Genetic Signatures of Positive Selection in Human Populations Adapted to High Altitude in Papua New Guinea.

Papua New Guinea (PNG) hosts distinct environments mainly represented by the ecoregions of the Highlands and Lowlands that display increased altitude and a predominance of pathogens, respectively. Since its initial peopling approximately 50,000 years ago, inhabitants of these ecoregions might have differentially adapted to the environmental pressures exerted by each of them. However, the genetic basis of adaptation in populations from these areas remains understudied. Here, we investigated signals of positive selection in 62 highlanders and 43 lowlanders across 14 locations in the main island of PNG using whole-genome genotype data from the Oceanian Genome Variation Project (OGVP) and searched for signals of positive selection through population differentiation and haplotype-based selection scans. Additionally, we performed archaic ancestry estimation to detect selection signals in highlanders within introgressed regions of the genome. Among highland populations we identified candidate genes representing known biomarkers for mountain sickness (SAA4, SAA1, PRDX1, LDHA) as well as candidate genes of the Notch signaling pathway (PSEN1, NUMB, RBPJ, MAML3), a novel proposed pathway for high altitude adaptation in multiple organisms. We also identified candidate genes involved in oxidative stress, inflammation, and angiogenesis, processes inducible by hypoxia, as well as in components of the eye lens and the immune response. In contrast, candidate genes in the lowlands are mainly related to the immune response (HLA-DQB1, HLA-DQA2, TAAR6, TAAR9, TAAR8, RNASE4, RNASE6, ANG). Moreover, we find two candidate regions to be also enriched with archaic introgressed segments, suggesting that archaic admixture has played a role in the local adaptation of PNG populations.

Clotting factor genes are associated with preeclampsia in high-altitude pregnant women in the Peruvian Andes.

Preeclampsia is a multi-organ complication of pregnancy characterized by sudden hypertension and proteinuria that is among the leading causes of preterm delivery and maternal morbidity and mortality worldwide. The heterogeneity of preeclampsia poses a challenge for understanding its etiology and molecular basis. Intriguingly, risk for the condition increases in high-altitude regions such as the Peruvian Andes. To investigate the genetic basis of preeclampsia in a population living at high altitude, we characterized genome-wide variation in a cohort of preeclamptic and healthy Andean families (n = 883) from Puno, Peru, a city located above 3,800 meters of altitude. Our study collected genomic DNA and medical records from case-control trios and duos in local hospital settings. We generated genotype data for 439,314 SNPs, determined global ancestry patterns, and mapped associations between genetic variants and preeclampsia phenotypes. A transmission disequilibrium test (TDT) revealed variants near genes of biological importance for placental and blood vessel function. The top candidate region was found on chromosome 13 of the fetal genome and contains clotting factor genes PROZ, F7, and F10. These findings provide supporting evidence that common genetic variants within coagulation genes play an important role in preeclampsia. A selection scan revealed a potential adaptive signal around the ADAM12 locus on chromosome 10, implicated in pregnancy disorders. Our discovery of an association in a functional pathway relevant to pregnancy physiology in an understudied population of Native American origin demonstrates the increased power of family-based study design and underscores the importance of conducting genetic research in diverse populations.

Whole genome variation in 27 Mexican indigenous populations, demographic and biomedical insights.

There has been limited study of Native American whole genome diversity to date, which impairs effective implementation of personalized medicine and a detailed description of its demographic history. Here we report high coverage whole genome sequencing of 76 unrelated individuals, from 27 indigenous groups across Mexico, with more than 97% average Native American ancestry. On average, each individual has 3.26 million Single Nucleotide Variants and short indels, that together comprise a catalog of 9,737,152 variants, 44,118 of which are novel. We report 497 common Single Nucleotide Variants (with allele frequency > 5%) mapped to drug responses and 316,577 in enhancer or promoter elements; interestingly we found some of these enhancer variants in PPARG, a nuclear receptor involved in highly prevalent health problems in Mexican population, such as obesity, diabetes, and insulin resistance. By detecting signals of positive selection we report 24 enriched key pathways under selection, most of them related to immune mechanisms. No missense variants in ACE2, the receptor responsible for the entry of the SARS CoV-2 virus, were found in any individual. Population genomics and phylogenetic analyses demonstrated stratification in a Northern-Central-Southern axis, with major substructure in the Central region. The Seri, a northern group with the most genetic divergence in our study, showed a distinctive genomic context with the most novel variants, and the most population specific genotypes. Genome-wide analysis showed that the average haplotype blocks are longer in Native Mexicans than in other world populations. With this dataset we describe previously undetected population level variation in Native Mexicans, helping to reduce the gap in genomic data representation of such groups.