2. 1 Chapter 3 Substitution Patterns 暨南大學資訊工程學系 黃光璿 (HUANG, Guan-Shieng) 2004/03/22

3. 2 Topic We discuss molecular evolution in this lecture.  This phenomenon happens at the DNA level.

4. 3 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）

5. 4 3.1.1 Mutation Rates

6. 5 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)

7. 6 Prokaryotic Gene

8. 7

9. 8 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

10. 9 Exercise: Compute the number of synonymous substitutions and the number of nonsynonymous substitutions from the standard genetic code.

11. 10 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)

12. 11 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

13. 12

14. 13 3.1.4 Substitutions v.s. Mutations mutation: DNA 發生改變 substitution: mutations that have passed through the filter of natural selection K s : synonymous substitution rate  ~mutation rate K a : nonsynonymous substitution rate

15. 14

16. 15 3.1.5 Fixation -- the state that gene pool reaches stable deterious mutation  0 advantageous mutation  1 neutral

17. 16 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

18. 17 3.2 Estimating Substitution Numbers Alignments with many differences might cause a significant underestimation

19. 18 3.2.1 Jukes-Cantor Model (1969)

20. 19

21. 20 3.2.2 Kimura ’ s Two Parameter Model 1980 transitions & transversions  transition (A  G, T  C) ： α  transversion ( 差異大 ) ： β

22. 21 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.

23. 22 3.2.4 Substitutions Between Protein Sequences More complicated!  PAM & BLOSUM matrices

24. 23 3.3 Variations in Evolutionary Rates Between Genes mutation rate natural selection  cause the difference k s >> k a 合理 k s << k a (why?) Natural selection favors variability in this case!

25. 24 3.4 Molecular Clocks E. Zuckerkandl & L. Pauling, 1960s  Substitution rates were so constant within homologous proteins  It is still a controversial issue.

26. 25

27. 26 3.4.1 Relative Rate Test Sarich & Wilson, 1973  the idea of outgroup  Molecular clock hypothesis implies that d A1 =d A2.

28. 27 3.4.2 Causes of Rate Variation in Lineages ( 世系 ) generation times  人 30 年 environment ( 環境 )

29. 28 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

30. 29 參考資料及圖片出處 1. Fundamental Concepts of Bioinformatics Dan E. Krane and Michael L. Raymer, Benjamin/Cummings, 2003. Fundamental Concepts of Bioinformatics