(Transcribed from Dr. Cadilla’s lecture, 20 Mar 2000 by Brian Buschman)
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Genetic recombination is when two pieces of DNA are joined together. There are two types of genetic recombination that exist.
1) Site-specific recombination which is when two completely different pieces are joined by an integrase. The common example of site-specific recombination is the insertion of the l phage into bacterial DNA by a viral integrase.
2) Homologous recombination is the recombination of two similar DNA sequences. The combination is common during meiosis.
Three nucleases, recB, recC and recD, act as endonucleases and helicases to straighten DNA and separate it into single strands. Then recA catalyzed the inversion which is where the strands are cut and the ends switched to the other strand and then rejoined by DNA ligase. After ligase does it’s work the result is a unit called the Holliday intermediate. The Holliday intermediate is composed of the two strands that are unchanged that are paired to two strands that have been crossed. Then ruvC comes into the picture and twists that holiday intermediate to sort it out into two unique double helix strands.
Hemophilia A is often the result of recombination of the factor VIII gene with other copies of the same gene that are close to the telomere. Because the chain bends back around on itself for the copying the first 22 of the 26 exons of the gene are inverted making it impossible to synthesize factor VIII.
Thalassemias are when one or more copies of one of the Hb genes have been recombined to give an unrecognizable sequence. The lack of the gene will lead to insufficient production of Hb and obvious problems transporting O2 in the blood stream.
Except for sperm and ovum all cells are diploid, meaning that they have two copies of each DNA strand. When a genetic mutation effects only one strand the mutations is said to be heterozygous and if it can be found in both strands it’s considered to be homozygous. Heterozygosity will only cause problems if the mutation is dominant. Otherwise the unmutated copy will be expressed. Homozygosity will always be expressed since there are no other copies of the given gene.
Mutations can be in any part of the DNA but only matter if they appear in either the coding or regulatory sequence of the DNA. If they are in the coding sequence then they will alter the peptide produced. If in the regulatory sequence they will affect the rate at which the sequence is transcribed.
Point mutations are a change in a single base.
Transitions are point mutations when a purine is replaced by another purine or a pyramidine by another pyramidine.
Transversions are when a purine replaces a pyramidine or vise versa.
Silent mutations are when a point mutation occurs that changed the codon to another codon for the same amino acid so no change results in the transcribed protein.
Nonsense mutations change a codon to a stop leading to premature chain termination and a piece of random peptide will be translated.
Deletions/insertions are when multiple bases are added or removed from the sequence.
Frame shift mutations involve the insertion or deletion of a number of bases not divisible by three. This results in a reading frame that is offset from what the original reading frame should be. One example is Hermansky-Pudlak syndrome which is a result of a 16 base pair insertion in one strand (it is heterozygous).
Translocation involves the bulk movement of a section of DNA within the chain. If the entire gene with it’s regulatory section are moved together it will usually have no effect.
Basal mutation rate is the rate of mutations that are normal results of errors in DNA replication.
Usually the repair enzymes are able to recognize which of the strands is the one that has been damaged. Repair mechanisms exist to correct most of the chemical changes that come to the bases. We will discuss three types of repair:
1) Base excision repair is the removal of the specific damaged bases. This is carried out by a DNA polymerase and the nick sealed by DNA ligase. It is only good for repairing a mutation involving the wrong base sitting in the position.
2) Nucleotide excision repair is the removal of an entire nucleotide. This is used over base excision repair when the mutation results in change of more then just the base but a chemical change to the sugar or phosphate as well.
3) Postreplication mismatch repair is the normal removal and correction by DNA polymerases of the errors that they made during translation.
Xerderma pigmentosum is when there is a failure of the DNA polymerases to carry out their repair functions. The patient will have all forms of skin pigmentation problems. Because of the lack of ability to repair mutations they will usually develop skin cancer in either the first or second decades even if they are very careful to stay out of the sun.
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