DNA Methylation Explains a Subset of Placental Gene Expression Differences Based on Ancestry and Altitude

Gundling, WE; Pantham, Priyadarshini; Illsley, Nicholas P.; Echalar, Lourdes; Zamudio, Stacy; Wildman, D.E.

doi:10.1101/261974

Cited by 3 publications

(18 citation statements)

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“…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.…”

Section: Genes Involved In Gestational Hypoxia and High Elevation Ada...mentioning

confidence: 99%

“…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.…”

Section: Rnaseq Data Generation and Analysis Tissue Was Homogenized Inmentioning

confidence: 99%

“…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…”

Section: Rnaseq Data Generation and Analysis Tissue Was Homogenized Inmentioning

confidence: 99%

“…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).…”

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confidence: 99%

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

Wilsterman

Moore

Schweizer

et al. 2022

Preprint

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Hypoxia at high elevations challenges gestational physiology in placental mammals, increasing rates of gestational complications. Adaptation to high elevation has limited many of these effects in humans and other mammals, offering potential insight into the developmental processes that lead to and protect against hypoxia-related gestational complications. However, our understanding of these adaptations has been limited by a lack of experimental work linking the functional, regulatory, and genetic underpinnings of gestational development in locally adapted populations. Here, we dissect high-elevation adaptation in the reproductive physiology of deer mice, (Peromyscus maniculatus), a rodent species with an exceptionally broad elevational distribution that has emerged as a model for hypoxia adaptation. Using experimental acclimations, we show that lowland mice experience pronounced fetal growth restriction when challenged with gestational hypoxia, while highland mice maintain normal growth by expanding the placental compartment that facilitates nutrient and gas exchange between dam and fetus. We then use layer-enriched transcriptome analyses to show that adaptive structural remodeling of the placenta is coincident with widespread changes in gene expression localized to this same compartment. Genes associated with fetal growth in deer mice overlap with genes involved in human placental development, pointing to conserved or convergent pathways underlying these processes. Finally, we overlayed our results with genetic data from natural populations to identify the subset of placental genes that form the genetic basis of placental adaptations. Collectively, these experiments advance our understanding of placental adaptation to hypoxic environments and illuminate physiological mechanisms underlying fetal growth trajectories during a key gestational window.

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Section: Genes Involved In Gestational Hypoxia and High Elevation Ada...mentioning

confidence: 99%

Section: Rnaseq Data Generation and Analysis Tissue Was Homogenized Inmentioning

confidence: 99%

Section: Rnaseq Data Generation and Analysis Tissue Was Homogenized Inmentioning

confidence: 99%

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confidence: 99%

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

Wilsterman

Moore

Schweizer

et al. 2022

Preprint

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“…We found that placental genes associated with cell fusion and proliferation, critical processes in placental development, were differentially expressed between individuals residing at high and low-altitude. Of 36 altitude-associated differentially expressed genes, 8 had significant correlation between gene expression and DNA methylation ( Gundling et al, 2018 ). One of these is dysferlin ( DYSF ).…”

Section: Introductionmentioning

confidence: 99%

Ancestry dependent balancing selection of placental dysferlin at high-altitude

Gundling¹,

Post

Illsley³

et al. 2023

Front. Cell Dev. Biol.

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Introduction: The placenta mediates fetal growth by regulating gas and nutrient exchange between the mother and the fetus. The cell type in the placenta where this nutrient exchange occurs is called the syncytiotrophoblast, which is the barrier between the fetal and maternal blood. Residence at high-altitude is strongly associated with reduced 3rd trimester fetal growth and increased rates of complications such as preeclampsia. We asked whether altitude and/or ancestry-related placental gene expression contributes to differential fetal growth under high-altitude conditions, as native populations have greater fetal growth than migrants to high-altitude.Methods: We have previously shown that methylation differences largely accounted for altitude-associated differences in placental gene expression that favor improved fetal growth among high-altitude natives. We tested for differences in DNA methylation between Andean and European placental samples from Bolivia [La Paz (∼3,600 m) and Santa Cruz, Bolivia (∼400 m)]. One group of genes showing significant altitude-related differences are those involved in cell fusion and membrane repair in the syncytiotrophoblast. Dysferlin (DYSF) shows greater expression levels in high- vs. low-altitude placentas, regardless of ancestry. DYSF has a single nucleotide variant (rs10166384;G/A) located at a methylation site that can potentially stimulate or repress DYSF expression. Following up with individual DNA genotyping in an expanded sample size, we observed three classes of DNA methylation that corresponded to individual genotypes of rs10166384 (A/A < A/G < G/G). We tested whether these genotypes are under Darwinian selection pressure by sequencing a ∼2.5 kb fragment including the DYSF variants from 96 Bolivian samples and compared them to data from the 1000 genomes project.Results: We found that balancing selection (Tajima’s D = 2.37) was acting on this fragment among Andeans regardless of altitude, and in Europeans at high-altitude (Tajima’s D = 1.85).Discussion: This supports that balancing selection acting on dysferlin is capable of altering DNA methylation patterns based on environmental exposure to high-altitude hypoxia. This finding is analogous to balancing selection seen frequency-dependent selection, implying both alleles are advantageous in different ways depending on environmental circumstances. Preservation of the adenine (A) and guanine (G) alleles may therefore aid both Andeans and Europeans in an altitude dependent fashion.

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

Wilsterman

Moore

Schweizer

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Environmental hypoxia challenges female reproductive physiology in placental mammals, increasing rates of gestational complications. Adaptation to high elevation has limited many of these effects in humans and other mammals, offering potential insight into the developmental processes that lead to and protect against hypoxia-related gestational complications. However, our understanding of these adaptations has been hampered by a lack of experimental work linking the functional, regulatory, and genetic underpinnings of gestational development in locally adapted populations. Here, we dissect high-elevation adaptation in the reproductive physiology of deer mice ( Peromyscus maniculatus ), a rodent species with an exceptionally broad elevational distribution that has emerged as a model for hypoxia adaptation. Using experimental acclimations, we show that lowland mice experience pronounced fetal growth restriction when challenged with gestational hypoxia, while highland mice maintain normal growth by expanding the compartment of the placenta that facilitates nutrient and gas exchange between gestational parent and fetus. We then use compartment-specific transcriptome analyses to show that adaptive structural remodeling of the placenta is coincident with widespread changes in gene expression within this same compartment. Genes associated with fetal growth in deer mice significantly overlap with genes involved in human placental development, pointing to conserved or convergent pathways underlying these processes. Finally, we overlay our results with genetic data from natural populations to identify candidate genes and genomic features that contribute to these placental adaptations. Collectively, these experiments advance our understanding of adaptation to hypoxic environments by revealing physiological and genetic mechanisms that shape fetal growth trajectories under maternal hypoxia.

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DNA Methylation Explains a Subset of Placental Gene Expression Differences Based on Ancestry and Altitude

Cited by 3 publications

References 77 publications

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

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

Ancestry dependent balancing selection of placental dysferlin at high-altitude

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

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