Evolution of catalytic RNAs, and the Origin of Life
University of Technology Darmstadt, Germany
LMU Munich, Germany
UC San Diego
UC San Diego
Whitehead Institute, Cambridge, MA
Awards and Academic Honors
NASA research award
NASA research award
NSF research award
NRSA fellowship from the NIH
Postdoctoral award from the German Research Council (DFG)
The Muller lab is interested in catalytic RNA molecules (ribozymes). Our main efforts are focused on the question: How did the RNA world, an early stage of life, function? To do this we develop catalytic RNAs by in vitro selection from random RNA sequences. Our long-term aim is to generate an RNA world organism and thereby recapitulate an early stage of life in the lab.
The earliest evolutionary stages of life most likely included a stage called the RNA world. In this scenario, RNA served both as genome and as the only genome-encoded catalyst; these functions were later mostly overtaken by DNA and by proteins. We are trying to generate a self-replicating system of catalytic RNAs, mimicking an RNA world. If we were able to generate such a system, it could show us how an RNA world could function, and how an RNA world was able to evolve into today's DNA/RNA/protein life forms.
The focus of our work is on ribozymes that generate chemically activated nucleotides, and polymerize chemically activated nucleotides. Both activities are essential for the self-replication of an RNA world organism. Using in vitro selection from more than 10^14 sequences, we identified ribozymes that are able to catalyze the triphosphorylation of RNA 5'-hydroxyl groups using trimetaphosphate. Because trimetaphosphate likely existed on early Earth, our findings show that trimetaphosphate could have been used as energy source for RNA world organisms. Current research in our lab aims to generate variants of these ribozymes that could fuel a primitive energy metabolism, and ultimately integrate them into a larger system of self-replicating ribozymes, an RNA world organism.
A second line of projects in the lab is focused on Group I intron ribozymes, and their evolution in cells. Natural group I intron ribozymes are cis-splicing; we work with engineered, trans-splicing variants. We engineered ribozyme variants that splice efficiently on two splice sites, and termed them 'spliceozymes'. Analogous to the spliceosome, these spliceozymes remove an internal sequence from a target RNA and join the flanking sequences, resulting in a translatable mRNA. We use these 'group I intron spliceozymes' for two purposes: First, the evolution of these spliceozymes may enable us to recapitulate biochemical steps in the evolution of the spliceosome. Second, evolved variants of the spliceosomes may be useful for the therapy of diseases in which specific introns are incompletely removed.
Primary Research Area
Advisory Service - Participant in developing the GE curriculum at Thurgood Marshall College in 2009. Thurgood Marshall College places an especially high importance on promoting diversity, for example in its specifically designed program Dimensions of Culture (DOC).
Recruitment Efforts - Assist in the recruitment efforts of the Thurgood-Marshall College, in two recruitment seasons.
Mentoring Efforts - Involvement in the Thurgood-Marshall mentorship program for transfer students, specifically aimed at helping disadvantaged transfer students.
My lab is dedicated to supporting an equal opportunity environment. This is reflected in the numbers of students in my lab: Three of the seven PhD students from my lab who have so far defended their thesis are female. Five of twelve undergraduate researchers who worked in my lab were female, and five of them were from an ethnic background (Asian/Hawaiian/African American).
The Muller lab. From left to right: Uli Muller, Logan Norrell, Joshua Arreola, Kevin Sweeney, Ishani Behera, Arvin Akoopie.
- Akoopie, A., Müller, U.F. "Lower temperature optimum of a smaller, fragmented triphosphorylation ribozyme", Physical Chemistry Chemical Physics, 2016, Vol. 18, 20118-20125
- Amini, Z.N., Müller, U.F. "Increased efficiency of evolved group I intron spliceozymes by decreased side product formation", RNA, 2015, Vol. 21, Issue 8, 1480-1489
- Dolan, G.F., Akoopie, A., Müller, U.F. "A faster triphosphorylation ribozyme", PLoS ONE, 2015, Vol. 10, Issue 11, e0142559
- Martin, L.L., Unrau, P.J., Müller, U.F. "RNA synthesis by in vitro selected ribozymes for recreating an RNA world", Life (Basel), 2015, Vol. 5, Issue 1, 247-268
- Amini ZN, Olson KE, Müller UF, "Spliceozymes: Ribozymes that Remove Introns from Pre-mRNAs in Trans.", PLoS One, 2014, Vol. 9, Issue 7, e101932
- Dolan G.F., Müller U.F. "Trans-splicing with the group I intron ribozyme from Azoarcus", RNA, 2014, Vol. 20, Issue 2, 202-213
- Moretti J.E., Müller U.F., "A ribozyme that triphosphorylates RNA 5'-hydroxyl groups.", Nucleic Acids Res., 2014, Vol. 42, Issue 7, 4767-4778
- Müller UF, Tor Y, "Citric acid and the RNA world.", Angew Chem Int Ed Engl, 2014, Vol. 53, Issue 21, 5245-7
- Olson KE, Dolan GF, Müller UF, "In vivo evolution of a catalytic RNA couples trans-splicing to translation.", PLoS One, 2014, Vol. 9, Issue 1, e86473
- Amini ZN, Müller UF, "Low selection pressure aids the evolution of cooperative ribozyme mutations in cells.", J Biol Chem, 2013, Vol. 288, Issue 46, 33096-106
- Meluzzi D, Olson KE, Dolan GF, Arya G, Müller UF, "Computational prediction of efficient splice sites for trans-splicing ribozymes.", RNA, 2012, Vol. 18, Issue 3, 590-602
- Olson KE, Müller UF, "An in vivo selection method to optimize trans-splicing ribozymes.", RNA, 2012, Vol. 18, Issue 3, 581-9
- Yao C, Moretti JE, Struss PE, Spall JA, Müller UF, "Arginine cofactors on the polymerase ribozyme.", PLoS One, 2011, Vol. 6, Issue 9, e25030
- Yao C, Müller UF, "Polymerase ribozyme efficiency increased by G/T-rich DNA oligonucleotides.", RNA, 2011, Vol. 17, Issue 7, 1274-81
- Müller UF, "Evolution of ribozymes in an RNA world.", Chem Biol, 2009, Vol. 16, Issue 8, 797-8
- Müller UF, Bartel DP, "Improved polymerase ribozyme efficiency on hydrophobic assemblies.", RNA, 2008, Vol. 14, Issue 3, 552-62
- Müller UF, "Re-creating an RNA world.", Cell Mol Life Sci, 2006, Vol. 63, Issue 11, 1278-93
- Müller UF, Bartel DP, "Substrate 2'-hydroxyl groups required for ribozyme-catalyzed polymerization.", Chem Biol, 2003, Vol. 10, Issue 9, 799-806
- Müller UF, Göringer HU, "Mechanism of the gBP21-mediated RNA/RNA annealing reaction: matchmaking and charge reduction.", Nucleic Acids Res, 2002, Vol. 30, Issue 2, 447-55
- Müller UF, Lambert L, Göringer HU, "Annealing of RNA editing substrates facilitated by guide RNA-binding protein gBP21.", EMBO J, 2001, Vol. 20, Issue 6, 1394-404