LAUSR

Humans inhabit an incredible range of environments across the globe, from arid deserts to frozen tundra, tropical rainforests, and some of the highest peaks on Earth. Indigenous populations that have lived in these extreme environments for thousands of years have adapted to confront the unique challenges that they present. Approximately 2% of people worldwide live permanently at high altitudes of over 2,500 m (1.5 miles), where oxygen is sparse, UV radiation is high, and temperatures are low. Native Andeans, Tibetans, Mongolians, and Ethiopians exhibit adaptations that improve their ability to survive such conditions. Andeans, for example, display increased chest circumference, elevated oxygen saturation, and a low hypoxic ventilatory response, enabling them to thrive at exceptionally high elevations. Although it is clear that there is a genetic component to these adaptations, exposure to high altitudes during early development is also known to play a role, although the underlying mechanism for this remains poorly understood. In a new study in Genome Biology and Evolution titled “Genome-Wide Epigenetic Signatures of Adaptive Developmental Plasticity in the Andes,” Ainash Childebayeva, a doctoral student at the University of Michigan at the time of the study, and her colleagues sought to answer this question by studying members of the Peruvian Quechua, who live at high altitudes in the Andes. Their work reveals that mechanisms like DNA methylation may be involved in adaptation to high altitudes, and their findings have potential implications for the long-term health of those living at such heights (Childebayeva et al. 2021). Adaptations are typically thought of as genetic changes leading to the manifestation of a certain physiological trait, or phenotype. In a phenomenon known as developmental adaptation or adaptive plasticity, however, a certain genetic background merely serves as the prerequisite, and exposure to a certain environmental stimulus—generally during early development—is further required for the trait to be expressed. According to Childebayeva and co-authors, “There are several examples of Andean high-altitude adaptive phenotypes where developmental adaptation plays a key role in the manifestation of the adult phenotype.” For example, Andeans who are lifelong residents of high altitude display greater lung volumes than those of Andean ancestry who were born and raised at sea level. To reveal the biological mechanisms enabling this interplay between environment, development, and genetics, Childebayeva and her collaborators focused on epigenetics, the study of modifications that alter the DNA molecule without changing the order of nucleotides. Methylation is one type of epigenetic mark in which a methyl group is added to the cytosine nucleotides contained in DNA. Methylation suppresses the transcription of associated genes, thereby influencing an organism’s biology by regulating protein expression. Importantly, DNA methylation patterns are established prenatally and in the early postnatal period, after which they remain relatively stable, providing an early developmental window during which environmental exposures may help shape an individual’s phenotype. The Quechua, an indigenous group native to Peru, have lived on the Andean Altiplano at an average elevation of 12,000 ft (over 3,600 m) for 11,000 years (fig. 1). In order to investigate the potential role of epigenetics in developmental adaptation to high altitudes, the study’s authors evaluated DNA methylation patterns across the genome in three groups of Peruvian Quechua with different altitude exposures: highaltitude Quechua, who had lifetime exposure to high altitude; migrant Quechua, who were born at high altitude but subsequently moved to low altitudes; and low-altitude Quechua, who were lifelong residents of low altitude, despite the fact that their parents and both sets of grandparents were of highland Quechua ancestry. By comparing which DNA positions were methylated in high-altitude and migrant Quechua, who shared early childhood exposure to high altitudes, with those methylated in low-altitude Quechua, who shared ancestry but were not exposed in childhood, the authors were able to untangle the effects of developmental exposure to altitude and genetics.