Deep-sea vents are the light-independent, highly productive ecosystems driven primarily by chemolithoautotrophic microorganisms, in particular by -Proteobacteria phylogenetically related to important pathogens. We analyzed genomes of two deep-sea vent -Proteobacteria strains, Sulfurovum sp. NBC37-1 and Nitratiruptor sp. SB155-2, which provide insights not only into their unusual niche on the seafloor, but also into the origins of virulence in their pathogenic relatives, Helicobacter and Campylobacter species. The deep-sea vent -proteobacterial genomes encode for multiple systems for respiration, sensing and responding to environment, and detoxifying heavy metals, reflecting their adaptation to the deep-sea vent environment. Although they are nonpathogenic, both deep-sea vent -Proteobacteria share many virulence genes with pathogenic -Proteobacteria, including genes for virulence factor MviN, hemolysin, invasion antigen CiaB, and the N-linked glycosylation gene cluster. In addition, some virulence determinants (such as the H2-uptake hydrogenase) and genomic plasticity of the pathogenic descendants appear to have roots in deep-sea vent -Proteobacteria. These provide ecological advantages for hydrothermal vent -Proteobacteria who thrive in their deep-sea habitat and are essential for both the efficient colonization and persistent infections of their pathogenic relatives. Our comparative genomic analysis suggests that there are previously unrecognized evolutionary links between important human/animal pathogens and their nonpathogenic, symbiotic, chemolithoautotrophic deepsea relatives.-Proteobacteria ͉ comparative microbial genomics ͉ deep-sea hydrothermal vent ͉ pathogenesis ͉ symbiosis D eep-sea hydrothermal vents are areas on the sea floor of high biological productivity fueled primarily by chemosynthesis. Most of the invertebrates thrive in this hostile environment through their relationship with chemolithoautotrophic proteobacterial symbionts. It has become evident that by far the most prevalent microorganisms at deep-sea vents belong to the -Proteobacteria (1, 2). They often account for Ͼ90% of total rRNA in various hydrothermal habitats as both epi-or endosymbionts of hydrothermal vent invertebrates (3-6) and freeliving organisms associated with actively venting sulfide deposits and in areas where vent fluids and seawater mix [supporting information (SI) Fig. 5] (7-9). Until recently, the metabolic role of these key players in the deep-sea vent ecosystem has remained unknown because of their resistance to cultivation. However, in a recent breakthrough, pure cultures of deep-sea ventProteobacteria provided evidence that the majority of these microbes were mesophilic to thermophilic (capable of growth at 4°C to 70°C) chemolithoautotrophs capable of oxidation of hydrogen and sulfur compounds coupled with the reduction of oxygen, nitrate, and sulfur compounds (9-11). These deep-sea vent -Proteobacteria diverge before their pathogenic relatives in small-subunit rRNA gene trees, and thus comparative genomics can pr...