Genetic approaches to understanding human adaptation to altitude in the Andes
1 Department of Pathology and Laboratory Medicine and
2 Department of Zoology, The University of British Columbia, Vancouver, Canada V6T 2B5
*e-mail: rupert{at}zoology.ubc.ca
Accepted July 2, 2001
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Summary |
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A complex trait is influenced by multiple genetic and environmental factors and, in humans, it is inherently very difficult to determine what proportion of the trait is dictated by an individuals genetic heritage and what proportion develops in response to the environment in which the person is born and raised. Looking for changes in putative adaptations in vertically migrant populations, determining the heritability of putative adaptive traits and genetic association analyses have all been used to evaluate the relative contributions of nurture and nature to the Andean phenotype. As the evidence for a genetic contribution to high-altitude adaptation in humans has been the subject of several recent reviews, this article instead focuses on the methodology that has been employed to isolate the effects of nature from those of nurture on the acquisition of the high-altitude phenotype in Andean natives (Quechua and Aymara). The principles and assumptions underlying the various approaches, as well as some of the inherent strengths and weaknesses of each, are briefly discussed.
Key words: altitude, Quechua, Aymara, human, evolution.
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The Andes: the mountains and the people |
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The altiplano lies in the central regions of the Andes Mountains and extends from central Peru into Bolivia. This extensive plateau, which ranges between 3000 and 4500m, is the site of numerous human habitations, ranging from small farming villages in Central Peru to the towns around Lake Titicaca (3800m) and to the cities of Cusco (3400m), Peru, and La Paz (3800m), the capital of Bolivia (Fig.1). The Andean high-altitude native population consists primarily of two linguistically defined ethnic populations: the Quechua and the Aymara. As of 1990, there were approximately 6.2 million Quechua speakers living in the highlands of Ecuador, Peru, Bolivia and Argentina and approximately 1.6 million Aymara living in the regions around Lake Titicaca and La Paz (Caviedes and Knapp, 1995). The two populations share similar environments and lifestyles, and the genetic distance separating them, as estimated by pair-wise comparisons of multiple polymorphic genetic loci, is relatively small. Salzano and Callegari-Jacques (Salzano and Callegari-Jacques, 1988) compared 21 South American Indian groups using 13 variable loci encoding red blood cell antigens and found that the genetic distance between the Aymara and the Quechua was less than that between these groups and any other group in the analysis.
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There is an extensive body of literature describing the morphology and physiology of the high-altitude native populations in South America and, although no consensus phenotype has emerged, a number of traits have been postulated to be characteristic of these people (Table1). Not all these characteristics are necessarily adaptive, and it is likely that there is substantial interdependence between some of them (e.g. the increase in lung capacity may be associated with the increase in chest size and in turn contribute to the increase in pulmonary diffusion capacity). Nevertheless, there is little doubt that Andean highlanders are better adapted to the hypoxic conditions extant at between 3200m and 4000m than are sea-level populations.
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Has there been time enough for evolution to have occurred in the Andeans? |
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Migration to a new environment may expose a population to new selective pressures and, as a consequence, favour the transmission of pre-existing variants that confer an advantage in the new conditions. Selective transmission would increase the frequency of these alleles and thereby increase the overall fitness of the population. Amplification of pre-existing variants could have contributed to the evolution of Andean populations, especially if there had been substantial genetic variation in the founder populations from which to draw such variants. DNA heterozygosity (a measure of genetic variation) seen in extant Native American populations may be evidence for ancestral diversity. Of the genetic loci examined in these populations, 90% were polymorphic (Kidd et al., 1991). Furthermore, mitochondrial DNA studies of current South American aboriginals (Monsalve et al., 1994) suggest that there was no significant bottleneck during the colonisation of South America, suggesting that the diversity in the North could have been retained during the migration to the South. There may have been, however, an important bottleneck in historic times. After (and probably as a result of) the arrival of Europeans in the Americas, the native population declined precipitously. Although population estimates for pre-Columbian New World populations vary considerably (Ubelaker, 1976), some estimates put the decline in Andean populations as high as 93% (from 9x106 to 6x105) between the years 1520 and 1620 (Cook, 1981). The extent to which the gene pool of the survivors differed from that of the pre-colonial populations is unknown, although it would certainly have been altered by the influx of European genes. Furthermore, the social upheaval, displacement and diseases that accompanied the arrival of the Europeans would have subjected the native population to new selective pressures during the critical period in which their populations were being re-established.
Both the archaeological evidence and studies of current aboriginal populations suggest that there was sufficient time and enough pre-existing genetic variation for evolutionary changes to have occurred in the ancestors of the current Andean people. However, for such change to have occurred, there must have been advantageous phenotypes that, at least to some extent, were genetically determined.
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Heritability studies |
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A common method of estimating the heritability of a trait is to compare the resemblance between relatives. This estimate will vary depending on the relationship chosen and, because there is a greater environmental covariance in sibling pairs than in parent/offspring pairs, the latter comparison is generally more sensitive to genetic differences. Values tend to be higher between mothers and offspring than between fathers and offspring as a result of both maternal effects and non-paternity, and a mid-parent mean is often used in an attempt to average out these effects (Vandemark, 1992).
Heritability estimates can be divided into two general categories depending on the sources of variation. Heritability in the broad sense (H2) is an estimate of the proportion of the phenotypic variability that can be attributed to total genetic variability and is defined as:
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Broad-sense heritability includes all sources of genetic variance such as the additive effects of the genes, dominance effects at loci and epistatic effects between genes. As the latter two are genotypic interactions, and therefore not inherited, a more restrictive parameter, heritability in the narrow sense (h2), gives a better estimate of the genetic variability transmitted between parents and offspring:
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The magnitude of h2 is a major determinant of the potential of a trait to respond to directional selection and of the rate at which it will do so (Hedrick, 2000). The greater the heritability, the greater the scope for selection to act. By favouring the inter-generational transmission of the genetic variants that contribute to a beneficial phenotype, selection will increase the frequency of those variants in the population at the expense of the less beneficial variants. In the end, this may result in a loss of genetic variation in the trait as selection eliminates all but the most beneficial variant. Indeed, many traits that are associated with reproductive success (the ultimate arbiter of evolutionary fitness) have low heritability (Hartl, 2000) (see Fig.3), and a number of studies in wild populations have shown that traits associated with increased fitness have low variability (Mousseau and Roff, 1987).
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Heritability studies in the Andes
In the mid-1800s, Denis Jourdanet, an early researcher into high-altitude adaptation, described the high-altitude native as having a vast chest [that] makes him comfortable in the midst of this thin air (Houston, 1987). This is one of the earliest descriptions of what may be the most commonly cited characteristic of New World high-altitude natives: the relatively large barrel chest. Alberto Hurtado (Hurtado, 1932) commented on this characteristic in Andean populations and postulated that the enlarged chest could allow for increased lung volumes and thereby increase oxygen uptake. Whether this chest morphology is a genetic characteristic has been the subject of numerous studies.
In a series of studies of Aymara-speaking natives from Camacani, Peru (3900m) (Eckhardt and Melton, 1992), a number of anthropometric measurements were made (including nine determinants of thoracic morphology), and the percentage heritability of each trait was estimated (Table2). A number of thoracic traits showed significant heritabilities, suggesting that there was a genetic component contributing to their variation. If there was a similar genetic influence on thoracic dimensions in this populations antecedents (and assuming that a larger chest conferred some advantage at altitude), then conditions were in place for selection to favour the acquisition of this trait. However, whether the current Andean barrel chest represents a genetically determined high-altitude adaptation cannot be determined from these data. Significant heritability can mean that selection has had little effect on these parameters. As Melton (Melton, 1992) points out, if genetic variation was lost as selection shifted the population towards larger chests, then the traits that do not show significant heritability may have been most influenced by selection.
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As mentioned above, comparison of heritabilities between populations is problematic. While the Andeans and the Himalayans have faced similar hypoxic stresses during their occupation of the highlands, the other selective pressures acting on the populations and the genetic backgrounds of their respective founder populations could have been quite different. The Andeans may have had somewhat more time to adapt than the Himalayans. There is substantial evidence supporting occupation of the Andes extending back at least 12000 years, but archaeological evidence suggests that the Himalayan plateau has only been occupied for approximately 5000 years (Cavalli-Sforza et al., 1994), and recent genetic analysis suggests that the ancestors of the current Himalayan Sino-Tibetan population were living in the upper-middle Yellow River basin (10002000m) approximately 10000 years ago (Su et al., 2000).
Heritability estimates are a valuable indicator of the potential for a trait to be subject to evolutionary change and are frequently used by animal and plant breeders to predict the efficacy of a selective breeding program (Hedrick, 2000). However, because the absence of heritability could mean either that selection has eliminated genetic variance or that there was no genetic variance to begin with, heritability estimates are of less value in determining whether evolution has already occurred. Resolving these two possibilities is difficult. Heritability is highly population- and environment-specific (Hartl, 2000), and caution must be taken when extrapolating from current populations to ancestral ones or to other current populations.
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Migration studies |
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Several researchers have taken advantage of population movements up to, and down from, the Andean altiplano to look for genetic contributions to the acquisition of a number of putative adaptive traits. Melton (Melton, 1992) compared physical development in children (Aymara and Quechua) born and raised in Puno, Peru (3900m), or in Tacna, Peru (800m), to parents who were recent migrants from Puno. A number of anthropometric measurements were made including 12 that reflected thoracic growth and development. Despite having been raised at a relatively low altitude, the children in Tacna still had the lengthened sternum characteristic of high-altitude populations and chests as large as those of the children raised at 3900m. The author concludes that this demonstrates a genetic component in the growth patterns of these Andean people. Both Hoff (Hoff, 1972) and Beall et al. (Beall et al., 1977) compared chest morphology of Quechua living at over 4000m with that of Quechua born, or raised from an early age, at lower altitudes. The results of both studies support the hypothesis that pronounced thoracic development is an intrinsic characteristic of the Quechua that will manifest regardless of the altitude at which the person is born and raised. Conversely, Frisancho et al. (Frisancho et al., 1975) found that Quechua native to 4150m had larger chest circumferences for a given height than Quechua born at a lower altitude (980m) and concluded that the greater maximum chest circumference of the highland subjects is probably of environmental origin. Whether the lowland Quechua still had larger chests than non-indigenous populations was not addressed. Overall, the lowland children were shorter than the highland children, whereas the opposite was seen in adults. The authors suggest that recent debilitating socio-economic trends that had affected the development of the lowland children could account for this observation. The paper illustrates the difficulty in isolating single environmental factors when studying migrant populations.
When interpreting migration studies that show that a translocated population is more like the population in their new home than that in their original environment, differential migration must be considered. Less adapted individuals may be more inclined to leave and therefore be disproportionately represented in the out-bound migrant population, although the magnitude of this effect may be mitigated by the co-migration of associates and family members who themselves were fully adapted. In the case of hypoxia adaptation, this would be more likely to result in downward migration because human populations are presumably well adapted to sea-level oxygen levels. Differential migration in response to other stresses (including those of socio-economic origin) should also be considered.
Another issue confounding comparisons between migrating populations is the possibility that the putative genetic predisposition to a trait manifests itself fully only in response to conditions extant in the original location and will therefore be less pronounced in the migrants regardless of genotype. Brutsaert et al. (Brutsaert et al., 1999) reported that the genetic potential for larger lung volumes at high altitude (3800m) depends upon developmental exposure to hypoxia in both Aymara and Quechua.
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Co-segregation of polygenic traits |
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Skin reflectance is one method of quantifying skin colour, and Greksa et al. (Greksa et al., 1991) demonstrated that skin reflectances could be used to estimate the extent of European admixture in a population of Aymara living at 3600m in La Paz. In essence, since the Aymara were darker-skinned than the Europeans, in a mixed population, individuals with lighter skins have a greater percentage of European genes than those with darker skins. This observation was consistent with the distribution of European surnames in the population, a previously confirmed indicator of admixture between the two populations. In a subsequent study, the correlation between skin reflectance and several measures of lung function was determined in the same Aymara population (Greksa, 1996). After removing the effects of tanning and vascularity, there was a significant correlation between several measures of lung function and skin reflectance and, in all such cases, values were greater in the darker-skinned Aymara (Fig.4) than in those with lighter skin. The author concludes that darker skin colour, which reflects an increase in the genes of Aymara origin, is associated with progressive increases in TLC [total lung capacity] and its components and that this is consistent with there being an important genetic component to the enhanced lung volume of Andean highlanders. However, the author also notes that previous studies in the same population had revealed a developmental component to the acquisition of enhanced lung volumes (Greksa et al., 1994), thereby supporting roles for both genetic and environmental factors in the development of this putative adaptive characteristic.
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Association analysis using polymorphisms in candidate genes |
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By choosing candidate genes that, by definition, have a prior probability of being involved in the genotype of interest (Cox and Bell, 1989), fewer tests are necessary and higher P values are obtainable. This reduces the chance of spurious associations while increasing the chance of detecting a valid association (to the extent that the candidacy is legitimate). Typically, candidate genes in high-altitude adaptation would be those whose products are involved in the uptake, transport and utilisation of oxygen, although genes with less direct impact could also be considered.
While analysis of functional variants may actually shed light on the physiology involved, silent variants can be informative as well. If alleles at phenotypically silent polymorphic loci are in linkage disequilibrium with the causative allele, then they can be used as a surrogate genetic marker to follow the nearby variant. This is particularly useful if there is an easy assay for the marker genotype, such as an altered restriction enzyme recognition site. Linkage disequilibrium refers to the non-random association of alleles at linked loci during meiosis, and the resultant co-segregating allele combinations that appear in populations are known as haplotypes (Fig.5). Unlike linkage, which is immutable (unless the genes physically move), haplotypic associations between alleles will decay over time as a result of genetic recombination. The rate at which this occurs is dependent on the genetic distance separating the linked loci (which may, or may not, reflect the physical distance separating them on the chromosome). The value of linkage disequilibrium in genetic analysis is substantial because the presence of one allele indicates the presence of the other(s), and therefore any allele in the haplotype can be used as a marker for any other allele. This allows detection of potentially significant associations even if potentially causal variants have not yet been identified, as well as the use of markers in more variable regions of the genome (e.g. introns). The region over which linkage disequilibrium spreads is estimated to average 3000 bases (Keavney, 2000). As recombination leads to equilibrium, the extent of linkage disequilibrium around a given site will depend on the frequency of recombinant events which, in turn, is a function of time (generations), genome location and population size. Maximum disequilibrium will be found in small populations that are recent descendants of a small founder population.
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Rupert et al. (Rupert et al., 1999a) used the candidate gene association analysis approach to determine whether selection against factors that contribute to blood viscosity could have played a role in altitude adaptation in the Quechua. Some degree of polycythaemia is common in Andean populations, and the increase in blood viscosity that accompanies high haematocrits can have pathological consequences (Dintenfass, 1981). Fibrinogen concentration is the primary determinant of plasma viscosity (Lowe et al., 1993), so Rupert et al. (Rupert et al., 1999a) postulated that reduced levels of fibrinogen might offset the increased blood viscosity resulting from elevated haematocrits and that, in high-altitude native populations, this might be reflected in lower frequencies of alleles associated with higher levels of fibrinogen. The results of that study showed that the alleles associated with lower fibrinogen level at three polymorphic loci in the ß-fibrinogen gene were more prevalent in the Quechua than in lowland populations, and the authors conclude that this observation is consistent with these alleles having been selected for in this population. This study serves to illustrate both the strengths and limitations of the candidate gene approach.
Genomic DNA is easy to prepare and store and, with the advent of polymerase chain reaction (PCR) amplification, a single, small blood sample can provide enough DNA for numerous experiments. In addition, an individuals genotype is unaffected by age, physical condition or lifestyle; thus, comparing genotypes avoids many of the confounding variables that plague phenotypic analyses. In the fibrinogen example, the potential phenotype (blood viscosity) is highly influenced by such diverse factors as gender, birth-control method, smoking history, occupation and physical fitness. However, the drawback to working exclusively with genotypes is that selection acts on the phenotype and not on the genotype. If the association (causal or otherwise) on which the analysis is based does not hold in the studied population, then an over-representation of alleles would not confer any selectable advantage to the population and might instead reflect stochastic fluctuations in allele frequency (i.e. genetic drift).
Another important issue to be addressed in designing association analyses is the choice of controls. Allele frequencies may vary between two populations by chance alone. In the example cited above, the under-represented ß-fibrinogen alleles may have been lost in the Quechua, or their ancestors, by chance, and this loss coincidentally was consistent with the predicted loss due to adaptation. The more closely the control population is related, the less likely are random deviations in allele frequency. Rupert et al. (Rupert et al., 1999a) determined ß-fibrinogen allele frequencies in the Na-Dene, a Native American population that is not considered to be closely related to the Quechua, as a lowland population control. While this provided some basis for comparison, the ideal control population would be the last group to separate from the Quechua before the latter migrated into the mountains. In that case, differences between the two groups will have arisen subsequent to the change in environment and are therefore more likely to be a consequence of adaptation to the new conditions (especially if frequencies for other markers for which there is no apparent phenotype are similar in the two populations). Alternatively, as postulated by Carlos Monge, the founding population may have had a high frequency of beneficial variants prior to its arrival in the Andes by chance, and this genetic composition facilitated occupation of the mountains. In this scenario, the difference would not be recognised in comparisons with recently separated lowland populations despite being of adaptive value.
Other issues that should be considered when designing association studies are population admixture, in which allele frequencies are altered by the influx of foreign DNA, and population stratification. In the latter situation, a segment of the population in which both an allele and a trait are common, although not linked, skews the analysis and gives a spurious association. This is less of a concern when the trait defines the population itself, as is the case when considering adaptive phenotypes.
Another gene whose role in altitude adaptation has been examined using association studies encodes the angiotensin-converting enzyme (ACE). One variant in this gene, detected by the presence of an intronic Alu repeat (the insertion or I allele), was reported to be over-represented in elite European climbers (Montgomery et al., 1997), and the authors postulated that ACE represented a gene for human performance. The alternative allele (the deletion or D allele) has been associated with hypertension and cardiovascular disease in a number of studies (Schunkert, 1997). Rupert et al. (Rupert et al., 1999b) found that, although the I allele was more prevalent in the Quechua than in Caucasians, the allele was equally common in other Native American populations and, in fact, was less common in the highland natives than in other indigenous South American populations. Neither of these studies (nor many others) took into consideration that phenotypes may depend on the interaction between alleles at more than one locus and that synergistic interactions between the intronic ACE polymorphism (or the functional variant to which it is linked) and alleles at other genes in the reninangiotensin pathway have been reported. The association between myocardial infarct and homozygosity for the ACE D allele was dependent on the presence of the C allele at the angiotensin 2 type 1 receptor (AT2R1) C/A1166 polymorphism (Tiret et al., 1994), and left ventricular mass index in male cardiovascular disease patients was predicted by the combination of the D/D genotype at the ACE loci and the C/C genotype at the angiotensinogen (AGT) T/C704 loci, but not by individual genotypes (Kim et al., 2000). If specific alleles of the AGT and AT2R1 genes are required to potentiate the effect of the ACE alleles, then frequency data for all loci should be considered. Selection may act to favour one allele only in the presence of the others.
Although differential representation of alleles in a population can mean that one of the alleles is subject to selection, an equally likely explanation is random genetic drift. One way to determine whether the over-representation is due to selective pressure favoring one allele is to establish that there is an associated phenotype that is both present, and of adaptive significance, in the populations under consideration. As mentioned above, this can be a challenge, especially if there are environmental factors involved as well. A less difficult alternative is a comparative approach. Similar allele over-representation observed in diverse high-altitude populations that presumably did not share recent ancestors would support the hypothesis that the allele confers a selective advantage. Lack of correlation between populations is less informative because there are a number of possible explanations. Regardless of benefit, the current frequency of an allele could be low in one of the populations if the allele was absent, or very rare, in the founding stock. Alternatively, the allele may not confer an advantage in one of the populations because of environmental conditions other than altitude, such as diet, social habits, disease, etc. Another possibility is that the same benefits are achieved but by an alternative pathway (e.g. one population reduces the production of a product while a second population increases its degradation). Phenotypically, the two populations would be similar, but genotypically they would differ.
Despite the limitations inherent in association studies and the difficulties in finding the appropriate controls, this approach remains a powerful method in looking for the influence of genetic variants on a complex trait. Significant over-representation of an allele that a priori would be predicted to be beneficial in the population in question may be sufficient reason to undertake the more costly and difficult analysis at the phenotypic level. Similar over-representation of a silent mutation could be followed up by gene mapping or sequence analysis in search of the causal variant. In a frequently cited article, Risch and Merikangas (Risch and Merikangas, 1996) argue that association analysis using candidate genes is the most effective way to determine the genetic basis of complex diseases. We consider that this may also be the case for non-pathological traits, such as adaptive phenotypes. Choice of candidate genes could be based on observed characteristics but would be substantially more powerful if the phenotype had a demonstrable genetic basis, as ascertained by heritability and migration studies. Advances in micro-array technology together with the nearly completed human genome project and the growth in the number of recognised single nucleotide polymorphisms will increase the efficiency and scope of this type of analysis. The limiting factor may be the procurement of DNA from the adapted populations because there may be a finite window of opportunity to collect samples of this sort. Advances in communication and transportation, as well as changing attitudes to cultural boundaries, will inevitably lead to a homogenisation of the species. As expressed by the eminent population geneticist Luca Cavalli-Sforza in 1991, the founding year of The Human Genome Diversity Project: The genetic diversity of people now living harbours clues to the evolution of our species, but the gate to preserve these clues is closing rapidly (Cavalli-Sforza et al., 1991).
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Acknowledgments |
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