Natural selection on TMPRSS6 associated with the blunted erythropoiesis and improved blood viscosity in Tibetan pigs

Abstract

Tibetan pigs, indigenous to Tibetan plateau, are well adapted to hypoxia. So far, there have been not any definitively described genes and functional sites responsible for hypoxia adaptation for the Tibetan pig. Here we conducted resequencing of the nearly entire genomic region (40.1 kb) of the candidate gene TMPRSS6 (Transmembrane protease, serine 6) associated with hemoglobin concentration (HGB) and red blood cell count (RBC) in 40 domestic pigs and 40 wild boars from five altitudes along the Tea-horse ancient road and identified 708 SNPs, in addition to an indel (CGTG/----) in the intron 10. Both the CGTG deletion frequency and the pairwise r 2 linkage disequilibrium showed an increase with elevated altitudes in 838 domestic pigs from five altitudes, suggesting that TMPRSS6 has been under Darwinian positive selection.As the conserved core sequence of hypoxia-response elements (HREs), the deletion of CGTG in Tibetan pigs decreased the expression levels of TMPRSS6 mRNA and protein in the liver revealed by real-time quantitative PCR and western blot, respectively. To explore whether reduced TMPRSS6 expression level could improve blood viscosity, the relationship between CGTG indel and hematologic and hemorheologic parameters in 482 domestic pigs from continuous altitudes was detected and dissected a genetic effect on reducing HGB by 13.25g/L in Gongbo'gyamda Tibetan pigs and decreasing MCV by 4.79 fl in Diqing Tibetan pigs.In conclusion, the CGTG deletion of TMPRSS6 resulted in lower HGB and smaller MCV, thereby blunting erythropoiesis and improving blood viscosity as well as erythrocyte deformability..

Cross-Species Insights Into Genomic Adaptations to Hypoxia

“…TMPRSS6 is a downstream gene of the HIF pathway that is associated with serum iron concentration and hemoglobin levels (Chambers et al, 2009;Tanaka et al, 2010). Hemoglobin also scaled with altitude in this study (Kong et al, 2019). The 5 -CGTG-3 intron sequence is associated with binding to HREs (Camenisch et al, 2001), suggesting that HIF modulation of blood properties is under Darwinian selection with increasing altitude in this species.…”

“…At the genetic level, genome analysis revealed that Tibetan pig populations (after considering various sub populations and back flow of genes from low altitude populations) exhibit a loss of function mutation in EPAS1 (Ai et al, 2013, Ai et al, 2014Li et al, 2013). In addition, another study demonstrated that mutations to an intron 5 -CGTG-3 sequence of TMPRSS6 increase with increasing residence altitude in Tibetan pigs (Kong et al, 2019). TMPRSS6 is a downstream gene of the HIF pathway that is associated with serum iron concentration and hemoglobin levels (Chambers et al, 2009;Tanaka et al, 2010).…”

High Altitude Adaptability and Meat Quality in Tibetan Pigs: A Reference for Local Pork Processing and Genetic Improvement

“…The extremely high-altitude adaptability of Tibetan pigs is not observable in other pig breeds [6]. In-depth research on Tibetan pigs also helps us understand the hypoxic adaptation of plateau species [7].…”

Vascular characteristics and expression of hypoxia genes in Tibetan pigs’ hearts

“…However, the HGB and RBC of Tibetan pigs and Landrace pigs in high altitude were higher than low altitude environment, and yak, Tibetan sheep and goats have similar features of HGB and RBC levels to increase the RBCs in hypoxia environment responsible for compensation by diffusion and the synthesis of HGB and increase the ability of pigs to carry oxygen (Beall et al, 2010; X. Y. Kong et al, 2014;X. Kong et al, 2019;Y.…”