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Abstract The increasing availability of next generation sequencing techniques in recent decades has led to new discoveries, and sometimes the redefinition of conventional hypotheses, regarding many complex human‐pathogen evolutionary relationships. These new discoveries are particularly poignant in studies of the Americas, where research into Indigenous ancestry and migration has historically been ignored. As a result, conventional hypotheses regarding the origin of global pathogens like tuberculosis, syphilis, and malaria in the Americas and their spread within the continents have been mischaracterized. Fortunately, recent studies using molecular techniques have now superseded these missteps, which were often based in anecdotal accounts from colonial missionary reports rather than rigorous scientific study. It is now clear that there was not a unidirectional pipeline of pathogen introduction that began with European contact; instead, a rich and varied microbiological landscape already existed in the Americas. This synthesis of research regarding the origin and spread of pathogens in the Americas examines the scope of this changing perception within the fields of paleogenomics and paleomicrobiology.
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