Tibetan and Andean contrasts in adaptation to high-altitude hypoxia.

High-altitude environments provide natural experimental settings to investigate adaptation to environmental stress. An important evolutionary and functional question is whether sea-level human biology constrains the adaptive response. This paper presents evidence that indigenous populations of the Tibetan and Andean plateaus exhibit quantitatively different responses to hypobaric hypoxic stress. At the same altitude, Tibetan mean resting ventilation and hypoxic ventilatory response were more than one-half standard deviation higher than Andean Aymara means while Tibetan mean oxygen saturation and hemoglobin concentration were more than one standard deviation below the Andean means. Quantitative genetic analyses of the familial patterning of these traits provided indirect evidence of population differences in genes influencing them. The Tibetan and Andean patterns of oxygen transport appear equally effective functionally as evaluated by birthweight and maximal aerobic capacity across a range of altitudes.

Tibetan and Andean patterns of adaptation to high-altitude hypoxia.

Understanding the workings of the evolutionary process in contemporary humans requires linking the evolutionary history of traits with their current genetics and biology. Unusual environments provide natural experimental settings to investigate evolution and adaptation. The example of high-altitude hypoxia illustrates some of the progress and many of the remaining challenges for studies of evolution in contemporary populations. Current studies exemplify the frequently encountered problem of determining whether large, consistent population differences in mean values of a trait reflect genetic differences. In this review I describe 4 quantitative traits that provide evidence that indigenous populations of the Tibetan and Andean plateaus differ in their phenotypic adaptive responses to high-altitude hypoxia. These 4 traits are resting ventilation, hypoxic ventilatory response, oxygen saturation, and hemoglobin concentration. The Tibetan means of the first 2 traits were more than 0.5 standard deviation higher than the Aymara means, whereas the Tibetan means were more than 1 standard deviation lower than the Aymara means for the last 2 traits. Quantitative genetic analyses of within-population variance revealed significant genetic variance in all 4 traits in the Tibetan population but only in hypoxic ventilatory response and hemoglobin concentration in the Aymara population. A major gene for oxygen saturation was detected among the Tibetans. These findings are interpreted as indirect evidence of population genetic differences. It appears that the biological characteristics of sea-level humans did not constrain high-altitude colonists of the 2 plateaus to a single adaptive response. Instead, microevolutionary processes may have operated differently in the geographically separated Tibetan and Andean populations exposed to the same environmental stress. Knowledge of the genetic bases of these traits will be necessary to evaluate these inferences. Future research will likely be directed toward determining whether the population means reflect differences identified at the chromosomal level. Future research will also likely consider the biological pathways and environmental influences linking genotypes to phenotypes, the costs and benefits of the Tibetan and Andean patterns of adaptation, and the question of whether the observed phenotypes are indeed adaptations that enhance Darwinian fitness.

Percent of oxygen saturation of arterial hemoglobin among Bolivian Aymara at 3,900-4,000 m.

A range of variation in percent of oxygen saturation of arterial hemoglobin (SaO2) among healthy individuals at a given high altitude indicates differences in physiological hypoxemia despite uniform ambient hypoxic stress. In populations native to the Tibetan plateau, a significant portion of the variance is attributable to additive genetic factors, and there is a major gene influencing SaO2. To determine whether there is genetic variance in other high-altitude populations, we designed a study to test the hypothesis that additive genetic factors contribute to phenotypic variation in SaO2 among Aymara natives of the Andean plateau, a population geographically distant from the Tibetan plateau and with a long, separate history of high-altitude residence. The average SaO2 of 381 Aymara at 3,900-4,000 m was 92+/-0.15% (SEM) with a range of 84-99%. The average was 2.6% higher than the average SaO2 of a sample of Tibetans at 3,800-4,065 m measured with the same techniques. Quantitative genetic analyses of the Aymara sample detected no significant variance attributable to genetic factors. The presence of genetic variance in SaO2 in the Tibetan sample and its absence in the Aymara sample indicate there is potential for natural selection on this trait in the Tibetan but not the Aymara population.

Hemoglobin concentration of high-altitude Tibetans and Bolivian Aymara.

Elevated hemoglobin concentrations have been reported for high-altitude sojourners and Andean high-altitude natives since early in the 20th century. Thus, reports that have appeared since the 1970s describing relatively low hemoglobin concentration among Tibetan high-altitude natives were unexpected. These suggested a hypothesis of population differences in hematological response to high-altitude hypoxia. A case of quantitatively different responses to one environmental stress would offer an opportunity to study the broad evolutionary question of the origin of adaptations. However, many factors may confound population comparisons. The present study was designed to test the null hypothesis of no difference in mean hemoglobin concentration of Tibetan and Aymara native residents at 3,800-4,065 meters by using healthy samples that were screened for iron deficiency, abnormal hemoglobins, and thalassemias, recruited and assessed using the same techniques. The hypothesis was rejected, because Tibetan males had a significantly lower mean hemoglobin concentration of 15.6 gm/dl compared with 19.2 gm/dl for Aymara males, and Tibetan females had a mean hemoglobin concentration of 14.2 gm/dl compared with 17.8 gm/dl for Aymara females. The Tibetan hemoglobin distribution closely resembled that from a comparable, sea-level sample from the United States, whereas the Aymara distribution was shifted toward 3-4 gm/dl higher values. Genetic factors accounted for a very high proportion of the phenotypic variance in hemoglobin concentration in both samples (0.86 in the Tibetan sample and 0.87 in the Aymara sample). The presence of significant genetic variance means that there is the potential for natural selection and genetic adaptation of hemoglobin concentration in Tibetan and Aymara high-altitude populations.

Ventilation and hypoxic ventilatory response of Tibetan and Aymara high altitude natives.

Newcomers acclimatizing to high altitude and adult male Tibetan high altitude natives have increased ventilation relative to sea level natives at sea level. However, Andean and Rocky Mountain high altitude natives have an intermediate level of ventilation lower than that of newcomers and Tibetan high altitude natives although generally higher than that of sea level natives at sea level. Because the reason for the relative hypoventilation of some high altitude native populations was unknown, a study was designed to describe ventilation from adolescence through old age in samples of Tibetan and Andean high altitude natives and to estimate the relative genetic and environmental influences. This paper compares resting ventilation and hypoxic ventilatory response (HVR) of 320 Tibetans 9-82 years of age and 542 Bolivian Aymara 13-94 years of age, native residents at 3,800-4,065 m. Tibetan resting ventilation was roughly 1.5 times higher and Tibetan HVR was roughly double that of Aymara. Greater duration of hypoxia (older age) was not an important source of variation in resting ventilation or HVR in either sample. That is, contrary to previous studies, neither sample acquired hypoventilation in the age ranges under study. Within populations, greater severity of hypoxia (lower percent of oxygen saturation of arterial hemoglobin) was associated with slightly higher resting ventilation among Tibetans and lower resting ventilation and HVR among Aymara women, although the associations accounted for just 2-7% of the variation. Between populations, the Tibetan sample was more hypoxic and had higher resting ventilation and HVR. Other systematic environmental contrasts did not appear to elevate Tibetan or depress Aymara ventilation. There was more intrapopulation genetic variation in these traits in the Tibetan than the Aymara sample. Thirty-five percent of the Tibetan, but none of the Aymara, resting ventilation variance was due to genetic differences among individuals. Thirty-one percent of the Tibetan HVR, but just 21% of the Aymara, HVR variance was due to genetic differences among individuals. Thus there is greater potential for evolutionary change in these traits in the Tibetans. Presently, there are two different ventilation phenotypes among high altitude natives as compared with sea level populations at sea level: lifelong sustained high resting ventilation and a moderate HVR among Tibetans in contrast with a slightly elevated resting ventilation and a low HVR among Aymara.

Salivary testosterone concentration of Aymara men native to 3600 m.

This paper explores the possibility that variation in the normal physiological range of testosterone concentration modulates men's adaptation to hypobaric high-altitude hypoxia through stimulating haemoglobin production and/or causing respiratory disturbances and exacerbated hypoxaemia during sleep. These effects of testosterone are observed clinically at sea level and have potentially opposing consequences at high altitude, the former perhaps enhancing and the latter diminishing the effectiveness of adaptations to hypoxia. Seventeen young (average age 27 years) and 22 older (average age 57 years) healthy adult high altitude native Aymara men tested at 3600 m have average morning salivary testosterone concentrations of 282 and 241 pmol/l, respectively. The 31 urban men of both age groups have higher testosterone concentrations than the eight rural men and have mean haemoglobin concentrations significantly 0.7-1.0 g/dl higher within the normal high-altitude range, consistent with known effects of testosterone at sea level. Older urban men have slightly more frequent respiratory disturbances during sleep, associated with significantly greater hypoxaemia. There appear to be modest benefits to testosterone concentrations in the upper end of the observed range; however, the direction of these responses towards more haemoglobin production and more hypoxaemia during sleep of older men suggests the hypothesis that very high testosterone concentrations such as those in the upper ranges of sea level values could compromise adaptation to high altitude, particularly among older men.

Hemoglobin levels in a Himalayan high altitude population.

This report presents data on hemoglobin concentrations in a sample of Himalayan high altitude natives measured at their habitual altitude of residence. In this sample of 270 healthy Tibetan adults resident at 3250-3560 m in Upper Chumik , Nepal, the mean hemoglobin concentration is 16.1 +/- 1.2 gm/dl among adult males, 14.4 +/- 1.4 gm/dl among premenopausal and 15.0 +/- 1.1 gm/dl among postmenopausal adult females. 123 of 126 (98%) males, 96 of 100 (96%) premenopausal and 36 of 44 (82%) postmenopausal females have hemoglobin concentrations within two standard deviations of the sea level mean. These data demonstrate that a healthy population may reside at high altitude without the degree of elevation in hemoglobin widely known and cited for Andean highlanders. Comparing published data on mean hemoglobin concentrations of adult Himalayan and Andean samples residing between 3200 m and 4100 m reveals that Himalayan means are systematically lower. This in turn may account for the reported population differences in the prevalence of chronic mountain sickness ( Monge 's disease). It is hypothesized that Himalayan and Andean highlanders represent alternative patterns of high altitude hematological adaptation.

Optimal birthweights in Peruvian populations at high and low altitudes.

This study tests the hypothesis that optimum birthweight for survival is lower among hospital-born infants in Puno, Peru (altitude 3860 m) than that among their counterparts at low altitude in Tacna, Peru (altitude 600 m). The data are derived from hospital birth records for 1971 and 1972 and municipal death records for 1971 through 1973. Linking these records permits analysis of the patterns of mortality in relation to birthweight. Stabilizing selection upon birthweight is operating in both populations. The high altitude population has a lower mean birthweight and a lower optimal birthweight. The Puno population is closer to its optimal birthweight distribution and, as a result of mortality during infancy, is approaching its optimum birthweight distribution for survival more rapidly than the Tacna population. It appears that the high altitude Puno population may well be adapted to its environment in the sense that there is less selective mortality on birthweight phenotypes.

Growth in a population of Tibetan origin at high altitude.

The report describes height, weight and triceps skinfold measurement for 239 individuals from 5 to 22 and 30 to 39 years of age living in the rural Tibetan village of Mugu, Nepal (altitude 3800m). It compares this population with a high-altitude Andean Quechua population and another high-altitude Tibetan population. A delay in height and weight is manifested by the Mugu population. Mugu children are shorter and lighter than the high-altitude Quechua sample during childhood and the early teens, yet they eventually achieve similar adult heights and weights. Mugu males are shorter and lighter than another Tibetan male sample. The reasons for the contrasting growth patterns are not known precisely due to present lack of thorough nutritional, epidemiological and genetical studies from Mugu.