Jürgen Brosius (born 1948 in Saarbrücken) is a German molecular geneticist and evolutionary biologist. He was professor and director of the Institute of Experimental Pathology at the University of Münster. 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.
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 nanomole range.Brosius J. Primary structure of Escherichia coli ribosomal protein L31 Biochemistry. 1978 Feb 7;17(3):501-8 This method was shortly thereafter superseded by automated protein sequencing operating in the low picomole range.Hunkapiller MW, Hood LE. Protein sequence analysis: automated microsequencing. Science. 1983 Feb 11;219(4585):650-9.
Postdoctoral fellowships From 1977 to 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.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. Although the chemical method was cumbersome, sequences could be determined entirely void of errors.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
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 German Research Foundation, 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,Brosius J. Plasmid vectors for the selection of promoters. Gene. 1984 Feb;27(2):151-60.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. 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.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.Amann E, Brosius J. "ATG vectors' for regulated high-level expression of cloned genes in Escherichia coli. Gene. 1985;40(2-3):183-90.
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 and the Irma T. Hirschl Trust.Irma T. Hirschl Trust 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.Core Facility TRAnsgenic animal and genetic engineering Models (TRAM) of the Medical Faculty Münster
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.Sutcliffe JG, Milner RJ, Gottesfeld JM, Reynolds W. Control of neuronal gene expression. Science. 1984 Sep 21;225(4668):1308-15 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 neuronsDeChiara TM, Brosius J. Neural BC1 RNA: cDNA clones reveal nonrepetitive sequence content. Proc Natl Acad Sci U S A. 1987 May;84(9):2624-8Tiedge 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):2093-7Kim 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 co-localizes with numerous components of the translation machinery.Tiedge H, Brosius J. Translational machinery in dendrites of hippocampal neurons in culture. J Neurosci. 1996 Nov 15;16(22):7171-81. Based on these findings, Brosius concluded as early as the eighties that:
1. Functional RNAs are not only fossils from a by-gone RNA worldBrosius J. Echoes from the past--are we still in an RNP world? Cytogenet Genome Res. 2005;110(1-4):8-24. 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,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. at the same time keeping genomes in flux and presenting raw material for the de novo evolution of genes.Brosius J, Tiedge H. Reverse transcriptase: mediator of genomic plasticity. Virus Genes. 1995;11(2-3):163-79.
3. Retroposition, not only segmental gene duplication, can also yield extra gene copies or smaller gene modules including regulatory elements for existing genes.Brosius J. Retroposons--seeds of evolution. Science. 1991 Feb 15;251(4995):753Weiner 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.
Together with Stephen J. Gould, Brosius took the concept of exaptation to the genomic level.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.Stephen Jay Gould, Elisabeth S. Vrba (1982) Exaptation – a missing term in the science of form. Paleobiology 8, 4–15Brosius J, Gould SJ. Molecular constructivity. Nature. 1993 Sep 9;365(6442):102
Encouraged by the stimulating findings surrounding BC1 RNA, in the mid-nineties he emphasized the significance of RNA coding genes in association with genome projectsBrosius J. More Haemophilus and Mycoplasma genes. Science. 1996 Mar 1;271(5253):1302a 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,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):2943-53Filipowicz W. Imprinted expression of small nucleolar RNAs in brain: time for RNomics. Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14035-7Cavaillé 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.
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.
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,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. 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.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. This was confirmed by an independent study.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
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.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
In addition to other RNomics discoveries, they were the first to demonstrate that certain tandem repeats were processed into CRISPR RNA units in Archaea.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