Download Mutations are heritable alteration in DNA sequence Most common

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Mutations are heritable alteration in DNA sequence
Most common chemical lesions
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DNA can be damaged by mutagens (exogenous or endogenous chemicals) produced in
cells, inhaled, or absorbed from the environment.
o Xenobiotic metabolism can produce epoxides that can act as DNA adducts
(interrupt G-C base pairing)
o Other common lesions
 Thymine dimers
 Benzopyrene adducts
 Acetylaminoflourene
Mutagens that cause normal cells to become cancer cells are known as carcinogens.
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Radiation- Induced mutations
o UV Radiation
 Can form Pyrimidine Dimers
o Ionizing Radiation
 damage through generation of highly reactive ions (e-, H●, and OH●) that
react with DNA
 Absorbed radiation dose measured in rads (or Grays)
Types of mutations
o Somatic mutations
 In tissues that do not involve gamete production
 Often do no affect phenotype
 Mutations caused can result in cancer
o Germ-line mutations
 Arise in cells whose genes are carried to gametes
 Usually what is being refered to when talking about mult-cellular
organisms
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Transitions and transversions
o Transition: is the substitution of a purine for a purine or of a pyrimidine for a
pyrimidine
o Transversion: is the substitution of a pyrimidine for a purine or of a purine for a
pyrimidine.
o Though more possiblities exist for transversions, transition mutations are more
common.
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DNA Repair Mechansims
o Basic steps
 Excision
 Repair
 Ligation
o Nucleotide Excision Repair (NER)
o Base Excision Repair
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Thymine dimers are excised (in bacteria) by UV-specific endonuclease
(called uvrABC exonuclease) that recognizes the dimer, and cleaves the
damaged strand on both the 5’-side and the 3’-side of the dimer
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Xeroderma Pigmentosum
 Caused by an inability to remove DNA in which pyrimidine dimers
have formed. This condition causes the freckle-like spots seen in
this picture and is linked to skin cancers.
o Mismatch Repair
 When a mismatch repair occurs, the E. coli mismatch repair proteins (Mut
proteins) must discriminate between the correct strand and the strand with
the mismatch.
 Discrimination is based on the degree of methylation.
 GATC sequences are methylated on the adenine residues.
 The newly synthesized DNA is not immediately methylated
 The methylated template strand is considered to be normal and it is the
non-methylated daughter strand that is repaired
 Mechanism unknown in humans
o Transcription Coupled Repair
 Completed during transcription process
 Pol III proofreading in prokaryotes
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Genetic rearrangements
o Homologous Recombination
 Mechanism by which similar strands of double-stranded DNA interact,
resulting in inter-strand exchange of bases
 is the basis for crossing over and gene conversion
o Translocations
 Usually precipitated by chemical or radiation treatment, translocations
result in exchange of large chromosomal fragments
 Translocations may be:
 Non-reciprocal where transfer is unidirectional from one
chromosome to another.
 Reciprocal where sequences are exchanged between two different
chromosomes.
 Can be the basis of disease
 Burkitt’s Lymphoma t(8:14) translocation)
o The translocation juxtaposes the c-myc proto-oncogene
(involved with cell growth), normally on chromosome 8,
with an immunoglobulin gene on chromosome 14.
o The c-myc gene is now controlled by the Ig gene promoter,
resulting in unregulated cell growth.
 Philadelphia chromosome t(9:22) translocation)
 If translocations are passed on to the next generation through germ
cells, the offspring could have partial trisomy and partial
monosomy due to the juxtaposition of chromosome DNA
 Robertsonian Translocation
o Translocation between two acrocentric chromosomes
o can result in the generation of a single metacentric
chromosome and the loss of the two short arms.
o A Familial form of Down Syndrome may be caused by this
type of translocation.
o Transposable Elements (transposons) “jumping genes”
 Discrete segments of DNA that can move from one location within the
genome to another.
 Two major classes of Transposons
 DNA-only (may be replicative or non-replicative)
o Moderately repetitive DNA (can be tandem or interspersed)
 LINE=Long (1000’s base-pairs) interspersed
elements
 SINE=Short (100’s base-pairs) interspersed
elements, e.g., Alu sequences
o Highly repetitive DNA (<10bp, often >105 copies)
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Retro-transposons (use RNA intermediate)
o L1 elements makeup about 15% of the genome --- few can
still mobilize.
o Alu sequences makeup about 10% of the genome. Most
cannot be transcribed and do not encode reverse
transcriptase.
Transposons introduced into a genome can “colonize” it and spread
throughout.
Movement of transposons into genes or their regulatory sequences can
drastically alter their functions.
Multiple copies of transposons provide sequences that can act as targets of
homologous recombination.
Chromosomal rearrangement often generate transposition