Allele-specific down-regulation of RPTOR expression induced by retinoids contributes to climate adaptations.
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.
Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America.
Chang
C
Sun
Catherine
C
Southard
David B
DB
Witonsky
Ralf
R
Kittler
Anna
A
Di Rienzo
D000222:Adaptation, Physiological / Q000235:genetics*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D001565:Benzoates / Q000494:pharmacology; D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D002980:Climate; D015536:Down-Regulation / Q000187:drug effects; D005787:Gene Frequency; D005828:Genetics, Population; D005843:Geography; D056945:Hep G2 Cells; D006801:Humans; D050811:Octamer Transcription Factor-1 / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D000076223:Regulatory-Associated Protein of mTOR; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology; D013696:Temperature; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013997:Time Factors; D024363:Transcription Initiation Site
D048868:Adaptor Proteins, Signal Transducing; D001565:Benzoates; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; C463659:RPTOR protein, human; D000076223:Regulatory-Associated Protein of mTOR; D047488:Retinoid X Receptors; D012176:Retinoids; D013764:Tetrahydronaphthalenes; C068073:Am 580