Jürgen Brosius

Jürgen Brosius (born 1948) in Saarbrücken) is a German molecular geneticist and evolutionary biologist. He was a professor at the University of Münster where he is the director of the Institute of Experimental Pathology. Some of his scientific contributions involve the first genetic sequencing of a ribosomal RNA operon, the design of plasmids for studying gene expression, expression vectors for high-level production of recombinant proteins and RNA, RNA biology, RNomics as well as the significance of retroposition for plasticity and evolution of genomes, genes and gene modules including regulatory sequences or elements.

Jürgen Brosius
Born1948
NationalityGerman
Known forsequencing ribosomal RNA, expression vectors for recombinant proteins, RNA biology, RNomics, role of retroposition in the evolution of genomes, genes, and gene modules
Scientific career
Fieldsmolecular genetics and evolutionary biology
InstitutionsUniversity of Münster

Biography

Early life and education

Brosius studied chemistry and pharmacy at the Goethe University of Frankfurt and in 1974 graduated and completed the Staatsexamen (state examination) in Pharmacy. Subsequently, he pursued his Ph.D. work in biochemistry and molecular biology at the Max Planck Institute for Molecular Genetics in Berlin Dahlem in which Heinz-Günter Wittmann was department head. While determining the primary structures of several E. coli ribosomal proteins, he developed manual micro-methods for isolating peptides using two-dimensional separation on cellulose thin layer plates (instead of using a series of chromatography columns) followed by dansyl-Edman degradation. This reduced the required protein material by one to two orders of magnitude towards the 100 nanomol range.[1] This method was shortly thereafter superseded by automated protein sequencing operating in the low picomol range.[2]

Postdoctoral fellowships

From 1977–1980, Brosius spent a postdoctoral fellowship supported by the Fogarty International Center in Harry F. Noller’s lab at the University of California, Santa Cruz. There, he sequenced the first large ribosomal RNAs via their genes utilizing the Maxam-Gilbert sequencing method. It took ~2.5 years to sequence the 7.5 kilobases encompassing the entire rrnB rRNA operon in addition to some flanking regions.[3] Although the chemical method was cumbersome, sequences could be determined entirely void of errors.[4]

During his stay at UCSC Brosius met visiting professor Carl Woese, who incited his interest in evolutionary thought and the power of molecular phylogenetic analysis.

His second postdoctoral fellowship (1980–1982), supported by the Deutsche Forschungsgesellschaft, took him to the laboratory of Walter Gilbert, Nobel prize laureate in Chemistry (1980), at Harvard University. Here, Brosius began to develop plasmid vectors for the selection of promoters and terminators,[5][6] as well as widely used vectors for the high-level expression of recombinant proteins in E. coli, often employing regulatory sequences or modules from the rRNA operon.[7][8]

Faculty positions

In 1982, Brosius established his own laboratory at Columbia University College of Physicians and Surgeons as Assistant Professor partially funded by the Alfred P. Sloan Foundation[9] and the Irma T. Hirschl Trust.[10] In 1988, he moved with his research group to Mount Sinai School of Medicine as Associate Professor and in 1994 as full Professor and Director of the Institute of Experimental Pathology to the University of Münster, Germany. In the mid-nineties, he established a transgenic and gene targeting facility serving the entire campus and beyond by generating, for example, mouse models designed for the study of human genetic disorders.[11] As of beginning 2015, he is also Visiting Professor at the newly founded private Medical School, Medizinische Hochschule Brandenburg Theodor Fontane.

Scientific contributions

In the early 1980s, Brosius became interested in a small brain-specific RNA that was thought to be a waste product of a mechanism orchestrating the expression of genes by RNA polymerase III transcription of identifier sequence (ID) repetitive elements, classified as SINEs, short interspersed repeats, located in the introns of brain-specific genes by making chromatin accessible to RNA polymerase II.[12] This attractive hypothesis was not tenable. Instead, the Brosius laboratory focused on this brain cytoplasmic BC1 RNA, cloned it as cDNA by developing a method for generating cDNA libraries based on non-polyadenylated RNAs, and isolated its single gene, which evolved from a retroposed copy of a transfer RNA (tRNAAla). It was shown that BC1 RNA is the source gene for ID repetitive elements in rodents, and his laboratory established that the dendritic localization of BC1 RNA in neurons[13][14][15] co-localizes with numerous components of the translation machinery.[16] Based on these findings, Brosius concluded as early as the eighties that:

1. Functional RNAs are not only fossils from a by-gone RNA world[17] but can arise de novo in modern cells and contribute to the functionality of a cell or organism; many more RNAs are yet to be discovered.

2. Retroposition (conversion of RNA to DNA) is an ancient process, but has persisted throughout the evolution of most eukaryotes. This process has contributed to the mass of genomes of modern multicellular organisms,[18] at the same time keeping genomes in flux and presenting raw material for the de novo evolution of genes.[19]

3. Retroposition, not only segmental gene duplication, can also yield extra gene copies or smaller gene modules including regulatory elements for existing genes.[20][19][21]

Together with Stephen J. Gould, Brosius took the concept of exaptation to the genomic level.[22][23][24]

Encouraged by the stimulating findings surrounding BC1 RNA, in the mid-nineties he emphasized the significance of RNA coding genes in association with genome projects[25] and embarked on generating more cDNA libraries based on non-protein coding RNAs from mice and various model organisms, ringing in the era of RNomics,[26][27][28]

A number of small nucleolar RNAs prevalently expressed in the brain as well as imprinted (only expressed by one parental chromosome) were discovered in mice and men.[26][28]

Several of these mapped to the human Prader-Willi Syndrome locus, a neurodevelopmental disorder. After the individual deletion of all protein coding gene candidates of this locus in mouse models by others,[29] the Brosius laboratory deleted the cluster of Snord116 snoRNA genes and the corresponding non-protein coding exons of the host gene. They observed some of the same phenotypes as the human disorder, such as failure to thrive and short stature, but not obesity later in life or infertility.[30] This was confirmed by an independent study.[31]

Earlier, Brosius and coworkers demonstrated that mice lacking the BC1 RNA gene had deficiencies in exploratory behaviour in the laboratory and under semi-natural conditions.[32]

In addition to other RNomics discoveries, they were the first to demonstrate that certain tandem repeats were processed into CRISPR RNA units in Archaea.[33]

Brosius remains a long-time advocate[34] for the significance and wealth of RNA molecules even in modern cells. Yet, he is skeptical of the drastic transformation in the perception of RNA within the scientific community. The idea of pervasive importance of RNA was formerly frequently rejected. Currently, the trend of thought is to raise any background transcript or any detectable snippet of a transcript after processing or decay to a functional status.[35][36][37][38][39]

He observed analogous trends in the field of repetitive or transposed genomic elements (TEs) including retroposed elements.[20] These elements were initially considered to be junk, littering genomes, and proposed by only a few to constitute raw material for fortuitous and only occasional exaptations,[40] and to be responsible for the plasticity of genomes and the modular architecture of genes.[19][41][40] The current tide is moving in the opposite direction.[42] A plethora of functions have been assigned to TEs, one example being the bewildering spectrum of tasks allocated to the evolutionarily young primate-specific Alu elements. Such sweeping interpretations should be challenged.[43]

Other research areas include:

Editorial boards
  • Associate Editor “PLoS Genetics” (2009- )
  • Associate Editor “Journal of Molecular Evolution” (2004-2012)
  • Editorial Board member "Scientific Reports" (2015- )
  • Editorial Board member “PLoS ONE” (2010- )
  • Editorial Board member “Mobile DNA” (2009- )
  • Editorial Board member “Biology Direct” (2007- )
  • Editorial Board member “RNA Biology” (2004- )
  • Editorial Board member “RepBase Reports” (2001- )
  • Editorial board member and European Editor "DNA and Cell Biology" (1986-2011)

Publications

References
  1. Brosius J. Primary structure of Escherichia coli ribosomal protein L31 Biochemistry. 1978 Feb 7;17(3):501-8
  2. Hunkapiller MW, Hood LE. Protein sequence analysis: automated microsequencing. Science. 1983 Feb 11;219(4585):650-9.
  3. Brosius J, Dull TJ, Sleeter DD, Noller HF. Gene organization and primary structure of a ribosomal RNA operon from Escherichia coli. J Mol Biol. 1981 May 15;148(2):107-27.
  4. Blattner FR, Burland V, Plunkett G 3rd, Sofia HJ, Daniels DL. Analysis of the Escherichia coli genome. IV. DNA sequence of the region from 89.2 to 92.8 minutes. Nucleic Acids Res. 1993 Nov 25;21(23):5408-17.y
  5. Brosius J. Plasmid vectors for the selection of promoters. Gene. 1984 Feb;27(2):151-60.
  6. Brosius J. Toxicity of an overproduced foreign gene product in Escherichia coli and its use in plasmid vectors for the selection of transcription terminators. Gene. 1984 Feb;27(2):161-72.
  7. Brosius J, Holy A. Regulation of ribosomal RNA promoters with a synthetic lac operator. Proc Natl Acad Sci U S A. 1984 Nov;81(22):6929-33.
  8. Amann E, Brosius J. "ATG vectors' for regulated high-level expression of cloned genes in Escherichia coli. Gene. 1985;40(2-3):183-90.
  10. Irma T. Hirschl Trust
  11. Core Facility TRAnsgenic animal and genetic engineering Models (TRAM) of the Medical Faculty Münster
  12. Sutcliffe JG, Milner RJ, Gottesfeld JM, Reynolds W. Control of neuronal gene expression. Science. 1984 Sep 21;225(4668):1308-15
  13. DeChiara TM, Brosius J. Neural BC1 RNA: cDNA clones reveal nonrepetitive sequence content. Proc Natl Acad Sci U S A. 1987 May;84(9):2624-8
  14. Tiedge H, Fremeau RT Jr, Weinstock PH, Arancio O, Brosius J. Dendritic location of neural BC1 RNA. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2093-7
  15. Kim J, Martignetti JA, Shen MR, Brosius J, Deininger P. Rodent BC1 RNA gene as a master gene for ID element amplification.Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3607-11
  16. Tiedge H, Brosius J. Translational machinery in dendrites of hippocampal neurons in culture. J Neurosci. 1996 Nov 15;16(22):7171-81.
  17. Brosius J. Echoes from the past--are we still in an RNP world? Cytogenet Genome Res. 2005;110(1-4):8-24.
  18. Brosius J. RNAs from all categories generate retrosequences that may be exapted as novel genes or regulatory elements. Gene. 1999 Sep 30;238(1):115-34.
  19. Brosius J, Tiedge H. Reverse transcriptase: mediator of genomic plasticity. Virus Genes. 1995;11(2-3):163-79.
  20. Brosius J. Retroposons--seeds of evolution. Science. 1991 Feb 15;251(4995):753
  21. Weiner AM. 2006. SINEs and LINEs: Troublemakers, saboteurs, benefactors, ancestors. In The RNAworld (ed. Gesteland RF, Cech TR, Atkins JF), pp. 507–533.Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY].
  22. Brosius J, Gould SJ. On "genomenclature": a comprehensive (and respectful) taxonomy for pseudogenes and other "junk DNA". Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10706-10.
  23. Stephen Jay Gould, Elisabeth S. Vrba (1982) Exaptation – a missing term in the science of form. Paleobiology 8, 4–15
  24. Brosius J, Gould SJ. Molecular constructivity. Nature. 1993 Sep 9;365(6442):102
  25. Brosius J. More Haemophilus and Mycoplasma genes. Science. 1996 Mar 1;271(5253):1302a
  26. Hüttenhofer A, Kiefmann M, Meier-Ewert S, O'Brien J, Lehrach H, Bachellerie JP, Brosius J. RNomics: an experimental approach that identifies 201 candidates for novel, small, non-messenger RNAs in mouse. EMBO J. 2001 Jun 1;20(11):2943-53
  27. Filipowicz W. Imprinted expression of small nucleolar RNAs in brain: time for RNomics. Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14035-7
  28. Cavaillé J, Buiting K, Kiefmann M, Lalande M, Brannan CI, Horsthemke B, Bachellerie JP, Brosius J, Hüttenhofer A. Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization. Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14311-6.
  29. Bervini S, Herzog H. Mouse models of Prader-Willi Syndrome: a systematic review. Front Neuroendocrinol. 2013 Apr;34(2):107-19. doi: 10.1016/j.yfrne.2013.01.002. Epub 2013 Feb 4.
  30. Skryabin BV, Gubar LV, Seeger B, Pfeiffer J, Handel S, Robeck T, Karpova E, Rozhdestvensky TS, Brosius J. Deletion of the MBII-85 snoRNA gene cluster in mice results in postnatal growth retardation. PLoS Genet. 2007 Dec 28;3(12):e235. doi: 10.1371/journal.pgen.0030235.
  31. Ding F, Li HH, Zhang S, Solomon NM, Camper SA, Cohen P, Francke U. SnoRNA Snord116 (Pwcr1/MBII-85) deletion causes growth deficiency and hyperphagia in mice. PLoS One. 2008 Mar 5;3(3):e1709. doi: 10.1371/journal.pone.0001709
  32. Lewejohann L, Skryabin BV, Sachser N, Prehn C, Heiduschka P, Thanos S, Jordan U, Dell'Omo G, Vyssotski AL, Pleskacheva MG, Lipp HP, Tiedge H, Brosius J, Prior H. Role of a neuronal small non-messenger RNA: behavioural alterations in BC1 RNA-deleted mice. Behav Brain Res. 2004 Sep 23;154(1):273-89
  33. Tang TH, Bachellerie JP, Rozhdestvensky T, Bortolin ML, Huber H, Drungowski M, Elge T, Brosius J, Hüttenhofer A. Identification of 86 candidates for small non-messenger RNAs from the archaeon Archaeoglobus fulgidus. Proc Natl Acad Sci U S A. 2002 May 28;99(11):7536-41
  34. Petherick A. Genetics: The production line. Nature. 2008 Aug 28;454(7208):1042-5. doi: 10.1038/4541042a
  35. Brosius J. Waste not, want not--transcript excess in multicellular eukaryotes. Trends Genet. 2005 May;21(5):287-8.
  36. Brosius J. The persistent contributions of RNA to eukaryotic gen(om)e architecture and cellular function. Cold Spring Harb Perspect Biol. 2014 Jul 31;6(12):a016089. doi: 10.1101/cshperspect.a016089.
  37. Raabe CA, Brosius J. Does every transcript originate from a gene? Ann N Y Acad Sci. 2015 Apr;1341:136-48. doi: 10.1111/nyas.12741.
  38. Brosius J, Raabe CA. What is an RNA? A top layer for RNA classification. RNA Biol. 2016 Feb;13(2):140-4. doi: 10.1080/15476286.2015.1128064
  39. RNA cartoon - bottom three
  40. Brosius J. The fragmented gene. Ann N Y Acad Sci. 2009 Oct;1178:186-93. doi: 10.1111/j.1749-6632.2009.05004.x
  41. Krull M, Brosius J, Schmitz J. Alu-SINE exonization: en route to protein-coding function. Mol Biol Evol. 2005 Aug;22(8):1702-11. Epub 2005 May 18
  42. Retrostuff cartoon - top three
  43. Graur D, Zheng Y, Price N, Azevedo RB, Zufall RA, Elhaik E. On the immortality of television sets: "function" in the human genome according to the evolution-free gospel of ENCODE. Genome Biol Evol. 2013;5(3):578-90. doi: 10.1093/gbe/evt028
  44. Krull M, Petrusma M, Makalowski W, Brosius J, Schmitz J. Functional persistence of exonized mammalian-wide interspersed repeat elements (MIRs). Genome Res. 2007 Aug;17(8):1139-45. Epub 2007 Jul 10
  45. Martignetti JA, Brosius J. Neural BC1 RNA as an evolutionary marker: guinea pig remains a rodent. Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9698-702
  46. Brosius J. Gene duplication and other evolutionary strategies: from the RNA world to the future. J Struct Funct Genomics. 2003;3(1-4):1-17
  47. Brosius J. From Eden to a hell of uniformity? Directed evolution in humans.Bioessays. 2003 Aug;25(8):815-21
  48. Patent U.S. # 5,670,318 and U.S # 5,736,329
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