breaks in the middle of a gene ($c$) disrupt its function.
  • Breaks in $a$ and $c$ can disrupt both genes.
• Oncogenes: Fusion of genes ($a$ and $c$) can create cancer-causing genes with aberrant functions.
• Polarity: Inversions must maintain polarity (3' to 5').

Types of Inversions

• Paracentric: Inversion does not involve the centromere.
• Pericentric: Inversion includes the centromere.

Paracentric Inversions

• Heterozygous example: One chromosome reads $a b c d$, the other $a d c b a$.
• Inversion loops form during meiosis for homologous chromosomes to pair up.
• Inversion Loops:
  • Necessary for gene sequence pairing during meiosis.
  • Involve twisting of DNA, predisposing to crossover.
• Crossover:
  • More crossover is likely due to torsion, but recombination frequency decreases.
• Recombination frequency drops because of acentric and dicentric fragments.
• Dicentric Bridge:
  • Two centromeres.
  • Microtubules pull centromeres apart, causing breakage at random locations.
• Acentric Fragment:
  • Missing a centromere. Information is lost during meiosis because it can't be grabbed onto.
  • Cannot be recovered because it lacks a centromere
• Gamete formation:
  • Normal gametes: $a b c d e f g$
  • Gametes with inversions.
  • Dicentric Bridge: Breaks randomly during meiosis II.
  • Acentric Fragment: Irrecoverable genetic information.
  • Recombination frequency: 0% due to lethality; parentals can be made, recombinants are not possible to recover.

Pericentric Inversions

• Centromere is involved.
• Still requires an inversion loop.
• Crossover within the loop.
• Gamete formation:
  • Normal gametes.
  • Parental gametes (with inversion).
• Recombinant gametes are lethal due to genetic imbalance (missing or duplicated genes).
• Recombination frequency: 0% due to lethality; parentals can be made, recombinants are not possible to recover.

Translocations

• Information moves from one place to another.
• Still able to generate viable organisms.
• Example: Two chromosomes swap material.
• Homologous chromosome pairs.
• Cross-like structure forms during meiosis.
• Segregation:
  • Alternate segregation: Results in viable gametes with all genetic information present.
  • Adjacent segregation: Non-viable gametes due to missing or extra genetic information.

Implications of Inversions and Translocations

• Most inversions of chromosome nine are asymptomatic unless information is gained or lost.
• Translocations are asymptomatic if balanced; reduced fertility may occur.
• Cri-du-chat syndrome: Severe translocation example with developmental problems.

Imbalanced Rearrangements

• Involve gaining or losing information.
• Severity depends on how much information is affected.

Deletions

• Losing information.
• Chromosomal break leads to loss of genetic material; severity depends on what is lost.
• Intragenic Deletions: Loss of a small piece of DNA in the middle of a single gene, which results in loss of the gene function.
• Multigenic deletions: Loss of multiple genes; more severe phenotype.
• Deletion Loops:
  • Scientists who know what they're looking for distinguish them from inversion loops.
  • Occur during meiosis when a region on one chromosome has been deleted and cannot pair with its homolog.
• Pseudodominance:
  • Expression of a normally recessive allele because there is no dominant allele to mask it.
  • Can result from deletions, where the wild-type allele is deleted.
• Krutyshaf syndrome: Example of pseudodominance.

Duplications

• Gaining information.
• Copying genetic material; effects depend on gene balance.
• Tandem Duplication: Duplicated region is located adjacent to the original region.
• Insertional Duplication: Duplicated region is located elsewhere in the genome.
• Scientists who know what they're looking for can see Loops: Extra information leads to loops during meiosis because there is nothing to pair up
• Nonreciprocal translocations: Deletion on one chromosome, insertion on another.
• Duplications lead to gene balance problems; severity depends on how much is duplicated.
• Robertsonian translocation: Chromosome 21 jumps up and becomes like the p arm of chromosome 14.