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Chapter 3 Substitution Patterns

Chapter 3 Substitution Patterns. 暨南大學資訊工程學系 黃光璿 (HUANG, Guan-Shieng) 2004/03/22. Topic. We discuss molecular evolution in this lecture. This phenomenon happens at the DNA level. 3.1 Patterns of Substitutions within Genes. “If it’s not broken, don’t fix it.”

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Chapter 3 Substitution Patterns

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

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

  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）

  4. 3.1.1 Mutation Rates

  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)

  6. Prokaryotic Gene

  7. 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

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

  9. 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)

  10. 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

  11. 3.1.4 Substitutions v.s. Mutations • mutation: DNA 發生改變 • substitution: mutations that have passed through the filter of natural selection • Ks: synonymous substitution rate • ~mutation rate • Ka: nonsynonymous substitution rate

  12. 3.1.5 Fixation -- the state that gene pool reaches stable • deterious mutation  0 • advantageous mutation  1 • neutral

  13. 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

  14. 3.2 Estimating Substitution Numbers • Alignments with many differences might cause a significant underestimation

  15. 3.2.1 Jukes-Cantor Model • (1969)

  16. 3.2.2 Kimura’s Two Parameter Model 1980 • transitions & transversions • transition (AG, TC)：α • transversion (差異大)：β

  17. 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.

  18. 3.2.4 Substitutions Between Protein Sequences • More complicated! •  PAM & BLOSUM matrices

  19. 3.3 Variations in Evolutionary Rates Between Genes • mutation rate • natural selection • cause the difference ks >> ka 合理 ks << ka (why?) Natural selection favors variability in this case!

  20. 3.4 Molecular Clocks • E. Zuckerkandl & L. Pauling, 1960s • Substitution rates were so constant within homologous proteins • It is still a controversial issue.

  21. 3.4.1 Relative Rate Test • Sarich & Wilson, 1973 • the idea of outgroup • Molecular clock hypothesis implies that dA1=dA2.

  22. 3.4.2 Causes of Rate Variation in Lineages (世系) • generation times • 人 30 年 • environment (環境)

  23. 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

  24. 參考資料及圖片出處 • Fundamental Concepts of BioinformaticsDan E. Krane and Michael L. Raymer, Benjamin/Cummings, 2003.

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