Adaptive Molecular Evolution
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Transcript of Adaptive Molecular Evolution
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Adaptive Molecular EvolutionNonsynonymous
vsSynonymous
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Reading for today
• Li and Graur chapter (PDF on website)
• Evolutionary EST paper (PDF on website)
• Page and Holmes pp. 231 - 243
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Predictions of neutral theory
• There is an inverse correlation between rate of substitution and degree of functional constraint.
• Patterns of base composition and codon usage reflect mutational rather than selective pressures.
• There is a constant rate of molecular evolution.
• The level of within species variation is the product of population size and mutation rate and is correlated with levels between species.
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The neutral theory of molecular evolution
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Well accepted “rule”:
Evolutionarily conservation
of genes and regions implies
functional importance
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QuickTime™ and aTIFF (LZW) decompressor
are needed to see this picture.
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What molecular changes are different between
species?
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% Amino Acid Sequence Divergence10 20 30 40 50 60 70
1000
800
600
400
200
NUMBER OF PAIRS
948
483
238 13857 12 2
Rodent x Human 1880 Orthologous Sequence Pairs (~4% of genes)
Makalowski & Bogusti, PNAS 95, 9407 (1998)
1. Genes involved in immune response
2. Genes involved in olfaction
3. Genes involved in reproduction
4. Genes implicated in human disease?
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Potential causes of rapid evolution
•Lack of constraint: Selectively neutral evolution
•Adaptive value for change: Positive “Darwinian” selection
Compare cDNA sequences.
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2 types of changes in codons
Synonymous = silent change (amino acid stays the same)Nonsynonymous = replacement change (changes amino acid)
ValGTC
ValGTG
AlaGCC
SynonymousChange
NonsynonymousChange
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Rates of synonymous changes is similar to pseudogenes
Synonymous changes
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Synonymous and nonsynonymous sites are both in coding regions.Synonymous sites are considered selectively neutral.Therefore, we can use synonymous sites as a “ruler” for nonsynonymous substitutions. When nonsynonymous changes exceeds synonymous changes, infer positive selection.
Prot. 1: Ile Cys Ile Lys Ala Leu Val Leu ThrDNA1: ATA TGT ATA AAG CGA GTC CTG TTA ACA
DNA2: ATA TGT ATA AAG CGA GTC CTG TTA ACAProt. 2: Ile Cys Ile Lys Ala Leu Val Leu Thr
There are more nonsynonymous than synonymous sites in coding DNA
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dN = # nonsynonymous substitutions/# nonsynonymous sites
dS = # synonymous substitutions/# synonymous sites
Test for selection by comparing dN and dS
dN /dS = 1: Neutral evolutiondN /dS < 1 : Purifying selectiondN /dS > 1 : Positive selection
The dN/dS ratio () measures the selective pressure
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Multiple methods for calculating dN /dS
• “Counting” methods– Nei and Gojobori– Li et al.
• Maximum likelihood methods (model of codon evolution)– Muse and Gaut– Neilsen and Yang
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Codon degeneracy
• Non-degenerate– All mutations produce nonsynonymous change
• Two-fold degenerate– one of the three possible changes is synonymous
• Four-fold degenerate– all mutations produce synonymous change
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When counting sites:
• Non-degenerate (1)– nonsynonymous
• Two fold degenerate (2)– 1/3 synonymous and 2/3 nonsynonymous
• Four fold degenerate (4)– synonymous
Note: Three fold degenerate treated as two-fold.
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Example:Degeneracy 1
Asp Thr Ala ValSequence 1 GAC ACA GCG GTT
How many synonymous sites in sequence 1?First, assign degeneracy to each codon position.
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Example:Degeneracy 1 1
Asp Thr Ala ValSequence 1 GAC ACA GCG GTT
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Example:Degeneracy 1 11
Asp Thr Ala ValSequence 1 GAC ACA GCG GTT
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Example:Degeneracy 1 112
Asp Thr Ala ValSequence 1 GAC ACA GCG GTT
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Example:Degeneracy 1 112 1
Asp Thr Ala ValSequence 1 GAC ACA GCG GTT
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Example:Degeneracy 1 112 11
Asp Thr Ala ValSequence 1 GAC ACA GCG GTT
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Example:Degeneracy 1 112 114
Asp Thr Ala ValSequence 1 GAC ACA GCG GTT
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Example:Degeneracy 1 112 114 1
Asp Thr Ala ValSequence 1 GAC ACA GCG GTT
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Example:Degeneracy 1 112 114 11
Asp Thr Ala ValSequence 1 GAC ACA GCG GTT
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Example:Degeneracy 1 112 114 114
Asp Thr Ala ValSequence 1 GAC ACA GCG GTT
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Example:Degeneracy 1 112 114 114 1
Asp Thr Ala ValSequence 1 GAC ACA GCG GTT
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Example:Degeneracy 1 112 114 114 11
Asp Thr Ala ValSequence 1 GAC ACA GCG GTT
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Example:Degeneracy 1 112 114 114 114
Asp Thr Ala ValSequence 1 GAC ACA GCG GTT
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Example:Degeneracy 1 112 114 114 114
Asp Thr Ala ValSequence 1 GAC ACA GCG GTT
How many nonsynonymous sites in sequence 1?
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Example:Degeneracy 1 112 114 114 114
Asp Thr Ala ValSequence 1 GAC ACA GCG GTT
How many nonsynonymous sites in sequence 1?8 nondegenerate sites 1 two fold degenerate site= 8.66 nonsynonymous sites
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Example:Degeneracy 1 112 114 114 114
Asp Thr Ala ValSequence 1 GAC ACA GCG GTT
How many synonymous sites in sequence 1?
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Example:Degeneracy 1 112 114 114 114
Asp Thr Ala ValSequence 1 GAC ACA GCG GTT
How many synonymous sites in sequence 1?3 four fould degenerate sites, 1 two fold =3.33 synonymous sites.
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Example:Degeneracy 1 112 114 114 114
Asp Thr Ala ValSequence 1 GAC ACA GCG GTTSequence 2 GCC ACT TCG GTT
Ala Thr Ser ValDegeneracy 2 114 114 114 114
Sequence 2 has 8 nonsynonymous sites and 4 synonymous sites.
For this comparison, we average number from both sequences.Nonsynonymous sites = (8.66 + 8)/2 = 8.33Synonymous sites = (3.33 + 4) = 3.67
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Example:Degeneracy 1 112 114 114 114
Asp Thr Ala ValSequence 1 GAC ACA GCG GTTSequence 2 GCC ACT TCG GTT
Ala Thr Ser ValDegeneracy 2 114 114 114 114
There are 2 nonsynonymous changes, So dn = 2/8.33 = 0.24
There is 1 silent change,So ds = 1/3.67 = 0.27
dn/ds = 0.23/0.27 = 0.88< 1 despite having more nonsynonymous changes.
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Other factors can effect calculation of dN/dS
• Transition/transversion ratio– Transitions typically more frequent
• Pathway of substitution• Codon bias
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Nearly all counting methods assume all pathways are equally likely.
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Codon Bias
• Unequal codon usage results in reduced number of effective codon sites.
• Ignoring codon bias leads to underestimate of ds.
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Maximum likelihood methods incorporate models of codon evolution / bias.
Transition
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Problems with dn/ds for detecting selection
• Positive selection acting only on a few sites (binding cleft).
• Burst of positive selection followed by purifying selection (lineage specific events).
• Positive selection in promoter and non-coding regions.
• Positive selection for post-translational modification (glycosylation).