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Chapter 5
Rate and Patterns of Nucleotide Substitution
Chau-Ti Ting
[email protected]
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1
§ Rate of nucleotide substitution
The rate of nucleotide substitution, r, is defined as
he number of substitutions per site per year. The
mean rate of substitution can be calculated by
dividing the number of substitutions, K, between
two homologous sequences by 2T, where T is the
time of divergence between the two sequences.
That is
r = K
2T
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 100. Sinauer Associates, Inc. Sunderland, MA, USA.
2
Coding region
Synonymous versus nonsynonymous
The rate of nonsynonymous substitution is extremely
variable among genes:
Range: effective zero in actin  3.1x10-9 in interferon 
Extreme case – ubiquitin, which is completely conserved
between human and fly and which differs among animal,
plant, and fungi by only 2 or 3 out of 76 amino acid residues.
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 101. Sinauer Associates, Inc. Sunderland, MA, USA.
In the vast majority of genes, the synonymous substitution
rate greatly exceeds the nonsynonymous substitution rate.
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 103. Sinauer Associates, Inc. Sunderland, MA, USA.
3
Transition versus transversion
At fourfold degenerate sites it is possible to compare the rate
of transitional substitution and transversional substitution,
since both types of substitution are synonymous.
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 104. Sinauer Associates, Inc. Sunderland, MA, USA.
Table 4.2 Rates of transitional and transversional substitutions (per site per 109 years) at
nondegenerae, twofold degenerate, and fourfold degenerate codon site.
Types of Substitution
Transition
Transversion
Total
Nondegenerae
0.40
0.38
0.78
Twofold degenerate
1,86
0.38
2.24
Fourfold degenerate
2.24
1.47
3.71
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 105. Sinauer Associates, Inc. Sunderland, MA, USA.
4
Intron
Intron
Flanking region
Flanking region
5’
Initiation
codon
GC box
CAAT box
TATA box
19-27 bp upstream
of the transcription
startpoint
Stop
codon
Transcription
initiation
Transcription
termination
AATAAA box
Poly(A) site
TACTAAC box
30 bp upstream
of the 3’ end of
the intron
Promoter region
Intron
5’
3’
Exon
Exon
Exon
GT
National Taiwan University Chau-Ti Ting
3’
AG
GT-AG rule
5
Pseudogenes
A pseudogene is a nongenic DNA segment that exhibits
a high degree of similarity to a functional gene but which
contains defects, such as nonsense and frameshift mutations,
that prevent it from being expressed properly.
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 28. Sinauer Associates, Inc. Sunderland, MA, USA.
6
Noncoding region
In almost all genes, the substitution rates in the 5’ and 3’ UTR are
lower than those at fourfold degenerate sites.
The rate in pseudogenes is slightly higher than that in the other
Source: Dan Graur and Wen-Hsiung Li
regions.
2000. Fundamentals of Molecular Evolution., p. 106. Sinauer Associates, Inc. Sunderland, MA, USA.
Table 4.4 Numbers of nucleotide substitutions per site
(K) between cow and goat globin genes
Region
5’ flanking
5’UTR
Fourfold degenerate sites
Introns
3’UTR
3’ flanking
Pseudogenes
K
5.3±1.2
4.0±2.0
8.6±2.5
8.1±0.7
8.8±2.2
8.0±1.5
9.1±0.9
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 107. Sinauer Associates, Inc.
Sunderland, MA, USA.
7
Intron
Intron
Flanking region
Flanking region
5’
Initiation
codon
GC box
CAAT box
TATA box
19-27 bp upstream
of the transcription
startpoint
Stop
codon
Transcription
initiation
Transcription
termination
AATAAA box
Poly(A) site
TACTAAC box
30 bp upstream
of the 3’ end of
the intron
Promoter region
Intron
5’
3’
Exon
Exon
Exon
GT
National Taiwan University Chau-Ti Ting
3’
AG
GT-AG rule
8
§ Causes of Variation in Substitution Rates
The rate of substitution is determined by two factors:
(1) the rate of mutations
(2) the probability of fixation of a mutation (Ch. 2)
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 108. Sinauer Associates, Inc. Sunderland, MA, USA.
9
Functional constraints
Functional constraints or selective constraints defines that
range of alternative nucleotides that is acceptable at a site
without affecting negatively the function or structure if the
gene or the gene product.
Kimura has illustrate this principle by a simple model
K = vT f 0
where vT is the total mutation rate by unit time, f0 is the
fraction of neutral or nearly neutral mutations and K is the
Dan Graur and Wen-Hsiung Li
substitution rate Source:
2000. Fundamentals of Molecular Evolution., p. 108. Sinauer Associates, Inc. Sunderland, MA,
USA.
Whenever a particularly conservative sequence is found,
researchers start looking for a specific function in this region
10
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 110. Sinauer Associates, Inc. Sunderland, MA, USA.
Patterns of substitution and replacement
The pattern of nucleotide substitution is defined as the relative
frequency with which a certain nucleotide changes into another
during evolution.
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 123. Sinauer Associates, Inc. Sunderland, MA, USA.
A
C
G
T
National Taiwan University Chau-Ti Ting
Pij=
nij
ni
Where nij is the number of substitutions
from i to j, and ni is the number of i
nucleotides in the ancestral sequence
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 124. Sinauer Associates,
Inc. Sunderland, MA, USA.
11
Inferring substitutions on a specific lineage
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 125.
Sinauer Associates, Inc. Sunderland, MA, USA.
12
55 processed pseudogene sequences from human
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 126. Sinauer Associates, Inc. Sunderland, MA, USA.
Pseudogenes are expected to become rich in A and
T
13
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 127. Sinauer Associates, Inc. Sunderland, MA, USA.
Mutation maybe different between the two strands!!
14
Patterns of amino acid replacement
Physicochemical distance are based on such properties of the
amino acid as polarity, molecular weight, and chemical
composition.
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 128. Sinauer Associates, Inc. Sunderland, MA, USA.
Grantham’s distance (1974, Table 4.7)
conserved replacement
LeuIle d=5
radical replacement
TrpCys d=215
typical amino acid
leucins, isoleucin, glutamin, methionine
Idiosyncratic amino acid
cysteine, tryptophan, tyrosine, glycine
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 128. Sinauer Associates, Inc. Sunderland, MA, USA.
15
Wikipedia Dancojocjri
16
Patterns of amino acid replacement
Physicochemical distance are based on such properties of the
amino acid as polarity, molecular weight, and chemical
composition.
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 128. Sinauer Associates, Inc. Sunderland, MA, USA.
Grantham’s distance (1974, Table 4.7)
conserved replacement
LeuIle d=5
radical replacement
TrpCys d=215
typical amino acid
leucins, isoleucin, glutamin, methionine
Idiosyncratic amino acid
cysteine, tryptophan, tyrosine, glycine
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 128. Sinauer Associates, Inc. Sunderland, MA, USA.
17
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 130. Sinauer Associates, Inc.
Sunderland, MA, USA.
18
Amino acid exchangeability
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 131. Sinauer Associates, Inc.
Sunderland, MA, USA.
19
Molecular Clock
In their comparative studies of hemoglobin and cytochrome c
protein sequences from different species, Zucherkandel and
Pauling (1962, 1965) and Margoliash (1963) first notice that
the rates of amino acid replacement were approximately the
same among various mammalian lineages.
Zucherkandel and Pauling (1965) therefore proposed that for
any given protein, the rate of molecular evolution is
approximately constant over time in all lineage or, in other
words, that there exists a molecular clock.
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 139. Sinauer Associates, Inc. Sunderland, MA, USA.
20
21
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 140. Sinauer Associates, Inc. Sunderland, MA, USA.
 If a proteins evolve at a constant rates, they can be used to
determine dates of species divergence and to reconstruct phylogeny
relationships among organisms.
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 139. Sinauer Associates, Inc. Sunderland, MA, USA.
Let us assume that the rate of nonsynonymous substitution for the 
chain of hemoglobin is 0.56 x 10-9 substitutions per site per year,
and that -globins from rat and human differ by 0.093 substitutions
per site. Then, under the molecular clock hypothesis, the
divergence time between the human and rat lineages is estimated to
be approximately 0.93/(2 x 0.56 x 10-9)= 80 million years ago.
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 139. Sinauer Associates, Inc. Sunderland, MA, USA.
Kimura (1983) – “For each protein, the rate of evolution in terms
of amino acid substitution is approximately constant per year per
site for various lineage, as long as the function is and tertiary
structure of the molecule remain essentially unaltered.”
Source: Motoo Kimura
22
1983. The Neutral Theory of Molecular Evolution., p. 98. Cambridge University Press,
Cambridge, USA.
Controversies and challenges
• Classical evolutionists argued against it because the suggestion of
rate constancy did not sit well with the erratic tempo of evolution at
the morphological and physiological levels.
• Based on molecular clock, the estimate divergence between humans
and other African apes is only 5 million years. However, the thenprevailing view among paleontologists was that human and apes
diverged at least 15 million years ago.
• Extreme high rate of amino acid replacement occurred following
the gene duplication that gave rise to the - and -hemoglobins, and
that the high rates were due to advantageous mutations that
improved the function of these globin chains.
• Protein sequence evolution often proceeds much more rapidly at
times of adaptive radiation than during periods in which no
speciation occurred.
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 141. Sinauer Associates, Inc. 23
Sunderland, MA, USA.
Relative Rate Test
The controversy over molecular clock hypothesis often involves
disagreement on dates of species divergence. To avoid this problem,
several test have been developed.
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 142. Sinauer Associates, Inc. Sunderland, MA, USA.
Margoliash, Sarich and Wilson’s test
Suppose that we want to compare the rates in lineage A and B. Then,
we use a third species, C, as an outgroup reference.
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 142. Sinauer Associates, Inc. Sunderland, MA, USA.
24
The number of substitutions between species A and B, KAB, is equal
to the sum of substitutions that have occurred frin point O to the
point A (KOA) and from point O to the point B (KOB). That is,
Similarly,
and
KAB = KOA + KOB
KAC = KOA + KOC
O
KBC = KOB + KOC
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 142. Sinauer
Associates, Inc. Sunderland, MA, USA.
A
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 143. Sinauer
Associates, Inc. Sunderland, MA, USA.
B
25
C
Since KAB, KAC, and KBC can be direct estimated from the nucleotide
sequences, we can easily solve the three equations to find the values
of KOA, KOB, and KOC
KOA = (KAC + KAB – KBC)/2
KOB = (KAB + KBC – KAC)/2
O
KOA = (KAC + KBC – KAB)/2
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 142. Sinauer
Associates, Inc. Sunderland, MA, USA.
A
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 143. Sinauer
Associates, Inc. Sunderland, MA, USA.
B
26
C
The time has passed since species A and B last shared a common
ancestor is by definition equal for both lineage. Thus, according to
the molecular clock hypothesis, KOA and KOB should be equal, i.e.,
KOA – KOB = 0.
KOA – KOB = (KAC + KAB – KBC)/2 – (KAB + KBC – KAC)/2
= KAC – KBC = d
O
where d is the difference in branch
length between the two lineages
leading from O to species A and B.
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 143. Sinauer
Associates, Inc. Sunderland, MA, USA.
A
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 143. Sinauer
Associates, Inc. Sunderland, MA, USA.
27
B
C
Nearly equal rates in mouse and rats
Using relative rate test, KAC–KBC values for both synonymous and
nonsynonymous are not significantly different from 0. Therefore,
the null hypothesis of equal substitution rates in mice and rats cannot
be rejected. The results are also consistent with the neutral mutation
hypothesis.
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 146. Sinauer Associates, Inc. Sunderland, MA, USA.
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 146. Sinauer Associates, Inc. Sunderland, MA, USA.
28
Tajima’s 1D (one-degree of freedom) method
We start with three aligned nucleotide sequences, 1, 2, and
3. Let nijk be the obsevered number of sites where
sequences 1, 2, and 3 have nucleotide i, j, and k,
respectively, where i, j, and k can be nucleotides A,G, C, or
T. If sequence 3 is the out group, then the expectation of
nijk should be equal to that of njik, i.e.,
E(nijk) = E(njik)
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 144. Sinauer Associates, Inc. Sunderland, MA, USA.
29
This equality holds regardless of the substitution model or
the pattern of variation in substitution rates among sites.
We define m1 as follows:
m1 = nijj = nAGG + nACC + nATT + nGAA + nGCC + nGTT
+ nCAA + nCGG + nCTT + nTAA + nTGG + nTCC
Similarly, we define m2 as
m2 = njij = nAGA + nACA + nATA + nGAG + nGCG + nGTG
+ nCAC + nCGC + nCTC + nTAT + nTGT + nTCT
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 144. Sinauer Associates, Inc. Sunderland, MA, USA.
Note that only sites in which exactly two types of nucleotides
exist in the three sequences are used in this analysis.
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 145. Sinauer
Associates, Inc. Sunderland, MA, USA.
30
When sequence 3 is outgroup, the expectation of m1 is equal to
that of m2 under molecular clock:
E(m1) = E(m2)
The equality can be tested by using 2 with one degree of
freedom, namely,
2= (m1– m2)2/( m1+ m2)
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 145. Sinauer Associates, Inc. Sunderland, MA, USA.
31
Source: Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 147. Sinauer Associates, Inc. Sunderland, MA, USA.
32
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Page
“The rate of nucleotide
substitution, r, is defined as
he number of substitutions
per site per year. … K,
between two homologous
sequences by 2T, where T is
the time of divergence
between the two sequences.
That is “
“
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 100. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P2
“The rate of
nonsynonymous … human
and fly and which differs
among animal, plant, and
fungi by only 2 or 3 out of 76
amino acid residues.”
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 101. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P3
“In the vast majority of genes,
the synonymous substitution
rate greatly exceeds the
nonsynonymous substitution
rate.”
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 103. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P3
“At fourfold degenerate sites
it is possible to compare the
rate of transitional
substitution …, since both
types of substitution are
synonymous.”
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 104. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
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Table 4.2 Rates of transitional and transversional substitutions (per site per 109 years) at
nondegenerae, twofold degenerate, and fourfold degenerate codon site.
Types of Substitution
Transition
Transversion
Total
Nondegenerae
0.40
0.38
0.78
Twofold degenerate
1,86
0.38
2.24
Fourfold degenerate
2.24
1.47
3.71
Author/Source
Page
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 105. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P4
P5, P8
National Taiwan University Chau-Ti Ting
“A pseudogene is a nongenic
DNA segment that exhibits a
high degree of similarity to a
functional gene but which
contains defects, such as
nonsense and frameshift
mutations, that prevent it
from being expressed
properly.”
“In almost all genes, the
substitution rates in the 5’
and 3’ UTR are lower than
those at … The rate in
pseudogenes is slightly
higher than that in the other
regions.”
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 28. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P6
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 106. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P7
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 107. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
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“The rate of substitution is
determined by two factors:(1)
the rate of
mutations(2)
the
probability of fixation of a
mutation (Ch. 2)“
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 108. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P9
“Functional constraints or
selective constraints
defines … nearly neutral
mutations and K is the
substitution rate”
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 108. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P10
“Whenever a particularly
conservative sequence is
found, researchers start
looking for a specific
function in this region “
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 110. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P10
“The pattern of nucleotide
substitution is defined as the
relative frequency with which
a certain nucleotide changes
into another during evolution.
“
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 123. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P11
35
Work
“Where nij is the number of
substitutions from i to j, and
ni is the number of i
nucleotides in the ancestral
sequence “
Licensing
Author/Source
Page
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 124. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P11
P11
National Taiwan University Chau-Ti Ting
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 125. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P12
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 126. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P13
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 127. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
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36
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“Physicochemical distance
are based on such properties
of the amino acid as polarity,
molecular weight, and
chemical composition. “
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 128. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P15, P17
Grantham’s distance (1974,
Table 4.7)
conserved
replacementLeuIle d=5
Radical … Idiosyncratic
amino acid
cysteine, tryptophan,
tyrosine, glycine
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 128. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P15, P17
Wikipedia Dancojocjri
http://en.wikipedia.org/wiki/File:Amino_Acids.svg
2012/07/25 visited
P16
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 130. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P18
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 131. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P19
37
Work
“In their comparative studies
of hemoglobin and
cytochrome … is
approximately constant over
time in all lineage or, in other
words, that there exists a
molecular clock.”
Licensing
Author/Source
Page
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 139. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P20
P20
Wiki brian0918™
http://en.wikipedia.org/wiki/File:ADN_animation.gif
2012/02/21 visited
P20
Open Clip Art Library fzap
http://openclipart.org/detail/16605/clock-sportstudio-design-by-fzap
2012/02/21 visited
“If a proteins evolve at a
constant rates, they can be
used to determine dates of
species divergence and to
reconstruct phylogeny
relationships among
organisms.”
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 140. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P21
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 139. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P22
38
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“Let us assume that the rate
of nonsynonymous
substitution for the  chain of
hemoglobin is … estimated
to be approximately 0.93/(2 x
0.56 x 10-9)= 80 million years
ago.”
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 139. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P22
“For each protein, the rate of
evolution in terms of amino
acid substitution is
approximately constant per
year per site for various
lineage, as long as the
function is and tertiary
structure of the molecule
remain essentially unaltered”
Motoo Kimura
1983. The Neutral Theory of Molecular Evolution., p. 98. Cambridge
University Press, Cambridge, USA.
http://books.google.com.tw/books?id=olIoSumPevYC&printsec=frontcover&d
q#v=onepage&q&f=false
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P22
“Classical evolutionists
argued against it because the
suggestion of rate constancy
did not sit well with …
adaptive radiation than
during periods in which no
speciation occurred”
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 141. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P23
“The controversy over
molecular clock hypothesis
often involves disagreement
on dates of species
divergence. To avoid this
problem, several test have
been developed.”
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 142. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P24
39
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Author/Source
Page
“Margoliash, Sarich and
Wilson’s test
Suppose that we want to
compare the rates in lineage
A and B. Then, we use a
third species, C, as an
outgroup reference.”
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 142. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P24
“The number of substitutions
between species A and B,
KAB, is equal to the sum of
substitutions that have
occurred frin point O to the
point A (KOA) and from point
O to the point B (KOB). That
is, ”
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 142. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P25
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 143. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P25, P26, P27
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 142. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P26
“Since KAB, KAC, and KBC
can be direct estimated from
the nucleotide sequences, we
can easily solve the three
equations to find the values
of KOA, KOB, and KOC”
Licensing
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“The time has passed since
species A and B last shared a
common ancestor is by
definition equal for both
lineage … between the two
lineages leading from O to
species A and B.”
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 143. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P27
“Using relative rate test,
KAC–KBC values for both
synonymous and … rates in
mice and rats cannot be
rejected. The results are also
consistent with the neutral
mutation hypothesis.”
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 146. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P28
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 146. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P28
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 144. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P29
“We start with three aligned
nucleotide sequences, 1, 2,
and 3. Let nijk be the
obsevered number of sites
where sequences …
expectation of nijk should be
equal to that of njik, i.e.,”
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“This equality holds
regardless of the substitution
model or the pattern of
variation in substitution rates
among sites. … ”
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 144. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P30
“Note that only sites in which
exactly two types of
nucleotides exist in the three
sequences are used in this
analysis.”
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 144. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P30
“When sequence 3 is
outgroup, the expectation of
m1 is equal to that of m2
under molecular clock: …”
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 145. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P31
Dan Graur and Wen-Hsiung Li
2000. Fundamentals of Molecular Evolution., p. 147. Sinauer Associates, Inc.
Sunderland, MA, USA.
It is used subject to the fair use doctrine of:
•Taiwan Copyright Act Articles 52 & 65
•The "Code of Best Practices in Fair Use for OpenCourseWare 2009
(http://www.centerforsocialmedia.org/sites/default/files/10-305-OCWOct29.pdf)" by A Committee of Practitioners of OpenCourseWare in the
U.S. The contents are based on Section 107 of the 1976 U.S. Copyright Act
P32
42