Genes Associated with Alzheimer’s Disease Show Accelerated Evolution
Post by Amanda McFarlan
What's the science?
Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by the presence of amyloid-beta plaques and neurofibrillary tangles in the brain. The development of AD is specific to humans —even non-human primates cannot develop a complete form of AD— which suggests that there may be an evolutionary component to the disease. Yet, there is very little information on the evolutionary age of AD-associated genes. This week in Molecular Psychiatry, Nitsche and colleagues used genome-wide RNA profiling to analyze the conservation of both protein-coding and non-protein-coding RNA transcripts associated with AD.
How did they do it?
The authors collected post-mortem brain tissue from 17 people with AD and 19 healthy controls who had no history of neurological disease. To establish their genome-wide RNA profile of AD-associated protein transcripts, the authors used genome tiling arrays, along with a custom array approach that allowed for the inclusion of computationally predicted gene loci and gene expression. They compared the brain tissue from individuals with AD and healthy controls to identify any differences in the expression of coding-RNAs and non-coding-RNAs. Next, the authors investigated the evolutionary conservation of these coding- and non-coding-RNAs by analyzing splice sites (regions where RNA splicing takes place) across 18 different vertebrates. As part of their analysis, they first identified whether a gene was present or absent across the different species to determine its evolutionary origin. Then, they determined whether the exact intron-exon structure of a gene was conserved since structural changes in a gene are likely to lead to functional changes as well.
What did they find?
The authors identified 154 coding-RNAs and 141 non-coding-RNAs that showed differences in gene expression between individuals with AD and healthy controls. Next, the authors determined that there was no difference in the conservation rate between AD-associated protein-coding genes and all protein-coding genes, suggesting that AD-associated protein-coding genes are evolutionarily conserved. Conversely, they found that the conservation rate of AD-associated non-coding RNAs decreased over time, suggesting that these genes were not well conserved and evolved quickly. Moreover, the authors determined that the exact intron-exon gene structure was not as well conserved in AD-associated non-coding-RNAs compared to non-coding-RNAs in general, suggesting that the evolution of gene structure for AD-associated non-coding-RNA has occurred at an accelerated rate.
What’s the impact?
This is the first study to show that AD-associated genes have evolved at an accelerated rate compared to the genome at large. Notably, the authors revealed that AD-associated non-coding-RNAs, but not coding-RNAs, were poorly conserved throughout evolution, suggesting that these genes that may play an important role in AD. In all, this research has shed light on how a phylogenetic approach to studying AD may help to shed light on the mechanisms involved in the progression of AD.
Nitsche et al. Alzheimer-related genes show accelerated evolution. Molecular Pyschiatry (2020). Access the original scientific publication here.