How Regulatory DNA Has Evolved To Impact Aging of the Brain

Noncoding cis-regulatory elements (CREs) of our genome are hypothesized to be a heavy contributor to evolved human phenotypes. However, the complex interplay of CRE functions across genes remains elusive, particularly in regards to aging of the human brain. We have not been able to attribute all evolutionary changes in the brain to coding mutations alone, so regulatory elements are a prime candidate of investigation for causes of evolutionary changes. In this study, datasets of two types of CREs were examined: those with high activity in the human brain, and those that have experienced recent positive selection in the genome when compared to non-human primates. In addition, known brain aging-related genes were analyzed against these CREs in order to detect signs of CREs regulating these aging-related genes. If evolutionarily selected CREs regulate aging genes, then these CREs and their methods of gene regulation may be unique to humans. We identified AKT3, CDH13, CDKAL1, CSMD1, UNC5D, and WWOX as genes regulated by selected and/or differentially expressed CREs. These genes are orthologous in non-human primates, so while the genes have been selectively retained in all primates studied, the regulation appears to be species specific. This provides insight into how our noncoding regulatory elements, such as enhancers or promoters, are linked to uniquely human aging processes. Because age is a major risk factor for neurodegenerative diseases, such as Alzheimer’s disease, we also gain a better understanding of regulatory factors that could be contributing to neurodegeneration.