Abstract: Lateral gene transfer (LGT), the transfer of DNA between diverse organisms, allows organisms to acquire new genes and phenotypes. Most described LGT events occur within a single domain of life with most cases described in eubacteria. More infrequently, interdomain LGT occurs where DNA moves between two domains of life (e.g. between eubacteria and eukaryotes). Interdomain LGT may have two medically important implications. About 120 million people are afflicted with the filariasis and an estimated 18% of the world?s population is at risk for developing the disease. Filarial nematodes (the causative agents) are known to acquire DNA from their bacterial endosymbionts, Wolbachia. Although in some nematodes Wolbachia are obligate endosymbionts, other lineages lack Wolbachia. Can lateral gene transfer facilitate endosymbiont loss? If so, can current antibiotic therapies drive endosymbiont loss? Can laterally transferred genes serve as alternative, novel drug targets? Our experiments aim to better characterize the extent and diversity of such transfers in filarial nematodes and to assess their functional significance. The second case involves LGT from bacteria to humans. Approximately 90% of the cells in the human body are commensal and pathogenic bacteria. Thus, our mucosal cells are bathed in bacterial DNA. Does this bacterial DNA get incorporated into the chromosomes of our somatic cells? Could such integrations lead to gene disruptions in somatic cells analogous to disease causing mutations resulting from insertion of retroviruses, transposons, or mitochondrial DNA? The American Cancer Society estimates that 10% of cancers in developed countries are linked to infections, although many of the mechanisms are unknown. Could proto- oncogene disruption by bacterial DNA lead to development of bacteria-associated cancers? Through a thorough analysis of available sequencing data, we have already identified potential cases of bacteria-human lateral gene transfer. We propose a more comprehensive survey as well as experiments aimed at validating such transfers. Public Health Relevance: The transfer of bacterial DNA to vertebrate animal genomes (including humans) may have important implications in (a) the control and treatment of human lymphatic filariasis and (b) mutating human genes leading to important diseases like cancer. The experiments proposed aim at a more comprehensive search for such events, validation of identified transfers, and functional characterization.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
1DP2OD007372-01
Application #
7981623
Study Section
Special Emphasis Panel (ZGM1-NDIA-O (01))
Program Officer
Basavappa, Ravi
Project Start
2010-09-30
Project End
2015-06-30
Budget Start
2010-09-30
Budget End
2015-06-30
Support Year
1
Fiscal Year
2010
Total Cost
$2,250,000
Indirect Cost
Name
University of Maryland Baltimore
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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Dunning Hotopp, Julie C; Slatko, Barton E; Foster, Jeremy M (2017) Targeted Enrichment and Sequencing of Recent Endosymbiont-Host Lateral Gene Transfers. Sci Rep 7:857
Sieber, Karsten B; Bromley, Robin E; Dunning Hotopp, Julie C (2017) Lateral gene transfer between prokaryotes and eukaryotes. Exp Cell Res 358:421-426
Cotton, James A; Bennuru, Sasisekhar; Grote, Alexandra et al. (2016) The genome of Onchocerca volvulus, agent of river blindness. Nat Microbiol 2:16216
Sieber, Karsten B; Gajer, Pawel; Dunning Hotopp, Julie C (2016) Modeling the integration of bacterial rRNA fragments into the human cancer genome. BMC Bioinformatics 17:134
Kumar, Nikhil; Lin, Mingqun; Zhao, Xuechu et al. (2016) Efficient Enrichment of Bacterial mRNA from Host-Bacteria Total RNA Samples. Sci Rep 6:34850
Dunning Hotopp, Julie C; Estes, Anne M (2014) Biology wars: the eukaryotes strike back. Cell Host Microbe 16:701-3
Klasson, Lisa; Kumar, Nikhil; Bromley, Robin et al. (2014) Extensive duplication of the Wolbachia DNA in chromosome four of Drosophila ananassae. BMC Genomics 15:1097
Tallon, Luke J; Liu, Xinyue; Bennuru, Sasisekhar et al. (2014) Single molecule sequencing and genome assembly of a clinical specimen of Loa loa, the causative agent of loiasis. BMC Genomics 15:788
Robinson, Kelly M; Dunning Hotopp, Julie C (2014) Mobile elements and viral integrations prompt considerations for bacterial DNA integration as a novel carcinogen. Cancer Lett 352:137-44

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