Faculty & Research
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Laura F. Landweber

Associated Faculty, Ecology and Evolutionary Biology

Laura Landweber

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Phone (609) 258-1947
locationGuyot Hal, 323
Phone Lab (609) 258-1933
Faculty Assistant
Ellen Ferry
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Phone (609) 258-6820

Research Focus

Molecular evolution, the origin of genetic systems, noncoding RNAs and RNA-mediated epigenetic inheritance

Research in my laboratory combines multiple approaches—from comparative genomics and bioinformatic sequence analysis to functional experiments—to study biological information processing. We specifically focus on early molecular evolution, the origin of genetic systems like the genetic code, and how cells and DNA solve complex biological problems, such as the creation and assembly of genes.

The current explosion of activity in 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. Furthermore, the discovery of catalytic RNA in ciliates has led to advances in the study of the origin of life, and suggests that there are other "molecular fossils," or primitive biological mechanisms, still present in modern species. Microbial eukaryotes, or protists, in particular, have surprised molecular biologists with a bewildering diversity of gene organization, from the impressive acrobatics of "scrambled genes" in ciliates to bizarre forms of RNA processing, including self-splicing and editing (Horton and Landweber 2002), as well as an abundance of nonstandard genetic codes (Lozupone et al. 2001). Therefore they seem to be the natural place to study primitive or aberrant genetic systems.

Gene unscrambling appears to be a recent invention in a group of microbial eukaryotes known as spirotrichous ciliates. A major focus of our laboratory is to understand how these genes become reordered from so many dispersed pieces, and also how these genes became scrambled over evolutionary time. This process of unscrambling can assemble patchwork genes from numerous tiny pieces, even if they are present on opposite strands of a chromosome or on unlinked loci. The permuted DNA fragments become linked together in the correct order and orientation, partly due to the presence of short direct repeats, termed pointers, 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, permits the assembly of protein-coding genes from 50 or more scrambled fragments (Landweber et al. PNAS 2000). This pathway resembles an intrinsically computational route to gene assembly.

As we currently embark on a genome sequencing project for the ciliate Oxytricha trifallax, we anticipate dealing with this assembly problem on a much grander scale, since as much as one-third of the entire germline genome (the micronucleus) is thought to be scrambled. At the same time, these ciliates possess a second genome in the same cell (the macronucleus) that contains just a small subset of the total DNA in the micronucleus, specifically the reassembled coding genes, having discarded almost all of the noncoding DNA. This makes genome annotation highly tractable for the macronucleus. These two projects will be in full swing through 2005 and will change the pace of science in ciliates, opening many new avenues for post-genomic experiments.

My laboratory also probes deep questions such as the origin of the genetic code (Knight et al. 1999). Most theories for the origin of the genetic code require specific recognition between nucleic acids and amino acids at some stage of the code's evolution. Examination of RNA molecules that bind amino acids allowed us to search for motifs that interact directly with the amino acid. Our studies of arginine provided the strongest support for an intrinsic affinity between an amino acid and its codons. This suggests that we are on the brink of understanding the role of chemical determinism in shaping the codon assignments for this and other amino acids and rejects the "frozen accident" hypothesis for the origin of the genetic code.


Selected Publications

Khurana JS, Wang X, Chen X, Perlman D, Landweber LF. (2014) Transcription-independent functions of an RNA polymerase II subunit, Rpb2, during genome rearrangement in the ciliate, Oxytricha trifallax. Genetics. May 1. [Epub ahead of print]

Goldman AD, Bernhard TM, Dolzhenko E, Landweber LF. (2013) LUCApedia: a database for the study of ancient life. Nucleic Acids Res. 41: D1079-82. Pubmed

Swart EC, Bracht JR, Magrini V,...Landweber LF. (2013) The Oxytricha trifallax macronuclear genome: A complex eukaryotic genome with 16,000 tiny chromosomes. PLoS Biol. 11: e1001473. PubMed

Bracht JR, Fang W, Goldman AD, Dolzhenko E, Stein EM, Landweber LF. (2013) Genomes on the edge: programmed genome instability in ciliates. Cell. 152: 406-16. PubMed

Fang W, Landweber LF. (2013) RNA-mediated genome rearrangement: Hypotheses and evidence. Bioessays. 35: 84-7. PubMed

Fang W, Wei Y, Kang Y, Landweber LF. (2012) Detection of a common chimeric transcript between human chromosomes 7 and 16. Biol Direct. 7: 49. Pubmed

Fang W, Wang X, Bracht JR, Nowacki M, Landweber LF. (2013) Piwi-Interacting RNAs Protect DNA against loss during Oxytricha genome rearrangement. Cell. 151: 1243-55. PubMed

Goldman AD, Bernhard TM, Dolzhenko E, Landweber LF. (2012) LUCApedia: a database for the study of ancient life. Nucleic Acids Res. 41: D1079-82. PubMed

Bracht JR, Perlman DH, Landweber LF. (2012) Cytosine methylation and hydroxymethylation mark DNA for elimination in Oxytricha trifallax. Genome Biol. 13: R99. PubMed

Swart EC, Nowacki M, Shum J,...Landweber LF. (2012) The Oxytricha trifallax mitochondrial genome. Genome Biol Evol. 4: 136-54. PubMed

Goldman AD, Landweber LF. (2012) Oxytricha as a modern analog of ancient genome evolution. Trends Genet. 28: 382-88. PubMed

Zoller SD, Hammersmith RL, Swart EC,...Landweber LF. (2012) Characterization and taxonomic validity of the ciliate Oxytricha trifallax (Class Spirotrichea) based on multiple gene sequences: Limitations in identifying genera solely by morphology. Protist.  163: 643-57. PubMed

Zhou Y, Wubneh H, Schwarz C, Landweber LF. (2011) A chimeric chromosome in the ciliate oxytricha resulting from duplication. J Mol Evol. 73: 70-73. PubMed

Jung S, Swart EC, Minx PJ,...Landweber LF, Eddy SR. (2011) Exploiting Oxytricha trifallax nanochromosomes to screen for non-coding RNA genes. Nucleic Acids Res. 39: 7529-47. PubMed

Nowacki M, Haye JE, Fang W, Vijayan V, Landweber LF. (2010) RNA-mediated epigenetic regulation of DNA copy number. Proc Natl Acad Sci. 107: 22140-44. PubMed

Nowacki M, Landweber LF. (2009) Epigenetic inheritance in ciliates. Curr Opin Microbiol. 12: 638-43. PubMed

Nowacki M, Higgins BP, Maquilan GM, Swart EC, Doak TG, Landweber LF. (2009) A functional role for transposases in a large eukaryotic genome. Science. 324: 935-38. PubMed

Nowacki M, Vijayan V, Zhou Y, Schotanus K, Doak TG, Landweber LF. (2007) RNA-mediated epigenetic programming of a genome-rearrangement pathway. Nature. 451: 153-58. PubMed

Landweber LF. (2007) Genetics. Why genomes in pieces? Science. 318: 405-07. PubMed

Zhou Y, Landweber LF. (2007) BLASTO: a tool for searching orthologous groups. Nucl Acids Res. 35: W678-82. PubMed

Liang H, Landweber LF. (2007) Hypothesis: RNA editing of microRNA target sites in humans? RNA. 13: 463-67. PubMed

Liang H, Zhou W, Landweber LF. (2006) SWAKK: a web server for detecting positive selection in proteins using a sliding window substitution rate analysis. Nucl Acids Res. 34: W382-84. PubMed

Cavalcanti AR, Stover NA, Landweber LF. (2006) On the paucity of duplicated genes in Caenorhabditis elegans operons. J Mol Evol. 62: 765-71. PubMed

Liang H, Landweber LF. (2006) A genome-wide study of dual coding regions in human alternatively spliced genes. Genome Res. 16: 190-96. PubMed

Chang WJ, Kuo S, Landweber LF. (2006) A new scrambled gene in the ciliate Uroleptus. Gene. 368: 72-77. PubMed

Wong LC, Landweber LF. (2006) Evolution of programmed DNA rearrangements in a scrambled gene. Mol Biol Evol. 23: 756-63. PubMed

McFarland CP, Chang WJ, Kuo S, Landweber LF. (2006) Conserved linkage of two genes on the same macronuclear chromosome in spirotrichous ciliates. Chromosoma. 115: 129-38. PubMed

Chang WJ, Bryson PD, Liang H, Shin MK, Landweber LF. (2005) The evolutionary origin of a complex scrambled gene. Proc Natl Acad Sci. 102: 15149-54. PubMed

Liang H, Landweber LF. (2005) Molecular mimicry: quantitative methods to study structural similarity between protein and RNA. 11: 1167-72. PubMed

Livstone MS, van Noort D and Landweber LF. (2003) Molecular computing revisited: a Moore's Law? Trends Biotechnol. 21: 98-101. PubMed

Horton TL, Landweber LF. (2002) Rewriting the information in DNA: RNA editing in kinetoplastids and myxomycetes. Curr Opin Microbiol. 5: 620-26. PubMed

Lozupone CA, Knight RD, Landweber LF. (2001) The molecular basis of nuclear genetic code change in ciliates. Curr Biol. 11: 65-74. PubMed

Landweber LF, Kuo TC, Curtis EA. (2000) Evolution and assembly of an extremely scrambled gene. Proc Natl Acad Sci. 97: 3298-303. PubMed

Faulhammer D, Cukras AR, Lipton RJ, Landweber LF. (2000) Molecular computation: RNA solutions to chess problems. Proc Natl Acad Sci. 97: 1385-89. PubMed

Knight RD, Freeland SJ, Landweber LF. (1999) Selection, history and chemistry: the three faces of the genetic code. Trends Biochem Sci. 24: 241-47. PubMed

Freeland SJ, Knight RD, Landweber LF. (1999) Do proteins predate DNA? Science. 286: 690-92. PubMed

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Lewis Thomas Laboratory at Princeton University

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