Results 1: Adaptive Andean genetic variant preserves mitochondrial oxygen consumption.
The hypoxic inducible factor (HIF) signaling system is a cellular oxygen sensing system that initiates changes to gene expression critical to cellular responses to low oxygen, as are experienced upon exposure to high altitude. Using whole genome sequence data obtained from male and female Andeans residing in Cerro de Pasco Peru (4340m) (n=40), we identified a novel genetic variant within the gene EPAS1, which encodes the protein HIF2A, a crucial component of the HIF signaling system. We incorporated this genetic variant into human cells using genome editing technologies (base editing). I designed a protocol to test the function of these cells in low oxygen (1%) for 24hrs. Cells carrying the Andean variant demonstrated lower levels of HIF gene expression, indicating suppression of the HIF signaling system. I also explored oxidative metabolism of these cells and revealed that those cells carrying the Andean variant displayed lower tissue oxygen consumption in normal oxygen conditions that was sustained in low oxygen. No change was evident in cell morphology, growth rate, viability or non-oxidative metabolism (glycolysis). These results indicate cellular mechanisms downstream of a novel Andean variant in EPAS1 that may prime cells for hypoxic exposure by preserving mitochondrial oxygen consumption. I presented this work through oral presentations in 2023 at: International Hypoxia Symposia, Canada where I was awarded the Tom Taplin Fellowship and MitOx, UK. My gene expression results are part of a manuscript accepted for publication in Science Advances on 18th Dec 2023: EPAS1/HIF2A missense variant is associated with hematocrit in Andean highlanders.
Results 2: Association of adaptive Andean genetic variants with metabolic phenotype in the Latino population.
Another cellular signaling system critical for cell function is termed Notch. Unlike HIF, far less is known about the role of Notch signaling in the context of high-altitude adaptation, although evidence suggests it has a crucial role in mediating the hypoxia cellular response. Using the whole genome sequence data outlined above, I identified two variants within NOTCH1 under selective pressure in Andeans that are also present at low frequencies in lowland Latino populations. To examine metabolic effects of these variants in lowland Latinos, we used the Hispanic community health study/study of Latinos (HCHS/SOL) database (n=11859) to associate the Notch variants with select phenotypes related to oxygen transport and metabolic function. We demonstrate associations between one NOTCH1 variant and both negative type 2 diabetes status and lower fasting glucose. In the second NOTCH1 variant, Significant associations were found with increased circulating triglycerides and % fat body composition, as well as lower forced vital capacity and forced expiratory volume. These results imply the phenotypic consequences of NOTCH1 variants may relate to metabolic function, specifically glucose and lipid homeostasis, and ventilatory control. I presented this work at a Gordon research conference, Notch signaling in health and disease, Maine, USA in 2022 as a poster. I published a review (https://doi.org/10.3390/life12030437 ) summarising Notch signaling and cross-talk in hypoxia and highlighting this pathway as a candidate for high-altitude adaptation.
Results 3: Genomic selection signals in Andean highlanders reveal adaptive placental metabolic phenotypes that are disrupted in preeclampsia.
I examined metabolic function of placenta obtained from Andean highlanders residing in La Paz, Bolivia (3600-4100m). This included healthy control pregnancy (n=40) and preeclampsia (n=39), a hypertensive disorder that can be lethal to mother and baby. I demonstrated suppressed placental metabolic function in preeclampsia compared to controls in term pregnancy (over 37 weeks of gestation). We also demonstrated a novel association between a maternal genetic signal within PTPRD and lower consumption of oxygen in the placenta. We postulate that in healthy Andean pregnancy, the lower placental oxygen consumption is adaptive by preserving oxygen delivery to the fetus, as shown by greater oxygen pressure in the umbilical cord. This association is lost in preeclampsia, indicating maladaptation that may harm fetal growth. Our findings therefore reveal insights into pathological placental mechanisms underlying preeclampsia whilst also highlighting adaptive metabolic mechanisms that may contribute to reproductive success at high-altitudes in Andeans. This work has been published:
https://doi.org/10.1161/HYPERTENSIONAHA.123.21748(opens in new window). I presented these results at the International Hypoxia Symposium 2023 as an oral presentation.
