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Developmental biology - tRNA

Hidden Genetic Rules For How Life Began

Researchers show how genes were first translated into proteins offering insight into a scientific mystery...


Researchers at the University of North Carolina at Chapel Hill and the University of Auckland in Australia, have teamed up to show how genes first were translated into proteins. Their collaboration reveals some of the hidden rules of genetics and how life on Earth began, offering insight into a long-thought over scientific mystery.

All living things use the genetic code to "translate" DNA-based gene information into proteins, the main working molecules of cells. Precisely how this complex process began on Earth more than four billion years is mysterious. But two theoretical biologists have made a significant advance in its resolution. Published in Nucleic Acids Research, they reveal previously hidden rules by which key translational molecules interact to suggest how much-simpler ancestors of these molecules began to work together at the dawn of life.

Charles Carter Jr, PhD, professor of biochemistry and biophysics at the University of North Carolina (UNC) School of Medicine, and Peter Wills PhD, an associate professor of biochemistry at the University of Auckland in Australia, are using advanced statistics to analyze how modern translational molecules fit together and perform the job of linking short gene sequences.
"I think we have clarified the underlying rules and the evolutionary history of genetic coding...unresolved for 60 years."

Charles W Carter PhD, Jr, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

"The pairs of molecular patterns we have identified may be the first that nature ever used to transfer information from one form to another in living organisms."

Peter R Wills PhD, Department of Physics, Centre for Computational Evolution, and Te Ao Marama Centre for Fundamental Enquiry, University of Auckland, Auckland, New Zealand.

Their discoveries center on a cloverleaf-shaped molecule called transfer RNA (tRNA), a key player in gene translation. A tRNA is designed to carry a simple protein building-block, known as an amino acid, into the assembly line of protein production within tiny molecular factories called ribosomes. When a copy or "transcript" of a gene called a messenger RNA (mRNA) emerges from the cell nucleus and enters a ribosome, it binds to tRNAs to carry their amino acid cargoes.

• Proteins in humans and most other life forms are made from 20 different amino acids. Each of these 20 distinct types of tRNA molecules are capable of linking to one particular amino acid. Their 20 tRNAs are 20 matching helper enzymes known as synthetases (aminoacyl-tRNA synthetases), that link their partner tRNAs with the correct amino acid. "You can think of these 20 synthetases and 20 tRNAs collectively as a molecular computer that evolution has designed to make gene-to-protein translation happen," Carter said.

• Biologists have long been intrigued by this molecular computer and the puzzle of how it originated billions of years ago. In recent years, Carter and Wills have made this puzzle their principal research focus. They have shown, for example, how the 20 synthetases, which exist in two structurally distinct classes of 10 synthetases each, likely arose from just two simpler, ancestral enzymes.

• A similar class division exists for amino acids, and Carter and Wills have argued that the same class division must apply to tRNAs. In other words, they propose that at the dawn of life on Earth, organisms contained just two types of tRNA, which would have worked with two types of synthetases to perform gene-to-protein translation using just two different kinds of amino acids.

• The idea is that over the course of eons this system became ever more specific, as each of the original tRNAs, synthetases, and amino acids was augmented or refined by new variants until there were distinct classes of 10 in place of each of the two original tRNAs, synthetases, and amino acids.

mRNA is essentially a string of genetic 'letters' that spell out protein-making instructions, and each tRNA recognizes a specific three-letter sequence on mRNA. This sequence is called a 'codon,' tRNA binds to the codon, the ribosome links its amino acid to the amino acid that came before it, elongating the growing peptide. When completed, the chain of amino acids is released as a newly born protein.

• In their most recent study, Carter and Wills examined modern tRNAs for evidence of this ancient duality. They analyzed the upper part of the tRNA molecule, known as the acceptor stem, where partner synthetases bind and their analysis showed that just three RNA bases, or letters, at the top of the acceptor stem carry an otherwise hidden code specifying rules that divide tRNAs into two classes - corresponding exactly to the two classes of synthetases. Carter: "It is simply the combinations of these three bases that determine which class of synthetase binds to each tRNA."

• By chance, the study found new evidence for another proposal about tRNAs. Today, each tRNA at its lower end has an 'anticodon' to recognize and stick to a complementary codon on an mRNA. The anticodon is relatively distant from the synthetase binding site, but since the early 1990s, scientists have speculated that tRNAs were once much smaller and combined anticodon and synthetase binding regions as one. Wills and Carter's analysis shows that the rules associated with one of the three class-determining bases - base number 2 in the overall tRNA molecule - effectively imply a trace of the anticodon in an ancient, truncated version of tRNA.

"This is a completely unexpected confirmation of a hypothesis that has been around for almost 30 years," explains Carter.
These findings strengthen the argument that the original translational system had just two primitive tRNAs, corresponding to two synthetases and two amino acid types. As this system evolved to recognize and incorporate new amino acids, new combinations of tRNA bases in the synthetase binding region would have emerged to keep up with the increasing complexity - but in a way that left detectable traces of the original arrangement.

Adds Carter: "These three class-defining bases in contemporary tRNAs are like a medieval manuscript whose original texts have been rubbed out and replaced by newer texts."

The findings narrow the possibilities for the origins of genetic coding. Moreover, they narrow the realm of future experiments scientists could conduct to reconstruct early versions of the translational system in the laboratory - and perhaps even make this simple system evolve into more complex, modern forms of the same translation system.

Abstract
Class I and II aaRS recognition of opposite grooves was likely among the earliest determinants fixed in the tRNA acceptor stem bases. A new regression model identifies those determinants in bacterial tRNAs. Integral coefficients relate digital dependent to independent variables with perfect agreement between observed and calculated grooves for all twenty isoaccepting tRNAs. Recognition is mediated by the Discriminator base 73, the first base pair, and base 2 of the acceptor stem. Subsets of these coefficients also identically compute grooves recognized by smaller numbers of aaRS. Thus, the model is hierarchical, suggesting that new rules were added to pre-existing ones as new amino acids joined the coding alphabet. A thermodynamic rationale for the simplest model implies that Class-dependent aaRS secondary structures exploited differential tendencies of the acceptor stem to form the hairpin observed in Class I aaRS•tRNA complexes, enabling the earliest groove discrimination. Curiously, groove recognition also depends explicitly on the identity of base 2 in a manner consistent with the middle bases of the codon table, confirming a hidden ancestry of codon-anticodon pairing in the acceptor stem. That, and the lack of correlation with anticodon bases support prior productive coding interaction of tRNA minihelices with proto-mRNA.

Authors: Charles W Carter, Jr and Peter R Wills.


Fundings
National Institute of General Medical Sciences [R01-78227 to C.W.C. Jr]. This publication was made possible also through the support of a grant from the John Templeton Foundation. The opinions expressed in this publication are those of the author(s) and do not necessarily reflect the views of the John Templeton Foundation. Funding for open access charge: Center for Scientific Review [GM78227].

Conflict of interest statement. None declared.


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In the beginning, somehow, basic genetic building blocks got translated into proteins
to lead to complex life as we know it. Image: Christ-claude Mowandza-ndinga


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