An Evolutionary Analysis of Lateral Gene Transfer in Thymidylate Synthase Enzymes

Abstract

Thymidylate synthases (Thy) are key enzymes in the synthesis of deoxythymidylate, 1 of the 4 building blocks of DNA. As such, they are essential for all DNA-based forms of life and therefore implicated in the hypothesized transition from RNA genomes to DNA genomes. Two evolutionally unrelated Thy enzymes, ThyA and ThyX, are known to catalyze the same biochemical reaction. Both enzymes are sporadically distributed within each of the 3 domains of life in a pattern that suggests multiple nonhomologous lateral gene transfer (LGT) events. We present a phylogenetic analysis of the evolution of the 2 enzymes, aimed at unraveling their entangled evolutionary history and tracing their origin back to early life. A novel probabilistic evolutionary model was developed, which allowed us to compute the posterior probabilities and the posterior expectation of the number of LGT events. Simulation studies were performed to validate the model's ability to accurately detect LGT events, which have occurred throughout a large phylogeny. Applying the model to the Thy data revealed widespread nonhomologous LGT between and within all 3 domains of life. By reconstructing the ThyA and ThyX gene trees, the most likely donor of each LGT event was inferred. The role of viruses in LGT of Thy is finally discussed.

The Evolutionary Pathway to Virulence of an RNA Virus

“…At each site we calculated the joint posterior probability of two characters a, b (where a, b ∈ { A, C, G, T }) populating the nodes along each branch of the tree: P ( a, b | X ) = P ( a, b ) / P ( X ), using the HKY model (Hasegawa et al, 1985). Full details of this calculation were described previously (Stern et al, 2010). Only sites and branches where P ( a, b | X ) >0.6 were reported.…”

Protein homeostasis imposes a barrier on functional integration of horizontally transferred genes in bacteria

“…However, after excluding the outliers (DHFR- 23, 35, 36, 38, and 43), the relationship between activity and growth follows flux dynamics theory that predicts that growth rate is proportional to total folate turnover (see the equation on the right; constants a and b depend on the number of enzymes and topology of the metabolic network) (green line, p-value=10 -4 ). B) Growth rate and activity after the evolution Post-Evolution 38 Ec Theoretical fit: abundance n.d.: (23,35,36,37,38) Growth rate for all theoretical fits in panels (A-D)).…”

“…Additionally, comparative genomics studies have demonstrated that HGT plays an important role in the evolution of the folate metabolic pathway, including the spread of antifolate resistance [22,23]. Moreover, DHFR is an essential enzyme in E. coli with a relatively low basal expression level (approximately 40 copies per cell on average [24]), and its activity is linked to bacterial fitness in a dosage-dependent manner [17].…”

The Place of RNA in the Origin and Early Evolution of the Genetic Machinery

“…In extant metabolisms two different thymidylate synthases (ThyA, ThyX) convert 2’-deoxyuridine-5’-monophosphate (dUMP) into 2’-deoxythymidine-5’-monophosphate (dTMP) [ 121 , 122 ] (followed by double phosphorylation). Both enzymes use CH 2 =H 4 folate as CH 3 -source for U → T conversion.…”