- 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