Lecture #29 - Human disease genetics Flashcards
What are mutations? (6)
- What’s the driving force for evolution?
- What are germline mutations?
- What are somatic mutations?
- Mutations are permanent changes to the DNA sequence.
- The effect of the mutation can also depend on
– Environmental effects (e.g. diet, exposure to toxins)
– Other genes (‘genetic background’)
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These two modify whether you have mutation that shows - just bc you hv mutation doesn’t mean it’s gonna show.
3. Genetic variation is a driving force for evolution
4. Mutations can have a beneficial effect, no effect, or a deleterious effect on the organism.
5. The vast majority of mutations are neutral, and have no effect at all
6. Mutations can be inherited or acquired
- Mutations that are inherited are called germline mutations and are passed on via the gametes (eggs and sperm)
- Mutations can also be acquired by somatic cells if DNA gets damaged or is copied incorrectly. Somatic mutations are not passed to the next generation.
Tell me about Silent Mutations (2) and Silent Mutations in Exons (3)
- Have no effect on phenotype.
- Often occur in non-coding regions such as intergenic regions and introns.
Note - just bs in intergenic region doesn’t mean it won’t hv effect bc stuff still lurks in intron region. It is less likely to have an effect though.
Silent Mutations in Exons:
- We can use a codon table* to determine the effect of a mutation in an exon.
- Mutations that don’t change the amino acid sequence of a coding region are silent
- The amino acid Valine can be coded by GTT, GTC, GTA or GTG
What’re missense mutations
Missense mutations change an amino acid which can alter the protein’s ability to function, as in sickle cell anaemia (haemoglobin).
One aa’ messed up which won’t affect way too much, It will only have a serious effect if e.g. active site is messed up else usually quite mild
Frameshift mutations
insertion or deletion of (normally) a single base pair in a coding region that changes the readout of DNA so that the resulting protein is altered from that point on (can also result in truncation).
Shifting the way you read it - all aa’ after it affected
Y12 summary of mutations
Base substitutions:
- Silent = same-sense —> aa’ same
- mis-sense —> aa’ different but barely any change in biological function
3. Non-sense —> a special case of point mutation when the base change results in the formation of a stop codon, so the protein chain terminates early (sometimes called truncation mutation).
- Frameshift - insertion/deletion etc
Triplet repeat expansion (3)
- Some genes contain stretches of triplet repeats- (very like the dinucleotide repeats of STRs)
- These repeats sometimes undergo catastrophic expansion leading to dysfunction
- Can alter protein function (Huntington Disease) or destabilise a chromosome (fragile X…X chromosome has triplet repeat expansion…most common retardation in males)
Chromosome re-arragements (2)
• Mutation effects can be larger scale and affect whole chunks of chromosomes- not just a single base or repeat sequence.
• Examples include;
– Translocations (changes domains and affects which genes on/off in cell)
– Inversions – Aneuploidy (lecture 19)
Monogenic diseases: Haemophila A and B (6)
-What, distinguish, high risk of..by..,treatment etc
- Haemophilias are disorders of blood clotting
- Haemophilia A (classic haemophilia) most common affecting 1/5000 males worldwide. Results from impaired or absent clotting factor VIII
- Haemophila B clinically indistinguishable, affects factor XI
- Untreated, high risk of death from uncontrolled bleeding
- Pain and tissue damage from internal bleeding
- Treated by intravenous infusion of missing protein
Treatable - not cureable and it’s basically lotsa burising and external bleeding. A and B can’t be distinguised clinically.
Inheritance of Haemophilia (7)
- Haemophilia A Caused by mutations (most commonly an inversion) in Factor VIII gene found on the X-chromosome
- Mutations are “loss of function”
- One intact copy protects against disease
- Women have 2 X-chromosomes and are rarely affected
- Both Haemophilia A and B are X-linked recessive disorders
- Sons of women who are carriers have a 0.5 probability of inheriting the disease
- Around 30% of cases have no family history (sporadic).
One normal copy of gene makes you normal - men don’t have 2 X’s so high rate in men. Gene mutates quite often.
Huntington Disease (3)
- Progressive tremor, involuntary movements, neurodegeneration
- Onset in mid-life (usually 30-50)
- No effective treatment
Inheritance of HD (3)
- Autosomal dominant inheritance
- Probability that individual 1 will contract HD is 0.5
- Probability that 2 will contract HD is 0.5 x 0.5 = 0.25
- Having one normal copy won’t protect you*
- Only need one defective chromosome to cause disease*
The genetic cause of HD (5)
- Mapped to chromosome 4 (autosomal)
- Gene codes for previously unknown protein called huntingtin (HTT gene)
- HD is caused by expansion of a CAG triplet repeat in HTT gene
- CAG codes for glutamine; protein has long polyglutamine tract
- The protein becomes unstable and fragments, clumping together in nerve cells and damaging them (loss of neuronal function)
Genetic testing for HD (10)
- Use PCR to determine length of CAG repeat
- Can determine who will develope the disease before the age at which symptoms develop
- 10-35 copies –normal
- 27-35 copies risk of descendants developing HD
- 36-40 copies risk of developing disease.
- 40+ copies – disease develops.
–> Longer repeat = get disease earlier in life - can say if gonna get it and when
- NOT EVERYONE WANTS TO KNOW
- Autosomal dominant inheritance
- Only affected people can pass on the gene
- Daughter’s test result will tell Amy whether she carries the gene
Cystic Fibrosis (CF) (2)
“Woe to that child which when kissed on the forehead tastes salty. He is bewitched and soon must die”. [German Folklore]
- Early reference to cystic fibrosis
- Refers to the observation that the CF mutation increases the saltiness of sweat- a method still used to screen for the disease.
CF Symptoms (4)
• Strange combination of symptoms including;
– Lung infections, pancreatic insufficiency, congenital absence of vas deferens in males, salty tasting skin
- Range from mild to severe
- Severe form:
– Frequent infections and hospitalisation
– reduced life expectancy
• Inheritance is autosomal recessive
- Have treatment but no cures*
- Offspring of two carriers can get it so rare*
The CF gene (4)
- Gene disrupted in CF was identified in 1979
- Predicted protein was new, function unknown
- Later proved to be chloride ion transporter (CFTR = cystic fibrosis transmembrane regulator)
- Reduced function of CFTR protein causes thickening of cell secretions
CF Mutations (2)
- Many different mutations in CFTR gene can cause CF
- Most common is a 3bp deletion, deltaF508
– Protein is abnormally processed and degraded
In photo - middle is mild form of CF and bottom is when protein doesn’t go to cell membrane so severe CF
Appreicate
Appreciate
Combination of genes - not just one (shared variantsin cases not in controls)
50% genetic variation but we can only find 10% (common variants)
