Allele-Specific Down-Regulation of RPTOR Expression Induced by Retinoids Contributes to Climate Adaptations 英文参考文献.docVIP
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Allele-Specific Down-Regulation of RPTOR Expression Induced by Retinoids Contributes to Climate Adaptations 英文参考文献
Allele-SpecificDown-RegulationofRPTORExpression
InducedbyRetinoidsContributestoClimateAdaptations
ChangSun,CatherineSouthard,DavidB.Witonsky,RalfKittler¤,AnnaDiRienzo*
DepartmentofHumanGenetics,UniversityofChicago,Chicago,Illinois,UnitedStatesofAmerica
Abstract
Themechanistictargetofrapamycin(MTOR)pathwayregulatescellgrowth,energyhomeostasis,apoptosis,andimmune
response.TheregulatoryassociatedproteinofMTORencodedbytheRPTORgeneisakeycomponentofthispathway.A
previous survey of candidate genes found that RPTOR contains multiple SNPs with strong correlations between allele
frequencies and climate variables, consistent with the actionof selective pressures that vary across environments. Using
data from a recent genome scan for selection signals, we honed in on a SNP (r 26kb upstream to the
transcriptionstartsiteofRPTORthatexhibitsthestrongestassociationwithtemperaturevariables.Transcriptionfactormotif
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,chromatinimmunoprecipitation(ChIP),andreportergeneassays,wedemonstratethatPOU2F1andRARA
dobindupstreamoftheRPTORgenetoregulateitsexpressioninresponsetoretinoids;thisregulationisaffectedbythe
allelestatusatriththederivedalleleresultinginlowerexpressionlevels.Weproposeamodelinwhichthe
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,consistentwiththeideathatselectionsignalsmaybeusedforSNPannotation.
Citation:SunC,SouthardC,WitonskyDB,KittlerR,DiRienzoA(2010)Allele-SpecificDown-RegulationofRPTORExpressionInducedbyRetinoidsContributesto
ClimateAdaptations.PLoSGenet6(10):e1001178.doi:10.1371/journal.pgen.1001178
Editor:Joshu
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