1 / 35

The COSTEX model: a cost-benefit model relating gene expression and selection

The COSTEX model: a cost-benefit model relating gene expression and selection. Daniel Kahn, Jean-François Gout & Laurent Duret Laboratoire de Biométrie & Biologie Evolutive Lyon 1 University, INRIA BAMBOO team & INRA MIA Department.

dglass
Download Presentation

The COSTEX model: a cost-benefit model relating gene expression and selection

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. The COSTEX model: a cost-benefit model relating gene expression and selection Daniel Kahn, Jean-François Gout & Laurent Duret Laboratoire de Biométrie & Biologie Evolutive Lyon 1 University, INRIA BAMBOO team & INRA MIA Department

  2. Whole genome duplications as a tool to investigate dosage selection Following whole-genome duplication (WGD) • Relative gene dosage is initially unchanged • Duplicated genes are gradually lost with probability inversely related to selective pressure • This may be exploited to analyze selective pressure on gene dosage

  3. Duplications in the Paramecium genome Aury et al., 2006, Nature 444:171-178

  4. Three successive rounds of WGD

  5. Gene content: 2 x 2 x 2  2

  6. Fate of genes after WGD A brief introduction about Whole-Genome Duplications (WGDs)‏ ohnologon • WGD creates identical copies of all genes (ohnologs)‏

  7. Fate of genes after WGD A brief introduction about Whole-Genome Duplications (WGDs)‏ • WGD creates identical copies of all genes (ohnologs)‏ • Mutations lead to pseudogenization of some ohnologs

  8. Fate of genes after WGD A brief introduction about Whole-Genome Duplications (WGDs)‏ • WGD creates identical copies of all genes (ohnologs)‏ • Mutations lead to pseudogenization of some ohnologs

  9. Fate of genes after WGD A brief introduction about Whole-Genome Duplications (WGDs)‏ • WGD creates identical copies of all genes (ohnologs)‏ • Mutations lead to pseudogenization of some ohnologs • Finally, only a few pairs of genes are retained

  10. Fate of genes after WGD A brief introduction about Whole-Genome Duplications (WGDs)‏ Ohnologon that lost one copy Retained ohnologon • WGD creates identical copies of all genes (ohnologs)‏ • Mutations lead to pseudogenization of some ohnologs • Finally, only a few pairs of genes are retained

  11. Relationship between gene retention and gene expression Frequency of gene retention Data from Paramecium post-genomics consortium Jean Cohen & coll. Expression level (log2)

  12. Model for expression-dependent selection • Protein expression has a cost =>Trade-off between cost and benefit • The model assumes that expression was optimal before WGD • In vitro evolution experiments have shown that an optimum can indeed be reached in only a few hundred generations (e.g. Dekel & Alon, 2005)

  13. Modelling the cost of expression expression cost expression level Dekel & Alon, 2005, Nature436:588-592 C(X) cost function X expression level k cost parameter M maximal capacity M

  14. Cost-benefit optimization fitness expression cost Xo Xo expression level Benefit : B(X) Cost: C(X) expression cost fitness

  15. The COSTEX model Express fitness as a function of expression x relatively to optimum level X0

  16. The COSTEX model Approximate fitness around optimum X0 by Taylor expansion: Therefore selection on expression can be quantified by:

  17. 1 Low X0 Medium X0 High X0 fitness Expression-dependent fitness Loss of duplication 0.5 1 1.5 0 Relative dosage or expression X/Xo

  18. Selection against loss of duplicated gene Fitness loss Optimal expression X0

  19. Selection against pseudogene formation Pseudogene formation after WGD entails a loss of fitness that can be expressed in the COSTEX model: Therefore the pseudogenization path to gene loss is also under expression-dependent selection: the higher the gene is expressed, the less likely is the fixation of disabling mutations.

  20. Expression constrains evolutionary rates More generally, mutations that decrease the benefit function by a fraction a are counter-selected in an expression-dependent manner in the COSTEX model: Mutations with an equivalent effect on protein function are more deleterious for highly expressed genes because of higher expression cost, a price the organism had to ‘pay’ for their function. This relationship also applies for potentially suboptimal expression X X0

  21. Expression constrains evolutionary rates Expression is the best predictor of evolutionary rates in coding sequences (Duret & Mouchiroud, 2000, Drummond etal., 2006)‏ Drummond et al, 2005 PNAS,102:14338

  22. Expression-dependent selection • The COSTEX model can explain the relationship between retention rate and gene expression • The model is also supported by gene knockout experiments in yeast (measure of fitness in heterozygotes wt/KO) • The model predicts that the level of expression is all the more conserved in evolution as expression is high • It also explains the observation that highly expressed genes have low rates of sequence evolution

  23. Retention of metabolic genes • Unexpected observation that metabolic genes are more retained than other genes following WGD • However little selective pressure is expected on the dosage of individual enzyme genes (Kacser & Burns, 1981) • Is this a paradox?

  24. Metabolic genes are more expressed

  25. High retention of metabolic genes: why? • Retention of metabolic genes is best explained by selection for gene expression • Although the loss of individual enzyme genes should generally be neutral, each successive loss will be more and more counter-selected. For instance in a linear pathway: • Ultimately this would result in half of the flux, which should be strongly counter-selected in general

  26. Metabolic fluxes are not proportional to enzyme activities • They typically show a hyperbolic dependency • Most enzymes have low control on flux • Summation theorem Kacser & Burns 1981, Genetics 97:639-666

  27. Therefore little selective pressure is expected on the dosage of individual enzyme genes • This a classical explanation of the recessivity of metabolic defects

  28. Ongoing dynamics of gene inactivation • 49% loss of duplicated genes following the recent WGD • Contrary to initial expectation, metabolic genes are more retained than other genes: 42% gene loss ( n = 1,144metabolic genes, P-value< 10-3 ) • Why? Gout, Duret & Kahn 2009, Mol. Biol. Evol., in press

  29. P. tetraurelia :the best model organism for studying WGDs • P. tetraurelia : 3 successive WGDs with different loss rates (Aury et al, 2006)‏ 92 % 76 % 49 %

More Related