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. 2019 Jan;14(1):1-15.
doi: 10.1080/15592294.2018.1561117. Epub 2019 Jan 9.

LINE-1 and EPAS1 DNA methylation associations with high-altitude exposure

Ainash Childebayeva  1   2 , Tamara R Jones  2 , Jaclyn M Goodrich  2 , Fabiola Leon-Velarde  3 , Maria Rivera-Chira  3 , Melisa Kiyamu  3 , Tom D Brutsaert  4 , Dana C Dolinoy  2   5 , Abigail W Bigham  1
Affiliations

LINE-1 and EPAS1 DNA methylation associations with high-altitude exposure

Ainash Childebayeva et al. Epigenetics. 2019 Jan.

Abstract

Recent discoveries indicate a genetic basis for high-altitude adaptation among human groups who have resided at high altitude for millennia, including Andeans, Tibetans, and Ethiopians. Yet, genetics alone does not explain the extent of variation in altitude-adaptive phenotypes. Current and past environments may also play a role, and one way to determine the effect of the environment is through the epigenome. To characterize if Andean adaptive responses to high altitude have an epigenetic component, we analyzed DNA methylation of the promoter region of EPAS1 and LINE-1 repetitive element among 572 Quechua individuals from high- (4,388 m) and low-altitude (0 m) in Peru. Participants recruited at high altitude had lower EPAS1 DNA methylation and higher LINE-1 methylation. Altitude of birth was associated with higher LINE-1 methylation, not with EPAS1 methylation. The number of years lived at high altitude was negatively associated with EPAS1 methylation and positively associated with LINE-1 methylation. We found four one-carbon metabolism SNPs (MTHFD1 rs2236225, TYMS rs502396, FOLH1 rs202676, GLDC rs10975681) that cumulatively explained 11.29% of the variation in average LINE-1 methylation. And identified an association between LINE-1 methylation and genome-wide SNP principal component 1 that distinguishes European from Indigenous American ancestry suggesting that European admixture decreases LINE-1 methylation. Our results indicate that both current and lifetime exposure to high-altitude hypoxia have an effect on EPAS1 and LINE-1 methylation among Andean Quechua, suggesting that epigenetic modifications may play a role in high-altitude adaptation.

Keywords: Andes; DNA methylation; Epigenetics; adaptation; hypoxia.

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Figures

Figure 1.
Figure 1.
Study Design. (A) Map of Peru depicting participant recruitment locations at high-altitude, Cerro de Pasco (4,338m), and low-altitude, Lima (0m); (B) LINE-1 DNA methylation was determined in 572 Peruvian Quechua with different exposures to high-altitude hypoxia over their lifetime. High-altitude Quechua (HAQ) were born, raised, and reside in or near Cerro de Pasco, Peru. Migrant Quechua (MQ) were born and raised at high altitude (>2,500 m), but moved to low-altitude Lima (0m) during the lifetime. Low-altitude Quechua (LAQ) were born, raised, and reside at sea-level in Lima.
Figure 2.
Figure 2.
Association between LINE-1 methylation and the first principle component (PC1) from the genome-wide PCA analysis (n = 572). PCA was performed on genome-wide SNP data generated using the Affymetrix Axiom Biobanking Array. All study participants are shown as filled circles. The blue line represents X. X is shown by the grey shading. Lower levels of European admixture are associated with higher levels of LINE-1 methylation (p-value = 0.0004). Individuals with lower levels of European admixture have higher values for PC1.
Figure 3.
Figure 3.
(A) LINE-1 methylation level comparison by CpG position between individuals born at high altitude (HAQ+MQ) and individuals born at low altitude (LAQ). LINE-1 methylation is significantly higher at p < 0.05 among born at high-altitude participants for CpG positions 1 and 2 and the average CpG, and at p < 0.10 for position 4. DNA methylation is not significantly different at position 3. Linear mixed models were corrected for sex, age, recruitment group (i.e. HAQ, MQ, or LAQ), PC1, and BMI. * significant at p < 0.05, † significant at p < 0.10 (B) LINE-1 methylation level comparison between individuals recruited in Lima, Peru (LAQ+MQ) and individuals recruited in Cerro de Pasco, Peru (HAQ). LINE-1 methylation is significantly higher in participants recruited in Cerro de Pasco for all 4 LINE-1 CpG positions and the average CpG. Linear mixed models were corrected for sex, age, recruitment group (i.e. HAQ, MQ, or LAQ), PC1, and BMI. * Significant at p < 0.05.Average CpG was calculated over 4 LINE-1 CpG sites including the technical replicates.
Figure 4.
Figure 4.
EPAS1 methylation level comparison between individuals recruited in Lima, Peru (LAQ+MQ) and individuals recruited in Cerro de Pasco, Peru (HAQ). EPAS1 methylation is significantly higher in participants recruited in Lima for all 4 EPAS1 CpG positions and the average methylation. * Significant at p < 0.05.
Figure 5.
Figure 5.
Whole-blood lead level WBLL (μg/dL) comparison between the participants from the three different groups: LAQ, MQ, and HAQ. WBLLs are significantly lower in LAQ (p-value = 3.56E-45) and MQ (p-value = 3.33E-48) compared to HAQ. WBLLs do not differ significantly between LAQ and MQ (p-value = 0.76).
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