The evolutionary history of the polyQ tract in huntingtin sheds light on its functional pro-neural activities.
Journal
Cell death and differentiation
ISSN: 1476-5403
Titre abrégé: Cell Death Differ
Pays: England
ID NLM: 9437445
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
24
06
2021
accepted:
24
11
2021
revised:
09
11
2021
pubmed:
3
1
2022
medline:
21
4
2022
entrez:
2
1
2022
Statut:
ppublish
Résumé
Huntington's disease is caused by a pathologically long (>35) CAG repeat located in the first exon of the Huntingtin gene (HTT). While pathologically expanded CAG repeats are the focus of extensive investigations, non-pathogenic CAG tracts in protein-coding genes are less well characterized. Here, we investigated the function and evolution of the physiological CAG tract in the HTT gene. We show that the poly-glutamine (polyQ) tract encoded by CAGs in the huntingtin protein (HTT) is under purifying selection and subjected to stronger selective pressures than CAG-encoded polyQ tracts in other proteins. For natural selection to operate, the polyQ must perform a function. By combining genome-edited mouse embryonic stem cells and cell assays, we show that small variations in HTT polyQ lengths significantly correlate with cells' neurogenic potential and with changes in the gene transcription network governing neuronal function. We conclude that during evolution natural selection promotes the conservation and purity of the CAG-encoded polyQ tract and that small increases in its physiological length influence neural functions of HTT. We propose that these changes in HTT polyQ length contribute to evolutionary fitness including potentially to the development of a more complex nervous system.
Identifiants
pubmed: 34974533
doi: 10.1038/s41418-021-00914-9
pii: 10.1038/s41418-021-00914-9
pmc: PMC8817008
doi:
Substances chimiques
Huntingtin Protein
0
Peptides
0
polyglutamine
26700-71-0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
293-305Subventions
Organisme : Fondazione Telethon (Telethon Foundation)
ID : GGP06250
Organisme : CHDI Foundation (CHDI Foundation, Inc.)
ID : JSC A11103
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021. The Author(s).
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