Download Slides 10/28 - Salamander Genome Project

What are the Patterns Of Nucleotide
Substitution Within Coding and
Non-coding Gene Regions?
Mouse vs Human
T = 80,000 my
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.
(4) Rate of transversional substitution is lower at
2-fold vs 4-fold degenerate sites.
(5) Rate of transitional substitution is higher than
transversional substitution at 4-fold sites.
(6) At nondegenerate sites, rate of transitional and
transversional substitution are similar.
Schematic of Eukaryotic Protein-Coding Locus
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
3’
Percent divergence between cow and
goat b- and g-globin genes and between cow and
goat b-globin pseudogenes.
Region
K
5’ flanking
5.3+1.2
5’ untranslated
4.0+2.0
4-fold degenerate
8.6+2.5
Introns
8.1+0.7
3’ flanking region
8.8+2.2
3’ untranslated
8.0+1.5
Pseudogenes
9.1+0.9
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
V0 = vT
fo
Neutral Theory Predicts k = V0 :
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
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.
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
V0 = vT
fo
Neutral Theory Predicts k = V0 :
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
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.
Why is the rate of substitution at 4-fold sites lower
than the rate within pseudogenes?
Synonymous substitutions are not selectively neutral!
Codon Usage is non-random: species-specific, and
patterns may vary among genes within a genome.