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Chapter 5Rate and Patterns of Nucleotide Substitution
1
Chau-Ti Ting
ctting@ntu.edu.tw
Unless noted, the course materials are licensed under Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Taiwan (CC BY-NC-SA 3.0)
§ 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
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 100. Sinauer Associates, Inc. Sunderland, MA, USA.
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Coding regionSynonymous versus nonsynonymousThe 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.
In the vast majority of genes, the synonymous substitution rate greatly exceeds the nonsynonymous substitution rate.
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 101. Sinauer Associates, Inc. Sunderland, MA, USA.
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 103. Sinauer Associates, Inc. Sunderland, MA, USA.
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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 Li2000. Fundamentals of Molecular Evolution., p. 104. Sinauer Associates, Inc. Sunderland, MA, USA.
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 105. Sinauer Associates, Inc. Sunderland, MA, USA.
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Exon Exon Exon
Intron Intron
5’ 3’
Flanking region Flanking region
GC box
CAAT boxTATA box
Transcription initiation
Initiation codon
Stop codon
AATAAA box
Transcription termination
Poly(A) site
Promoter region
GT AG
Intron
19-27 bp upstream of the transcription startpoint
TACTAAC box
30 bp upstream of the 3’ end of the intron
GT-AG rule
5’ 3’
5
PseudogenesA 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 Li2000. Fundamentals of Molecular Evolution., p. 28. Sinauer Associates, Inc. Sunderland, MA, USA.
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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 regions.
Table 4.4 Numbers of nucleotide substitutions per site (K) between cow and goat globin genes
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 106. Sinauer Associates, Inc. Sunderland, MA, USA.
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 107. Sinauer Associates, Inc. Sunderland, MA, USA. 7
National Taiwan University Chau-Ti Ting
Exon Exon Exon
Intron Intron
5’ 3’
Flanking region Flanking region
GC box
CAAT boxTATA box
Transcription initiation
Initiation codon
Stop codon
AATAAA box
Transcription termination
Poly(A) site
Promoter region
GT AG
Intron
19-27 bp upstream of the transcription startpoint
TACTAAC box
30 bp upstream of the 3’ end of the intron
GT-AG rule
5’ 3’
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§ Causes of Variation in Substitution RatesThe 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 Li2000. Fundamentals of Molecular Evolution., p. 108. Sinauer Associates, Inc. Sunderland, MA, USA.
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Functional constraintsFunctional 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
where vT is the total mutation rate by unit time, f0 is the fraction of neutral or nearly neutral mutations and K is the substitution rate
Whenever a particularly conservative sequence is found, researchers start looking for a specific function in this region
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 108. Sinauer Associates, Inc. Sunderland, MA, USA.
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 110. Sinauer Associates, Inc. Sunderland, MA, USA.
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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.
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 Li2000. Fundamentals of Molecular Evolution., p. 123. Sinauer Associates, Inc. Sunderland, MA, USA.
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 124. Sinauer Associates, Inc. Sunderland, MA, USA.
A
T
G
C
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Inferring substitutions on a specific lineageSource: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 125. Sinauer Associates, Inc. Sunderland, MA, USA.
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55 processed pseudogene sequences from human
Pseudogenes are expected to become rich in A and T
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 126. Sinauer Associates, Inc. Sunderland, MA, USA.
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Mutation maybe different between the two strands!!
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 127. Sinauer Associates, Inc. Sunderland, MA, USA.
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Patterns of amino acid replacement
Physicochemical distance are based on such properties of the amino acid as polarity, molecular weight, and chemical composition.
Grantham’s distance (1974, Table 4.7)conserved replacement LeuIle d=5radical replacement TrpCys d=215
typical amino acidleucins, isoleucin, glutamin, methionine
Idiosyncratic amino acidcysteine, tryptophan, tyrosine, glycine
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 128. Sinauer Associates, Inc. Sunderland, MA, USA.
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 128. Sinauer Associates, Inc. Sunderland, MA, USA.
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Patterns of amino acid replacement
Physicochemical distance are based on such properties of the amino acid as polarity, molecular weight, and chemical composition.
Grantham’s distance (1974, Table 4.7)conserved replacement LeuIle d=5radical replacement TrpCys d=215
typical amino acidleucins, isoleucin, glutamin, methionine
Idiosyncratic amino acidcysteine, tryptophan, tyrosine, glycine
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 128. Sinauer Associates, Inc. Sunderland, MA, USA.
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 128. Sinauer Associates, Inc. Sunderland, MA, USA.
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Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 130. Sinauer Associates, Inc. Sunderland, MA, USA.
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Amino acid exchangeability
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 131. Sinauer Associates, Inc. Sunderland, MA, USA.
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Molecular ClockIn 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 Li2000. Fundamentals of Molecular Evolution., p. 139. Sinauer Associates, Inc. Sunderland, MA, USA.
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Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 140. Sinauer Associates, Inc. Sunderland, MA, USA.
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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.
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.
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: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 139. Sinauer Associates, Inc. Sunderland, MA, USA.
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 139. Sinauer Associates, Inc. Sunderland, MA, USA.
Source: Motoo Kimura1983. The Neutral Theory of Molecular Evolution., p. 98. Cambridge University Press, Cambridge, USA.
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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 then-prevailing 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 Li2000. Fundamentals of Molecular Evolution., p. 141. Sinauer Associates, Inc. Sunderland, MA, USA.
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Relative Rate TestThe controversy over molecular clock hypothesis often involves disagreement on dates of species divergence. To avoid this problem, several test have been developed.
Margoliash, Sarich and Wilson’ s testSuppose 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 Li2000. Fundamentals of Molecular Evolution., p. 142. Sinauer Associates, Inc. Sunderland, MA, USA.
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 142. Sinauer Associates, Inc. Sunderland, MA, USA.
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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,
KAB = KOA + KOB
Similarly,KAC = KOA + KOC
andKBC = KOB + KOC
O
A B C
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 142. Sinauer Associates, Inc. Sunderland, MA, USA.
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 143. Sinauer Associates, Inc. Sunderland, MA, USA.
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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
KOA = (KAC + KBC – KAB)/2
O
A B C
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 142. Sinauer Associates, Inc. Sunderland, MA, USA.
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 143. Sinauer Associates, Inc. Sunderland, MA, USA.
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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. 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
where d is the difference in branch length between the two lineages leading from O to species A and B.
O
A B CSource: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 143. Sinauer Associates, Inc. Sunderland, MA, USA.
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 143. Sinauer Associates, Inc. Sunderland, MA, USA.
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Nearly equal rates in mouse and ratsUsing 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 Li2000. Fundamentals of Molecular Evolution., p. 146. Sinauer Associates, Inc. Sunderland, MA, USA.
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 146. Sinauer Associates, Inc. Sunderland, MA, USA.
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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 Li2000. Fundamentals of Molecular Evolution., p. 144. Sinauer Associates, Inc. Sunderland, MA, USA.
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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
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 Li2000. Fundamentals of Molecular Evolution., p. 144. Sinauer Associates, Inc. Sunderland, MA, USA.
Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 145. Sinauer Associates, Inc. Sunderland, MA, USA.
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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 Li2000. Fundamentals of Molecular Evolution., p. 145. Sinauer Associates, Inc. Sunderland, MA, USA.
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Source: Dan Graur and Wen-Hsiung Li2000. Fundamentals of Molecular Evolution., p. 147. Sinauer Associates, Inc. Sunderland, MA, USA.
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“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 Li2000. 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-OCW-Oct29.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 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 Li2000. 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-OCW-Oct29.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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“In the vast majority of genes, the synonymous substitution rate greatly exceeds the nonsynonymous substitution rate.”
Dan Graur and Wen-Hsiung Li2000. 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-OCW-Oct29.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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“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 Li2000. 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-OCW-Oct29.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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Dan Graur and Wen-Hsiung Li2000. 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-OCW-Oct29.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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“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.”
Dan Graur and Wen-Hsiung Li2000. 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-OCW-Oct29.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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“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 Li2000. 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-OCW-Oct29.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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Dan Graur and Wen-Hsiung Li2000. 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-OCW-Oct29.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 Li2000. 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-OCW-Oct29.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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“Functional constraints or selective constraints defines … nearly neutral mutations and K is the substitution rate”
Dan Graur and Wen-Hsiung Li2000. 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-OCW-Oct29.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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“Whenever a particularly conservative sequence is found, researchers start looking for a specific function in this region “
Dan Graur and Wen-Hsiung Li2000. 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-OCW-Oct29.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 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 Li2000. 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-OCW-Oct29.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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“Where nij is the number of substitutions from i to j, and ni is the number of i nucleotides in the ancestral sequence “
Dan Graur and Wen-Hsiung Li2000. 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-OCW-Oct29.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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Dan Graur and Wen-Hsiung Li2000. 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-OCW-Oct29.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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Dan Graur and Wen-Hsiung Li2000. 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-OCW-Oct29.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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Dan Graur and Wen-Hsiung Li2000. 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-OCW-Oct29.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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“Physicochemical distance are based on such properties of the amino acid as polarity, molecular weight, and chemical composition. “
Dan Graur and Wen-Hsiung Li2000. 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-OCW-Oct29.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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Grantham’s distance (1974, Table 4.7)conserved replacementLeuIle d=5Radical … Idiosyncratic amino acid
cysteine, tryptophan, tyrosine, glycine
Dan Graur and Wen-Hsiung Li2000. 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-OCW-Oct29.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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Wikipedia Dancojocjrihttp://en.wikipedia.org/wiki/File:Amino_Acids.svg2012/07/25 visited
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Dan Graur and Wen-Hsiung Li2000. 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-OCW-Oct29.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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Dan Graur and Wen-Hsiung Li2000. 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-OCW-Oct29.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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“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.”
Dan Graur and Wen-Hsiung Li2000. 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-OCW-Oct29.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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Open Clip Art Library fzaphttp://openclipart.org/detail/16605/clock-sportstudio-design-by-fzap2012/02/21 visited
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Dan Graur and Wen-Hsiung Li2000. 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-OCW-Oct29.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
“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 Li2000. 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-OCW-Oct29.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
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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 Li2000. 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-OCW-Oct29.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 Kimura1983. The Neutral Theory of Molecular Evolution., p. 98. Cambridge University Press, Cambridge, USA.http://books.google.com.tw/books?id=olIoSumPevYC&printsec=frontcover&dq#v=onepage&q&f=falseIt 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-OCW-Oct29.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 Li2000. 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-OCW-Oct29.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 Li2000. 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-OCW-Oct29.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
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“Margoliash, Sarich and Wilson’ s testSuppose 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 Li2000. 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-OCW-Oct29.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 Li2000. 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-OCW-Oct29.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 Li2000. 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-OCW-Oct29.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
“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”
Dan Graur and Wen-Hsiung Li2000. 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-OCW-Oct29.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
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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 Li2000. 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-OCW-Oct29.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 Li2000. 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-OCW-Oct29.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 Li2000. 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-OCW-Oct29.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
“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.,”
Dan Graur and Wen-Hsiung Li2000. 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-OCW-Oct29.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
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Work Licensing Author/Source Page
“This equality holds regardless of the substitution model or the pattern of variation in substitution rates among sites. … ”
Dan Graur and Wen-Hsiung Li2000. 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-OCW-Oct29.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 Li2000. 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-OCW-Oct29.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 Li2000. 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-OCW-Oct29.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 Li2000. 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-OCW-Oct29.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
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