Transcript mutations - Université d`Ottawa

MUTATIONS
- any detectable change in DNA sequence
eg. errors in DNA replication/repair
- inherited ones of interest in evolutionary studies
Deleterious
- will be selected against and lost (purifying selection)
Advantageous
- will be fixed in population by natural selection
- rare occurrence
Neutral
- will have not effect on phenotype
- may be fixed in population by genetic drift
TYPES OF MUTATIONS
1. Point mutations
Transition
Transversion
= purine to purine
or pyrimidine to pyrimidine
= purine to pyrimidine
How many possible transitions? transversions?
p.38 “In animal nuclear DNA, ~ 60-70% of all point mutations
are TRANSITIONS, whereas if random expect 33%”
Missense mutation - different aa specified by codon
Nonsense mutation - change from sense codon to stop codon
Non-synonymous
- amino acid altered
Synonymous
- “silent” change
2. Insertions or deletions (“indels”)
- frameshift mutations within coding sequences
Fig. 1.12
Short insertions or deletions
(short “indels”)
eg. if slippage during DNA replication
-rapid evolution change in copy number
of short tandem repeats
microsatellites
Fig.1.18
Do you agree or disagree with the following statement?
“A synonymous mutation may not always be silent.”
see p.27
Fig. 6.23
“Triplet repeat expansion” mutations
- increased copy number of tandem repeats of triplets within
gene (or regulatory region)
- certain human genetic (neurodegenerative) diseases
- repeat number strongly correlates with age of onset of disease
and severity
>200
7-22
5’ UTR
Repeat copy number in normal = green;
red = disease condition
Karp p.435
intron
200 - >2000
5-40
3’ UTR
Fragile X syndrome
female
male
male II-1 asymptomatic
hemizygous carrier
daughter III-1 asymptomatic,
but expanded repeat in germ line
wt
mutant
Snustad Fig. 5.12
3. Inversions, translocations, etc.
Inversion
through chromosome
breakage & rejoining
Fig. 1.20
- shown as single stranded, but both DNA strands inverted
- if recombination between
direct repeats
B
C
A B
A
A
Fig. 1.20
D
C D
- if recombination between
indirect repeats in genome
D
B C
Fig. 1.17
MUTATIONS vs POLYMORPHISMS?
Polymorphisms
- two or more natural variants (alleles, phenotypes,
sequence variants) which occur at “significant” frequencies
in a population
if present in < 2% population, called “mutation or “mutant allele”
Alleles
- alternative forms of a gene (or DNA sequence) at
a particular locus (chromosomal site)
- frequency in population determined by natural selection
and random genetic drift
if allele frequency = 1, FIXATION
if allele frequency = 0, EXTINCTION (LOSS)
Dynamics of gene substitution
Advantageous mutations
Neutral mutations
_
t = mean conditional fixation time
1/K = mean time between 2 consecutive fixation events
K = rate of substitution (# mutations fixed per unit time)
Fig. 2.7
SELECTIONIST THEORY (Neo-Darwinian)
Natural selection for advantageous mutations which
improve fitness is primary source of genetic variation
“Survival of the fittest”
NEUTRAL THEORY OF MOLECULAR EVOLUTION (Kimura)
At molecular level, most evolutionary changes occur by
random genetic drift of alleles which are selectively neutral
(or nearly so)
“Survival of the luckiest”
BUT …. presence of different neutral alleles in population
important
eg. if environment changes, certain alleles may be advantageous
& selected
Some observations leading to Kimura’s theory
1. Relatively high rate of amino acid sequence evolution
- variable among proteins, but in many cases about
0.5 – 1.5 x 10-9 changes per non-synonymous (ie. amino
acid-altering) site per year (Table 4.1)
2. Relatively constant rate of evolution for given protein
over time
- based on pairwise comparisons of proteins (eg a-globin)
among species (Figure 4.15)
“Molecular clock”
3. Rate of evolution can differ along protein sequence
- functionally important regions (eg active site of enzyme)
change at slower rate (Figure 4.5)
4. High degree of genetic variation (polymorphisms) within
populations (Figure 2.9)
Polymorphic sites in Drosophila Adh gene
Fig. 2.9
Asterisk = site of Lys-for-Thr replacement responsible for
mobility difference between fast (F) and slow (S) electrophoretic
alleles
Interpretation of data shown in figure?
Bromham & Penny “The modern molecular clock”
Nature Rev Genet 4:216, 2003
Selectionist theory: assumption that all mutations affect fitness
Neutral theory: for most proteins, neutral mutations exceed
advantageous ones (and more neutral sites would produce a
faster overall rate of change
Nearly neutral theory: fate of mutations with only slightly positive or
negative effect on fitness will depend on factors like population size