Genetic Variations in the TP53 Pathway in Native Americans Strongly Suggest Adaptation to the High Altitudes of the Andes.

Vanessa Cristina Jacovas,Patricia Ashton-Prolla,Orlando Peréz,Francisco Mauro Salzano,Virginia Ramallo,José Raul Sandoval,Alberto Salazar-Granara,Rafael Bisso-Machado,Maria Cátira Bortolini,Mercedes Villena,Soledad De Azevedo,Maria Luiza Petzl-Erler,Jean-Michel Dugoujon,Diego Luiz Rovaris,Gabriel Souza Macedo

doi:10.1371/journal.pone.0137823

Abstract

The diversity of the five single nucleotide polymorphisms located in genes of the TP53 pathway (TP53, rs1042522; MDM2, rs2279744; MDM4, rs1563828; USP7, rs1529916; and LIF, rs929271) were studied in a total of 282 individuals belonging to Quechua, Aymara, Chivay, Cabanaconde, Yanke, Taquile, Amantani, Anapia, Uros, Guarani Ñandeva, and Guarani Kaiowá populations, characterized as Native American or as having a high level (> 90%) of Native American ancestry. In addition, published data pertaining to 100 persons from five other Native American populations (Surui, Karitiana, Maya, Pima, and Piapoco) were analyzed. The populations were classified as living in high altitude (≥ 2,500 m) or in lowlands (< 2,500 m). Our analyses revealed that alleles USP7-G, LIF-T, and MDM2-T showed significant evidence that they were selected for in relation to harsh environmental variables related to high altitudes. Our results show for the first time that alleles of classical TP53 network genes have been evolutionary co-opted for the successful human colonization of the Andes.

Highlights

The product of the TP53 gene is a transcription factor (p53) that activates or represses a large number of target genes that regulate a broad array of extremely important cellular functions, such as cell cycle, metabolism, DNA repair, senescence, and apoptosis
Our analyses revealed that alleles USP7-G, LIF-T, and MDM2-T showed significant evidence that they were selected for in relation to harsh environmental variables related to high altitudes
Special issues in scientific journals, dedicated to these topics, have been published. This overwhelming number of studies contrasts with the rarity of studies of an evolutionary context, which are indispensable for explaining differences in the TP53 network allele distributions along human populations, which often cannot be understood as a result of stochastic processes

Summary

Introduction

The product of the TP53 gene is a transcription factor (p53) that activates or represses a large number of target genes that regulate a broad array of extremely important cellular functions, such as cell cycle, metabolism, DNA repair, senescence, and apoptosis. This factor is essential for maintaining genome integrity [1]. The TP53 gene is constitutively expressed in all cell types, but p53 does not accumulate in non-stressed cells, since it is rapidly degraded by the proteasome via ubiquitination [4, 5]. The p53 levels increase in response to various stress signals, such as UV irradiation, low oxygen concentrations (hypoxia), and exposure to high temperatures [6, 7, 8, 9]

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Results

Conclusion