REST, a master regulator of neurogenesis, evolved under strong positive selection in humans and in non human primates

Research output: Contribution to journalArticle

Abstract

The transcriptional repressor REST regulates many neuronal genes by binding RE1 motifs. About one third of human RE1s are recently evolved and specific to primates. As changes in the activity of a transcription factor reverberate on its downstream targets, we assessed whether REST displays fast evolutionary rates in primates. We show that REST was targeted by very strong positive selection during primate evolution. Positive selection was also evident in the human lineage, with six selected sites located in a region that surrounds a VNTR in exon 4. Analysis of expression data indicated that REST brain expression peaks during aging in humans but not in other primates. Because a REST coding variant (rs3796529) was previously associated with protection from hippocampal atrophy in elderly subjects with mild cognitive impairment (MCI), we analyzed a cohort of Alzheimer disease (AD) continuum patients. Genotyping of two coding variants (rs3796529 and rs2227902) located in the region surrounding the VNTR indicated a role for rs2227902 in modulation of hippocampal volume loss, indirectly confirming a role for REST in neuroprotection. Experimental studies will be instrumental to determine the functional effect of positively selected sites in REST and the role of REST variants in neuropreservation/neurodegeneration.

Original languageEnglish
Pages (from-to)9530
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - Aug 25 2017

Fingerprint

Neurogenesis
Primates
Minisatellite Repeats
Atrophy
Exons
Alzheimer Disease
Transcription Factors
Brain
Genes

Keywords

  • Journal Article

Cite this

@article{92ca0fcbdaca48b2b7cf498a5e2602c8,
title = "REST, a master regulator of neurogenesis, evolved under strong positive selection in humans and in non human primates",
abstract = "The transcriptional repressor REST regulates many neuronal genes by binding RE1 motifs. About one third of human RE1s are recently evolved and specific to primates. As changes in the activity of a transcription factor reverberate on its downstream targets, we assessed whether REST displays fast evolutionary rates in primates. We show that REST was targeted by very strong positive selection during primate evolution. Positive selection was also evident in the human lineage, with six selected sites located in a region that surrounds a VNTR in exon 4. Analysis of expression data indicated that REST brain expression peaks during aging in humans but not in other primates. Because a REST coding variant (rs3796529) was previously associated with protection from hippocampal atrophy in elderly subjects with mild cognitive impairment (MCI), we analyzed a cohort of Alzheimer disease (AD) continuum patients. Genotyping of two coding variants (rs3796529 and rs2227902) located in the region surrounding the VNTR indicated a role for rs2227902 in modulation of hippocampal volume loss, indirectly confirming a role for REST in neuroprotection. Experimental studies will be instrumental to determine the functional effect of positively selected sites in REST and the role of REST variants in neuropreservation/neurodegeneration.",
keywords = "Journal Article",
author = "Alessandra Mozzi and Guerini, {Franca Rosa} and Diego Forni and Costa, {Andrea Saul} and Raffaello Nemni and Francesca Baglio and Monia Cabinio and Stefania Riva and Chiara Pontremoli and Mario Clerici and Manuela Sironi and Rachele Cagliani",
year = "2017",
month = "8",
day = "25",
doi = "10.1038/s41598-017-10245-w",
language = "English",
volume = "7",
pages = "9530",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - REST, a master regulator of neurogenesis, evolved under strong positive selection in humans and in non human primates

AU - Mozzi, Alessandra

AU - Guerini, Franca Rosa

AU - Forni, Diego

AU - Costa, Andrea Saul

AU - Nemni, Raffaello

AU - Baglio, Francesca

AU - Cabinio, Monia

AU - Riva, Stefania

AU - Pontremoli, Chiara

AU - Clerici, Mario

AU - Sironi, Manuela

AU - Cagliani, Rachele

PY - 2017/8/25

Y1 - 2017/8/25

N2 - The transcriptional repressor REST regulates many neuronal genes by binding RE1 motifs. About one third of human RE1s are recently evolved and specific to primates. As changes in the activity of a transcription factor reverberate on its downstream targets, we assessed whether REST displays fast evolutionary rates in primates. We show that REST was targeted by very strong positive selection during primate evolution. Positive selection was also evident in the human lineage, with six selected sites located in a region that surrounds a VNTR in exon 4. Analysis of expression data indicated that REST brain expression peaks during aging in humans but not in other primates. Because a REST coding variant (rs3796529) was previously associated with protection from hippocampal atrophy in elderly subjects with mild cognitive impairment (MCI), we analyzed a cohort of Alzheimer disease (AD) continuum patients. Genotyping of two coding variants (rs3796529 and rs2227902) located in the region surrounding the VNTR indicated a role for rs2227902 in modulation of hippocampal volume loss, indirectly confirming a role for REST in neuroprotection. Experimental studies will be instrumental to determine the functional effect of positively selected sites in REST and the role of REST variants in neuropreservation/neurodegeneration.

AB - The transcriptional repressor REST regulates many neuronal genes by binding RE1 motifs. About one third of human RE1s are recently evolved and specific to primates. As changes in the activity of a transcription factor reverberate on its downstream targets, we assessed whether REST displays fast evolutionary rates in primates. We show that REST was targeted by very strong positive selection during primate evolution. Positive selection was also evident in the human lineage, with six selected sites located in a region that surrounds a VNTR in exon 4. Analysis of expression data indicated that REST brain expression peaks during aging in humans but not in other primates. Because a REST coding variant (rs3796529) was previously associated with protection from hippocampal atrophy in elderly subjects with mild cognitive impairment (MCI), we analyzed a cohort of Alzheimer disease (AD) continuum patients. Genotyping of two coding variants (rs3796529 and rs2227902) located in the region surrounding the VNTR indicated a role for rs2227902 in modulation of hippocampal volume loss, indirectly confirming a role for REST in neuroprotection. Experimental studies will be instrumental to determine the functional effect of positively selected sites in REST and the role of REST variants in neuropreservation/neurodegeneration.

KW - Journal Article

U2 - 10.1038/s41598-017-10245-w

DO - 10.1038/s41598-017-10245-w

M3 - Article

C2 - 28842657

VL - 7

SP - 9530

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

ER -