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Article ; Online: Modeling the integration of bacterial rRNA fragments into the human cancer genome.

Sieber, Karsten B / Gajer, Pawel / Dunning Hotopp, Julie C

2016 Volume 17, Page(s) 134

Abstract: Background: Cancer is a disease driven by the accumulation of genomic alterations, including the integration of exogenous DNA into the human somatic genome. We previously identified in silico evidence of DNA fragments from a Pseudomonas-like bacteria ... ...

Abstract	Background: Cancer is a disease driven by the accumulation of genomic alterations, including the integration of exogenous DNA into the human somatic genome. We previously identified in silico evidence of DNA fragments from a Pseudomonas-like bacteria integrating into the 5'-UTR of four proto-oncogenes in stomach cancer sequencing data. The functional and biological consequences of these bacterial DNA integrations remain unknown. Results: Modeling of these integrations suggests that the previously identified sequences cover most of the sequence flanking the junction between the bacterial and human DNA. Further examination of these reads reveals that these integrations are rich in guanine nucleotides and the integrated bacterial DNA may have complex transcript secondary structures. Conclusions: The models presented here lay the foundation for future experiments to test if bacterial DNA integrations alter the transcription of the human genes.
MeSH term(s)	5' Untranslated Regions ; Antigens, CD/genetics ; Antigens, Differentiation, B-Lymphocyte/genetics ; Carcinoembryonic Antigen/genetics ; Cell Adhesion Molecules/genetics ; GPI-Linked Proteins/genetics ; Genome, Human ; Histocompatibility Antigens Class II/genetics ; Host-Parasite Interactions/genetics ; Humans ; Neoplasms/genetics ; Neoplasms/pathology ; Nucleic Acid Conformation ; Pseudomonas/genetics ; RNA, Ribosomal/chemistry ; RNA, Ribosomal/genetics ; RNA, Ribosomal/metabolism ; Recombination, Genetic
Chemical Substances	5' Untranslated Regions ; Antigens, CD ; Antigens, Differentiation, B-Lymphocyte ; CEACAM5 protein, human ; CEACAM6 protein, human ; Carcinoembryonic Antigen ; Cell Adhesion Molecules ; GPI-Linked Proteins ; Histocompatibility Antigens Class II ; RNA, Ribosomal ; invariant chain
Language	English
Publishing date	2016-03-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2041484-5
ISSN	1471-2105 ; 1471-2105
ISSN (online)	1471-2105
ISSN	1471-2105
DOI	10.1186/s12859-016-0982-0
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Lateral gene transfer between prokaryotes and eukaryotes.

Sieber, Karsten B / Bromley, Robin E / Dunning Hotopp, Julie C

Experimental cell research

2017 Volume 358, Issue 2, Page(s) 421–426

Abstract: Lateral gene transfer (LGT) is an all-encompassing term for the movement of DNA between diverse organisms. LGT is synonymous with horizontal gene transfer, and the terms are used interchangeably throughout the scientific literature. While LGT has been ... ...

Abstract	Lateral gene transfer (LGT) is an all-encompassing term for the movement of DNA between diverse organisms. LGT is synonymous with horizontal gene transfer, and the terms are used interchangeably throughout the scientific literature. While LGT has been recognized within the bacteria domain of life for decades, inter-domain LGTs are being increasingly described. LGTs between bacteria and complex multicellular organisms are of interest because they challenge the long-held dogma that such transfers could only occur in closely-related, single-celled organisms. Scientists will continue to challenge our understanding of LGT as we sequence more, diverse organisms, as we sequence more endosymbiont-colonized arthropods, and as we continue to appreciate LGT events, both young and old.
MeSH term(s)	Animals ; Bacteria/genetics ; Eukaryota/genetics ; Evolution, Molecular ; Gene Transfer, Horizontal/genetics ; Gene Transfer, Horizontal/physiology ; Humans ; Mitochondria/metabolism ; Prokaryotic Cells/cytology
Language	English
Publishing date	2017-02-09
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	1493-x
ISSN	1090-2422 ; 0014-4827
ISSN (online)	1090-2422
ISSN	0014-4827
DOI	10.1016/j.yexcr.2017.02.009
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Article ; Online: Network and pathway expansion of genetic disease associations identifies successful drug targets.

MacNamara, Aidan / Nakic, Nikolina / Amin Al Olama, Ali / Guo, Cong / Sieber, Karsten B / Hurle, Mark R / Gutteridge, Alex

Scientific reports

2020 Volume 10, Issue 1, Page(s) 20970

Abstract: Genetic evidence of disease association has often been used as a basis for selecting of drug targets for complex common diseases. Likewise, the propagation of genetic evidence through gene or protein interaction networks has been shown to accurately ... ...

Abstract	Genetic evidence of disease association has often been used as a basis for selecting of drug targets for complex common diseases. Likewise, the propagation of genetic evidence through gene or protein interaction networks has been shown to accurately infer novel disease associations at genes for which no direct genetic evidence can be observed. However, an empirical test of the utility of combining these approaches for drug discovery has been lacking. In this study, we examine genetic associations arising from an analysis of 648 UK Biobank GWAS and evaluate whether targets identified as proxies of direct genetic hits are enriched for successful drug targets, as measured by historical clinical trial data. We find that protein networks formed from specific functional linkages such as protein complexes and ligand-receptor pairs are suitable for even naïve guilt-by-association network propagation approaches. In addition, more sophisticated approaches applied to global protein-protein interaction networks and pathway databases, also successfully retrieve targets enriched for clinically successful drug targets. We conclude that network propagation of genetic evidence can be used for drug target identification.
MeSH term(s)	Drug Delivery Systems ; Gene Regulatory Networks ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Hyperlipidemias/genetics ; Models, Genetic ; Molecular Targeted Therapy ; Signal Transduction/genetics
Language	English
Publishing date	2020-12-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-77847-9
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Article ; Online: A review of bacteria-animal lateral gene transfer may inform our understanding of diseases like cancer.

Robinson, Kelly M / Sieber, Karsten B / Dunning Hotopp, Julie C

PLoS genetics

2013 Volume 9, Issue 10, Page(s) e1003877

Abstract: Lateral gene transfer (LGT) from bacteria to animals occurs more frequently than was appreciated prior to the advent of genome sequencing. In 2007, LGT from bacterial Wolbachia endosymbionts was detected in ~33% of the sequenced arthropod genomes using a ...

Abstract	Lateral gene transfer (LGT) from bacteria to animals occurs more frequently than was appreciated prior to the advent of genome sequencing. In 2007, LGT from bacterial Wolbachia endosymbionts was detected in ~33% of the sequenced arthropod genomes using a bioinformatic approach. Today, Wolbachia/host LGT is thought to be widespread and many other cases of bacteria-animal LGT have been described. In insects, LGT may be more frequently associated with endosymbionts that colonize germ cells and germ stem cells, like Wolbachia endosymbionts. We speculate that LGT may occur from bacteria to a wide variety of eukaryotes, but only becomes vertically inherited when it occurs in germ cells. As such, LGT may happen routinely in somatic cells but never become inherited or fixed in the population. Lack of inheritance of such mutations greatly decreases our ability to detect them. In this review, we propose that such noninherited bacterial DNA integration into chromosomes in human somatic cells could induce mutations leading to cancer or autoimmune diseases in a manner analogous to mobile elements and viral integrations.
MeSH term(s)	Animals ; Chromosomes/genetics ; Chromosomes/microbiology ; DNA, Bacterial/genetics ; Gene Transfer, Horizontal/genetics ; Humans ; Interspersed Repetitive Sequences ; Neoplasms/genetics ; Neoplasms/microbiology ; Neoplasms/virology ; Phylogeny ; Symbiosis/genetics ; Wolbachia/genetics
Chemical Substances	DNA, Bacterial
Language	English
Publishing date	2013-10-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1003877
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Article ; Online: Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

Thomas W. Winkler / Humaira Rasheed / Alexander Teumer / Mathias Gorski / Bryce X. Rowan / Kira J. Stanzick / Laurent F. Thomas / Adrienne Tin / Anselm Hoppmann / Audrey Y. Chu / Bamidele Tayo / Chris H. L. Thio / Daniele Cusi / Jin-Fang Chai / Karsten B. Sieber / Katrin Horn / Man Li / Markus Scholz / Massimiliano Cocca /

Matthias Wuttke / Peter J. van der Most / Qiong Yang / Sahar Ghasemi / Teresa Nutile / Yong Li / Giulia Pontali / Felix Günther / Abbas Dehghan / Adolfo Correa / Afshin Parsa / Agnese Feresin / Aiko P. J. de Vries / Alan B. Zonderman / Albert V. Smith / Albertine J. Oldehinkel / Alessandro De Grandi / Alexander R. Rosenkranz / Andre Franke / Andrej Teren / Andres Metspalu / Andrew A. Hicks / Andrew P. Morris / Anke Tönjes / Anna Morgan / Anna I. Podgornaia / Annette Peters / Antje Körner / Anubha Mahajan / Archie Campbell / Barry I. Freedman

Communications Biology, Vol 5, Iss 1, Pp 1-

2022 Volume 20

Abstract: A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease. ...

Abstract	A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Integrated Functional Genomic Analysis Enables Annotation of Kidney Genome-Wide Association Study Loci.

Journal of the American Society of Nephrology : JASN

2019 Volume 30, Issue 3, Page(s) 421–441

Abstract: Background: Linking genetic risk loci identified by genome-wide association studies (GWAS) to their causal genes remains a major challenge. Disease-associated genetic variants are concentrated in regions containing regulatory DNA elements, such as ... ...

Abstract	Background: Linking genetic risk loci identified by genome-wide association studies (GWAS) to their causal genes remains a major challenge. Disease-associated genetic variants are concentrated in regions containing regulatory DNA elements, such as promoters and enhancers. Although researchers have previously published DNA maps of these regulatory regions for kidney tubule cells and glomerular endothelial cells, maps for podocytes and mesangial cells have not been available. Methods: We generated regulatory DNA maps (DNase-seq) and paired gene expression profiles (RNA-seq) from primary outgrowth cultures of human glomeruli that were composed mainly of podocytes and mesangial cells. We generated similar datasets from renal cortex cultures, to compare with those of the glomerular cultures. Because regulatory DNA elements can act on target genes across large genomic distances, we also generated a chromatin conformation map from freshly isolated human glomeruli. Results: We identified thousands of unique regulatory DNA elements, many located close to transcription factor genes, which the glomerular and cortex samples expressed at different levels. We found that genetic variants associated with kidney diseases (GWAS) and kidney expression quantitative trait loci were enriched in regulatory DNA regions. By combining GWAS, epigenomic, and chromatin conformation data, we functionally annotated 46 kidney disease genes. Conclusions: We demonstrate a powerful approach to functionally connect kidney disease-/trait-associated loci to their target genes by leveraging unique regulatory DNA maps and integrated epigenomic and genetic analysis. This process can be applied to other kidney cell types and will enhance our understanding of genome regulation and its effects on gene expression in kidney disease.
Language	English
Publishing date	2019-02-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2018030309
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Article ; Online: Bacteria-human somatic cell lateral gene transfer is enriched in cancer samples.

Riley, David R / Sieber, Karsten B / Robinson, Kelly M / White, James Robert / Ganesan, Ashwinkumar / Nourbakhsh, Syrus / Dunning Hotopp, Julie C

PLoS computational biology

2013 Volume 9, Issue 6, Page(s) e1003107

Abstract: ... that such integrations are detected more frequently in (a) tumors than normal samples, (b) RNA than DNA samples, and (c ...

Abstract	There are 10× more bacterial cells in our bodies from the microbiome than human cells. Viral DNA is known to integrate in the human genome, but the integration of bacterial DNA has not been described. Using publicly available sequence data from the human genome project, the 1000 Genomes Project, and The Cancer Genome Atlas (TCGA), we examined bacterial DNA integration into the human somatic genome. Here we present evidence that bacterial DNA integrates into the human somatic genome through an RNA intermediate, and that such integrations are detected more frequently in (a) tumors than normal samples, (b) RNA than DNA samples, and (c) the mitochondrial genome than the nuclear genome. Hundreds of thousands of paired reads support random integration of Acinetobacter-like DNA in the human mitochondrial genome in acute myeloid leukemia samples. Numerous read pairs across multiple stomach adenocarcinoma samples support specific integration of Pseudomonas-like DNA in the 5'-UTR and 3'-UTR of four proto-oncogenes that are up-regulated in their transcription, consistent with conversion to an oncogene. These data support our hypothesis that bacterial integrations occur in the human somatic genome and may play a role in carcinogenesis. We anticipate that the application of our approach to additional cancer genome projects will lead to the more frequent detection of bacterial DNA integrations in tumors that are in close proximity to the human microbiome.
MeSH term(s)	Bacteria/genetics ; Bacteria/isolation & purification ; Base Sequence ; DNA, Bacterial/genetics ; Gene Transfer, Horizontal ; Genes, Bacterial ; Genome, Human ; Humans ; Molecular Sequence Data ; Neoplasms/genetics ; Neoplasms/metabolism ; Sequence Homology, Nucleic Acid
Chemical Substances	DNA, Bacterial
Language	English
Publishing date	2013-06-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1003107
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Article ; Online: Bacteria-human somatic cell lateral gene transfer is enriched in cancer samples.

David R Riley / Karsten B Sieber / Kelly M Robinson / James Robert White / Ashwinkumar Ganesan / Syrus Nourbakhsh / Julie C Dunning Hotopp

PLoS Computational Biology, Vol 9, Iss 6, p e

2013 Volume 1003107

Abstract: ... that such integrations are detected more frequently in (a) tumors than normal samples, (b) RNA than DNA samples, and (c ...

Abstract	There are 10× more bacterial cells in our bodies from the microbiome than human cells. Viral DNA is known to integrate in the human genome, but the integration of bacterial DNA has not been described. Using publicly available sequence data from the human genome project, the 1000 Genomes Project, and The Cancer Genome Atlas (TCGA), we examined bacterial DNA integration into the human somatic genome. Here we present evidence that bacterial DNA integrates into the human somatic genome through an RNA intermediate, and that such integrations are detected more frequently in (a) tumors than normal samples, (b) RNA than DNA samples, and (c) the mitochondrial genome than the nuclear genome. Hundreds of thousands of paired reads support random integration of Acinetobacter-like DNA in the human mitochondrial genome in acute myeloid leukemia samples. Numerous read pairs across multiple stomach adenocarcinoma samples support specific integration of Pseudomonas-like DNA in the 5'-UTR and 3'-UTR of four proto-oncogenes that are up-regulated in their transcription, consistent with conversion to an oncogene. These data support our hypothesis that bacterial integrations occur in the human somatic genome and may play a role in carcinogenesis. We anticipate that the application of our approach to additional cancer genome projects will lead to the more frequent detection of bacterial DNA integrations in tumors that are in close proximity to the human microbiome.
Keywords	Biology (General) ; QH301-705.5
Subject code	612
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Do bacteria shape the soil structure by EPS production?

Bettermann, Antje / Zethof, Jeroen / Vogel, Cordula / Rühmann, Broder / Sieber, Volker / Kalbitz, Karsten / Smalla, Kornelia

2018

Keywords	Text ; abstract_or_summary ; ddc:630
Language	English
Publishing country	de
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Alexander Teumer / Yong Li / Sahar Ghasemi / Bram P. Prins / Matthias Wuttke / Tobias Hermle / Ayush Giri / Karsten B. Sieber / Chengxiang Qiu / Holger Kirsten / Adrienne Tin / Audrey Y. Chu / Nisha Bansal / Mary F. Feitosa / Lihua Wang / Jin-Fang Chai / Massimiliano Cocca / Christian Fuchsberger / Mathias Gorski /

Anselm Hoppmann / Katrin Horn / Man Li / Jonathan Marten / Damia Noce / Teresa Nutile / Sanaz Sedaghat / Gardar Sveinbjornsson / Bamidele O. Tayo / Peter J. van der Most / Yizhe Xu / Zhi Yu / Lea Gerstner / Johan Ärnlöv / Stephan J. L. Bakker / Daniela Baptista / Mary L. Biggs / Eric Boerwinkle / Hermann Brenner / Ralph Burkhardt / Robert J. Carroll / Miao-Li Chee / Miao-Ling Chee / Mengmeng Chen / Ching-Yu Cheng / James P. Cook / Josef Coresh / Tanguy Corre / John Danesh / Martin H. de Borst / Alessandro De Grandi

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 19

Abstract: Urinary albumin-to-creatinine ratio (UCAR) is associated with various clinical outcomes such as kidney disease and cardiovascular disease. Here, the authors report genome-wide meta-analysis in over 500,000 individuals and find 68 UACR loci, followed by ... ...

Abstract	Urinary albumin-to-creatinine ratio (UCAR) is associated with various clinical outcomes such as kidney disease and cardiovascular disease. Here, the authors report genome-wide meta-analysis in over 500,000 individuals and find 68 UACR loci, followed by statistical fine-mapping, gene prioritization and experimental validation in flies.
Keywords	Science ; Q
Language	English
Publishing date	2019-09-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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