Recognition of Unknown Conserved Alternatively Spliced Exons 英文参考文献.docVIP

RecognitionofUnknownConserved AlternativelySplicedExons Uwe Ohler*¤,Noam Shomron, Christopher B.Burge* DepartmentofBiology,MassachusettsInstituteofTechnology,Cambridge,Massachusetts,UnitedStatesofAmerica The split structure of most mammalian protein-coding genes allows for the potential to produce multiple different mRNAandproteinisoformsfromasinglegenelocusthroughtheprocessofalternativesplicing(AS).Weproposea computationalapproachcalledUNCOVERbasedonapairhiddenMarkovmodeltodiscoverconservedcodingexonic sequencessubjecttoASthathavesofargoneundetected.ApplyingUNCOVERtoorthologousintronsofknownhuman andmousegenespredictsskippedexonsorretainedintronspresentinbothspecies,whilediscriminatingthemfrom conserved noncoding sequences. The accuracy of the model is evaluated on a curated set of genes with known conservedASevents.Thepredictionofskippedexonsinthe;1%ofthehumangenomerepresentedbytheENCODE regions leads to more than 50 new exon candidates. Five novel predicted AS exons were validated by RT-PCR and sequencinganalysisof15intronswithstrongUNCOVERpredictionsandlackingESTevidence.Theseresultsimplythat aconsiderablenumberofconservedexonicsequencesandassociatedisoformsarestillcompletelymissingfromthe current annotation of known genes. UNCOVER also identifies a small number of candidates for conserved intron retention. Citation:OhlerU,ShomronN,BurgeCB(2005)Recognitionofunknownconservedalternativelysplicedexons.PLoSCompBiol1(2):e15. for genes expressed at lower levels or under limited conditions. It becomes increasingly hard to distinguish Introduction Almost all protein-coding genes of humans and other mammals have a split structure with several exons and introns. Intronic sequences are removed from the primary transcript by the process of pre-mRNA splicing [1], an essentialstepineukaryoticgeneexpression.Thenumberof functional variants generated from one transcript can be greatlyincreasedbyalternativesplicing(AS),inwhichoneor more exons or parts thereof are skipped,