Abstract
The antagonistic pleiotropy theory hypothesizes that evolutionary adaptations maximizing the fitness in early age increase disease burden after reproduction. This theory remains largely untested at the molecular level. Here, we analyzed enhancer evolution in primates to investigate the relationships between aging-related diseases and enhancers acquired after the human-chimpanzee divergence. We report a 5-fold increased evolutionary rate of enhancers that are activated in neural tissues, leading to fixation of ∼100 human-specific enhancers potentially under adaptation. These enhancers show prognostic expression levels and correlations with driver genes in cancer, and their nearby genes are enriched in known loci associated with aging-related diseases. Using CRISPR/Cas9, we further functionally validated an enhancer on chr8p23.1 as activator counteracting REST, a master regulator known to be a transcriptional suppressor of Alzheimer disease. Our results suggest an evolutionary origin of aging-related diseases: the side effects of human-specific, neural-tissue expressed enhancers. Thus, adaptive molecular changes in human macroevolution may introduce vulnerabilities to disease development in modern populations. Chen et al. identify ∼100 human-specific enhancers that are activated in neural tissues and were potentially fixed under adaptation. These enhancers are associated with key genes in aging-related diseases such as cancer and Alzheimer's disease.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 604-611.e4 |
| Journal | Cell Systems |
| Volume | 6 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 23 2018 |
Keywords
- Alzheimer disease
- REST
- adaptive change
- cancer genes
- enhancer regulation
- human evolution
- trade-offs
ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Histology
- Cell Biology
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