The Andean adaptive toolkit to counteract high altitude maladaptation: genome-wide and phenotypic analysis of the Collas

Abstract

During their migrations out of Africa, humans successfully colonised and adapted to a wide range of habitats, including extreme high altitude environments, where reduced atmospheric oxygen (hypoxia) imposes a number of physiological challenges. This study evaluates genetic and phenotypic variation in the Colla population living in the Argentinean Andes above 3500 m and compares it to the nearby lowland Wichí group in an attempt to pinpoint evolutionary mechanisms underlying adaptation to high altitude hypoxia. We genotyped 730,525 SNPs in 25 individuals from each population. In genome-wide scans of extended haplotype homozygosity Collas showed the strongest signal around VEGFB, which plays an essential role in the ischemic heart, and ELTD1, another gene crucial for heart development and prevention of cardiac hypertrophy. Moreover, pathway enrichment analysis showed an overrepresentation of pathways associated with cardiac morphology. Taken together, these findings suggest that Colla highlanders may have evolved a toolkit of adaptative mechanisms resulting in cardiac reinforcement, most likely to counteract the adverse effects of the permanently increased haematocrit and associated shear forces that characterise the Andean response to hypoxia. Regulation of cerebral vascular flow also appears to be part of the adaptive response in Collas. These findings are not only relevant to understand the evolution of hypoxia protection in high altitude populations but may also suggest new avenues for medical research into conditions where hypoxia constitutes a detrimental factor.

Figure 1. ADMIXTURE components of Argentinean Natives in a worldwide context.

Populations are divided by six admixture proportions as K = 6 indicated the best fit for the data. The main proportions are derived from Yoruba (k3), Han Chinese (k4), Europeans (k6), Mexicans (Mixe/Pima, k2), Andean populations (k1) and Wichí (k5). Collas are indistinguishable from Aymara and Quechua, while Chilean Andeans mainly consist of Andean (k1) and Mixe/Pima (k2) characteristic admixture proportions. Gran Chaco populations (Kaingang, Chané, Guaraní and Toba) carry Wichí specific admixture proportions among others. The population name is displayed underneath the admixture plot while the sample origin is listed above (A: Argentina, B: Brazil, Bo: Bolivia, C: Colombia, Ch: Chile, G: Guatemala, M: Mexico, P:Paraguay) The population name is followed by a sign designating its study (°: HapMap, ∧: Reich et al , ‘: HGDP, “: Mao et al , *: this study).

Figure 2. PCA of Native Americans from Mexico to Chile.

Triangles: populations of this study; squares: HGDP, Quechua (Peru) and Aymara (Bolivia) were first published by Mao et al , remaining populations by Reich et al . Wichí were included from this study and Reich et al and Quechua and Aymara were both published by Mao et al and Reich et al . PC2 separates Wichí from Andean highland populations (Collas, Quechua and Aymara). PC1 distinguishes Mexican Pima and Mixe from the remaining populations. Collas cluster among Aymara and Quechua. The next closest populations are Chileans also from the Andean language family (Hulliche, Chilote, Chono and Yaghan). Gran Chaco populations (Wichí, Chané, Guaraní, Toba and Kaingang) show the widest spread while Wichí are as distinct to the Andean populations as Pima from Mexico.

Figure 3. Consensus maximum likelihood tree for a reduced number of populations with 10 migration events.

Non-bold numbers are bootstrap estimates based on 100 iterations with a support greater than 70%. Quechua, Aymara and Collas form one clade and group with Chilean Andean speakers (Yaghan, Hulliche, Chono and Chilote). Gran Chaco populations (Toba, Wichí, Guaraní, Chané and Kaingang) form a clade with Brazilians (Suruí and Karitiana) and Colombians (Piapoco). Mixe and Pima from Mexico cluster outside all South Americans and Kaqchikel from Guatemala. Branch length refers to the amount of drift experienced but is also increased in populations with more individuals in the data set. Black arrows indicate migrations confirmed as significant by f4 test, while grey arrows indicate insignificant f4 results. Bold numbers represent admixture proportions for black arrows: Toba received 40% admixture proportion from Wichí. Gene flow among Chilean Andeans was strongly supported: Hulliche contributed 100% admixture to Chono and HA Andeans 16%. An ancestral population of Chilote and Chono contributed 37% to Chono and 20% to Chilote. Yaghan contributed 0.05% admixture proportion to Chono.

Figure 4. Manhattan plot of iHS window p-values across all chromosomes in Collas.

The y-axis denotes the empirical p-value of the windows. The blue line indicates the 1% cut off. 12 windows in the top 1% of Collas were excluded since they overlapped with the top 5% of Wichí iHS windows. The highest empirical p-values in each bin were 0 and thus arbitrarily set to 0.001 to display them as highest values as the calculation of log₁₀ (0) is not permitted. Chromosome 11 harbours the top window, with the highest p-value and greatest bin-score containing VEGFB; windows ±1 MB in this region are highlighted in green. The highest ranking window in the bin containing >80 SNPs included MDC1, a gene controlling DNA repair in response to hypoxia. The top window of the bin with 60–79 SNPs, which is located 16 Mb downstream from MDC1, did not contain plausible candidate genes. SEMA3B is involved in neuron development and IL17F in can inhibit angiogenesis. The highest window on chromosome 14 did not contain any genes.