Allele-specific down-regulation of RPTOR expression induced by retinoids contributes to climate adaptations

Chang Sun, Catherine Southard, David B. Witonsky, Ralf Kittler, Anna Di Rienzo

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The mechanistic target of rapamycin (MTOR) pathway regulates cell growth, energy homeostasis, apoptosis, and immune response. The regulatory associated protein of MTOR encoded by the RPTOR gene is a key component of this pathway. A previous survey of candidate genes found that RPTOR contains multiple SNPs with strong correlations between allele frequencies and climate variables, consistent with the action of selective pressures that vary across environments. Using data from a recent genome scan for selection signals, we honed in on a SNP (rs11868112) 26 kb upstream to the transcription start site of RPTOR that exhibits the strongest association with temperature variables. Transcription factor motif scanning and mining of recently mapped transcription factor binding sites identified a binding site for POU class 2 homeobox 1 (POU2F1) spanning the SNP and an adjacent retinoid acid receptor (RAR) binding site. Using expression quantification, chromatin immunoprecipitation (ChIP), and reporter gene assays, we demonstrate that POU2F1 and RARA do bind upstream of the RPTOR gene to regulate its expression in response to retinoids; this regulation is affected by the allele status at rs11868112 with the derived allele resulting in lower expression levels. We propose a model in which the derived allele influences thermogenesis or immune response by altering MTOR pathway activity and thereby increasing fitness in colder climates. Our results show that signatures of genetic adaptations can identify variants with functional effects, consistent with the idea that selection signals may be used for SNP annotation.

Original languageEnglish (US)
Article numbere1001178
Pages (from-to)1-10
Number of pages10
JournalPLoS Genetics
Volume6
Issue number10
DOIs
StatePublished - Oct 2010

Fingerprint

retinoids
Retinoids
Climate
Single Nucleotide Polymorphism
binding sites
allele
Down-Regulation
Alleles
alleles
climate
gene
Binding Sites
Sirolimus
transcription factors
immune response
Transcription Factors
genes
TOR Serine-Threonine Kinases
cold zones
heat production

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Allele-specific down-regulation of RPTOR expression induced by retinoids contributes to climate adaptations. / Sun, Chang; Southard, Catherine; Witonsky, David B.; Kittler, Ralf; Di Rienzo, Anna.

In: PLoS Genetics, Vol. 6, No. 10, e1001178, 10.2010, p. 1-10.

Research output: Contribution to journalArticle

Sun, Chang ; Southard, Catherine ; Witonsky, David B. ; Kittler, Ralf ; Di Rienzo, Anna. / Allele-specific down-regulation of RPTOR expression induced by retinoids contributes to climate adaptations. In: PLoS Genetics. 2010 ; Vol. 6, No. 10. pp. 1-10.
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