7.1 Types of chromosomal aberrations

Radiation can wreak havoc on our chromosomes, causing various types of damage. From deletions and duplications to inversions and translocations, these changes can mess with our genetic material in different ways. It's like a molecular game of mix-and-match gone wrong.

Understanding these aberrations is crucial in radiobiology. They can lead to cell death, genetic disorders, or even cancer. By studying how radiation messes with our chromosomes, we can better grasp its effects on our bodies and develop ways to protect ourselves.

Chromosomal aberrations from radiation

Types of radiation-induced chromosomal changes

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• Radiation exposure induces various chromosomal aberrations
  • Deletions involve loss of genetic material (small segments to entire chromosome arms)
  • Duplications repeat chromosomal segments leading to excess genetic material
  • Inversions reverse orientation of chromosomal segment within same chromosome
  • Translocations exchange genetic material between non-homologous chromosomes
  • Ring chromosomes form when both chromosome ends fuse creating circular structure
• Radiation causes numerical aberrations
  • Aneuploidy alters chromosome number (gain or loss of chromosomes)
  • Polyploidy creates multiple sets of chromosomes (triploid, tetraploid)

Mechanisms of aberration formation

• Ionizing radiation damages DNA through direct and indirect effects
  • Direct effects break chemical bonds in DNA molecule
  • Indirect effects produce free radicals that attack DNA (hydroxyl radicals)
• DNA double-strand breaks lead to chromosomal aberrations if misrepaired
  • Non-homologous end joining can cause deletions or translocations
  • Homologous recombination errors may result in duplications or inversions
• Centromere dysfunction from radiation damage can cause numerical aberrations
  • Impaired spindle attachment leads to chromosome missegregation (aneuploidy)
  • Centrosome amplification results in multipolar mitosis (polyploidy)

Numerical vs structural aberrations

Characteristics of numerical aberrations

• Numerical aberrations alter chromosome number without changing structure
  • Aneuploidy involves gain or loss of individual chromosomes (trisomy, monosomy)
  • Polyploidy creates extra sets of entire genome (triploidy, tetraploidy)
• Typically result from errors in cell division processes
  • Mitotic nondisjunction causes aneuploidy in somatic cells
  • Meiotic nondisjunction leads to aneuploidy in gametes
• Detection methods for numerical changes
  • Karyotyping visualizes entire chromosome set
  • Fluorescence in situ hybridization (FISH) with chromosome-specific probes
  • Flow cytometry measures total DNA content (polyploidy)

Characteristics of structural aberrations

• Structural aberrations modify chromosome structure without altering overall count
  • Deletions remove chromosomal segments (terminal, interstitial)
  • Duplications repeat genetic material (tandem, inverted)
  • Inversions reverse segment orientation (paracentric, pericentric)
  • Translocations exchange material between chromosomes (reciprocal, Robertsonian)
• Often caused by DNA damage and improper repair mechanisms
  • Ionizing radiation induces DNA double-strand breaks
  • Chemical mutagens form DNA adducts leading to strand breaks
• Detection techniques for structural changes
  • Molecular cytogenetic methods (FISH, spectral karyotyping)
  • Comparative genomic hybridization (CGH) arrays
  • Next-generation sequencing approaches (whole genome, mate-pair)

Stable vs unstable aberrations

Properties of stable aberrations

• Persist through cell divisions without significant genetic loss or dysfunction
  • Balanced translocations exchange equal genetic material (reciprocal translocations)
  • Inversions maintain genetic content in reversed orientation
  • Small interstitial deletions or duplications may have minimal impact
• More likely transmitted to daughter cells
  • Stable aberrations can persist in cell populations over time
  • May become heritable if present in germ cells
• Examples of stable aberrations
  • Philadelphia chromosome in chronic myeloid leukemia (BCR-ABL fusion)
  • Inversions in factor VIII gene causing hemophilia A

Characteristics of unstable aberrations

• Lead to cell death or further genetic instability during subsequent divisions
  • Acentric fragments lack centromere, causing loss during mitosis
  • Dicentric chromosomes form bridges during anaphase, disrupting division
  • Ring chromosomes undergo breakage-fusion-bridge cycles
• Often result in asymmetric cell division
  • Formation of micronuclei containing lagging chromosomes
  • Nucleoplasmic bridges from dicentric chromosomes
• Examples of unstable aberrations
  • Dicentric chromosomes in radiation-exposed lymphocytes
  • Ring chromosomes in ataxia telangiectasia syndrome

Consequences of chromosomal aberrations

Cellular and molecular effects

• Alter gene expression causing cellular dysfunction
  • Deletions or duplications change gene dosage
  • Translocations disrupt regulatory sequences or create fusion genes
• Impact cell cycle and survival
  • Large-scale changes trigger cell cycle arrest or apoptosis
  • Accumulation of aberrations leads to cellular senescence
• Influence DNA repair and genomic stability
  • Aberrations may impair DNA damage response pathways
  • Chromosomal instability promotes further mutations

Health and developmental impacts

• Associated with genetic disorders and developmental abnormalities
  • Trisomy 21 causes Down syndrome (developmental delays, characteristic facial features)
  • 22q11.2 deletion syndrome leads to DiGeorge syndrome (heart defects, immune deficiency)
• Increase cancer risk through various mechanisms
  • Activation of oncogenes (MYC translocation in Burkitt lymphoma)
  • Loss of tumor suppressor genes (RB1 deletion in retinoblastoma)
• Affect reproductive function and fertility
  • Balanced translocations can cause recurrent miscarriages
  • Sex chromosome aneuploidies impact fertility (Klinefelter syndrome, Turner syndrome)
• Contribute to aging process and age-related diseases
  • Accumulation of aberrations in somatic cells over time
  • Mosaic loss of chromosome Y in males associated with increased mortality