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Project description

RNA World is a distributed supercomputer that uses Internet-connected computers to advance RNA research. This system is dedicated to identify, analyze, structurally predict and design RNA molecules on the basis of established bioinformatics software in a high-performance, high-throughput fashion.

In contrast to classical bioinformatic approaches, RNA World does not rely on individual desktop computers, web servers or supercomputers. Instead, it represents a continuously evolving cluster of world-wide distributed machines of any type. As such, RNA World is very heterogenous and, depending on the sub-project, currently addresses Internet-connected computers running Linux, Windows and OSX operating systems - your computer could be an important part of it. The fact that hardware and electricity costs are shared among the volunteer contributors raises the possibility of performing interesting analyses which under economical aspects would often not be affordable. In return, RNA World is not for profit, exclusively uses open source code and will make its results available to the public.

In its present form, RNA World runs a fully automated high-throughput analysis software version of Infernal1, a program suite originally developed in Sean Eddys laboratory for the systematic identification of non-coding RNAs. The goal of this RNA World sub-project is to systematically identify all known RNA family members in all organisms known to date and make the results available to the public in a timely fashion. With your help, we also aim at supplying established bioinformatic databases such as Rfam2 with our results to help reduce their future maintenance costs.

In contrast to other distributed and grid computing projects, the RNA World developers are currently designing generalized user interfaces that, in parallel to the projects our own research team is following up, allow non-associated individual scientists to submit their own projects in a manner similar to using a web server interface - of course, free of cost.

RNA World is developed by the German non-profit association Rechenkraft.net e.V. and is solely operated by volunteers. At present, it is in closed alpha phase. Cooperation partners are the Philipps-University of Marburg (Germany) and the Indian Institute of Science in Bangalore (India); further cooperation partners are welcome. Scientists having suggestions for specific RNA relevant software that is worth considering integration into the RNA World distributed supercomputer are welcome to contact us with a brief proposal.

Why RNA?

Every protein in a cell is produced from a transiently synthesized messenger molecule, termed mRNA. This mRNA is then recognized by a cellular machinery that translates the base sequence of mRNA into its corresponding protein (which is a sequence of amino acids). This protein synthesis machinery, termed ribosome, is actually a ribozyme, i.e. it is a catalytically active assembly of several RNA molecules. Consequently, RNAs do not only serve as messenger molecules or perform structural functions as e.g. in tRNA but may also act as catalysts that perform biochemical reactions as is the case for protein enzymes. Of course, the ribosome also contains numerous proteins as it is a very complex ribonucleoprotein particle but these predominantly serve structural functions, e.g. to give the ribosome its shape.

Fascinatingly, the initial analysis of the human genome sequence revealed that, apparently, only a very small fraction of the DNA of our genome is encoding proteins. Scientists at first thought "what is all this junk DNA about?" or "can't we just delete it?". Today, it has become clear that probably a major fraction of regulatory events taking place in a human cell might be governed by small RNAs, the so-called miRNAs. Among other functions, these appear responsible for making sure that a skin cell becomes a skin cell while a muscle, liver or hair cell differentiates to a muscle, liver or hair cell during development and all this although the genetic material (DNA) of all of these very different cell types is essentially identical. On top of that it seems that many cancer types are accompanied by or even result from a deregulated miRNA profile in the affected cell. Moreover, viruses have been discovered to bring along miRNAs to modify the target cell's regulatory network leading to diseases.

Hence, we can clearly state that investing into RNA research, e.g. by supporting the RNA World distributed supercomputer project, will ultimately lead to important discoveries that might also have significant impact on future health care.

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The CRISPR elements are part of a prokaryotic defence system directed against external attacks by e.g. viruses and may be viewed as a simple immune system of microorganisms.

By employing RNA World to systematically screen organisms for the presence of the various types of this defence machinery, we hope to acquire important information on the global distribution and varieties of this system. There is an enormous repertoire of potential applications to the results of such analyses ranging from the improvement of industrially relevant microbial food production to novel ways of coping with multi-drug resistant pathogenic bacteria.

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The GEMM RNA motif is a so-called cis-acting riboswitch designed to detect the second messenger cyclic di-GMP. The bottom line is that GEMM is an upstream terminal part of an mRNA that can bind to this small signal molecule. Upon binding, its structure is modulated such that the downstream part of the mRNA which encodes a protein is affected in such a way that, depending on the type of GEMM motif, the corresponding protein production is either activated or inactivated. Hence, GEMM serves as an RNA-based molecular switch to control protein production.

The reason for why we are interested in this RNA module is twofold: (1) its switch properties make it very useful for synthetic biology applications and (2) GEMM controls production of proteins that are essential for the capability of certain pathogens to attack human cells. Examples for such pathogens are the cholera-causing bacterium Vibrio cholerae or Bacillus anthracis which is responsible for anthrax. What RNA World does is a systematical screen of all completely sequenced organisms in order to identify this GEMM motif.

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6S RNA is a small non-coding RNA of about 200 nucleotides in size which is widespread among bacteria and occasionally even occours in multiple gene copies within a given species. It appears to represent a system to preserve RNA polymerase under conditions of nutrient limitation. Interestingly, due to its special structure, this RNA may serve as a template for bacterial house-keeping RNA polymerase to generate small miRNA-sized RNAs upon nutrient re-supply, thereby demonstrating that RNA polymerases can act as both DNA-dependent RNA polymerases and RNA-dependent RNA polymerases.

In this project we attempt to chart the presence of this regulatory system in all completely sequenced organisms.

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All organisms examined so far to this respect respond to a sudden decrease in ambient temperature by inducing a specialized genetic program termed the cold shock response (CSR). This cellular stress response is designed to cope with a broad variety of temperature-dependent modulations of molecular structures, transport processes, chemical reactivities, and many more.

The goal of this project is to systematically identify non-coding RNAs (ncRNAs) involved in thermoregulation in all organisms whose genomes have been completely sequenced.

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Mycobacterium tuberculosis is the the causative agent of tuberculosis (TB) which is a world-wide pandemic that is contagious and spreads through the air. Scaringly, more than two billion people, equal to one third of the world’s total population, are infected with TB bacilli. Even worse, multidrug-resistant TB (MDR-TB) is a form of TB that does not respond to the standard treatments using first-line drugs and is present in virtually all countries surveyed by WHO and its partners. Strikingly, a total of 1.77 million people died from TB in 2007, equal to about 4800 deaths a day which makes TB one of the world's major causes of death.

Since it is known that certain non-coding RNAs (ncRNAs) are required to control the ability of many pathogens to infect their hosts, in this project we undertake an exhaustive search to map all ncRNAs known to date in this organism. Moreover, including the leprosy-causing agent Mycobacterium leprae, we extend our bioinformatic analyses to all fully sequenced strains of the genus Mycobacterium and also compare pathogenic versus non-pathogenic strains to possibly identify ncRNA-based differences that might be involved in virulence processes. To validate the biological and medical relevance of our computational investigations, laboratory experiments are performed in cooperation with our research partners in India. It is clear that the potentially possible identification of a ncRNA which is essential for pathogenicity of this organism may represent an excellent novel drug target to battle TB in the future.

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Ribozymes are non-coding RNA molecules that, like protein enzymes, catalyze chemical reactions. Examples are the hammerhead ribozyme, the HDV ribozyme, the hairpin ribozyme and many more.

In this project we are screening the kingdom of life for the presence of ribozymes. We also include artificially designed ribozymes in order to find out whether natural analogs exist.

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tRNAs are essential components of the cellular protein production machinery but also serve a number of additional functions as e.g. regulating gene expression in conjunction with the T-box element or are utilized as primers for reverse transcription of the HIV genome, a process essential for viral integration into the host genome. Moreover, tRNAs are also required for building the bacterial cell wall and occur in certain lipids making them an extremely versatile molecule family. Interestingly, a number of tRNA-like sequences have been identified in plant virus genomes and appear to be linked to the regulation of viral replication.

In this project, we aim at compiling a complete survey on the occurrence of tRNAs and tRNA-like sequences hoping to identify even more variety in this fundamental molecule class.

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The T-box leader is part of the 5' end of a number of mRNAs and represents an RNA element that serves a regulatory function in controlling protein production by interacting with non-charged tRNAs.

In this project, the RNA World supercomputer is utilized to identify T-box elements throughout the kingdom of life.

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Whenever a new genome sequence is published, its sequence of letters (i.e. the bases of the DNA molecules it contains) is annotated computationally. During this process, all regions are being identified that, based on the standard genetic code and a number of well-known rules, code for proteins. Besides ribosome-related RNAs such as rRNAs and tRNAs and a number of universally occurring non-coding RNAs, the majority of ncRNAs usually escape detection. In this project, we focus on exclusively filling in the gaps resulting from current protein-focused genome annotation procedures by systematically identifying ncRNAs and by adding our results to those generated by the standard methods.

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