The Most Difficult Problem in Computational Biology

The real revolution in computational biology is taking place without much public attention. Temple Smith, who is famous for Smith-Waterman algorithm, is using computational methods to work on what Francis Crick called the most difficult problem in genetics - the evolutionary origin of ribosome and translational apparatus. This ‘translation’ problem got buried inside the genetic code, but Woese argued that its evolutionary aspect needs to be understood properly to get full understanding of the evolution of organisms (including large eukaryotic mammals).

The Evolution of the Ribosome and the Genetic Code

The evolution of the genetic code is mapped out starting with the aminoacyl tRNA-synthetases and their interaction with the operational code in the tRNA acceptor arm. Combining this operational code with a metric based on the biosynthesis of amino acids from the Citric acid, we come to the conclusion that the earliest genetic code was a Guanine Cytosine (GC) code. This has implications for the likely earliest positively charged amino acids. The progression from this pure GC code to the extant one is traced out in the evolution of the Large Ribosomal Subunit, LSU, and its proteins; in particular those associated with the Peptidyl Transfer Center (PTC) and the nascent peptide exit tunnel. This progression has implications for the earliest encoded peptides and their evolutionary progression into full complex proteins.

Readers are encouraged to check other recent papers of Smith written in collaboration with Hartman (such as GTPase and the origin of the ribosome).

Speaking of relevance of translation to the development of mammals, readers may check work from Maria Barna at Stanford -

RNA regulons in Hox 5? UTRs confer ribosome specificity to gene regulation

Emerging evidence suggests that the ribosome has a regulatory function in directing how the genome is translated in time and space. However, how this regulation is encoded in the messenger RNA sequence remains largely unknown. Here we uncover unique RNA regulons embedded in homeobox (Hox) 5? untranslated regions (UTRs) that confer ribosome-mediated control of gene expression. These structured RNA elements, resembling viral internal ribosome entry sites (IRESs), are found in subsets of Hox mRNAs. They facilitate ribosome recruitment and require the ribosomal protein RPL38 for their activity. Despite numerous layers of Hox gene regulation, these IRES elements are essential for converting Hox transcripts into proteins to pattern the mammalian body plan. This specialized mode of IRES-dependent translation is enabled by an additional regulatory element that we term the translation inhibitory element (TIE), which blocks cap-dependent translation of transcripts. Together, these data uncover a new paradigm for ribosome-mediated control of gene expression and organismal development.

Speaking of difficult problems, interestingly Smith also has his eye on origin of the cilia and eukaryotes. For a full list of other problems, readers may take a look at -

Crossroads (iii) a New Direction for Bioinformatics with Twelve Fundamental Problems