Impact of Bacterial-Animal Lateral Gene Transfer on Human Health

描述(由申请人提供) 摘要：侧向基因转移(LGT)是不同生物体之间的DNA转移，使生物体获得新的基因和表型。大多数被描述的LGT事件发生在生命的单一领域内，大多数病例发生在真细菌中。更少见的是，当DNA在生命的两个领域之间(例如在真细菌和真核生物之间)移动时，就会发生域间LGT。跨域LGT可能有两个重要的医学意义。约有1.2亿人患有丝虫病，据估计，全世界约有18%的S人口面临罹患丝虫病的风险。众所周知，丝虫线虫(病原体)从它们的细菌内共生体沃尔巴克氏菌中获得DNA。虽然在一些线虫中，沃尔巴克氏菌是专性内共生体，但其他线虫谱系中没有沃尔巴克氏菌。横向基因转移能促进内共生菌丢失吗？如果是这样的话，目前的抗生素疗法是否会导致内共生菌的丧失？横向转移的基因可以作为替代的、新的药物靶点吗？我们的实验旨在更好地描述丝虫体内这种转移的程度和多样性，并评估它们的功能意义。第二个病例涉及从细菌到人类的LGT。人体内约90%的细胞是共生菌和致病菌。因此，我们的粘膜细胞沐浴在细菌DNA中。这种细菌DNA会被整合到我们体细胞的染色体中吗？这种整合是否会导致体细胞中的基因中断，就像疾病一样，通过插入逆转录病毒、转座子或线粒体DNA而导致突变？美国癌症协会估计，发达国家有10%的癌症与感染有关，尽管许多机制尚不清楚。细菌DNA对原癌基因的破坏是否会导致细菌相关癌症的发生？通过对现有测序数据的彻底分析，我们已经确定了细菌-人类横向基因转移的潜在案例。我们提议进行一项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转移到脊椎动物基因组(包括人类)可能在(A)控制和治疗人类淋巴丝虫病以及(B)导致癌症等重要疾病的人类基因突变方面具有重要意义。提出的实验旨在更全面地寻找这类事件，验证已识别的转移，并进行功能表征。

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.