Mutations Flashcards
Two main sources of genetic variation:
Mutations and Recombination
Mutations as sources of genetic variation
- Permanent alteration to DNA sequence
- Mutations create new alleles in population
Recombination as sources of genetic variation.
Independent assortment of chromosomes and genetic crossing over between chromatids of homologous chromosomes during meiosis > 8 million possible combinations
Why without mutations would evolution not be possible?
Without mutations, evolution would not be possible: mutations provide the “raw material” upon which the mechanisms of natural selection can act; by way of this process, those mutations that furnish individual organisms with characteristics better adapted to changing environmental conditions are passed on to offspring at an increased rate, thereby influencing the future of the species.
Silent mutation
base substitution results in the generation of a codon for the same aa (redundancy of genetic code) (wobble effect)
Missense mutation
base substitution results in a codon that specifies a different amino acid and this leads to a different polypeptide sequence;
-> can be conservative (Val -> Ala) or nonconservative
Nonsense Mutation
base substitution results in the generation of a stop codon (UAA, UGA, UAG)
Examples of the effect of a point mutation - missense?
K-Ras proto-oncogene is activated by missense mutation
The most frequent K-Ras mutation in human cancers is K-RasG12V
A consequence of missense mutation:
GGC -> GTC resulting in a change of Gly to Val at position 12
K-Ras mutations are observed in what % of all cancers?
K-Ras mutations are observed in 17%–25% of all cancers;
most frequently in pancreatic (80% - 90%),
Lung (~30%)
Colorectal (30% - 40%) cancers
Examples of the effect of a point mutation - missense? SSA
Sickle Cell Anaemia:
HbSS mutant protein is a result of missense mutation
GAG -> GTG in the β-globin gene
A consequence of which is glutamate (E/Glu) being substituted by valine (V/Val) at position 6 (E6V substitution)
POINT MUTATION INSERTION effect?
Insertion or deletion of just one base pair can lead to a frameshift mutation (change in the reading frame) resulting in a change of amino acid sequence and sometimes in premature termination of translation (truncated protein).
Example of a Point Deletion: Cystic Fibrosis:
CF is caused by a mutation in the gene CFTR encoding for cystic fibrosis transmembrane conductance regulator (CFTR) protein
The most common mutation, ΔF508, is a deletion of three nucleotides that results in a loss of the amino acid phenylalanine (Phe/F) at position 508 on the protein
More than 1500 other mutations are associated with CF
Where can mutations also occur ? - In promoter or enhancer* sequences of a gene - TERT
Mutation effect in the promotor region:
Activation of TERT oncogene by mutation
TERT gene promoter mutations generate de novo consensus binding motif for ETS/TCF transcription factors resulting in increased expression of TERT gene
TERT gene promoter mutations are observed in ~ 30% of primary melanomas
Where can mutations also occur ? - In splice donor and acceptor sites - β-thalassemia
β-thalassemia
Abnormal processing of the β-globin primary RNA transcript in humans with the β-thalassemia.
The disease (severe anaemia due to aberrant haemoglobin synthesis) is caused by splice-site mutations found in the genomes of affected patients.
Where can mutations also occur ? - In splice donor and acceptor sites - PKU
Phenylketonuria (PKU)
A single base mutation (GT-to-AT) that corresponds to a change from 5’-GU to 5’-AU in the splice donor site of Intron 12 that makes the site unrecognizable by the splicing enzymes.
This results in Exon 12 being excised along with Introns 11 & 1
Individuals with this mutation have a 156bp deletion in the mRNA, corresponding precisely to the length of Exon 12 that leads to a truncated PAH (phenylalanine hydroxylase) protein that is unstable with almost zero PAH activity.
