How Placenta Promotes the Successful Reproduction in High-Altitude Populations: A Transcriptome Comparison between Adaptation and Acclimatization

Abstract

As the best adapted high altitude population, Tibetans feature a relatively high offspring survival rate. Genome-wide studies have identified hundreds of candidate SNPs related to high altitude adaptation of Tibetans, although most of them have unknown functional relevance. To explore the mechanisms behind successful reproduction at high altitudes, we compared the placental transcriptomes of Tibetans, sea level Hans (SLHan), and Han immigrants (ImHan). Among the three populations, placentas from ImHan showed a hyperactive gene expression pattern. Their increased activation demonstrates a hypoxic stress response similar to sea level individuals experiencing hypoxic conditions. Unlike ImHan, Tibetan placentas were characterized by the significant up-regulation of placenta-specific genes, and the activation of autophagy and the tricarboxylic acid cycle. Certain conserved hypoxia response functions, including the antioxidant system and angiogenesis, were activated in both ImHan and Tibetans, but mediated by different genes. The coherence of specific transcriptome features linked to possible genetic contribution was observed in Tibetans. Furthermore, we identified a novel Tibetan-specific EPAS1 isoform with a partial deletion at exon six, which may be involved in the adaption to hypoxia through the EPAS1-centred gene network in the placenta. Overall, our results show that the placenta grants successful pregnancies in Tibetans by strengthening the natural functions of the placenta itself. On the other hand, the placenta of ImHan was in an inhabiting time-dependent acclimatization process representing a common hypoxic stress response pattern.

Adaptive structural and functional evolution of the placenta protects fetal growth in high elevation deer mice

“…We first examined expression within an a priori gene set that included genes hypothesized to be relevant to altitude adaptation, placental physiology, and fetal growth outcomes in humans (43)(44)(45)(46)(47)(48)(49)(50)(51). Across its evolution, placentas have repeatedly co-opted genetic toolboxes and gene duplications from other tissues (52-54), and thus we might not expect there to be substantial overlap at the gene level between human and deer mouse gene sets that are associated with fetal growth outcomes and hypoxia responses.…”

“…After filtering, mapping, and feature D R A F T assignment, our analysis included an average of 29.5M reads from our junctional zone/decidua samples (Range: 16.2 -39.3M), and an average of 31.3M reads from our labyrinth zone samples (Range: a priori dataset generation and analysis. We compiled a priori genes of interest from the literature, including genes hypothesized to be relevant to altitude adaptation and protection of fetal growth in 787 humans as well as genes with empirical evidence for differential 788 expression among lowland and highland human populations in the 789 placenta (39,45). Neither (39) nor (45) associate gene expression 790 with fetal growth outcomes, but instead focus on genes are differ-791 entially expressed between highlanders (Tibetans or Andeans) and lowlanders and hypoxia sensitivity.…”

“…We compiled a priori genes of interest from the literature, including genes hypothesized to be relevant to altitude adaptation and protection of fetal growth in 787 humans as well as genes with empirical evidence for differential 788 expression among lowland and highland human populations in the 789 placenta (39,45). Neither (39) nor (45) associate gene expression 790 with fetal growth outcomes, but instead focus on genes are differ-791 entially expressed between highlanders (Tibetans or Andeans) and lowlanders and hypoxia sensitivity. From Wu et al51, we selected only the top 10% of genes that were differentially expressed between whether a priori genes were more likely to be correlated with fetal 796 growth or other factors of interest than the full dataset by compar-797 ing the proportion of genes within each with a nominal p-value of…”

“…We first examined expression within an a priori set of 270 genes hypothesized to be relevant to high elevation adaptation, 271 placental physiology, and fetal growth outcomes in humans 272 (38)(39)(40)(41)(42)(43)(44)(45)(46). Placental evolution within and outside of mammals S6).…”

Allometric scaling relationships in mouse placenta

“…Effects of hypoxia have been investigated in high-altitude pregnancies [22]. It has been shown that placental natural functions are strengthened for the well-adapted inhabitants of high altitude, representing a preserved relationship between the placenta and fetus [23]. However, short-time exposure to hypoxic conditions as a result of immigration to high-altitude places showed common hypoxic stress response [23].…”