Cytogenetics CH 10

• Gene Mutation


  Change in a DNA sequence that is rare in a population and typically affects the phenotype

  
• Gene Mutation


  • Can range from substitution of a single DNA base; to deletion or duplication of tens, hundreds, thousands, or even millions of bases; to missing or extra entire chromosomes

  
• Mutation refers to genotype, Mutant refers to phenotype

  
• Germline mutation


  The change occurs during the DNA replication that precedes meiosis

  
• Somatic mutation


  Happens during DNA replication before amitotic cell division, and is passed to the next generation of cells, not individuals

  
• Collagen


  Major component of connective tissue

  
• Different disease phenotypes can be caused by mutations in the same gene
• The same gene can underlie different diseases in different ways
• A pair of allelic disorders may result from mutations in different parts of the gene

  
• Mutations can be localized (a single base change) or catastrophic (a missing gene); or alter the protein in ways that affect its interactions with other proteins
• Spondyloepimetaphyseal dysplasia with joint laxity, type 1 (SEMD-JL1)


  Allelic disorder caused by mutation in gene B3GALT6
• Ehlers-Danlos syndrome


  Allelic disorder caused by mutation in gene B3GALT6
• Mutagen


  Agent that causes mutation
• Spontaneous Mutation


  Can stem from the tendency of free DNA bases to exist in two slightly different chemical structures, called tautomers

  
• Spontaneous Mutation Mechanism


  1. DNA bases exist fleetingly in alternate forms

  2. A replication fork encountering a base in its unstable form can insert a noncomplementary base

  3. After another round of replication, one of the daughter cells has a different base pair than the one in the corresponding position in the original DNA

  
• The gene which causes neurofibromatosis type 1 has a high spontaneous mutation rate

  
• Mutation arising 40 to 100 of every million gametes for the neurofibromatosis type 1 gene

  
• Neurofibromatosis type 1 occurs in 1 in 3,000 births, about half in families with no prior cases
• Gonadal mosaicism


  Some sperm or oocytes have the mutation, because a spontaneous mutation occurred in the developing testis or ovary, and was transmitted only to the cells descended from the original cell bearing the mutation
• Gonadal mosaicism is not detectable by blood testing
• As a result of gonadal mosaicism, a child may have the syndrome at birth but was not detected through the screening of parents. This is still considered spontaneous or de novo
• Sometimes the first child is unaffected but the second child is, due to gonadal mosaicism
• Mutational Hot Spots


  Regions where the DNA sequence is repetitive, where mutations are more likely to occur

  
• Disorders associated with mutational hot spots

  • Hemophilia B
  • Alpha Thalassemia
• Induced Mutation


  When a gene's normal function is inferred most of the time to hasten the mutation rate

  
• Site-directed mutagenesis


  1. A gene is mass produced, but it includes an intentionally substituted base, just as an error in a manuscript is printed in every copy of a book

  2. Site-directed mutagenesis is faster and more precise than waiting for nature or a mutagen to produce a useful variant
• Ames Test


  Assesses how likely a substance is to harm the DNA of rapidly reproducing bacteria
• Acute radiation poisoning is NOT genetic
• Natural environmental sources of radiation

  • Cosmic rays
  • Sunlight
  • Radioactive minerals in the earth's crust, such as radon
• Jobs with increased exposure to radiation

  • Radiologic Technology
  • Weapons facilities
  • Research laboratories
  • Health care facilities
  • Nuclear power plants
  • Certain manufacturing plants
• Ionizing Radiation


  Has sufficient energy to remove electrons from atoms which breaks the DNA sugar-phosphate backbone
• Alpha radiation


  • Least energetic and most short-lived
  • Skin absorbs most of it
  • Tend not to harm health, although they can do damage if inhaled or eaten
• Beta radiation


  • Penetrate the body farther
  • Tend not to harm health, although they can do damage if inhaled or eaten
• Gamma rays


  • Can penetrate the body, damaging tissues
  • Form of radiation used to kill cancer cells
• X rays


  • Major source of exposure to human-made radiation
  • They have less energy and do not penetrate the body to the extent that gamma rays do
• Categories of Mutation


  • Chromosome Mutation
  • Gene Mutation

  
• Chromosome Mutation


  • May involve changing the structure of a chromosome
  • May involve the loss or gain of part of a chromosome
• Gene Mutation


  • Change in the nucleotide sequence of a gene
  • May only involve a single nucleotide
  • May be due to copying errors, chemicals, viruses, etc.
• Deletion


  A piece of a chromosome is lost due to breakage
• A deletion that removes three or a multiple of three bases will not cause a frameshift, but can still alter the phenotype