Topic 17.  Gene mutations, DNA repair,
    and transposable elements

Mutations are inheritable changes in the genetic material

1. DNA as the genetic material has four functions:
   A. Replication
   B. Storage
   C. Expression
   D. Variation by mutation
   E. In a sense, mutation is the failure to store genetic information faithfully
   
   
2. Spontaneous vs. induced mutations
   A. Spontaneous mutations occur for no known reason, they just happen
       Typically, in the 3 X 10-5 to 1 X 10-6 range / gamete / generation
   B. Induced mutations are caused by an external factor
   
   
3. Categories of mutations
   A. Gametic vs. somatic mutations
       1. Gametic mutations produces cells that will be transmitted to the next generation
       2. Somatic mutations are in cells that will not be transmitted to the next generation
   B. Mutations can be nuclear or extranuclear (in mitochondria or chloroplasts)
   C. Mutations can be changes in chromosome number (euploidy or aneuploidy)
   D. Mutations can be changes in chromosome structure (chromosome aberrations =
       deficiencies, duplications, inversions, translocations, ring chromosomes)
   E. Gene mutations = mutations involving a single gene
   F. Morphological mutations = mutations that affect the morphology of an organism
   G. Nutritional or biochemical mutations = auxotrophs
   H. Behavioral mutations affect the behavior of an organism
   I. Regulatory mutations , a mutation in a gene that regulates another gene
   J. Lethal mutations, mutations that are lethal to the organism
       1. Conditional lethal mutations, mutant under certain conditions but not lethal under other conditions
           e.g., lethal at high temperatures but not lethal at low temperatures (temperature-sensitive mutation)
   
   
4. Induced mutations
   A. Introduction:  all mutations studied before 1927 including the 85 studied in Morgan's lab were
       spontaneous mutations
       From 1907-1927, many scientists attempted to increase the mutation frequency above the
       spontaneous mutation frequency with various treatments.  All results were negative or uncertain
   B. Muller's ClB method (published in 1927)
       1. Discussed in class and on handout
       2. Proved that X-rays (a physical mutagen) caused mutations
       3. The ClB method measures the frequency of X-linked recessive mutations at many loci
       4. Results:
           a. Control, 5/6016 single pair matings had no male progeny (0.083%)
           b. X-rayed P1 males for 24 minutes @ 16 cm., 49/676 single pair matings had no male progeny
           c. X-rayed P1 males 48 minutes @ 16 cm, 89/772 single pair matings had no male progeny
           d. Clearly, X-ray (a physical mutagen) is causing mutations
           e. Muller was awarded the Nobel prize for this work
           f. Practical importance of Muller's work: geneticists must have mutant genes to do genetic studies,
               and the frequency of mutations could be increased over 100 fold using this procedure.
           g. Theoretical importance of Muller's work: could ask theoretical questions about the nature of
               genes.  e.g., are they more susceptible to mutation under certain conditions, etc.
   C. Demonstration of mutation induction by a chemical agent (mustard gas)
       1. 1941, Auerbach and Robson discovered that Mustard gas caused mutations
       2. Treated male flies with mustard gas and mated them to ClB females
       3. Found a great increase in recessive sex-linked mutations in treated flies
       4. Not published until 1946 because mustard gas was an agent of warfare and the work was classified
   
   
5. Gene mutations
   A. Base substitutions = point mutations, one nucleotide is changed to a different nucleotide
       1. Missense mutation, the mutant codon codes for a different amino acid
       2. Silent mutation, the mutant codon codes for the same amino acid
           (due to degeneracy in the genetic code)
       3. Nonsense mutation, the mutant codon is a chain termination codon
       4. Transitions vs. transversions
           a. Transitions, a purine is replaced by a purine or a pyrimidine is replaced by a pyrimidine
           b. Transversions, a purine is replaced by a pyrimidine or vice versa.
   B. Frameshift mutations, a base is inserted or deleted in the DNA
       1. Everything beyond the mutation is altered because the reading frame is shifted
       2. If both an insertion and a deletion occur in the same gene, the function of the gene
           may be restored because the correct reading frame is reestablished
       3. Crick and Brenner's study of phage with reading frame mutations
           a. They found that if one or two bases were inserted or deleted, the gene's function was lost
           b. They found that if three bases were inserted into a gene, in some cases,
               the gene's function was restored
           c. This was strong evidence that the genetic code was made up of 3-base codons
   C. Trinucleotide repeats:  the same triplet of bases is repeated many times in a gene
       1. Several conditions are caused when the copy number of a trinucleotide repeat is above a threshold
       2. Examples are Huntington disease, Myotonic dystrophy, and fragile-X syndrome
   
   
6. Mutagenesis
   A. Terminology
       1. Mutant: a nindividual carrying a mutation
       2. Mutagen: something capable of causing mutations
       3. Mutagenic: capable of causing mutations
       4. Physical mutagen: a physical agent that causes mutations (UV light, X-ray, gamma rays, etc.)
       5. Chemical mutagen: a chemical that causes a mutation
   B. Mutagenic studies are usually carried out using lower organisms such as bacterial, viruses, fungi
       1. Large numbers of individuals can be efficiently analyzed
       2. Typically they are haploids, so both dominant and recessive mutations are immediately detectable
   C. Forward mutations, mutations from non-mutant to mutant
       1. Example given in class where wild-type bacteria are red and mutant bacteria are white
   D. Back mutation, mutations from mutant to non-mutant (reversion)
       1. We are looking at back mutations in our cigarette smoke condensate lab
       2. Plate a nutritional-requiring mutant (auxotroph) on minimal medium and
           determine the proportion of the cells that can grow (prototrophs)
   
   
7. DNA repair systems: systems which identify mutations in the cell and correct them
   A. Xeroderma pigmentosum, a human disease due to an autosomal recessive
       1. Individuals with this mutation are extremely sensitive to UV light
       2. Due to a defective DNA repair system
   
   
8. Transposable genetic elements
   A. Also referred to as transposons, jumping genes, or mobile genetic elements
   B. Pieces of DNA can move from place to place within a genome
   C. Discovered by Barbara McClintock who first reported her work in 1950
   D. She described the Ds-Ac system in maize
       1. Ds = dissociation: breaks chromosomes at the site where this gene is located
       2. Ac = activator:  A factor which is necessary for Ds to be active
       3. McClintock found that both Ds and Ac could move (transpose) from one location
           to other locations in the maize genome
   E. Many other transposable elements were subsequently described in other organisms
   F. McClintock was awarded the Nobel prize in 1983 for her discovery of transposable elements

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Updated 12/4/00