Digital Commons @ University of South Florida - Undergraduate Research Conference: Human Adaptation to High Altitude via Tripartite Methylation at an Intronic CACNA1C CpG-SNP in the Placenta
 

Human Adaptation to High Altitude via Tripartite Methylation at an Intronic CACNA1C CpG-SNP in the Placenta

Presenter Information

Sasha Post

Mentor Information

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.

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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.