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.

Genetic and Phenotypic Differentiation of an Andean Intermediate Altitude Population

“…We used the software PLINK (Purcell et al 2007) to determine a set of autosomal SNPs shared between our Calchaqu ı sample and the following populations: Karitiana, Suru ı, Pima, and Colombians from the Human Genome Diversity Project (HGDP) (Li et al 2008), Han Chinese and Utah residents from the HapMap project (International HapMap-Consortium 2003), Aymara and Quechua published by Mao et al (2007), Wich ı and Collas from Eichstaedt et al (2014), and a subset of Native American populations (Reich et al 2012). The final dataset for this ancestry analysis consisted of 17,374 shared SNPs in random association (r 2 < 0.1).…”

“…We used four different tests (integrated Haplotype Score, iHS; Cross Population Extended Haplotype Homozygosity, XP-EHH; Population Branch Statistic, PBS and the Fixation Index, F ST ) to screen for empirical outliers in our data likely driven by natural selection following the methods described previously (Weir and Cockerham 1984;Sabeti et al 2007;Pickrell et al 2009;Yi et al 2010;Eichstaedt et al 2014). Similar to Pickrell et al (2009), we used 200 kb windows in iHS and XP-EHH scans binned by SNP numbers to compensate for unequal SNP distribution in the Illumina OmniExpress SNP-chip data.…”

“…F ST and PBS tests, which emphasize maximum SNP values, were performed on 100 kb windows using lowland Wich ı population from Argentina and Siberian Eskimos, NCBI GEO series number GSE55586, as outgroups. The top 1% windows of all four tests were compared to an a priori candidate gene list (n = 213) details specified in Table S2, Eichstaedt et al (2014) to identify genes closely implicated in hypoxia response. The top 1% was chosen as a conservative cut-off, compared to 5% used in other studies investigating Andean genetic adaptations (Bigham et al 2009(Bigham et al , 2010.…”

“…We also need to better understand the interplay between hypobaric hypoxia and other co-occurring environmental and socioeconomic stressors, and between phenotypic plasticity and genetic adaptation (Storz et al 2010). The latter was suggested by a number of studies (Alkorta-Aranburu et al 2012;Simonson et al 2012;Bigham et al 2013;Eichstaedt et al 2014), and even reported to occur at IA (Pagani et al 2012;HuertaSanchez et al 2013). However, the functional relevance of these genomic signatures remains largely unassessed.…”

“…However, other stressors such as increased radiation, aridity, broader temperature ranges, and poorer diets may also affect developmental characteristics in these environments (Leonard 1989;West et al 2007;Pomeroy et al 2014). Evidence for HA adaptation was shown in Tibetans (Beall et al 2010;Bigham et al 2010;Yi et al 2010;Peng et al 2011;Simonson et al 2012), Andeans Bigham et al 2009Bigham et al , 2010Zhou et al 2013;Eichstaedt et al 2014), and Ethiopians (Alkorta-Aranburu et al 2012;Scheinfeldt et al 2012;Huerta-Sanchez et al 2013;Udpa et al 2014), thus demonstrating the effects of long-term exposure to hypoxia above 3000 m. However, little is known about the effects of moderate levels of hypoxia on human physiology, such as those found at intermediate altitudes (IA), which we define hereafter as altitudes between 2000 and 3000 m. Some indication that moderate hypoxia may have a physiological impact comes from evidence of an albeit modest occurrence of Acute Mountain Sickness (AMS), High Altitude Pulmonary Edema (HAPE) (West et al 2007), and birth weight reduction (Mortola et al 2000) just above 2000 m.…”