HMOX2Functions as a Modifier Gene for High-Altitude Adaptation in Tibetans

Abstract

Tibetans are well adapted to high-altitude environments. Among the adaptive traits in Tibetans, the relatively low hemoglobin level is considered a blunted erythropoietic response to hypoxic challenge. Previously, EPAS1 and EGLN1, the major upstream regulators in the hypoxic pathway, were reportedly involved in the hemoglobin regulation in Tibetans. In this study, we report a downstream gene (HMOX2) involved in heme catabolism, which harbors potentially adaptive variants in Tibetans. We first resequenced the entire genomic region (45.6 kb) of HMOX2 in Tibetans, which confirmed the previously suspected signal of positive selection on HMOX2 in Tibetans. Subsequent association analyses of hemoglobin levels in two independent Tibetan populations (a total of 1,250 individuals) showed a male-specific association between the HMOX2 variants and hemoglobin levels. Tibetan males with the derived C allele at rs4786504:T>C displayed lower hemoglobin level as compared with the T allele carriers. Furthermore, our in vitro experiments indicated that the C allele of rs4786504 could increase the expression of HMOX2, presumably leading to a more efficient breakdown of heme that may help maintain a relatively low hemoglobin level at high altitude. Collectively, we propose that HMOX2 contributes to high-altitude adaptation in Tibetans by functioning as a modifier in the regulation of hemoglobin metabolism.

Thin Air Resulting in High Pressure: Mountain Sickness and Hypoxia-Induced Pulmonary Hypertension

“…In particular, a missense mutation in EGLN1 prevents hypoxia-induced and HIF-mediated enhancement of erythropoiesis [142]. Moreover, HMOX2 (heme oxygenase 2; downstream of HIF) has recently been identified as a relevant modifier of hb metabolism and contributor to high-altitude adaptation in Tibetan highlanders [143]. In addition, variants of the major upstream transcriptional regulator EPAS1 were also significantly associated with low hb concentrations in Tibetan highlanders [144].…”

Genetics of human origin and evolution: high-altitude adaptations

“…HMOX2 recently has been proposed as a modifier of hemoglobin metabolism [39]. Other long-term resident populations of the Qinghai-Tibetan plateau (Sherpa and Ayurveda) as well as recent migrants to the area (Mongolians) show patterns of natural selection that are consistent with Tibetan adaptation [40–43].…”

Genome-Wide Association Study Using Individual Single-Nucleotide Polymorphisms and Haplotypes for Erythrocyte Traits in Alpine Merino Sheep

“…Haase et al found that, under low-oxygen conditions, the body can stimulate the synthesis and release of erythropoietin through cellular oxygen-sensing pathways such as HIF-1X, thus promoting hemoglobin production and erythrocyte proliferation to adapt to a harsh environment (Haase, 2013). Yang et al (2016) found that HMOX2 (also known as HO-2, heme oxygenase 2) as a modified gene could regulate the metabolism of downstream hemoglobin in the hypoxic metabolic pathway, indicating a mechanism for genetic adaptation of the Tibetan population to low-altitude hypoxia. Zou et al (2008) identified 101 QTLs affecting RBCs traits on wild boar (Sus scrofa) chromosomes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 13 .…”