- 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 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 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 rapid evolution change in copy number of short tandem repeats eg. if slippage during DNA replication microsatellites

Fig 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 within gene (or regulatory region) - certain human genetic (neurodegenerative) diseases - repeat number strongly correlates with age of onset of disease and severity Karp p.435 > > ’ UTR 3’ UTR intron Repeat copy number in normal = green; red = disease condition

Fragile X syndrome Snustad Fig femalemale 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 Inversion through chromosome breakage & rejoining

Fig if recombination between indirect repeats in genome - if recombination between direct repeats A B C D A BC 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 selection and 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 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 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  -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) within populations (Figure 2.9) “Molecular clock”

Polymorphic sites in Drosophila Adh gene Asterisk = site of Lys-for-Thr replacement responsible for mobility difference between fast (F) and slow (S) electrophoretic alleles 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 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