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- any detectable change in DNA sequenceeg. 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
MUTATIONS
TYPES OF MUTATIONS
1. Point mutations
Transition = purine to purine or pyrimidine to pyrimidine
Transversion = 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
Nonsense mutation
Synonymous
2. Insertions or deletions (“indels”)
Fig. 1.12
Non-synonymous
- different aa specified by codon
- change from sense codon to stop codon
- amino acid altered
- “silent” change
- frameshift mutations within coding sequences
Short insertions or deletions(short “indels”)
Fig.1.18
-rapid evolution change in copy numberof short tandem repeats
eg. if slippage during DNA replication
microsatellites
Fig. 6.23
Do you agree or disagree with the following statement? see p.27
“A synonymous mutation may not always be silent.”
“Triplet repeat expansion” mutations
- increased copy number of tandem repeats of triplets withingene (or regulatory region)
- certain human genetic (neurodegenerative) diseases
- repeat number strongly correlates with age of onset of diseaseand severity
Karp p.435
>200
7-22
200 - >2000
5-40
5’ UTR 3’ UTRintron
Repeat copy number in normal = green; red = disease condition
Fragile X syndrome
Snustad Fig. 5.12
female male
male II-1 asymptomatic hemizygous carrier
daughter III-1 asymptomatic,but expanded repeat in germ line
wt
mutant
3. Inversions, translocations, etc.
- shown as single stranded, but both DNA strands inverted
Fig. 1.20
Inversion
through chromosome breakage & rejoining
Fig. 1.20
- if recombination between indirect repeats in genome
- if recombination between direct repeats
A B C D
A
B
C
D
A 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 selectionand random genetic drift
if allele frequency = 1, FIXATION
if allele frequency = 0, EXTINCTION (LOSS)
Advantageous mutations
Neutral mutations
Fig. 2.7
Dynamics of gene substitution
_t = mean conditional fixation time
1/K = mean time between 2 consecutive fixation events
K = rate of substitution (# mutations fixed per unit time)
SELECTIONIST THEORY (Neo-Darwinian)
Natural selection for advantageous mutations whichimprove fitness is primary source of genetic variation
“Survival of the fittest”
NEUTRAL THEORY OF MOLECULAR EVOLUTION (Kimura)
At molecular level, most evolutionary changes occur byrandom genetic drift of alleles which are selectively neutral(or nearly so)
“Survival of the luckiest”
BUT …. presence of different neutral alleles in populationimportant
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 about0.5 – 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 proteinover time
- based on pairwise comparisons of proteins (eg -globin)among species (Figure 4.15)
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) withinpopulations (Figure 2.9)
“Molecular clock”
Polymorphic sites in Drosophila Adh gene
Asterisk = site of Lys-for-Thr replacement responsible formobility difference between fast (F) and slow (S) electrophoreticalleles
Fig. 2.9
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 exceedadvantageous 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