Genetics (III) Mutations Flashcards
What are gene mutations & types
Change in nucleotide sequence of DNA at a single locus
1. Base pair substitution
2. Base pair deletion/addition
-> Point mutation, change in only 1 base pair
What are the 3 possible outcomes of base pair sub
1) Silent mutation
- Genetic code degenerate, diff 3rd base but codes for same amino acid
- pri structure remains unchanged
2) Diff amino acid coded
- Base sub results in diff amino acid
- Diff properties
- Altered tertiary structure (more/less active, non-functional)
- Truncated
- Premature stop codon
What are the outcomes of base pair insertion/deletion?
- Truncated protein
- Premature stop codon
- non-functional protein - Diff amino acids
- reading frame is altered
- sequence of amino acids completely diff
- non functional protein
If not in multiple of 3, FRAMESHIFT MUTATION
If in multiples or 3, no frameshift
- Extra/missing 1 amino acid
- Polypeptide folding in diff way
-> diff 3d config
-> Protein more/less active, non functional
How does sickle cell anemia occur?
Single base substitution
Beta globin gene 17th nucleotide changed from
5’ GAG 3’ to 5’ GTG 3’
Transcription 5’ to 3’
Read from 3’ to 5’
Changed from 3’ CTC 5’ to 3’ CAC 5’
mRNA hence 5’ GAG 3’ to 5’ GUG 3’
HENCE, from hydrophilic charged glutamic acid to hydrophobic valine
Affects tertiary & quaternary structure of haemoglobin.
Why is sickle cell anemia bad?
Healthy -> biconcave
SCA -> Sickle shaped
Valine inserts into hydrophobic pocket or another beta globin
-> HbS crystallises, fibrous HbS becomes sickle shaped
Sickle shaped -> Stiff and sticky, forming clumps
Obstruct blood flow, rupture easily causing anemia
Describe DNA repair (excision)
Excision repair:
Cutting out damaged segment
fill resulting gap properly paired nucleotides using intact strand as template
What are chromosomal mutations?/aberration
Change in number/structure of chromosomes
Results in aneuploid/polyploid
Aneuploidy
- Result of nondisjunction during meiosis either n+1 or n-1 chromosome
- Offspring could be trisomic or monosomic
How & when can disjunction occur?
- Meiosis 1, nondisjunction of HC
- Bivalents fail to separate, results in 1 pole having an extra chromosome
Meiosis II normal,
Result: 2 daughters (n+1) 2 daughters (n-1) - Meiosis nondisjunction of sister chromatids
In meiosis II, sister chromatids of 1 chromosome fail to separate, 2 daughter cells n, 1 has (n+1) other has (n-1) - Anaphase of mitosis (nondisjunction of sister chromatids)
During mitosis 1 chromosome (sister chromatids fail to separate) 1 pole w extra chromosome, other pole w 1 less chromosome
1 daughter cell has 2n-1 other has 2n+1
How does polyploidy occur? (3)
1) Failure of cytokinesis to occur
2) Failure of spindle fibre formation
3) Failure in disjunction, chromosomes pulled only to 1 pole
What are the 4 types of chromosomal aberration?
- Deletion (loss of region of chromosome)
- Duplication (gene replicated)
- Inversion (Region breaks off, rotates thru 180°)
- Translocation
Non-reciprocal - breaks & rejoins other end of same chromosome (intrachromosomal) or another nonHC (interchromosomal)
Reciprocal - 2 non HC break & exchange fragments
What mutations lead to cancer?
GoF mutation in proto oncogene
LoF mutation in tumour suppressor gene
Activation of telomerase gene
Causes DYSREGULATION of cell cycle checkpts, accumulation of mutations-> cancer
Describe GoF mutations of pOG
pOG mutates to OG by GoF mutation,
OG is a dominant allele only 1/2 pOG mutated to induce cancer
-
EXCESSIVE AMT -> INCREASED TRANSCRIPTION & TRANSLATION
- Point mutation in promoter, binds to transcription factors stronger
- Amplified pOG,
Repeated gene duplication -> excessive protein produced
- Translocation of pOG to active promoter or CE, increased rate of transcrp & translate protein stimulating cell div -
HYPERACTIVE PROTEIN
- Point mutation in pOG, hence hyperactive protein due to change in 3D conformation
Describe GoF of ras pOG
Describe LoF mutation in tsg
TSG FN
- inhibit uncontrolled cell div
- Detect DNA dmg
- Repair damaged DNA
- Control adhesion of normal cells to each other
- Receptors for hormones to inhibit cell proliferation
- activate apoptosis
Mutated TSG are recessive, both copies need to be mutated then tumour suppressor protein no longer produced
- Mutations in promoter, CE, decreased expression
- No protein produced, decreased affinity or non functional protein
- HDAC deacetylates histones, TSG silenced/ excessive histone methylation
Describe LoF of p53 tsg
