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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 The canonical Thy enzyme Almost all Eukarya, E.coli The mystery of the slime mold (Mycetozoa) ThyA 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 ThyX distribution Lateral gene transfer (LGT) - Myllykallio et al. Science (297) 2002 Lateral Gene Transfer (LGT) is any process in which an organism transfers genetic material to another organism that is not its offspring Evolution of thymidylate synthases Goals 1. 2. 3. Quantify and locate events of LGT Find origins of each LGT event using gene trees When did Thy originate? Studying Thy LGT Map ThyA and ThyX on the species tree Reconstruct ThyA / ThyX / both at each ancestor Thy mapping on species tree: BLAST against ~400 whole genomes Legend: - ThyA - ThyX - ThyX & Thy A Deinococcales: the coloring means there are some deinococci which encode for ThyA and others for ThyX Thy mapping on species tree How to reconstruct ? Evolutionary models What are evolutionary models useful for? Which one is more likely? X X A A A A A A+ X X A A A A A X X X A A A A ThyX gain ThyA loss ThyX loss ThyX gain, ThyA loss X A A X A Evolutionary models The aim of an evolutionary model: to describe (often in probabilistic terms) the evolutionary biological reality A C G T A 0.73 0.08 0.11 0.08 C 0.11 0.8 0.01 0.08 G 0.08 0.2 0.68 0.04 T 0.02 0.01 0.1 0.87 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 A A A X A A A+ X X X A A X A A A A X A A X X A A A X A A gain-loss evolutionary model A X A 1 0 X 0 2 A+X 3 3 A+X 1 2 3 4 An evolutionary model A X A 1 0 X 0 2 A+X 3 3 Rate of loss μ1, μ2, μ3, μ4 are maximum-likelihood estimates A+X 1 2 3 4 Rate of gain Results rate of loss >> rate of gain rate of gain of ThyA > gain of ThyX Results – Maximum Likelihood Reconstruction At least: 14 LGT events where ThyA was swapped by ThyX (or vice versa) 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 Two possible explanations 1. 2. Mycetozoa eat bacteria digested some bacterial DNA The ancestor of mitochondria is known to be an α-proteobacteria mitochondrial involvement? Viruses Myoviridae Viral sequences’ distribution Siphoviridiae Herpesviridae Podoviridae Early life 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 RNA DNA world Controversy around how DNA evolved Bacteria Eukarya Archaea 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 Viruses and Thy in early life ThyA gene tree T4 like phages hosts T4 like phages ThyA gene tree T4-like phages ? Archaea Bacteria (hosts) Eukarya A model for Thy evolution in early life RNA world and RNA viruses LGT Viruses modify their genome to evade host defense Thymidine Thymidylate synthase dCMP hydroxymethylase )CH( In fact – T4 like phages use a similar tactic today! Thymidine Thymidine Hydroxymethylated cytosine CH Interestingly, CH and ThyA are homologs (sequentially and structurally) Song et al. EMBO J (18) 1999 Summary Open questions: When did ThyX come in and how? Who predated who? Why is there so much LGT between these two enzymes? Thank you …. Dr. Tal Pupko Shaul Shaul, Itay Mayrose Dr. Uri Gophna Lab members: Adi Doron Eyal Privman Nimrod Rubinstein Osnat Penn Dudu Burstein Ofir Cohen