Human Genetic Adaptation to High Altitudes: Current Status and Future Prospects

Abstract

The question of whether human populations have adapted genetically to high altitude has been of interest since studies began there in the early 1900s. Initially there was debate as to whether genetic adaptation to high altitude has taken place based, in part, on disciplinary orientation and the sources of evidence being considered. Studies centered on short-term responses, termed acclimatization, and the developmental changes occurring across lifetimes. A paradigm shift occurred with the advent of single nucleotide polymorphism (SNP) technologies and statistical methods for detecting evidence of natural selection, resulting in an exponential rise in the number of publications reporting genetic adaptation. Reviewed here are the various kinds of evidence by which adaptation to high altitude has been assessed and which have led to widespread acceptance of the idea that genetic adaptation to high altitude has occurred. While methodological and other challenges remain for determining the specific gene or genes involved and the physiological mechanisms by which they are exerting their effects, considerable progress has been realized as shown by recent studies in Tibetans, Andeans and Ethiopians. Further advances are anticipated with the advent of new statistical methods, whole-genome sequencing and other molecular techniques for finer-scale genetic mapping, and greater intradisciplinary and interdisciplinary collaboration to identify the functional consequences of the genes or gene regions implicated and the time scales involved.

Keywords: AMPK; HIF; evolution; fetal growth; pregnancy.

Figure 1

High-altitude (>2500 m or 8250 ft) regions of the world where human populations permanently reside and approximate numbers of residents (Jarvis et al., 2008; Moore et al., 1998b).

Figure 2

The O₂ transport system is comprised of two pumps (the lungs and the heart) and two diffusion steps. The lungs bring in O₂ from the atmosphere and the heart pumps it via the blood throughout the organism. O₂ diffuses across the alveolar membrane to enter the blood where it is reversibly bound to hemoglobin, and then diffuses from the blood into cells where it is consumed in the mitochondria to generate chemical energy in the form of adenosine triphosphate (ATP).

Figure 3

Physiological adaptation increases with time. The changes in the various components of the O₂ transport system that occur within minutes to days or months are termed acclimatization, those occurring during the period of growth and development are referred to as developmental responses, and those taking place across generations as genetic adaptation. Newcomers are acclimatized European or other persons of low-altitude origin and Natives are Andeans or Tibetans (see (Beall, 2007; Gilbert-Kawai et al., 2014; Moore et al., 1998b) for review). Abbreviations: V_E = ventilation, SaO₂ = arterial O₂ saturation, Hb = hemoglobin concentration, C.O. = cardiac output.

Figure 4

Panel A summarizes birth weight data from a total of 305,935 infants from 15 studies in which birth weights were collected by the same investigator at both low (sea level) and high altitude (~3600 m) and five (5) in which birth weights collected at one altitude are compared to the group value at the other altitude. Lines connect the low- and high-altitude data obtained in a single study and points show mean values (with bars showing the standard error of the mean) at either low or high altitude. Panel B shows resting pulmonary arterial pressures in response to decreasing arterial p0₂ as summarized for young male residents of European descent residing at high altitudes in North America and for young Andean men. Values are also shown from studies in young Tibetan men and, as extrapolated, young male Ethiopian high-altitude residents. Panel C presents data for the prevalence of chronic mountain sickness (CMS) as reported for persons of various ancestry groups residing at the altitudes shown. Figure is adapted from (Niermeyer et al., 2015) where the original references may be found.

Figure 5

The number of studies identified using the search term “genetic adaptation to high altitude” in the National Library of Medicine’s PubMed data base has risen exponentially. Shown are the number of studies over 5-year intervals from 1975 through 2015.