A highland-adaptation variant near MCUR1 reduces its transcription and attenuates erythrogenesis in Tibetans

To identify genomic regions subject to positive selection that might contain genes involved in high-altitude adaptation (HAA), we performed a genome-wide scan by whole-genome sequencing of Tibetan highlanders and Han lowlanders. We revealed a collection of candidate genes located in 30 genomic loci under positive selection. Among them, MCUR1 at 6p23 was a novel pronounced candidate. By single-cell RNA sequencing and comprehensive functional studies, we demonstrated that MCUR1 depletion leads to impairment of erythropoiesis under hypoxia and normoxia. Mechanistically, MCUR1 knockdown reduced mitochondrial Ca2+ uptake and then concomitantly increased cytosolic Ca2+ levels, which thereby reduced erythropoiesis via the CAMKK2-AMPK-mTOR axis. Further, we revealed rs61644582 at 6p23 as an expression quantitative trait locus for MCUR1 and a functional variant that confers an allele-specific transcriptional regulation of MCUR1. Overall, MCUR1-mediated mitochondrial Ca2+ homeostasis is highlighted as a novel regulator of erythropoiesis, deepening our understanding of the genetic mechanism of HAA.