Mutations. Lectures 7 and 8 Flashcards
Polymorphic gene
A gene that exists in a population where there is more than one allele with a frequency of 1% or greater. These alleles may be referred to as wild type alleles or common variants
Monomorphic Gene
One one common allele of a gene
Forward Mutation
Change of a wild type allele to a mutant allele.
Reverse Mutation
Change of a mutant allele to wild type allele
Purine Nucleotides
Adenine or guanine
Pyramidine Nucleotides
Cytosine and thymine
Substitution Transition Mutation
Purine for purine or pyramidine for pyramidine. i.e. AG or CT
Substitution Transversion Mutation
Purine for pyramidine or pyramidine for purine.
Substitution
Replacement of a base by another
Deletion
block of 1 or more base pairs lost from DNA
Insertion
block of 1 or more base pairs added to DNA
Inversion
180 degree rotation of a segment of DNA
Reciprocal Translocation
Parts of two nonhomologous chromosomes change places
RNA polymerase
Transcribes DNA to produce RNA transcript
RNA transcript
Serves directly as mRNA in prokaryotes; processed to become mRNA in eukaryotes.
Ribosomes
Translate the mRNA sequence to synthesize a polypeptide
Number of codons
61
Number of amino acids
20
Silent Mutation
Change in base that does not change the encoded amino acid
Missense mutation
change in base that changes the encoded amino acid
Nonsense Mutation
Change in base that changes an amino acid encoding codon to a stop codon. Results in a truncated protein.
Frameshift mutation
Insertion or deletion of bases that change the reading frame for translation. Will change all the encoded amino acids downstream of the insertion or deletion unless the insertion or deletion is a multiple of three bases.
Conservative Missense Mutation
Chemical properties of new amino acid are similar to original amino acid and is therefore less likely to have a significant effect on protein function.
Nonconservative Missense Mutation
Chemical properties of new amino acid are different than original amino acid.
Regulatory Mutation
Change in base of DNA in promotor of a gene or in sequences associated with the promoter of gene. Possible effects of a regulatory mutation include a change in the timing, change in location of gene expression in the body, change in the level to which the gene is expressed.
Loss of Function Mutation
activity of encoded protein is reduced or absent. Null and hypomorphic loss of function mutation. Generally a recessive gene.
Null Mutation
(amorphic mutation) Encoded protein has no activity.
Hypomorphic mutation
encoded protein has reduced activity.
Gain of function mutation
the activity of encoded protein is increased or different. Hypermorphic or neomorphic. Usually a dominant gene.
Hypermorphic
More protein produced or the protein has a higher level of activity.
Neomorphic mutation
encoded protein has a different activity
Halopinsufficiency
In a heterozygote for a loss of function allele, one wild type copy of a gene doesn’t produce enough activity protein.
Depurination
Loss of a purine base from a nucleotide. Not recognized during DNA replication
Deamination
Loss of an amino group from a base. Converts cytosine to uracil. During DNA replication a T is added to a new strand.
Oxidation by reactive oxygen species (ROS)
May come from normal cell metabolism. ionization of water by ionizing radiation. Exposure to chemical oxidizing agent. May convert base to oxidized base that is misread during DNA replication; wrong base then added to new strand.
Exposure to x-ray radiation
High x-ray dose may cause double strand breaks in DNA. Can cause deletions of several or many nucleotides.
Exposure to ultraviolet (UV) Radiation
May cause pyrimidine dimers to form; formation of covalent bonds between adjacent pyrimidines, especially thymine. Creates a problem for DNA polymerase in DNA replication
Mistakes in DNA replication
May result in unequal crossing over. Starts by misalignment between non-sister chromatids during pairing of homologs in prophase 1 on meiosis. Most common is where there are repeated or similar sequences in DNA. Will generate one chromatid with a deletion and another with a duplication. May create “hybrid” genes; genes made up of segments of two different genes.
Transposable elements
Dna segments with repetitive sequence that can move from one location in the genome to another. Can “transpose” in two ways to create insertion mutation.
Overview of Mutation Mechanisms
Oxidation/hydroxylation od DNA bases. Deamination of DNA bases. Mimicry of DNA bases and insertion into DNA (base analogs). Attachment of alkyl groups to DNA bases (alkylating agents). Insertion between strands of DNA: intercalcating agents.
Proofreading DNA
DNA polymerases have a proofreading function that checks that proper complimentary base has been added to the newly forming DNA strand. If wrong base is detected it is excised by the 3-5 exonuclease activity of DNA polymerase. Some mismatches may escape detection by DNA polymerase proofreading.
DNA Repair Mechanisms
Exonuclease activities of DNA polymerase. Homology-dependent DNA repair: base excision repair. Enzymatic reversal of alterations to DNA: alkyltransferase removes alkyl groups attached to DNA bases. Photolayase breaks covalent bonds of thymidine dimers.
DNA repair: Mismatch Repair
After DNA replication, each new strand is checked if complementary to original “template” strand.
Methyl-directed mismatch repair.
Exists in bacteria. Prior to DNA replication, methyl groups are attached to adenosines in GATC sequences; during DNA replication, new DNA is not methylated. This allows mismatch repair enzymes to determine which is the original strand (methylated) and which is the new strand. If there are any mismatched bases in new DNA, a sequence around mismatch is removed and replaced with correct sequence. Eukaryotes have similar mismatch repair mechanisms, but it is unknown how original vs new strands are recognized.
DNA glycosylase
where a uracil or damaged base is detected, the base portion of the nucleotide is first removed by this enzyme.
Base excision repair
DNA is periodically checked for presence of uracil and certain types of damage to bases. Base portion of the nucleotide is removed by DNA glycosylase. Stretch of nucleotides, including nucleotide with out base is removed. New sequence is inserted and is sealed by DNA ligase. Type of homology dependent repair since it uese the undamaged strand to determine proper bases to add.
DNA Repair: Nucleotide Excision Repair
Type of homology dependent repair. Detects and fixes DNA damage that cannot be detected by DNA glycosylases. Endonucleases that can recognize damage make cuts upstream 5’ and downstream 3’ of damage. Segment of DNA is removed. New sequence of DNA is added and sealed by DNA ligase.
N-Terminus
The first part of the protein that exits the ribosome during protein biosynthesis.
C-Terminus
The end of an amino acid chain, terminated by a free carboxyl group.
