DNA Mutations Flashcards
Exons and splicing
EXON: contain the coding sequence.
If there is alternative splicing different proteins can be made from same gene
Exon shuffling allows new proteins to be made e.g. the immune system
Thus exon shuffling enable huge variants of antibodies etc. to be produced
Types of variant
Duplications of genes or part of gene
Deletions (whole gene or some exons)
Variants within the regulatory sequence
Splice site variants
Introduce premature stop codon-nonsense variant
Replace one amino acid in protein with another – mis-sense variant
Expansion of trinucleotide repeats
Out of frame Deletions
Clearly disrupts the protein
e.g.deletion causing absence of dystrophin in DMD
e.g. deletion causing the absence of dystrophin in duchenne muscular dystrophy. If C is lost, the sequence shifts to the right once meaning the reading frame of the
ATC GTT TAC GCG
gene is changed. Can cause quite catastrophic effects - early mortality
In frame deletions
In frame deletion in dystrophin truncated protein causing milder Becker Muscular dystrophy
In frame deletion leads to a complete codon is removed thus only one amino acid is lost. This ATC GTC TTA GCG is less catastrophic. Known as in frame deletion since the reading frame is not altered. Results is a milder disease - later onset death typically
ATC GTC GCG TGC
Splice-Site Variant
Affects the accurate removal of an intron
- Enzyme recognises CGAT as cutting site, A changes to C and then enzyme no longer recognises the sequence so excision does not occur thus sequence of intron is translated and proteins are synthesised.
Non-sense variant/mutation
• Change codon to stop codon
• Out of frame deletion produces a stop codon either at deletion site or further along
-results in an incomplete, usually non-functional protein. E.g. Duchenne’s muscular dystrophy
• RNA detaches from the ribosome and is eliminated
This process is called Nonsense mediated decay
Mis-sense variant/mutation
• Single base substitution
• Changes the type of amino acid in the protein
• May or may not be pathogenic (cause disease)
• May be a polymorphism of no functional significance
This can have a varied affect and can result in a silent mutation and a non functional protein E.g Sickle cell disease where CAG was replaced with CTG. May or may not be pathogenic could be a polymorphism or of no functional significance
Expansion of a tri-nucleotide repeat
Huntington’s disease CAG
- Triple repeat is repeated several times in the first part of the coding sequence
- The normal range of repeats is 15-20
- If the repeats are larger than 36, the patient will develop Huntington’s, if repeats
number is larger than 36 then onset of disease will be earlier. If repeats are less than 36 than no disease
Myotonic dystrophy CTG
Fragile X CGG
Anticipation
repeat gets bigger when transmitted to the next generation and so symptoms develop earlier and are more severe
Example; muscle dystrophy
Heterogeneity
One gene, one variant, one disease e.g. Huntingtons
ALLELIC HETEROGENEITY
Lots of different variants in one gene e.g. cystic fibrosis
Can give rise to different clinical conditions- genotype/phenotype correlations
LOCUS HETEROGENEITY
Variants in different genes give the same clinical condition e.g. hypertrophic cardiomyopathy
Dominant variants
manifest the disease phenotype in the heterozygous state i.e. the condition occurs if there is one variant and one normal allele
Recessive variants
only manifest the disease in the homozygous state i.e. there have to be variants in both alleles. The majority of pathogenic variants are recessive.
Mechanisms of Dominance
Loss-of-function variants
Gain of Function variants
Dominant-negative variants
