Convergent evolution of complex adaptive traits modulates angiogenesis in high-altitude Andean and Himalayan human populations

Abstract

Convergent adaptations represent paradigmatic examples of the capacity of natural selection to influence organisms' biology. However, the possibility to investigate the genetic determinants underpinning convergent complex adaptive traits has been offered only recently by methods for inferring polygenic adaptations from genomic data. Relying on this approach, we demonstrate how high-altitude Andean human groups experienced pervasive selective events at angiogenic pathways, which resemble those previously attested for Himalayan populations despite partial convergence at the single-gene level was observed. This provides additional evidence for the drivers of convergent evolution of enhanced blood perfusion in populations exposed to hypobaric hypoxia for thousands of years.

Fig. 1. Population structure analyses performed to investigate genetic relationships between high-altitude Andean groups and low-altitude Central and South American populations.

a PCA representing PC1 versus PC2 computed for the 43 un-admixed Native American groups reported in the legend at the bottom right of the plot. Individuals are colour-coded according to their country of origin as reported in the bottom-left legend. The box at the top of the plot details the position of Bolivian Aymara WGS in the considered genetic space with respect to the other high-altitude Andean populations. b Heat map of values for the outgroup-f3 statistic representing the estimated amount of shared genetic drift between the Andean population cluster (marked by a star-like symbol) and each of the considered populations from Central and Southern America (indicated in their approximate geographic locations) A gradient ranging from green to red is specifically used to indicate lower-to-higher levels of genetic affinity as reported by the corresponding colour scale. c Fine-scale patterns of genetic clustering and proportions of ancestry components inferred at the individual level. The fineSTRUCTURE hierarchical clustering dendrogram obtained for Andean, Central and South American individuals included in the assembled dataset is reported, along with ancestry components inferred for each subject with ADMIXTURE analysis at K = 8. For each genetic cluster pinpointed by the fineSTRUCTURE analysis, the corresponding individuals and their admixture proportions are specifically detailed, along with the symbols used in the PCA plot for the populations they belong to. The source data used to generate the figures are reported in Supplementary Data 2—Tables 1–3.

Fig. 2. Functional relationships between genes putatively mediating polygenic adaptations evolved by Andean populations and their role in angiogenic processes.

a Circular network build with Cytoscape v3.10.3 and displaying protein-protein functional interactions inferred for the entire set of adaptive genes belonging to significant pathways identified by H12-based and nSL-based signet analyses according to both WGS and imputed datasets. Genes pointed out by LASSI-based signet analyses as participating to the Focal Adhesion/PI3K-Akt signalling pathways are also reported. Gene products that establish similar connections in the network are placed next to each other, comporting the delineation of two well-distinguishable functional clusters. In detail, non-angiogenesis related genes (e.g., belonging to the Herpes simplex virus 1 infection pathway) are reported as light-grey circles, while angiogenesis-related genes (i.e., belonging to the Focal adhesion/PI3K-Akt signalling pathways) are displayed with pink (when supported by H12 and/or nSL) and light blue (when supported by LASSI) ellipses. The source data used to generate the plot is reported in Supplementary Data 2—Table 4. b Scheme displaying functional interactions between PI3K-Akt signalling and Focal adhesion adaptive genes contributing to improved angiogenesis in Andean populations according to the KEGG database. During the early phases of angiogenesis molecular compounds made available in the extracellular matrix, such as those building the basement vascular membrane (e.g., COL4A1) and angiogenetic factors (e.g., VEGFA and PDGFD), interact with integrin and target receptors (e.g., IGF1R) stimulating protein kinases (e.g., PRKCB and PTK2), which subsequentially activate those signalling cascades essential for migration of endothelial cells and formation of new vascular structures. The yellow stars mark those genes previously identified as loci putatively mediating polygenic adaptation to hypobaric hypoxia in Tibetan/Sherpa populations^,,, thus providing evidence for partial genetic convergence between Andean and Himalayan adaptive traits in addition to the remarkable convergence observed at the biological function/pathway level.

Fig. 3. Candidate genes presenting eQTLs in putative adaptive genomic windows identified by the LASSI method and able to influence their expression in specific tissues.

Schematic representation of the body districts in which the expression of the COL4A1, IGF1R, PDGFD, ITGA8, RYR3, LAMC2, PLCE1 and PRKCE candidate adaptive genes is modulated by eQTLs annotated in the GTEx portal. Genes reported in bold/red are those previously proposed to play an adaptive a role also in populations of Tibetan/Sherpa ancestry^,,,. Illustration from NIAID NIH BIOART Source (https://bioart.niaid.nih.gov/bioart/519; https://bioart.niaid.nih.gov/bioart/420).