Pervasive Cryptic Epistasis in Molecular Evolution 英文参考文献.docVIP

PervasiveCrypticEpistasisinMolecularEvolution MarkLunzer1,G.BrianGolding2,AntonyM.Dean1,3,4* 1BioTechnology Institute, University of Minnesota, St. Paul, Minnesota, United States of America, 2Department of Biology, McMaster University, Hamilton, Ontario, Canada, 3Department of Ecology, Evolution and Behavior, University of Minnesota, St. Paul, Minnesota, United States of America, 4Instituto Gulbenkian de Cie?ncia, Oeiras,Portugal Abstract The functionaleffectsof most aminoacid replacements accumulated during molecular evolutionareunknown, because mostarenotobservednaturallyandthepossiblecombinationsaretoonumerous.Wecreated168singlemutationsinwild- type Escherichia coli isopropymalate dehydrogenase (IMDH) that match the differences found in wild-type Pseudomonas aeruginosaIMDH.104mutantenzymesperformedsimilarlytoE.coliwild-typeIMDH,onewasfunctionallyenhanced,and63 were functionally compromised. The transition from E. coli IMDH, or an ancestral form, to the functional wild-type P. aeruginosaIMDHrequiresextensiveepistasistoamelioratethecombinedeffectsofthedeleteriousmutations.Thisresult stands in marked contrast with a basic assumption of molecular phylogenetics, that sites in sequences evolve independentlyofeachother.ResiduesthataffectfunctionarescatteredhaphazardlythroughouttheIMDHstructure.We screenedforcompensatorymutationsatthreesites,allofwhichlieneartheactivesiteandallofwhichareamongtheleast activemutants.Nocompensatorymutationswerefoundattwositesindicatingthatasinglesitemayengageincompound epistatic interactions. One complete and three partial compensatory mutations of the third site are remote and lie in a different domain. This demonstrates that epistatic interactions can occur between distant (.20A)? sites. Phylogenetic analysisshowsthatincompatiblemutationswerefixedindifferentlineages. Citation: Lunzer M, Golding GB, Dean AM (2010) Pervasive Cryptic Epistasis in Molecular Evolution. PLoS Genet 6(10): e1001162. doi:10.1371/ journal.pgen.1001162 Edit