Download 09-Mutations-2012 - mr-youssef-mci

Rate of mutations in the
Human Genome
 A study published in Current Biology in 2009,
shows that in total, we all carry 100-200 new
mutations in our DNA.
 This is equivalent to one mutation in each 15 to 30
million nucleotides.
 Fortunately, most of these are harmless and have
no apparent effect on our health or appearance.
Mutations
 mutations – errors in the DNA
 can have a bad resultant effect
 can have no effect
 can have a positive resultant effect
Mutations are usually not an issue because
we have two copies of each gene.
Mutations
Changes in DNA result in:
1.
silent mutations
2.
missense mutations
3.
nonsense mutations
Silent Mutations
 silent mutation – has no effect on the function of the
cell; sequence of amino acids is not affected
 often found in the non-coding regions (introns)
 If introns in mRNA are spliced out, then the mutation
never surfaces
 Some amino acids can be coded for by multiple
codons. (referred to as redundancy in the genetic
code)
 It is possible that one change in the base pair will still
produce the same amino acid
Missense Mutation
 missense mutation – nucleotide sequence is
changed such that a different amino acid is coded for
 protein function may or may not be affected
Sickle cell anemia is a result of a missense mutation.
Sickle Cell Anemia
Wild-type hemoglobin DNA
3
Mutant hemoglobin DNA
5
C T
T
In the DNA, the
mutant template
strand has an A where
the wild-type template
has a T.
G U A
The mutant mRNA has
a U instead of an A in
one codon.
3
5
T
C A
mRNA
mRNA
G A
A
5
3
5
3
Normal hemoglobin
Sickle-cell hemoglobin
Glu
Val
The mutant (sickle-cell)
hemoglobin has a valine
(Val) instead of a glutamic
acid (Glu).
Sickle Cell Anemia
Type I diabetes mellitus – a
misense mutation
 Mutations affecting ER processing of insulin, appear
to result in loss of β-cells (cells of the pancreas that
produce insulin).
 The severity of the defect, as well as other factors that
define the β-cell’s capacity to cope with ER stress,
determine the rate of β-cell death and thus the age of
onset and severity of clinical disease
Nonsense Mutations
 nonsense mutation – nucleotide sequence is
changed such that an amino acid is replaced with an
early stop codon
 short proteins are made; usually digested by
proteases
 nonsense mutations usually are lethal, even if a child
is born with a nonsense mutation they usually do not
live very long
DNA:
5' - ATG ACT CAC CGA GCG CGA AGC TGA - 3‘
3' - TAC TGA GTG GCT CGC GCT TCG ACT - 5'
Template
Strand
mRNA: 5' - AUG ACU CAC CGA GCG CGA AGC UGA - 3'
Protein:
Met Thr His Arg Ala Arg Ser Stop
DNA:
5' - ATG ACT CAC TGA GCG CGA AGC TGA - 3‘
3' - TAC TGA GTG ACT CGC GCT TCG ACT - 5‘
mRNA: 5' - AUG ACU CAC UGA GCG CGU AGC UGA - 3‘
Protein:
Met Thr His Stop
Mutation
Other Types of DNA Changes
Point Mutation (Base-Pair Substitution)
2. Frameshift Mutation
3. Chromosomal Mutation
1.
Type of DNA Change:
Point Mutations
 point mutation – nucleotide changes where one base
pair (bp) is replaced by another bp. Point mutation
are specific to one base pair
Point mutations are also known as substitution
mutations and include silent, insertion and deletion
mutations.
Silent
mutation
Type of DNA Change:
Frameshift Mutation
 frameshift mutations – changes in the DNA
sequence which modify the translation reading frame
1. Deletions – removal of one or more NTs
2. Insertions – addition of one or more NTs
Cystic Fibrosis
This disease is caused by mutations which occur in a huge gene (>6000
nucleotides) on chromosome 7 that encodes a protein of 1480 amino acids
called the cystic fibrosis transmembrane conductance regulator (CFTR).
The CFTR protein transports chloride ions out of cells and when mutated
causes problems that involves both the lungs and the gastrointestinal tract.
This disease results from a number of different mutations in the CFTR
gene. These include the deletion of a codon resulting in the deletion of the
amino acid phenylalanine, a missense mutation resulting in an aspartic acid
being substituted for a glutamic acid, a nonsense mutation resulting in a
stop codon instead of one that codes for glycine and hence a truncated
protein.
Type of DNA Change:
Chromosomal Mutations
Sections of chromosomes can break off and reattach
abnormally.
1. Translocation mutations
2. Inversion mutations
Chromosomal Mutation
 translocation mutations – large portions of DNA are
exchanged
Translocation
Philadelphia Chromsome
Philadelphia Chromsome - is a translocation
that fuses parts of chromosomes 9 and 22,
which produces a new gene product that
functions as an oncogene called Abl, which is
implicated in chronic myelogenous leukemia.
Chromosomal Mutations
 inversion mutations – sections of a chromosome are
reversed
Causes of Mutations
1.
spontaneous errors due to enzymes
2.
induced errors due to mutagenic agents



3.
UV radiation
X-rays
chemical (Agent Orange)
transposable elements
Spontaneous Errors
 A replication error may
arise in regions
of DNA containing
tandemly repeated
sequences.
 This slippage displaces
the newly synthesized
strand back along
the template strand
(dark blue), with its 3′
end still paired with the
template.
 As a result, the DNAsynthesizing enzymes
copy a region of the
template strand a second
time, leading to an
increase in length of nine
nucleotides (yellow) in
this example
Visualization of Mutations
http://www.youtube.com/watch?v=QHQ4p0vJW2A
http://www.youtube.com/watch?v=CuoQNLNYZbU
Transposable Elements
 some DNA sequences
naturally move
themselves around
the genome –
transposons
Classwork/Homework
 Pg. 263 #1-8