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Genetic Variation in Healthy Oldest-Old 英文参考文献.doc

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Genetic Variation in Healthy Oldest-Old 英文参考文献

GeneticVariationinHealthyOldest-Old JuliusHalaschek-Wiener1,MahsaAmirabbasi-Beik1,NasimMonfared1,MarkusPieczyk1 ,Christian Sailer1,2,AnitaKollar1,RuthThomas1,GeorgiosAgalaridis1,SoYamada1,LisaOliveira1,JenniferA. Collins1,GraydonMeneilly3,MarcoA.Marra1,KennethM.Madden3,NhuD.Le4,JosephM.Connors5, AngelaR.Brooks-Wilson1,6 * 1Canada’s Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada, 2Institute of Plant Biology, University of Zu¨rich,Zu¨rich,Switzerland,3DepartmentofMedicine,UniversityofBritishColumbia,Vancouver,BritishColumbia,Canada,4CancerControlResearch,BritishColumbia CancerAgency,Vancouver,BritishColumbia,Canada,5CentreforLymphoidCancer,BritishColumbiaCancerAgency,Vancouver,BritishColumbia,Canada,6Department ofBiomedicalPhysiologyandKinesiology,SimonFraserUniversity,Burnaby,BritishColumbia,Canada Abstract Individualswholiveto85andbeyondwithoutdevelopingmajorage-relateddiseasesmayachievethis,inpart,bylacking disease susceptibility factors, or by possessing resistance factors that enhance their ability toavoid disease and prolong lifespan. Healthy aging is a complex phenotype likely to be affected by both genetic and environmental factors. We sequenced24candidatehealthyaginggenesinDNAsamplesfrom47healthyindividualsagedeighty-fiveyearsorolder (the‘oldest-old’),tocharacterizegeneticvariationthatispresentinthisexceptionalgroup.Thesehealthyseniorswerenever diagnosed with cancer, cardiovascular disease, pulmonary disease, diabetes, or Alzheimer disease. We re-sequenced all exons,intron-exonboundariesandselectedconservednon-codingsequencesofcandidategenesinvolvedinaging-related processes, including dietary restriction (PPARG, PPARGC1A, SIRT1, SIRT3, UCP2, UCP3), metabolism (IGF1R, APOB, SCD), autophagy(BECN1,FRAP1),stemcellactivation(NOTCH1,DLL1),tumorsuppression(TP53,CDKN2A,ING1),DNAmethylation (TRDMT1,DNMT3A,DNMT3B)Progeriasyndromes(LMNA,ZMPSTE24,KL)andstressresponse(CRYAB,HSPB2).Wedetected 935 variants, includ