Jürgen Brosius
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Jürgen Brosius (born 1948 in
Saarbrücken Saarbrücken (; Rhenish Franconian: ''Sabrigge'' ; ; ; ; ) is the capital and largest List of cities and towns in Germany, city of the state of Saarland, Germany. Saarbrücken has 181,959 inhabitants and is Saarland's administrative, commerci ...
) is a German molecular geneticist and evolutionary biologist. He was professor and director of the Institute of Experimental Pathology at the
University of Münster The University of Münster (, until 2023 , WWU) is a public research university located in the city of Münster, North Rhine-Westphalia in Germany. With more than 43,000 students and over 120 fields of study in 15 departments, it is Germany's ...
. Some of his scientific contributions involve the first genetic sequencing of a
ribosomal RNA Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA which is the primary component of ribosomes, essential to all cells. rRNA is a ribozyme which carries out protein synthesis in ribosomes. Ribosomal RNA is transcribed from ribosomal ...
operon In genetics, an operon is a functioning unit of DNA containing a cluster of genes under the control of a single promoter. The genes are transcribed together into an mRNA strand and either translated together in the cytoplasm, or undergo splic ...
, the design of
plasmid A plasmid is a small, extrachromosomal DNA molecule within a cell that is physically separated from chromosomal DNA and can replicate independently. They are most commonly found as small circular, double-stranded DNA molecules in bacteria and ...
s for studying gene expression,
expression vector An expression vector, otherwise known as an expression construct, is usually a plasmid or virus designed for gene expression in cells. The vector (molecular biology), vector is used to introduce a specific gene into a target cell, and can command ...
s for high-level production of recombinant proteins and
RNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...
, RNA biology, RNomics as well as the significance of retroposition for plasticity and evolution of genomes, genes and gene modules including
regulatory sequences Regulation is the management of complex systems according to a set of rules and trends. In systems theory, these types of rules exist in various fields of biology and society, but the term has slightly different meanings according to context. F ...
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 protein A ribosomal protein (r-protein or rProtein) is any of the proteins that, in conjunction with rRNA, make up the ribosomal subunits involved in the cellular process of translation. ''E. coli'', other bacteria and Archaea have a 30S small subunit ...
s, he developed manual micro-methods for isolating
peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...
s 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 The mole (symbol mol) is a unit of measurement, the SI base unit, base unit in the International System of Units (SI) for ''amount of substance'', an SI base quantity proportional to the Particle number, number of elementary entities of a substa ...
range. This method was shortly thereafter superseded by automated protein sequencing operating in the low picomole range.


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 The University of California, Santa Cruz (UC Santa Cruz or UCSC) is a public university, public Land-grant university, land-grant research university in Santa Cruz, California, United States. It is one of the ten campuses in the University of C ...
. 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. Although the chemical method was cumbersome, sequences could be determined entirely void of errors. During his stay at UCSC Brosius met visiting professor
Carl Woese Carl Richard Woese ( ; July 15, 1928 – December 30, 2012) was an American microbiologist and biophysicist. Woese is famous for defining the Archaea (a new domain of life) in 1977 through a pioneering phylogenetic taxonomy of 16S ribosomal ...
, who incited his interest in evolutionary thought and the power of molecular
phylogenetic In biology, phylogenetics () is the study of the evolutionary history of life using observable characteristics of organisms (or genes), which is known as phylogenetic inference. It infers the relationship among organisms based on empirical dat ...
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 Harvard University is a Private university, private Ivy League research university in Cambridge, Massachusetts, United States. Founded in 1636 and named for its first benefactor, the History of the Puritans in North America, Puritan clergyma ...
. Here, Brosius began to develop plasmid vectors for the selection of promoters and terminators, 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.


Faculty positions

In 1982, Brosius established his own laboratory at
Columbia University College of Physicians and Surgeons The Columbia University College of Physicians and Surgeons (officially known as Columbia University Roy and Diana Vagelos College of Physicians and Surgeons) is the medical school of Columbia University, located at the Columbia University Irvin ...
as assistant professor partially funded by the Alfred P. Sloan Foundation and the 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 The University of Münster (, until 2023 , WWU) is a public research university located in the city of Münster, North Rhine-Westphalia in Germany. With more than 43,000 students and over 120 fields of study in 15 departments, it is Germany's ...
, Germany. In the mid-nineties, he established a transgenic and
gene targeting Gene targeting is a biotechnological tool used to change the DNA sequence of an organism (hence it is a form of Genome Editing). It is based on the natural DNA-repair mechanism of Homology Directed Repair (HDR), including Homologous Recombinat ...
facility serving the entire campus and beyond by generating, for example, mouse models designed for the study of human
genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders ...
s.


Scientific contributions

In the early 1980s, Brosius became interested in a small brain-specific
RNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...
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
intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e., a region inside a gene."The notion of the cistron .e., gen ...
s of brain-specific genes by making
chromatin Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important r ...
accessible to
RNA polymerase II RNA polymerase II (RNAP II and Pol II) is a Protein complex, multiprotein complex that Transcription (biology), transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNA pol ...
. This attractive hypothesis was not tenable. Instead, the Brosius laboratory focused on this brain cytoplasmic BC1 RNA, cloned it as
cDNA In genetics, complementary DNA (cDNA) is DNA that was reverse transcribed (via reverse transcriptase) from an RNA (e.g., messenger RNA or microRNA). cDNA exists in both single-stranded and double-stranded forms and in both natural and engin ...
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 Transfer ribonucleic acid (tRNA), formerly referred to as soluble ribonucleic acid (sRNA), is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes). In a cell, it provides the physical link between the gene ...
(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
neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
s co-localizes with numerous components of the
translation Translation is the communication of the semantics, meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The English la ...
machinery. 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 The RNA world is a hypothetical stage in the evolutionary history of life on Earth in which self-replicating RNA molecules proliferated before the evolution of DNA and proteins. The term also refers to the hypothesis that posits the existence ...
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
eukaryote The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...
s. This process has contributed to the mass of
genome A genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding genes, other functional regions of the genome such as ...
s of modern multicellular organisms, 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 A regulatory sequence is a segment of a nucleic acid molecule which is capable of increasing or decreasing the expression of specific genes within an organism. Regulation of gene expression is an essential feature of all living organisms and vir ...
for existing genes.Brosius J. Retroposons--seeds of evolution. Science. 1991 Feb 15;251(4995):753 Together with Stephen J. Gould, Brosius took the concept of
exaptation Exaptation or co-option is a shift in the function of a trait during evolution. For example, a trait can evolve because it served one particular function, but subsequently it may come to serve another. Exaptations are common in both anatomy and be ...
to the genomic level. 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 and embarked on generating more cDNA libraries based on non-protein coding RNAs from mice and various
model organism A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workings of other organisms. Mo ...
s, 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):2943-53Cavaillé 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 Neurodevelopmental disorders are a group of mental conditions negatively affecting the development of the nervous system, which includes the brain and spinal cord. According to the American Psychiatric Association Diagnostic and Statistical Manu ...
. 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. This was confirmed by an independent study. 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 CRISPR (; acronym of clustered regularly interspaced short palindromic repeats) is a family of DNA sequences found in the genomes of prokaryotic organisms such as bacteria and archaea. Each sequence within an individual prokaryotic CRISPR is d ...
RNA units in
Archaea Archaea ( ) is a Domain (biology), domain of organisms. Traditionally, Archaea only included its Prokaryote, prokaryotic members, but this has since been found to be paraphyletic, as eukaryotes are known to have evolved from archaea. Even thou ...
. Brosius remains a long-time advocate 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. He observed analogous trends in the field of repetitive or transposed genomic elements (TEs) including retroposed elements. 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,Brosius J. The fragmented gene. Ann N Y Acad Sci. 2009 Oct;1178:186-93. doi: 10.1111/j.1749-6632.2009.05004.x and to be responsible for the plasticity of genomes and the modular architecture of genes. The current tide is moving in the opposite direction. 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 element An Alu element is a short stretch of DNA originally characterized by the action of the ''Arthrobacter luteus (Alu)'' restriction endonuclease. ''Alu'' elements are the most abundant transposable elements in the human genome, present in excess o ...
s. Such sweeping interpretations should be challenged. Other research areas include: * de novo evolution of genes and parts thereof * the use of retroposon markers to establish phylogenetic relationships * the origin and evolution of life * evolutionary thought to address bioethical questions * RNA as diagnostic markers for various diseases including cancerPatent U.S. # 5,670,318 and U.S # 5,736,329


External links


Institute of Experimental Pathology


Publications


Brosius J NCBI Publication list


References

{{DEFAULTSORT:Brosius, Jurgen German geneticists German evolutionary biologists 1948 births Living people