Alzheimer-related genes show accelerated evolution.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
received:
21
06
2017
accepted:
03
02
2020
revised:
27
01
2020
pubmed:
24
3
2020
medline:
3
2
2022
entrez:
24
3
2020
Statut:
ppublish
Résumé
Alzheimer's 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.
Identifiants
pubmed: 32203153
doi: 10.1038/s41380-020-0680-1
pii: 10.1038/s41380-020-0680-1
pmc: PMC8758480
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5790-5796Informations de copyright
© 2020. The Author(s).
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