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Causes of Variation in Substitution Rates
Rate of Substitution is determined by:
(1) Mutation rate
Among genes
Among gene regions
(2) Probability of fixation
Neutral, advantageous, deleterious
Functional constraint: Range of alternative nucleotides
that is acceptable at a site without negatively affecting
the function or structure of a protein.
Fraction of
Selectively Neutral
Mutations
Total Mutation
Rate per Unit Time
Rate of Neutral
Mutation
mo = vT fo
Neutral Theory Predicts k = mo :
Rate of substitution
So,
k = vT fo
k = vT fo
So, rate of substitution will be greatest when fo is 1.0
i.e.
Highest Rate of Substitution is Expected in
Sequence That Does Not Have A Function
Pseudogenes!
Expect an inverse relationship between the intensity of the
functional constraint and the rate of neutral evolution
Also expect pattern of substitution
to vary within genes
5’ UTR
5’
3’ UTR
Intron 2
Intron 1
Exon 1
Exon 2
GT
Signal Initiation
Sequences codon
AG
Ex 3
GT AG
Stop
codon
Schematic of Eukaryotic Protein-Coding Locus
3’
Given this relationship:
Also, expect higher rates of substitution for
synonymous vs nonsynonymous sites.
Logic:
(1) Mutations that result in amino acid replacements have
a higher probability of causing a deleterious effect on the
structure/function of the protein.
(2) Accordingly, the majority of nonsynonomous mutations
will be eliminated from the population by purifying selection.
(3) As a result, there will be a reduction in the rate of
nonsynonymous substitution vs synonymous substitution.
How do we explain variation in rates of nonsynonymous
substitution among genes?
What are the Patterns Of Nucleotide
Substitution Within Coding and
Non-coding Gene Regions?
Mouse vs Human
Time of divergence ~ 80,000 mya
rate = substitutions / site / 109 years
(1) Rates of substitution are extremely variable,
more so for nonsynonymous substitutions.
# Codons
NSyn Rate
Syn Rate
(2) In the majority of genes, the synonymous substitution
rate greatly exceeds the nonsynonymous rate.
# Codons
NSyn Rate
Syn Rate
(3) Overall rate of substitution is lowest for nondegenerate sites, highest for 4-fold degenerate sites.
Table 7.2
Positive Selection
KA/NA >
# nonsyn. substitutions
nonsyn. site
>
KS/NS
# syn. substitutions
syn. site
Examples
•Immunity (immunoglobulins, major histocompatibility)
•Self / non-self recognition
•Sex-related genes
Map of the Human Leukocyte (HLA)
Loci on Chrom. 6
Class I
Class II
Gene DPB1 DPA1
21
4
DQB1 DQA1
17
12
DRB1 DRB3 DRA
47
4
1
B
C
A
50
14
32
Number of alleles
•HLA loci encode glycoproteins that present pieces of
bacteria and viral protein on the surface of cells for
possible recognition by the immune system
Structure of
MHC Class I Molecule
(1) Expressed on surface of all
nucleated somatic cells
(2) Presents peptides
to cytotoxic T-cells
Why is the rate of substitution at 4-fold
degenerate sites lower
than the rate within pseudogenes?
Sub/Site/106
Synonymous substitutions
are not selectively neutral!
4 fold deg
pseudo
Codon Usage is non-random:
species-specific, and
patterns may vary among
genes within a genome.
Four fold degenerate site
CUG
CUA
CUC
CUU
Leucine
No matter what nucleotide is
substituted, the codon specifies
the same amino acid
Frequency of
tRNA species
Frequency of codon
usage for highly
expressed genes
Frequency of codon
usage for lowly
expressed genes
Gene Expression and Codon Bias in Unicellular Organisms
Highly Expressed Genes
Lowly Expressed Genes
• Strong selection for
translational efficiency
• Weak selection for
translational efficiency
• Restricted tRNAs used
• More tRNAs used
• Strong Codon Bias
• Weak Codon Bias
• Low rate of synonymous
substitution (fewer
neutral mutations)
• High rate of synonymous
substitution (more
neutral mutations)
Subs / Syn Site
Prediction: If there is purifying selection against
synonymous substitutions, there should be
a lower rate of evolution in genes with high codon
bias.
Low
Codon Bias
High
What about Multicellular Organisms?
High Codon Bias
Low Codon Bias