This dissertation explores the relationship between the environment and the epigenome.
Using gene-specific and genome-wide epigenetic approaches, this project answers two main questions: 1) Is there an epigenetic contribution to high-altitude adaptation in the Andes? 2) Does inorganic lead exposure affect the epigenomes of the indigenous Quechua?
Epigenetics is a study of changes to the DNA that do not change the sequence of the nucleotides, but can influence gene expression. Epigenetic modifications are mitotically, and sometimes meiotically heritable, and can be reversible. DNA methylation, histone tail modifications, and non-coding RNAs are the main epigenetic modifications. This study focuses on DNA methylation.
The following findings are reported. Global LINE-1 methylation is affected by exposure to high altitude at birth and current altitude exposure. Gene-specific methylation at the high-altitude adaptive gene, EPAS1, also is affected by current altitude exposure. This is the first study to show a decrease in its methylation associated with the altitude of recruitment. Moreover, we found significant DNA methylation changes associated with the altitude of birth.
We performed an epigenome-wide association study (EWAS) between the altitude of birth and DNA methylation, and found one significant position in the promoter region of NPY1R , a gene associated with pulmonary hypertension (PH), which is considered adaptive in Andeans. In addition, we identified 155 differentially methylated regions associated with hypoxic regulation, blood pressure, and pulmonary hypertension (PH).
DNA methylation changes in genes associated with neurological function and metal-ion binding have been reported with lead exposure. Additionally, a positive association between hemoglobin levels and inorganic lead, the distance from mining and lead exposure, and lead levels and the number of days since the last menstruation for women are reported. These findings demonstrate that even low levels of lead exposure can have a significant effect on the epigenome.
Overall, this dissertation research demonstrates that the environment, both past and present, can have a profound impact on epigenetic modifications. DNA methylation patterns can be affected by various exposures simultaneously making the study of epigenetics with regards to one specific exposure challenging. We have shown that both high-altitude hypoxia and lead are affecting the epigenome leading to changes that may be involved in adaptation to high altitude and buffering against the adverse effects of lead exposure.PHDAnthropology & Toxicology PhDUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/149898/1/ainash_1.pd
