Alzheimer-related genes show accelerated evolution

Anne Nitsche,Thomas Arendt,Peter F Stadler,Jörg Fallmann,Kristin Reiche,Christian Arnold,Friedemann Horn,Uwe Ueberham,Jörg Hackermüller

doi:10.1038/s41380-020-0680-1

Abstract

Alzheimerʼs disease (AD) is a neurodegenerative disorder of unknown cause with complex genetic and environmental traits. While AD is extremely prevalent in human elderly, it hardly occurs in non-primate mammals and even non-human-primates develop only an incomplete form of the disease. This specificity of AD to human clearly implies a phylogenetic aspect. Still, the evolutionary dimension of AD pathomechanism remains difficult to prove and has not been established so far. To analyze the evolutionary age and dynamics of AD-associated-genes, we established the AD-associated genome-wide RNA-profile comprising both protein-coding and non-protein-coding transcripts. We than applied a systematic analysis on the conservation of splice-sites as a measure of gene-structure based on multiple alignments across vertebrates of homologs of AD-associated-genes. Here, we show that nearly all AD-associated-genes are evolutionarily old and did not originate later in evolution than not-AD-associated-genes. However, the gene-structures of loci, that exhibit AD-associated changes in their expression, evolve faster than the genome at large. While protein-coding-loci exhibit an enhanced rate of small changes in gene structure, non-coding loci show even much larger changes. The accelerated evolution of AD-associated-genes indicates a more rapid functional adaptation of these genes. In particular AD-associated non-coding-genes play an important, as yet largely unexplored, role in AD. This phylogenetic trait indicates that recent adaptive evolution of human brain is causally involved in basic principles of neurodegeneration. It highlights the necessity for a paradigmatic change of our disease-concepts and to reconsider the appropriateness of current animal-models to develop disease-modifying strategies that can be translated to human.

Highlights

Alzheimer’s disease (AD) is an age-related chronic neurodegenerative disorder of unknown cause
The diagnosis of AD was made on the basis of both clinical and neuropathological evidence according to the criteria of the International Working Group (IWG) for New Research Criteria for the diagnosis of AD in the revision of 2014 (IWG-2) [16], the NIA-AA diagnostic criteria in the revision of 2011 [17] and the NIA-AA guidelines for the neuropathological assessment of AD [18, 19]
We designed a custom array comprising 931 898 probes derived from Agilents Whole Human Genome Oligo array, long non-coding RNA probes extracted from public databases, computationally predicted loci of structured RNAs, and lncRNA probes experimentally identified by transcriptome-wide expression variation studies based on the Affymetrix Human Tiling 1.0 array comparing AD patients with control samples (Supplementary methods and results; Supplementary Tables S1, S2)

Summary

Introduction

Alzheimer’s disease (AD) is an age-related chronic neurodegenerative disorder of unknown cause. While deposits of Aß have been described in birds, fish, and various mammalian species, neurofibrillary tangles are found almost exclusively in humans, and even non-human primate only develop an incomplete form of the disease [5,6,7] This exclusivity of AD to human brain clearly implies a phylogenetic aspect of the disease and most likely indicates that adaptive changes of cerebral structure and function that have occurred during human evolution may have rendered the human brain sensitive to AD [8]. Clear cut phylogenetic traits of the AD pathomechanism might have far reaching consequences with respect to our approaches of disease prevention and therapy including defining appropriate animal model systems. Still, this evolutionary dimension remains difficult to prove and has not been established unequivocally so far. To test the hypothesis that brain evolution critically contributes towards the AD pathomechanism, here, we established the AD-associated genome-wide RNA profile comprising both protein-coding (cRNA) and non-proteincoding (ncRNA) transcripts and applied a systematic analysis on the conservation of splice sites as a measure of the evolution of gene structure

Methods

Results

Discussion

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