LAPTI research interests.

The sea gets deeper as you go further into it.

Venetian proverb according to Nassim Taleb

Чем дальше в лес тем больше дров.

parallel Russian proverb

The main theme of our research is the understanding of how genetic information is decoded from DNA into RNA and proteins. Someone may find this topic a little strange and argue that we already know how this is happening. Indeed, it is probably common knowledge (at least among sufficiently curious individuals) that RNA molecules are synthesized from their DNA templates according to the rules of complementarity between nucleotides (A <-> T(U) and G <-> C) while proteins are synthesized according to the genetic code, in which triplets of nucleotides specify amino acids in synthesized proteins.

However, Life, with its aptitude for exploration of the possible to find advantageous, does not tend to be limited by very strict laws. Researchers have documented a significant number of specific alterations (many would prefer the word extension) of the above rules. In most cases such alterations of standard rules are known to serve important biological functions. At present LAPTI research is mainly focused on two categories of such "non-standard" events, translational recoding and RNA editing.

Translational recoding.

In brief, translational recoding can be defined as functional utilization of non-standard translation events. The two major types of recoding are programmed ribosomal frameshifting and codon redefinition. Ribosomal frameshifting is a process in which ribosomes change translation phases at specific locations, consequently producing protein products encoded by multiple open reading frames. Codon redefinition is a process in which standard meaning of a specific codon is redefined at certain locations within mRNA. Recoding events have been observed virtually in all organisms, though the number of genes that are known to utilize recoding is very small relative to the total.

In LAPTI we develop algorithms and computer programs for identification, analysis and annotation of those genes that utilize recoding. To understand how recoding works, we compare sequences of these genes and disseminate the sequence features associated with recoding and test these associations experimentally. LAPTI also maintains the Recode database, a public Internet resource dedicated to the genes in which recoding events occur.

RNA editing.

RNA editing can be broadly defined as a process in which a sequence of an RNA molecule is modified, so that small discrepancies are introduced relative to its DNA template. There is a large number of mechanisms responsible for such modifications. They vary from relatively straight-forward hydrolitic deamination of nucleotide bases resulting in adenosine-to-inosine or cytidine-to-uridine conversions or mechanistically simple heterogeneous transcription of nucleotide repeats (aka transcriptional slippage or stuttering) to more sophisticated modifications of RNA nucleotides guided by specific small RNA molecules and catalyzed by specialized enzymes.

Similarly to translational recoding, RNA editing events have been found in all types of organisms and they are utilized for a variety of functional purposes. LAPTI is working on the development of algorithms that identify and predict RNA editing cases and validation of these prediction using massively parallel sequencing.

Evolution of the genetic code and translation.

Since the decipherment of the nearly-universal genetic code, researchers have struggled trying to explain how the genetic code has originated. The trouble is that the protein biosynthesis requires accurate discrimination between triplets in nucleic acids (codons) that encode amino acid residues. But this process requires elaborate protein machinery. In other word, genetic decoding and proteins are mutually dependent: proteins are required to produce proteins.

In a search for plausible explanations for the origin of the genetic code, we hypothesized that the initial decoding in RNA World involved longer-than-triplet interactions. The stability of such interactions would be sufficient for their accurate discrimination without assistance of protein factors, see Baranov et al. 2009. Then, such interactions would evolve towards shorter triplet interactions in parallel with the evolution of the decoding apparatus. In LAPTI we perform in silico simulations to model this process in order to investigate whether transitions between codon sizes are possible in a continues manner, without impairment of the accuracy of the protein biosynthesis. Recent work on engineering quadruplet decoding ribosomes (Neumann et al. 2010) holds a promise to a possibility of testing our hypothesis experimentally in the future.

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