Human Adaptation to High Altitude via Tripartite Methylation at an Intronic CACNA1C CpG-SNP in the Placenta
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Dr. Derek E Wildman
Description
Migrants to high altitudes report higher incidences of hypoxemic obstetrical syndromes such as preeclampsia. In indigenous Andeans who have adapted to reduce their risk, a tripartite methylation pattern at a CpG in DYSF was conserved via ancestry-dependent balancing selection, where GG is hypermethylated, GA is hemi-methylated, and AA is hypomethylated. We found other instances of tripartite methylation and determined whether the distribution was facilitating adaptation via balancing selection. A prior study assessed differences in methylation between 95 placental DNA isolates representing highland (3600m, La Paz) Andean (HA, n=24) and European (HE, n=24) and lowland (400m, Santa Cruz) Andean (LA, n=24) and European (LE, n=23) women using Illumina 450k Methylation Arrays. We investigated rs1990322 (G/A) in CACNA1C because of its expression in placentas, regulation by methylation, and being linked to hypertensive disorders such as preeclampsia. DNA was genotyped and methylation observed by pyrosequencing. Allele frequencies (A/G) were determined: HA 0.96/0.04; HE 0.56/0.44; LA 0.90/0.10; LE 0.87/0.13; overall 0.82/0.18. There was limited significant violation of Hardy-Weinberg Equilibrium at high altitudes (p=0.010) and overall (p=0.039). Average M values were determined: AA -5.63; AG -0.24; GG 4.33. This evidence does not support the hypothesis of balancing selection. Instead, the frequencies indicate a non-genomic regulatory mechanism and directional selection. Reduced genetic diversity indicates assortative mating is occurring, while gene flow from other populations may contribute to 16.1% of genetic variation attributable to population subdivisions. This investigation provides insight into the molecular mechanisms influencing the adaptive response to environmental stress and the causes of placental malperfusion.
Human Adaptation to High Altitude via Tripartite Methylation at an Intronic CACNA1C CpG-SNP in the Placenta
Migrants to high altitudes report higher incidences of hypoxemic obstetrical syndromes such as preeclampsia. In indigenous Andeans who have adapted to reduce their risk, a tripartite methylation pattern at a CpG in DYSF was conserved via ancestry-dependent balancing selection, where GG is hypermethylated, GA is hemi-methylated, and AA is hypomethylated. We found other instances of tripartite methylation and determined whether the distribution was facilitating adaptation via balancing selection. A prior study assessed differences in methylation between 95 placental DNA isolates representing highland (3600m, La Paz) Andean (HA, n=24) and European (HE, n=24) and lowland (400m, Santa Cruz) Andean (LA, n=24) and European (LE, n=23) women using Illumina 450k Methylation Arrays. We investigated rs1990322 (G/A) in CACNA1C because of its expression in placentas, regulation by methylation, and being linked to hypertensive disorders such as preeclampsia. DNA was genotyped and methylation observed by pyrosequencing. Allele frequencies (A/G) were determined: HA 0.96/0.04; HE 0.56/0.44; LA 0.90/0.10; LE 0.87/0.13; overall 0.82/0.18. There was limited significant violation of Hardy-Weinberg Equilibrium at high altitudes (p=0.010) and overall (p=0.039). Average M values were determined: AA -5.63; AG -0.24; GG 4.33. This evidence does not support the hypothesis of balancing selection. Instead, the frequencies indicate a non-genomic regulatory mechanism and directional selection. Reduced genetic diversity indicates assortative mating is occurring, while gene flow from other populations may contribute to 16.1% of genetic variation attributable to population subdivisions. This investigation provides insight into the molecular mechanisms influencing the adaptive response to environmental stress and the causes of placental malperfusion.
