Date of Award
Doctor of Philosophy (PhD)
Genomics & Computational Biology
Life is organized. Organization is largely achieved via composability -- that at some level of abstraction, a system consists of smaller parts that serve as building blocks -- and modularity -- the tendency for these blocks to be independent units that recombine to form functionally different systems. Here, we explore the organization, composition, and modularity of ribonucleic acid (RNA) molecules, biopolymers that adopt three-dimensional structures according to their specific nucleotide sequence. We address three themes: the efficacy of specific sequences to function as modules or as the context in which modules are inserted; the sources of novel modules in modern genomes; and the resolutions at which functionally relevant modules exist in RNA.
First, we investigate the structural modularity of RNA sequences by developing the Self-Containment Index, a method to quantify in silico the degree to which RNA structures deviate in changing genomic contexts. We show that although structural modularity is not a general property of natural RNAs, precursor microRNAs are strongly modular, which we hypothesize is a consequence of their unique biogenesis and evolutionary history.
Next, we consider the role of modularity in the regulation of subcellular localization. We identify a novel module, the ID element retrotransposon, contained in the introns of rat neuronal genes, and demonstrate that it is sufficient to drive localization of mRNAs to dendrites via regulated retention of intron sequence. This mechanism shows that introns can provide the context for functional module insertion, and that transposable elements can be co-opted as source material for these modules. As a further example, we present evidence that a Camk2a localization signal can be mimicked by Alu retrotransposon sequence.
Finally, we propose that RNAs can be conceptually decomposed into sets of basic RNA functions. To identify these, we automatically construct an ontology of RNA function using Wikipedia documents. We show that many of the functions encoded in ontology terms are significantly associated with common structural features, highlighting an underlying structure-function relationship that can be encapsulated in elemental RNA building-block units.
In sum, we show how the phenomena of organization, composition, and modularity can frame RNA research in an evolutionary context.
Lee, Miler T., "Modular Organization and Composability of RNA" (2009). Publicly Accessible Penn Dissertations. 244.