On the Use of Gene Ontology Annotations to Assess Functional Similarity among Orthologs and Paralogs A Short Report 英文参考文献.docVIP

OntheUseofGeneOntologyAnnotationstoAssess FunctionalSimilarityamongOrthologsandParalogs:A ShortReport PaulD.Thomas1*,ValerieWood2,ChristopherJ.Mungall3,SuzannaE.Lewis3,JudithA.Blake4,onbehalf oftheGeneOntologyConsortium 1DivisionofBioinformatics,DepartmentofPreventiveMedicine,UniversityofSouthernCalifornia,LosAngeles,California,UnitedStatesofAmerica,2CambridgeSystems BiologyCentre and Department ofBiochemistry, Universityof Cambridge,Cambridge,United Kingdom, 3Genomics Division, Lawrence Berkeley NationalLaboratory, Berkeley,California,UnitedStatesofAmerica,4BioinformaticsandComputationalBiology,TheJacksonLaboratory,BarHarbor,Maine,UnitedStatesofAmerica Abstract A recent paper (Nehrt et al., PLoS Comput. Biol. 7:e1002073, 2011) has proposed a metric for the ‘‘functional similarity’’ between two genes that uses only the Gene Ontology (GO) annotations directly derived from published experimental results. Applying this metric, the authors concluded that paralogous genes within the mouse genome or the human genomearemorefunctionallysimilaronaveragethanorthologousgenesbetweenthesegenomes,anunexpectedresult with broad implications if true. We suggest, based on both theoretical and empirical considerations, that this proposed metricshouldnotbeinterpretedasafunctionalsimilarity,andthereforecannotbeusedtosupportanyconclusionsabout the‘‘orthologconjecture’’(or,moreproperly,the‘‘orthologfunctionalconservationhypothesis’’).First,wereexaminethe case studies presented by Nehrt et al. as examples of orthologs with divergent functions, and come to a very different conclusion:theyactuallyexemplifyhowGOannotationsfororthologousgenesprovidecomplementaryinformationabout conserved biological functions. We then show that there is a global ascertainment bias in the experiment-based GO annotations for human and mouse genes: particular types of experiments tend to be performed in different model organisms.Weconcludethatthereportedstatisticaldifferencesinannotationsbetweenpairsoforthologo