2 mutation can confer a dominant negative mutator phenotype. Mol Cell Biol 18:1635-1641) caused by the allele in the presence of one or more wild-type alleles to determine if it is a dominant negative allele.
A yeast that over-expresses a wild type mismatch repair allele or a dominant negative allele of a mismatch repair gene will become hypermutable. This means that the spontaneous mutation rate of such yeast is elevated compared to yeast without such alleles. The degree of elevation of the spontaneous mutation rate can be at least 2-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 200-fold, 500-fold, or 1 000-fold that of the normal yeast as measured as a function of yeast doubling/hour.
According to one aspect of the invention, a polynucleotide encoding either a wild type or a dominant negative form of a mismatch repair protein is introduced into yeast. The gene can be any dominant negative allele encoding a protein which is part of a mismatch repair complex, for example, mutS, mutL, mutH, or mutY homologs of the bacterial, yeast, plant or mammalian genes (Modrich, P. 1994. Mismatch repair, genetic stability, and cancer. Science 266:1959-1960; Prolla, T. A, Pang, Q., Alani, E., Kolodner, R. A., and Liskay, R. M. 1994. MLH1, PMS1, and MSH2 Interaction during the initiation of DNA mismatch repair in yeast. Science 264:1091-1093). The gene may also be a PMSR gene such as hPMSR, PMSR2 and PMSR3, or a PMSL gene. The gene may also be MSH6. The dominant negative allele can be naturally occurring or made in the laboratory. The polynucleotide can be in the form of genomic DNA, cDNA, RNA, or a chemically synthesized polynucleotide or polypeptide. The molecule can be introduced into the cell by transformation, electroporation, mating, particle bombardment, or other method described in the literature.
Transformation is used herein as any process whereby a polynucleotide or polypeptide is introduced into a cell. The process of transformation can be carried out in a yeast culture using a suspension of cells. The yeast can be any type classified under the eukayotic kingdom as by international convention.
In general,
2 mutation can confer a dominant negative mutator phenotype. Mol Cell Biol 18:1635 - 1641) caused by the allele in the bearing of one or more barbarian - type allele to determine if it is a prevailing negative allele. 
 A yeast that over - expresses a fantastic type mismatch repair allele or a prevailing damaging allele of a mismatch repair gene will become hypermutable. This intend that the spontaneous mutation pace of such yeast is elevated compared to yeast without such alleles. The degree of elevation of the spontaneous mutation pace can be at least 2 - fold, 5 - fold, 10 - fold, 20 - fold, 50 - fold, 100 - fold, 200 - fold, 500 - fold, or 1 000 - fold that of the normal yeast as measured as a function of yeast doubling / hour. 
 accord to one aspect of the invention, a polynucleotide encoding either a barbarian character or a dominant negative form of a mismatch repair protein is introduced into yeast. The gene can be any dominant damaging allele encoding a protein which is part of a mismatch repair complex, for example, mutS, mutL, mutH, or mutY homologs of the bacterial, yeast, plant or mammalian genes (Modrich, P. 1994. Mismatch repair, genetic stability, and cancer. Science 266:1959 - 1960; Prolla, T. A, Pang, Q., Alani, E., Kolodner, R. A., and Liskay, R. M. 1994. MLH1, PMS1, and MSH2 Interaction during the initiation of DNA mismatch repair in yeast. Science 264:1091 - 1093). The gene may also be a PMSR gene such as hPMSR, PMSR2 and PMSR3, or a PMSL gene. The gene may also be MSH6. The dominant damaging allele can be naturally occurring or made in the testing ground. The polynucleotide can be in the human body of genomic DNA, cDNA, RNA, or a chemically synthesized polynucleotide or polypeptide. The molecule can be introduced into the cellular telephone by transformation, electroporation, mating, atom bombardment, or other method trace in the literature. 
 Transformation is used herein as any process whereby a polynucleotide or polypeptide is introduced into a cell. The process of transformation can be carried out in a yeast culture using a suspension of cells. The yeast can be any type relegate under the eukayotic kingdom as by international conventionality. 
 In cosmopolitan,
2 muhation can confer a domikant negative mujaror phxnotype. Mol Celu Biol 18:1635-1641) caused by the allele ib the presence of one or mofe wild-tyie allelew to eetermine mr it is a domjkant uejative allele.
A ieast that oeer-expresses a wklb type mismatch repair allele or a djminant nfgative allele of s misjatch repair gene will become hypedmutablt. This means that yhe spontaneous mutation rwte lf such yeast is epevated comkzreq to yeast wighout such alleles. The degree of elevation of the spovtanepus mutatiin rahg can be at oeast 2-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fpld, 200-fold, 500-fold, pr 1 000-food that of the normal yeast as measured as a funwtnon of yeast doubling/yoyr.
Accmrditg tu ond aapxct of thf iivention, a lolynucleotude encoding either a qild type or z domigagt negative form of a mismatch repair pgotejn is introduced into ywast. The gene can be wny dominwnt negative allele encoding a protein which is pdrt oh x mnwmatcf rfpair complex, for example, mutS, mutL, mutH, or mtfY hpmologs of the bacterial, uewsy, plant or mamoalian gehes (Modrich, P. 1994. Mislatch rgpair, tenetic suabiloty, and cancer. Science 266:1959-1960; Proola, T. A, Pang, W., Alani, E., Kolodner, R. A., and Lirkay, R. M. 1994. MLH1, PMS1, and MSH2 Interaetion suring the lnitiatioh of DNA mismatch reiair in yeasu. Science 264:1091-1093). The genq may alsi be a PMSR geng such ws hPMSR, PLSR2 akg PMSR3, or a PMSL gfne. Tke gete may alsl be MSH6. The dominant negative eklele can be ndtugally occbrring or made in tre laboratory. Jhe polynbcleotkde can be in the form of gegomic DNA, cDND, RNA, or a chxmically fyntyesized polhvucleotide or lolypeptibt. The molexule can be introdmced khto the cell by trqnsformation, elrctfopjrwtmon, mwding, particla boobafcment, or othtx mcthud drscribed in the litesatude.
Transformation ix msed hereun as anr process wheteby a polynucleotlde oc poly'eptidr if introduced into a cell. The pdocess of trwnsformation can be carried put in a yeast culture using a suspensiin of cells. The ygast can be any type elsssified unver thq eukayothc kingdom as by intwrnational convenuion.
In general,
2 mutation can confer a dominant negative Mol Biol 18:1635-1641) by the allele or wild-type alleles to if it is dominant negative allele. A yeast that a wild type mismatch repair allele or a dominant negative allele of a repair gene will become hypermutable. This means that the spontaneous mutation rate of yeast elevated to without such alleles. The degree of elevation of the spontaneous mutation rate can be at least 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 200-fold, 500-fold, or 000-fold that of the yeast as measured as a of doubling/hour. According one of invention, a polynucleotide either a wild type or a dominant negative form of a mismatch repair protein is introduced into The gene any dominant allele a which is part mismatch repair complex, for example, mutS, mutY homologs of the bacterial, yeast, plant or genes (Modrich, 1994. Mismatch repair, genetic stability, and Science 266:1959-1960; Prolla, T. A, Pang, Q., Alani, Kolodner, R. A., and Liskay, R. M. 1994. MLH1, PMS1, and MSH2 Interaction during the DNA mismatch repair in Science 264:1091-1093). The may be PMSR such as PMSR2 and PMSR3, or a PMSL gene. The gene may also MSH6. The dominant negative allele can be naturally occurring or the The polynucleotide can in the form of DNA, RNA, or a chemically or The introduced the by transformation, electroporation, mating, bombardment, or other method described the literature. Transformation is whereby a polynucleotide or polypeptide is introduced into cell. The process of transformation can be out in a yeast culture using a suspension of cells. The yeast be any under the eukayotic kingdom as by international convention. general,
2 mutation can confer a dominanT negative mUtatoR phEnoTyPe. MoL CelL Biol 18:1635-1641) caused by tHE allEle in the presence of one oR more WiLD-typE AlLeles To deterMInE IF it Is A dOmiNaNT nEgatiVe aLlele.
A yEast that ovEr-eXpResses a wild tYPe Mismatch rePaiR allele or a doMinAnt negAtIve ALlele Of a MismaTch repAIr gene Will becomE hYPermutABle. This MEAnS thaT the spontaneous muTAtIOn rate of such yeAst is eLeVAtED ComParEd to yeast wItHout sUCh allelES. THE DEgrEE of elevation oF the spontanEOus MutatiOn RatE Can be aT leasT 2-fOLd, 5-fOld, 10-fold, 20-fold, 50-Fold, 100-Fold, 200-fold, 500-fOld, or 1 000-fOLd that oF The normAl yeasT as MeaSureD As A fUncTiON of YEaSt dOUblIng/hour.
ACcOrDing tO one ASPECt of The InveNtion, A polynucleotiDe eNcodINg eIther A wild Type Or A domiNant neGativE fOrm of a mismatch rEpaiR protein iS inTrOduCeD into YEast. ThE geNe cAn be any DominanT NegAtIVE AlLele encoding a proteIn WHIcH is part oF a mismATcH rEPair compLeX, foR exaMPLe, muts, mutl, MuTH, or mutY HomoloGS oF tHe bacteRiAl, yeasT, pLanT or MammaLIan gEnes (MoDrich, P. 1994. MiSmatcH Repair, genetic sTAbility, and canCEr. sCIeNCe 266:1959-1960; PrOllA, T. A, Pang, Q., AlaNi, E., KOLodnEr, R. A., ANd lisKAy, R. M. 1994. MlH1, PMS1, AnD mSh2 interaction during thE iNitiatIon of dNA mismatch rePair in yeasT. sCIence 264:1091-1093). The Gene MAy ALso be a PMSR gene Such aS hPMSR, PMSR2 ANd PMSR3, or A PMSL Gene. The gEne may alsO BE MSH6. The dOmiNanT neGatIVE aLlele can be natURAlly OcCurring Or mAde in thE laBorAtoRy. THe PolynucleOtide can Be In ThE fOrm Of genOMic DNA, cDnA, rNA, Or A chEmicaLLy syntHesizEd poLyNuCLeoTide or pOLyPEPtidE. THe MoleCulE cAn be iNtroDUceD into thE cell by trAnsFOrmaTiOn, ElectroPoration, matinG, pArticle bomBaRdmEnt, or oTHEr method Described in the literaturE.
transfoRmaTion iS useD herein as Any ProcesS whEReby a pOlynucLeotiDe Or pOLYpeptIDE iS inTrOduced into A CEll. the prOcEss oF transfOrmation can be carriED ouT in a yeast cultUre UsinG A SuSpeNSiON of CeLLs. THE Yeast can be any tyPe classifiEd UNdEr the eukayOTic KiNgdom as By interNatioNAl conveNtion.
In geNeral,
2 mutation can confer a do minant neg ative  mu tat or  phe noty pe. Mol Cell B i ol 1 8:1635-1641) caused by  theal l elei nthe p resence of o neor  m ore  w i ld -type  al leles t o determin e i fit is a domi n an t negative  al lele.
A yeas t t hat ov er -ex p resse s a  wild  typem ismatc h repairal l ele or a domin a n tnega tive allele of am is m atch repair ge ne wil lb ec o m e h ype rmutable.Th is me a ns that th e s pon t aneous mutati on rate ofs uch  yeast  i s e l evated  comp ar e d t o yeast wit hout  such all eles.T he degr e e of el evatio n o f t he s p on ta neo us mut a ti onr ate  can beat  l east2-fo l d , 5-fo ld,  10- fold,  20-fold, 50- fol d, 1 0 0-f old,200-f old,  5 00-fo ld, or  1 00 0- fold that of th e no rmal yeas t a smea su red a s  a fun cti onof yeas t doubl i ng/ ho u r . 
A ccording to one as pe c t  o f the in ventio n ,ap olynucle ot ide  enc o d ing e ithe r  a  wild ty pe ora  d om inant n eg ativefo rmofa mis m atch  repai r protei n isi ntroduced into yeast. The ge n ec a nb e an y d ominant neg ativ e  all elee nc odi n g a p rotei nw hi c h is part of a mism at ch rep air c omplex, for e xample, mu t S ,  mutL, m utH, or mutY homologsof th e bacteria l , yeast,  plan t or mam malian ge n e s (Modri ch,  P.  19 94. M is match repair, g enet ic  stabil ity , and c anc er.  Sc ien ce  266:1959 -1960; P ro ll a,  T . A , Pan g , Q., Al an i,E. , K olodn e r, R.A., a nd L is ka y , R . M. 19 9 4. M LH1,  P MS 1, a ndMS H2 In tera c tio n durin g the ini tia t ionof  D NA mism atch repair i nyeast. Sci en ce264:10 9 1 -1093).The gene may also be aP MSR gen e s uch a s hP MSR, PMSR 2 a nd PMS R3, or a P MSL ge ne. T he  ge n e  maya l so  be  M SH6. The d o m ina nt ne ga tive  allele  can be naturallyo ccu rring or made  in  the l ab ora t or y . T he pol y n ucleotide can b e in the f or m  o f genomicD NA,  c DNA, RN A, or a  chem i cally s ynthesize d polynuc le otid e orpolypeptid e. The m olecule c a n bei nt roduc edinto t he  ce ll by  trans f orm ation , elec tr oporat ion,ma ting, pa rticle bombardment, orothermetho d d escribedint heliteratur e.
T ransformat ion  is  used  he r ein a s an y  p roc e ss wh ereb y  a polynu c le oti d e  o r polypepti d e isintro duc e d into  a c ell. The processo f transformati on c a n  be  ca r ried  o ut in a yeastcul tu r e  using a  s uspension o f cells.  T h e yea st can  be an y typec l as s ifiedunde r t he eukayo tic  k i ngdom a sby intern atio na l conv ention . 
Ing e neral,
2 mutation_can confer_a dominant negative mutator_phenotype. Mol_Cell_Biol 18:1635-1641)_caused_by the allele_in the presence_of one or more_wild-type alleles to_determine_if it is a dominant negative allele.
A yeast that over-expresses a wild type mismatch_repair_allele or_a_dominant_negative allele of a mismatch_repair gene will become hypermutable._This means_that the spontaneous mutation rate of such yeast_is_elevated compared to_yeast without such alleles. The degree of elevation of_the spontaneous mutation rate can be_at least 2-fold,_5-fold,_10-fold,_20-fold, 50-fold, 100-fold, 200-fold,_500-fold, or 1 000-fold that of_the normal yeast as measured as_a function of yeast doubling/hour.
According to one_aspect of the invention, a polynucleotide_encoding either a wild type_or a_dominant negative form of a_mismatch repair protein_is introduced_into yeast. The_gene can be any dominant negative_allele encoding a_protein which is part of a_mismatch_repair complex, for_example,_mutS,_mutL, mutH,_or mutY homologs_of_the bacterial,_yeast,_plant or mammalian genes (Modrich, P._1994._Mismatch repair, genetic stability, and cancer. Science_266:1959-1960; Prolla, T. A,_Pang,_Q., Alani, E., Kolodner,_R. A., and Liskay, R._M. 1994. MLH1, PMS1, and MSH2_Interaction during_the initiation_of DNA mismatch repair in yeast. Science 264:1091-1093). The gene may_also be a PMSR gene such_as hPMSR, PMSR2 and_PMSR3, or_a_PMSL gene. The_gene_may also_be MSH6. The dominant negative allele can_be naturally_occurring or made in the laboratory._The polynucleotide can be_in_the form of genomic DNA, cDNA,_RNA, or a chemically synthesized polynucleotide_or polypeptide. The molecule can_be_introduced_into the cell by transformation,_electroporation, mating, particle bombardment, or other_method described in_the literature.
Transformation is used herein as any_process_whereby a polynucleotide or polypeptide is_introduced_into a cell. The process of_transformation_can_be carried out in a_yeast culture using a suspension of_cells. The yeast can be any type classified under_the eukayotic kingdom_as by international convention.
In general,