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Research :

Laura Landweber

Below is a snapshot of our research. Click here for a CV or a full research summary .
Research in my laboratory combines multiple approaches - from comparative genome sequence analysis to functional experiments - to study early molecular evolution, the origin of complex genetic systems, and how cells and DNA solve biological problems, such as the creation and assembly of genes.

     The current explosion of activity in comparative genomics and molecular biology has permitted us to study the process of evolution at its most fundamental level. DNA sequence analysis, for example, provides us with insight into the mechanisms of selection and evolution at the level of the gene. The discoveries of catalytic RNA, furthermore, and unusual forms of RNA splicing have led to advances in the study of the origin of life, and suggest that there are other "molecular fossils," or primitive biological mechanisms, still present in modern species (Landweber 2007). Protists, in particular, have surprised molecular biologists with a bewildering diversity of genome organization (e.g. Swart et al. 2013), from the impressive scrambled genes in ciliates to bizarre forms of RNA processing, including splicing and RNA editing, as well as an abundance of nonstandard genetic codes. Therefore they are a natural place to study primitive or aberrant genetic systems.

      Gene unscrambling appears to be a recent invention in some species of ciliates. A major focus of our laboratory since 2000 has been to understand how these genes become reordered from so many dispersed parts with every round of conjugation (inset), how these genes became scrambled over evolutionary time, and, more recently, how noncoding RNA-guided epigenetic mechanisms orchestrate the cascade of events leading to genome remodeling. Genome editing and descrambling assemble patchwork genes from constituent pieces, and can occur at different levels (RNA or DNA) and via different routes in different species. In gene unscrambling, disordered DNA fragments become linked together in the correct order and orientation by the presence of short direct repeats, or pointers, sequences of microhomology at their ends. The process of matching up these DNA sequence words like AATAAGC, uniquely present at the end of piece 3 and the beginning of piece 4, for example (figure below), permits the assembly of protein-coding genes from dozens of scrambled pieces. This pathway resembles an intrinsically computational route.


     Current functional lines of experiments use RNAi or microinjection of small (27nt) or long noncoding RNA molecules to manipulate the pathway of genome rearrangement (see Fang et al. 2012, Cell and Nowacki et al. 2008, Nature, for two respective examples). Earlier work in our lab used test-tube evolution experiments to test the emergence of catalytic function from random RNA sequences (Landweber and Pokrovskaya PNAS 1999) and also to develop robust quantitative tests for the role of RNA-amino acid interactions in the origin of the Genetic Code (see Knight and Landweber 1998, 2000). Perhaps surprisingly, this same in vitro selection procedure also allowed us to construct a molecular computer out of RNA that can find and describe solutions to small mathematical search problems (Faulhammer et al. PNAS 2000). The ability to isolate new ribozymes from random sequences (e.g. Landweber and Pokrovskaya PNAS 1999) and to infer properties present in the last common ancestor of all life (Goldman et al. 2013) has fueled excitement about the possibility of discovering early pathways of RNA and protein evolution (e.g. Goldman et al. 2013). Ultimately, such surveys will make the world of possible primordial enzyme functions accessible even when the molecules are no longer present in modern species.