Impact of Bacterial-Animal Lateral Gene Transfer on Human Health

细菌-动物横向基因转移对人类健康的影响

• 批准号: 7981623
• 负责人: Julie Dunning Hotopp
• 金额: $ 225万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7981623
• 关键词: American Cancer Society; Animals; Antibiotic Therapy; Bacteria; Bacterial DNA; Bathing; Cells; Chromosomes; DNA; Data; Developed Countries; Development; Disease; Drug Delivery Systems; Eubacterium; Eukaryota; Event; Filariasis; Gene Transfer; Genes; Health; Horizontal Gene Transfer; Human; Human body; Infection; Lead; Life; Link; Malignant Neoplasms; Mitochondrial DNA; Nematoda; Organism; Phenotype; Population; Proto-Oncogenes; Retroviridae; Risk; Somatic Cell; Surveys; Wolbachia; disease-causing mutation; novel; pathogenic bacteria; research study

DESCRIPTION (Provided by the applicant) 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.

描述（由申请人提供） 翻译后摘要：横向基因转移（LGT），不同的生物体之间的DNA转移，允许生物体获得新的基因和表型。大多数描述的LGT事件发生在单个生命领域内，大多数病例在真细菌中描述。更罕见的是，域间LGT发生在DNA在两个生命域之间移动的地方（例如真细菌和真核生物之间）。域间LGT可能具有两个重要的医学意义。大约有1.2亿人患有丝虫病，估计世界人口的18%有患这种疾病的危险。已知丝状线虫（致病因子）从其细菌内共生体Wolbachia获得DNA。虽然在某些线虫中，沃尔巴克氏体是专性内共生体，但其他谱系缺乏沃尔巴克氏体。横向基因转移能促进内共生体的丢失吗？如果是这样的话，目前的抗生素治疗是否会导致内共生体的损失？横向转移基因能否作为替代的新型药物靶点？我们的实验旨在更好地表征丝虫中这种转移的程度和多样性，并评估其功能意义。第二个案例涉及从细菌到人类的LGT。人体中大约90%的细胞是细菌和致病菌。因此，我们的粘膜细胞沐浴在细菌DNA中。这种细菌DNA会被整合到我们的体细胞染色体中吗？这种整合是否会导致体细胞中的基因破坏，类似于逆转录病毒、转座子或线粒体DNA插入导致的疾病突变？美国癌症协会估计，发达国家10%的癌症与感染有关，尽管许多机制尚不清楚。细菌DNA破坏原癌基因会导致细菌相关癌症的发生吗？通过对现有测序数据的全面分析，我们已经确定了细菌-人类横向基因转移的潜在案例。我们提出了一个更全面的调查，以及旨在验证这种转移的实验。 公共卫生相关性：将细菌DNA转移到脊椎动物（包括人类）的基因组中可能在（a）控制和治疗人类淋巴丝虫病和（B）突变导致重要疾病（如癌症）的人类基因方面具有重要意义。提出的实验旨在更全面地搜索这些事件，验证所确定的传输和功能特性。

项目成果

Horizontal gene transfer between bacteria and animals.

• DOI: 10.1016/j.tig.2011.01.005
• 发表时间: 2011-04
• 期刊: TRENDS IN GENETICS
• 影响因子: 11.4
• 作者: Hotopp, Julie C. Dunning

Extensively duplicated and transcriptionally active recent lateral gene transfer from a bacterial Wolbachia endosymbiont to its host filarial nematode Brugia malayi.

• DOI: 10.1186/1471-2164-14-639
• 发表时间: 2013-09-22
• 期刊: BMC genomics
• 影响因子: 4.4
• 作者: Ioannidis P;Johnston KL;Riley DR;Kumar N;White JR;Olarte KT;Ott S;Tallon LJ;Foster JM;Taylor MJ;Dunning Hotopp JC
• 通讯作者: Dunning Hotopp JC

Distinguishing potential bacteria-tumor associations from contamination in a secondary data analysis of public cancer genome sequence data.

在公共癌基因组序列数据的二级数据分析中，区分潜在的细菌肿瘤关联与污染。

• DOI: 10.1186/s40168-016-0224-8
• 发表时间: 2017-01-25
• 期刊: Microbiome
• 影响因子: 15.5
• 作者: Robinson KM;Crabtree J;Mattick JS;Anderson KE;Dunning Hotopp JC
• 通讯作者: Dunning Hotopp JC

Genomics of Loa loa, a Wolbachia-free filarial parasite of humans.

• DOI: 10.1038/ng.2585
• 发表时间: 2013-05
• 期刊: NATURE GENETICS
• 影响因子: 30.8
• 作者: Desjardins, Christopher A.;Cerqueira, Gustavo C.;Goldberg, Jonathan M.;Hotopp, Julie C. Dunning;Haas, Brian J.;Zucker, Jeremy;Ribeiro, Jose M. C.;Saif, Sakina;Levin, Joshua Z.;Fan, Lin;Zeng, Qiandong;Russ, Carsten;Wortman, Jennifer R.;Fink, Doran L.;Birren, Bruce W.;Nutman, Thomas B.
• 通讯作者: Nutman, Thomas B.

Mobile elements and viral integrations prompt considerations for bacterial DNA integration as a novel carcinogen.

移动元件和病毒整合促使人们考虑将细菌 DNA 整合作为一种新型致癌物。

• DOI: 10.1016/j.canlet.2014.05.021
• 发表时间: 2014
• 期刊: Cancer letters
• 影响因子: 9.7
• 作者: Robinson,KellyM;DunningHotopp,JulieC
• 通讯作者: DunningHotopp,JulieC