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Epistasis, Molecular mechanism, Importance Xudong Zou Prof. Yun-Dong Wu Dr. Zhiqiang Ye 8 th Nov. 2013 1.

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Presentation on theme: "Epistasis, Molecular mechanism, Importance Xudong Zou Prof. Yun-Dong Wu Dr. Zhiqiang Ye 8 th Nov. 2013 1."— Presentation transcript:

1 Epistasis, Molecular mechanism, Importance Xudong Zou Prof. Yun-Dong Wu Dr. Zhiqiang Ye 8 th Nov

2  Definition 1.Biological epistasis 2.Statistical epistasis 3.Other definitions  Molecular mechanism 1.Physical interactions between molecules 2.Functional redundancy 3. Other potential mechanisms  Importance to study epistasis Content: 2

3 Flower color in sweet peas The development of pigment involves a metabolic pathway with many steps. In sweet peas, gene C codes for one of the enzymes and gene R codes for another enzyme in this pathway. 3

4 Purple : White = 9 : 7 According to Mendel’s heredity the ratio should be: Purple : White = 3:1 4

5 Biological epistasis William Bateson (1861 ~ 1926) Effects of one genetic variant masked by another. In some dihybrid crosses, not all possible phenotypic classes were be observed and/or that some gene combinations resulted in novel phenotypes. Mendel’s Principles of Heredity, 1909, Cambridge University Press. Ben Lehner, Cell, 2011; Phillips, NRG,2008 5

6 F2: 9 grey : 3 black : 4 albino Bateson W., Mendel’s Principles of Heredity, 1909 A genetic essay on coat color of rabbit 6

7 R. A. Fisher (1890 ~ 1962) Epistacy is the deviation of the effects of two or more mutations on phenotype from additive effects of individual mutation on phenotype. Fisher introduce the epistasis into quantitative traits. Ben Lehner, Cell, 2011; Phillips, NRG,2008 Statistical epistasis 7

8 Biological epistasis VS Statistical epistasis Jason H. Moore, Scott M. Williams, BioEssays,2005 Biological epistasis Statistical epistasis ? Population Individual 8

9 Other definitions Patrick C. Philips, NRG,

10 Molecular mechanisms of epistasis(I) Physical interactions between molecules Ben Lehner, Cell,

11 S12/S4/S5: 30S ribosomal protein L19: 50S ribosomal protein S12 affects the elongation rate and accuracy of translation. It found that the substitute K42N in S12 can be compensated by mutations in L19. Compensatory evolution reveals functional interactions between ribosomal proteins Sophie Maisnier-Patin, Wilhelm Paulander et al. JMB,

12 Sophie Maisnier-Patin, Wilhelm Paulander et al. JMB,2007 Effects of mutants in S12 and L19 on fitness Fitness ~ translational elongation rate + translational accuracy 12

13 Effect of L19 mutations on fitness. Grey bar represent the wild-type and non-evolved Sm R strains of S. typhimurium, black bars mean the compensated Sm R lineages carrying mutations in S12 and L19, and hatched bars the L19 mutatans with wt S12 protein. Mutants Q40R, Q40L and Q40H in L19 compensate the fitness caused by mutation in S12. Sophie Maisnier-Patin, Wilhelm Paulander et al. JMB,

14 Location of the mutated residues in L19 and S12 proteins on the structure of the ribosomal subunits 30S and 50S of E. coli. Sophie Maisnier-Patin, Wilhelm Paulander et al. JMB,2007 rRNA 30S and 50S subunits were bridged by rRNA and located closely on the rRNA. 14

15 Molecular mechanisms of epistasis(II) Functional redundancy by gene duplication: duplicates(A1 and A2) Common function Negative epistasis Ben Lehner, Cell,

16 E. Jedediah Dean et al. PLoS Genet

17 E. Jedediah Dean et al. PLoS Genet Carrying single and double gene deletions of genes within duplicate gene set as well as singleton gene set. Comparing single gene to double genes deletion fitness values. W A W B > W AB means there exists functional redundancy Duplicate gene pairs Singleton gene pairs 17

18 18 Molecular mechanisms of epistasis(III) Metabolic Pathway

19 19

20 Other potential mechanisms Physical constraints: It assume that a trait has a finite maximum or minimum value, then combinations of mutations can have a smaller effect than the additive expectation, simple because this maximum or minimum effect is reached. Complex regulatory network: many epistatic interactions between mutations actually reflect the non-linear dynamics of regulatory networks. Pleiotropy: mutations simultaneously affecting multiple phenotypes, it’s thought as a precondition for epistasis. Ben Lehner, Cell, 2011; J. Arjan G.M. de Visser, Proc. R. B,2011; 20

21 Michael S. Breen, Nature, Epistasis as the primary factor in molecular evolution The importance of epistasis

22 Michael S. Breen, Nature,2012 Hypothesis: epistasis is rare Average 8 aa-substitution per site: the expected substitution rate is 3/5 lower than the rate of neutral evolution The actually aa-substitution rate is 20 times lower than the rate neutral evolution Epistasis is pervasive in protein evolution 22

23 Michael S. Breen, Nature,2012 Conclusion 1: Most amino-acid substitutions have different fitness effects in different species. Conclusion 2: Epistasis provides the primary conceptual framework to describe the tempo and mode of long-term protein evolution. 23

24 2.Epistasis becomes a big challenge in interpretation between genotype and phenotype. genotype phenotype genotype phenotype … epistasis 24

25 Thanks for your attention! 25


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