Gene mutation and DNA repair

• Gene


  A section of a DNA molecule whose sequence of building blocks specifies the sequence of amino acids in a particular protein
• Polymorphic gene


  A gene with several common alleles in natural populations
• Wild-type allele


  The allele found on the large majority of chromosomes in the population under consideration
• Mutation


  A change in a DNA sequence that is rare in a population and typically affects the phenotype
• Mutate


  The process of altering a DNA sequence
• Mutations


  • Can range in magnitude from substitution of a single DNA base to deletion or duplication of entire chromosomes
  • Can affect any part of the genome including sequences that encode proteins, control transcription, introns, repeats
  • Not all DNA sequences are equally likely to mutate
• Loss-of-function mutation


  A mutation that stops or slows production of a protein, overproduce it, or impair the protein's function
• Gain-of-function mutation


  A mutation that changes the gene's activity
• Forward mutation


  A mutation that changes a wild-type allele of a gene to a different allele
• Reverse mutation


  A mutation that causes a novel mutant allele to revert back to wild type
• Polymorphism


  A general term meaning "many forms"
• Single nucleotide polymorphism (SNP)


  A single base change
• Variant


  A term used to mean both polymorphism and mutation
• Germline mutation


  A mutation that occurs during the DNA replication that precedes meiosis, present in all cells of the individual and transmitted to the next generation
• Somatic mutation


  A mutation that happens during DNA replication before mitosis, passed to the next generation of cells but not to all cells in the individual's body
• Somatic mosaicism


  A condition where an individual has some cells with a mutation and some without
• Somatic mutations are more likely to occur in cells that divide often, such as skin and blood cells, because there are more opportunities for DNA replication errors
• Sequencing the genomes of individual cells from different organs has shown that somatic mosaicism is not as rare as had been thought
• Beta-globin gene


  A gene that when mutated causes sickle cell disease
• Sickle cell disease


  1. Substitution of valine for glutamic acid in the beta globin polypeptide chain

  2. Changes the surfaces of hemoglobin molecules so they aggregate and form rigid, fragile sickle shapes

  3. Cells lodge in narrow blood vessels, cutting off local blood supplies
• Collagen gene


  A gene that when mutated causes Marfan syndrome
• Marfan syndrome


  1. Mutations in the collagen gene lead to abnormal collagen structure

  2. Affects connective tissues throughout the body including the skeleton, eyes, heart, and blood vessels

  3. Can cause skeletal abnormalities, eye lens dislocation, and aortic aneurysm
• The first genetic illness understood at the molecular level was sickle cell disease
• Sickle cell disease


  Caused by a tiny mutation that substitutes the amino acid valine for the glutamic acid that is normally the sixth amino acid in the beta globin polypeptide chain
• DNA level change


  CTC is changed to a CAC, corresponding to RNA codons GAG and GUG
• Valine substitution


  • Changes the surfaces of hemoglobin molecules so that in low-oxygen conditions they attach at many more points than they would if the wild type glutamic acid were at the site
  • Aggregated hemoglobin molecules form ropelike cables that make red blood cells sticky and able to deform, and then bend the cells into rigid, fragile sickle shapes
  • Cells lodge in narrow blood vessels, cutting off local blood supplies
  • Sickling speeds up and spreads as the oxygen level falls
• The result is great pain in the blocked body parts, particularly the hands, feet, and intestines. The bones ache, and depletion of normal red blood cells causes the great fatigue of anemia
• Thalassemia


  Severe anemia in Italian children, also called "Cooley's anemia"
• Thalassemia major


  Severe form resulting from a homozygous mutation in the beta globin gene at a site other than the one that causes sickle cell disease
• Thalassemia minor


  Milder form affecting some individuals who are heterozygous for the mutation
• Without enough beta globin chains, not enough hemoglobin molecules are assembled to effectively deliver oxygen to tissues. Fatigue and bone pain arise during the first year of life as the child depletes fetal hemoglobin, and the "adult" beta globin genes are not transcribed and translated on schedule
• As severe beta thalassemia progresses, red blood cells die because the excess of alpha globin chains prevents formation of hemoglobin molecules. Liberated iron slowly destroys the heart, liver, and endocrine glands
• Periodic blood transfusions can control the anemia, but they hasten iron buildup and organ damage. Drugs called chelators that entrap the iron can extend life past early adulthood, but they are costly and not available in some nations
• Collagen


  A major component of connective tissue, accounting for more than 60 percent of the protein in bone and cartilage and providing 50 to 90 percent of the dry weight of skin, ligaments, tendons, and the dentin of teeth
• Genetic control of collagen synthesis and distribution

  • More than 35 collagen genes encode more than 20 types of collagen molecules
  • Other genes affect collagen too
• Collagen disorders


  Particularly devastating, not only because collagen is nearly everywhere, but because collagen has an extremely precise conformation that is easily disrupted, even by slight alterations that might have little effect in proteins with other shapes
• Procollagen


  Consists of many repeats of the amino acid sequence glycine-X-Y (where X is frequently proline and Y is often hydroxyproline)<|>Three procollagen chains entwine, with two identical chains encoded by one gene and the other encoded by a second gene with a different amino acid sequence<|>Enzymes snip off the ragged ends of the polypeptides, forming mature collagen<|>The collagen fibrils continue to associate with each other outside the cell, building the fibrils and networks that hold the body together
• A mutation that controls placement of a single hydroxyl group (-OH) on collagen causes a form of osteogenesis imperfecta ("brittle bone disease")
• Other collagen mutations remove procollagen chains, kink the triple helix, and disrupt aggregation outside the cell
• Aortic aneurysm


  A serious connective tissue abnormality that can occur by itself or as part of Marfan syndrome