CONSEQUENCES OF MUTATION Flashcards
Humans appear different because of
normal genetic
variation
Variation arises because of
- Mutation
- Other processes (genetic drift, founder effects,
selection)
where is DNA found
in nucleus and mitochondria
where is RNA found
in the nucleolus and cytoplasm
Central Dogma of Molecular
Biology
DNA= RNA= PROTEIN replication=transcription= translation
Eukaryotic gene structure
- promotor region = CAAT and TATA box
- start point of transcription is just after the TATA box
- initiated codon for protein synthesis= AUG
- TERMINATer region= UGA, UAA,UAG
what is a mutation
Definition: a change in a genomic sequence
- Can be a single base or duplication of entire
segments or chromosomes - NOT ALWAYS PATHOGENIC (disease-causing)
- It’s a matter of how RARE it is
possible consequences of mutation
- Silent (no effect)
- Beneficial (good effect)
- Deleterious (bad effect)
Exogenous (outside of the cell) causes of mutation
- Chemicals
- Radiation
- Pollutants
Endogenous (inside of the cell) causes of mutation
- Spontaneous damage
- Replication and recombination errors
- Repair errors
Mutation rate – how often do
Do mutations occur?
- In humans and other mammals, uncorrected errors (=
mutations) occur at the rate of about 1 in every 50
million (5 x 107) nucleotides added to the chain. - But with 6 x 109 nucleotides in a human cell, that
means that each new cell contains some 120 new
mutations (EXCLUDING exogenous causes of
mutation). - Most of these mutations will be in non-coding regions
types of mutation
- Point
- Silent
- Missense
- Nonsense
- Static
- Dynamic
- Insertions/Deletions
- In-frame and frameshift
- Splice-site
- Acquired
- Germline
acquired mutation= somatic
- occurs in non-germline tissues
- can not be inherited
- e.g mutation in tumor only
germline mutation
- present in the egg and sperm
- can be inherited
- cause cancer family syndrome
- all cells are affected on the offspring
static mutation
STATIC variants – do not change when passed to offspring
- Point mutations (single nucleotide substitutions)
- Deletion / Insertion mutations
- Splice site mutations
dynamic mutation
DYNAMIC variants – have the potential to change when passed to
offspring
(e.g. triplet repeats)
point mutation
- Single nucleotide substitutions (one base is changed
to another) that occur in less than 1% of the studied
population - Reminder: if the substitution is seen in more than 1%
of the population, it is referred to as a polymorphism - Point mutations include
- Silent mutations
- Nonsense mutations
- Missense mutations
silent mutation- point mutation- static mutation
- Silent mutations do not change the amino acid coded for
missense mutations
- Missense mutations result in an amino acid change
sickle cell disease
- The mutation causing sickle is the
replacement of ‘A’ by ‘T’ at the
17th nucleotide of the gene for the
the beta chain of hemoglobin.
* The mutation changes the codon GAG (for glutamic acid) to GTG (which encodes valine). Thus the 6th amino acid in the chain becomes valine instead of glutamic acid.
- A classic example of a missense
mutation.
nonsense mutation
- Nonsense mutations result in a stop codon instead of an amino
acid.
summary of point mutation
- Silent mutation
- (no amino acid change in protein)
- Missense mutation
- (results in an amino acid change to another amino acid)
- Nonsense mutation
- (results in an amino acid change to a STOP codon)
impact of silent mutation
- No effect on the amino acid sequence
* Can influence the kinetics of protein folding and RNA splicing
impact of a missense mutation
the effect depends on:
- Nature of the amino acid substitution
- Chemistry (e.g. polar to non-polar?)
- Location (conserved or non-conserved region of the gene)
- Size (can the amino acid chain still fold correctly?)
impact of nonsense mutation
- Conversion of a codon into a stop codon
- No protein (Nonsense Mediated Decay) or premature
termination of protein with altered function (truncated)
Insertions/Deletions (INDELS)
- Multiples of three → in-frame mutation
- If NOT multiples of three → frameshift
mutations
impact of deletion
- The entire gene eg. a globin gene in a-thalassemia
- Part of the gene eg. p.F508del mutation in CF
- Frameshift or in-frame?
impact of insertion
- Insertion of 3 bp or multiples of 3 bp
- Extra amino acids in the protein
- Insertion ≠ 3 bp or ≠ to multiple of 3 bp results in a frameshift during translation
- Altered protein sequence 3’ of the mutation
Frameshift indels generally lead to:
- The possible introduction of a stop codon
- Altered or abolished protein function
Splice site mutations
SD – splice
donor
SA – splice
acceptor
~15% of disease-causing mutations in humans affect RNA splicing
How does the spliceosome know
where to cut?
- The splice donor (SD) site is a stretch of conserved
sequence around the beginning of an intron. The first
two nucleotides of most introns are “GT” - The splice acceptor (SA) is a stretch of conserved
sequence around the end of an intron. The last two
nucleotides of most introns are “AG” - This is known as the “GT-AG rule”
impact of splice site mutation
- Prevention of correct splicing
- Inactivation of
donor/acceptor splice site
prevents splicing - Exon skipping or intron
retention – difficult to predict
