1 Chapter 3 Substitution Patterns 暨南大學資訊工程學系 黃光璿 (HUANG, Guan-Shieng) 2004/03/22.

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Chapter 3Substitution Patterns

暨南大學資訊工程學系黃光璿 (HUANG, Guan-Shieng)2004/03/22

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Topic

We discuss molecular evolution in this lecture. This phenomenon happens at the DNA

level.

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3.1 Patterns of Substitutions within Genes “If it’s not broken, don’t fix it.”

Most genes are very close to optimal in its typical environment.

Mutations disadvantageous （有害的） advantageous （有益的） neutral （中性的）

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3.1.1 Mutation Rates

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3.1.2 Functional Constraint

Natural selection （天擇） Functional constraint

catalytic ( 催化的 ) or structural properties tend to accumulate changes very slowly

Table 3.1 (Shamir 7, p 13)

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Prokaryotic Gene

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3.1.3 Synonymous v.s. Nonsynonymous Substitutions synonymous （同義的） Synonymous substitution

改變 codon 但不改變所生成的胺基酸 GGG, GGA, GGU, GGC glycine

Nonsynonymous substitution 換過之後會改變所生成的胺基酸

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Exercise:

Compute the number of synonymous substitutions and the number of nonsynonymous substitutions from the standard genetic code.

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Classification of Nonsynonymous substitutions

nondegenerate sites (1+1+1+1) UUU (phe) CUU (leu), AUU (iso), GUU (val)

twofold degenerate sites (2+2) GAU, GAC (asp) GAA, GAG (glu)

fourfold degenerate sites (4) GGG, GGA, GGU, GGC (gly)

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Why not consider the other cases? (3+1)

AUU, AUC, AUA (ile) AUG (met) (2+1+1)

UUG, CUG (leu) AUG (met), GUG (val)

4 = 1+1+1+1 = 2+1+1 = 2+2 = 3+1

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3.1.4 Substitutions v.s. Mutations mutation: DNA 發生改變 substitution: mutations that have passed t

hrough the filter of natural selection

Ks: synonymous substitution rate ~mutation rate

Ka: nonsynonymous substitution rate

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3.1.5 Fixation

-- the state that gene pool reaches stable deterious mutation 0 advantageous mutation 1 neutral

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the cause of genetic differences mutation random genetic drift

saturation mutagenesis: make all possible changes to the nucleotide sequence of a gene to determine the effect

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3.2 Estimating Substitution Numbers Alignments with many differences

might cause a significant underestimation

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3.2.1 Jukes-Cantor Model

(1969)

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3.2.2 Kimura’s Two Parameter Model 1980 transitions & transversions

transition (AG, TC) ： α transversion ( 差異大 ) ： β

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3.2.3 Models with Even More Parameters 12 (=4x3)parameters 反而變糟了！因為需要更多的假設 .

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3.2.4 Substitutions Between Protein Sequences More complicated! PAM & BLOSUM matrices

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3.3 Variations in Evolutionary Rates Between Genes mutation rate natural selection cause the differenceks >> ka 合理ks << ka (why?)Natural selection favors variability in this cas

e!

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3.4 Molecular Clocks

E. Zuckerkandl & L. Pauling, 1960s Substitution rates were so constant within hom

ologous proteins It is still a controversial issue.

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3.4.1 Relative Rate Test

Sarich & Wilson, 1973 the idea of outgroup

Molecular clock hypothesis implies that dA1=dA2.

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3.4.2 Causes of Rate Variation in Lineages ( 世系 ) generation times

人 30 年 environment ( 環境 )

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3.4.3 Evolution in Organelles ( 胞器 ) mitochondrial ( 粒線體 ) DNA

只從母親來 , 在人類約有 16000 bps. mutate in 10 times

chloroplastic ( 葉綠體 ) DNA ～ 120000 to 220000

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參考資料及圖片出處

1. Fundamental Concepts of BioinformaticsDan E. Krane and Michael L. Raymer, Benjamin/Cummings, 2003.