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We investigated the evolutionary history of the complement system and of bacterial\u2010encoded complement\u2010interacting proteins. Complement components targeted by several pathogens evolved under strong selective pressure in primates, with selection acting on residues at the contact interface with microbial\/viral proteins. Positively selected sites in <jats:styled-content style=\"fixed-case\">CFH<\/jats:styled-content> and C4<jats:styled-content style=\"fixed-case\">BPA<\/jats:styled-content> account for the human specificity of gonococcal infection. Bacterial interactors, evolved adaptively as well, with selected sites located at interaction surfaces with primate complement proteins. These results epitomize the expectation under a genetic conflict scenario whereby the host's and the pathogen's genes evolve within binding avoidance\u2010binding seeking dynamics. <jats:italic>In silico<\/jats:italic> mutagenesis and protein\u2013protein docking analyses supported this by showing that positively selected sites, both in the host's and in the pathogen's interacting partner, modulate binding.<\/jats:p>","DOI":"10.1111\/mec.13558","type":"journal-article","created":{"date-parts":[[2016,2,2]],"date-time":"2016-02-02T20:47:28Z","timestamp":1454446048000},"page":"1324-1339","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["The mammalian complement system as an epitome of host\u2013pathogen genetic conflicts"],"prefix":"10.1111","volume":"25","author":[{"given":"Rachele","family":"Cagliani","sequence":"first","affiliation":[{"name":"Bioinformatics Scientific Institute IRCCS E. 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