Reconstructing the Origin and Demographic Expansion of the TP53 p.R337H Founder Variant in Brazil

The TP53 p.R337H variant is a well-characterized founder mutation with an unusually high prevalence in Brazil, particularly in the South and Southeast regions, where it affects approximately one in 300 individuals. It is recurrently associated with pediatric adrenocortical tumors and malignancies within the Li-Fraumeni syndrome spectrum but exhibits markedly incomplete penetrance, suggesting the influence of additional genetic and/or environmental modifiers. Although TP53 p.R337H occurs at low frequencies in the Iberian Peninsula, its origin, timing, and dissemination pattern within Brazil have remained unresolved.

We integrated population-genetic inference with historical demographic modeling to reconstruct the introduction and expansion of the TP53 p.R337H in Brazil.

Our analyses support a founder effect arising from a single founding event of European origin during the early Portuguese colonization period. The subsequent geographic dissemination of the variant parallels historical population growth, particularly in southern Brazil. The striking regional enrichment can be explained without invoking multiple introduction events or complex migratory scenarios.

These findings clarify the evolutionary and demographic history of TP53 p.R337H in Brazil and underscore its founder effect origin during European colonization.

This study highlights the value of integrating population genetics with historical data to elucidate the spread of medically relevant founder variants. Understanding the dissemination of TP53 p.R337H will enhance public health planning and genetic counseling strategies in Brazil. See related In the Spotlight, p. 187.