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On the evolution of thymidine synthesis: lateral gene transfer, viral involvement and early life

On the evolution of thymidine synthesis: lateral gene transfer, viral involvement and early life. Adi Stern Under the supervision of Tal Pupko. What makes DNA what it is? . Deoxy-nucleotides Thymidine. Thymidylate Synthase (Thy). Synthesizes dTMP (T), one of the DNA building blocks.

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On the evolution of thymidine synthesis: lateral gene transfer, viral involvement and early life

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  1. On the evolution of thymidine synthesis: lateral gene transfer, viral involvement and early life Adi Stern Under the supervision of Tal Pupko

  2. What makes DNA what it is? • Deoxy-nucleotides • Thymidine

  3. Thymidylate Synthase (Thy) • Synthesizes dTMP (T), one of the DNA building blocks

  4. The canonical Thy enzyme • Almost all Eukarya, E.coli • The mystery of the slime mold (Mycetozoa) ThyA

  5. An alternative Thy enzyme • In 1989/2002, an alternative mechanism for Thymidylate synthesis was discovered, and the enzyme was named ThyX – flavin dependent ThyA ThyX

  6. - ThyX distribution Lateral gene transfer (LGT) Myllykallio et al. Science (297) 2002

  7. Lateral Gene Transfer(LGT)is any process in which an organism transfers genetic material to another organism that is not its offspring

  8. Evolution of thymidylate synthases

  9. Goals • Quantify and locate events of LGT • Find origins of each LGT event using gene trees • When did Thy originate?

  10. Studying Thy LGT • Map ThyA and ThyX on the species tree • Reconstruct ThyA / ThyX / both at each ancestor

  11. Thy mapping on species tree:BLAST against ~400 whole genomes Legend:- ThyA- ThyX- ThyX & Thy ADeinococcales: the coloring means there are some deinococci which encode for ThyA and others for ThyX

  12. Thy mapping on species tree How to reconstruct ? Evolutionary models

  13. What are evolutionary models useful for? Which one is more likely? X X X X X A A X A A A A A A A A A A A A A X A+ X X A A ThyX gain ThyX gain, ThyA loss ThyA loss ThyX loss

  14. Evolutionary models • The aim of an evolutionary model: to describe (often in probabilistic terms) the evolutionary biological reality

  15. X X A X A A A A A A A X X X A X A A A A A A A A+ X X A Likelihood • An evolutionary model enables us to compute the likelihood that a certain scenario describes the biological reality we observe. • Learn the different probabilities from the data

  16. A X A+X A X A+X A gain-loss evolutionary model

  17. A X A+X A X A+X An evolutionary model Rate of gain Rate of loss μ1, μ2, μ3, μ4 are maximum-likelihood estimates

  18. Results • rate of loss >> rate of gain • rate of gain ofThyA> gain ofThyX

  19. Results – Maximum Likelihood Reconstruction At least: 14 LGT events where ThyA was swapped by ThyX (or vice versa)

  20. Origin of Mycetozoa ThyX To find the origin of an LGT, we look at the gene tree based on the multiple sequence alignment of one of the genes

  21. Two possible explanations • Mycetozoa eat bacteria  digested some bacterial DNA • The ancestor of mitochondria is known to be an α-proteobacteria  mitochondrial involvement?

  22. Viruses

  23. Myoviridae Viral sequences’ distribution Siphoviridiae Herpesviridae Podoviridae

  24. Early life

  25. Beginning of life - RNA world • “…The universal ancestor is not a discrete entity. It is, rather, a diverse community of cells that survives and evolves as a biological unit…“ (Woese, 1998) LUCA – the last universal common ancestor, is a communal “swamp” LGT

  26. Bacteria Eukarya Archaea RNA  DNA world • Controversy around how DNA evolved

  27. Founder Viruses • “…Viruses played a critical role in the emergence of DNA…several independent transfers [from viruses] produced the two cell types (prokaryote/eukaryote) and the three cellular domains …” (Forterre PNAS(103) 2006) Bacteria virus Eukarya Archaea

  28. Viruses and Thy in early life

  29. ThyA gene tree T4 like phages hosts T4 like phages

  30. ThyA gene tree T4-like phages ? Archaea Bacteria(hosts) Eukarya

  31. A model for Thy evolution in early life

  32. RNA world and RNA viruses LGT

  33. Thymidine Viruses modify their genome to evade host defense Thymidylate synthase

  34. Thymidine Thymidine dCMP hydroxymethylase )CH( • In fact – T4 like phages use a similar tactic today! Hydroxy-methylated cytosine CH

  35. Interestingly, CH and ThyA are homologs (sequentially and structurally) Song et al. EMBO J (18) 1999

  36. Summary • Open questions: • When did ThyX come in and how? • Who predated who? • Why is there so much LGT between these two enzymes? ThyA

  37. Thank you …. • Dr. Tal Pupko • Shaul Shaul, Itay Mayrose • Dr. Uri Gophna • Lab members:Adi DoronEyal PrivmanNimrod RubinsteinOsnat PennDudu BursteinOfir Cohen

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