Uncovering Signals of Positive Selection in Peruvian Populations from Three Ecological Regions

Abstract

Perú hosts extremely diverse ecosystems which can be broadly classified into three major ecoregions: the Pacific desert coast, the Andean highlands, and the Amazon rainforest. Since its initial peopling approximately 12,000 years ago, the populations inhabiting such ecoregions might have differentially adapted to their contrasting environmental pressures. Previous studies have described several candidate genes underlying adaptation to hypobaric hypoxia among Andean highlanders. However, the adaptive genetic diversity of coastal and rainforest populations has been less studied. Here, we gathered genome-wide SNP-array data from 286 Peruvians living across the three ecoregions and analysed signals of recent positive selection through population differentiation and haplotype-based selection scans. Among highland populations, we identify candidate genes related to cardiovascular function (TLL1, DUSP27, TBX5, PLXNA4, SGCD), to the Hypoxia-Inducible Factor pathway (TGFA, APIP), to skin pigmentation (MITF), as well as to glucose (GLIS3) and glycogen metabolism (PPP1R3C, GANC). In contrast, most signatures of adaptation in coastal and rainforest populations comprise candidate genes related to the immune system (including SIGLEC8, TRIM21, CD44 and ICAM1 in the coast; CBLB and PRDM1 in rainforest and the BRD2- HLA-DOA- HLA-DPA1 region in both), possibly as a result of strong pathogen-driven selection. This study identifies candidate genes related to human adaptation to the diverse environments of South America.

Genomic evidence for adaptation to tuberculosis in the Andes before European contact

“…BRINP3 is thought to be important for adaptation to hypoxic conditions via the cardiovascular system and has been identified for high probability of recent positive selection in Bolivian Aymara and highland Peruvian populations. 8 , 33 All other genes with SNPs under high probability of selection related to hypoxia or cardiovascular function in our study differed from those identified in other Andean and worldwide high-altitude population studies ( Table S6 ). 8 , 9 , 10 This suggests there are more complex modes of genetic adaptation to hypoxic conditions in the Andes that are yet to be understood.…”

“… 10 , 11 However, this particular EGLN3 SNP from the present study has yet to be characterized in the functional genomics literature, though EGLN3 was recently also identified as being under selection in highland populations in Peru, as was the GALNT13 gene. 33 In addition, an SNP near the BRINP3 gene was identified as a candidate for positive selection in the present study in the Loja analysis group. BRINP3 is thought to be important for adaptation to hypoxic conditions via the cardiovascular system and has been identified for high probability of recent positive selection in Bolivian Aymara and highland Peruvian populations.…”

“… 32 However, it should be noted that this particular EGLN3 SNP, unlike the EGLN1 polymorphism characteristic of Tibetan populations, has yet to be characterized in the functional genomics literature, though the EGLN3 gene was recently identified as being under selection in highland populations in Peru. 11 , 33 Furthermore, an intergenic SNP near the ANAPC7 gene with significant probability of being under positive selection is a known transcription factor binding site for GATA-2, which has been implicated in the HIF hypoxia response pathway. 22 , 23 Also among the top hits were genes implicated in immune and anti-TB response pathways.…”

“… 35 CD44 was recently identified as being under selection in highland populations in Peru. 33 Top hits also included intronic SNPs on the ADGRE1 gene, an important and well-known marker of macrophages and the FCRL4 gene, which codes for an immunoglobulin receptor important to the function of memory B-cells. 36 , 37 , 38 Furthermore, an intergenic polymorphism found to be under significant probability of positive selection located near the KCNA3 gene, a regulator of antigen specificity in memory T-cells, is an eQTL for the CD53 gene.…”

“… 25 , 29 , 34 The SLC8A1 gene was recently identified as being under strong positive selection in highland populations in Peru. 33 An additional top candidate for positive selection was an intergenic SNP near the CXCL12 gene, which codes for a chemokine known to be upregulated in severe TB infections that include pleurisy, the severe inflammation of thin layers which cover the lungs. 42 Relating to high-altitude, the top hit from this iHS scan was an intergenic SNP near the HAND1 gene, which is a transcription factor regulated by hypoxic conditions.…”