Epistasis, Molecular mechanism, Importance

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

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

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

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

5. Biological epistasis 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. William Bateson (1861 ~ 1926) Mendel’s Principles of Heredity, 1909, Cambridge University Press. Ben Lehner, Cell, 2011; Phillips, NRG,2008

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

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

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

9. Other definitions After Bateson’s and Fisher’s definitions, epistasis has been used more extensively by scientists. Thus lead to more other specific but similar definitions: Positive epistasis means that phenotype is greater than expected. Negative epistasis means that the phenotype is lower than expected. Deviation from multiplicative model was used by population genetists in the late 1960’s. That can be formulated as : Patrick C. Philips, NRG, 2008

10. Molecular mechanisms of epistasis(I) Physical interactions between molecules Ben Lehner, Cell, 2011

11. Compensatory evolution reveals functional interactions between ribosomal proteins Sophie Maisnier-Patin, Wilhelm Paulander et al. JMB,2007 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.

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

13. Mutants Q40R, Q40L and Q40H in L19 compensate the fitness caused by mutation in S12. Effect of L19 mutations on fitness. Grey bar represent the wild-type and non-evolved SmR strains of S. typhimurium, black bars mean the compensated SmR lineages carrying mutations in S12 and L19, and hatched bars the L19 mutatans with wt S12 protein. Sophie Maisnier-Patin, Wilhelm Paulanderet al. JMB,2007

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

15. Molecular mechanisms of epistasis(II) Functional redundancy by gene duplication: duplicates(A1 and A2) Common function Negative epistasis Ben Lehner, Cell, 2011

16. E. Jedediah Dean et al. PLoS Genet. 2008

17. 90 289 Duplicate gene pairs Singleton gene pairs 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. WAWB > WAB means there exists functional redundancy. E. Jedediah Dean et al. PLoS Genet. 2008

18. Molecular mechanisms of epistasis(III) Metabolic Pathway

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;

21. The importance of epistasis 1. Epistasis as the primary factor in molecular evolution Michael S. Breen, Nature ,2012

22. 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 Michael S. Breen, Nature ,2012

23. 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. Michael S. Breen, Nature ,2012

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

25. Thanks for your attention!