Genetic insights into the peoples who shaped the American continent

The initial peopling of America left a deep genetic legacy in Indigenous peoples and their admixed descendants. This narrative review recenters studies involving Indigenous populations and, inspired by the work of Francisco M. Salzano and Darcy Ribeiro's historical and cultural framework, adopts the working notions of "witness," "introduced," "transplanted," and "new" genetic signatures. We first clarify terminology to avoid neocolonial bias, using America to denote the continent and Native American to refer to all Indigenous peoples of America, and then synthesize the literature on initial peopling, post-contact demography, and natural selection, with particular emphasis on Brazil. We also present an illustrative example drawn from ongoing research conducted by our group, using genome editing to investigate a candidate adaptive allele in the context of high-altitude adaptation. Finally, we connect evolutionary history to contemporary health, highlighting mitonuclear interactions, dietary transitions, and pathogen exposures that may modulate disease risk, with implications for precision public health. Collectively, this review showcases ancestry-aware approaches tailored to Native American contexts and demonstrates why models developed elsewhere should not be uncritically extrapolated to America, advancing a continent-wide, Brazil-anchored perspective on Indigenous resilience and scientific significance.