, 1379 (1990): Sharpe, M. J., et al., EMBO J., 10, 2139 (1991): Betz, A. G., et al., Cell, 77, 239 (1994): Yelamos, J., et al., Nature, 376, 225 (1995): Peters, A., et al., Immunity, 4, 57 (1996): 11-16), λ-chain (Klotz, E., et al., J. Immunol., 157, 4458 (1996):17) and H-chain transgenic mice (Durdik, J., et al., Proc. Natl. Acad. Sci. USA, 86, 2346 (1989): Sohn, J., et al., J. Exp. Med., 177, 493 (1993): Tumas-Brundage, K. M. and Manser, T., J. Exp. Med., 185, 239 (1997):18-20).
As stated above, the present inventor prepared transgenic mice carrying chloramphenicol acetyltransferase (CAT) gene that is driven by VH17.2.25 (Loh, D. Y., et al., Cell, 33, 85 (1983): Grosschedl, R. and Baltimore, D., Cell, 41, 885 (1985): 22, 23) and J-C intron enhancer (hereafter abbreviated to Eμ) (Gillies, S. D., et al., Cell, 33, 715 (1983): Banerji, J., et al., Cell, 33, 729 (1983):24, 25)/matrix attachment region (hereafter abbreviated to MAR) (Forrester, W. C., et al., Science, 265, 1221 (1994):26). As a result, somatic hypermutation was detected in CAT but not in VH promoter or Eμ/MAR flanking. However, the frequency of mutation was approximately 1/10 that observed in endogenous VH-D-JH, suggesting that these cis-acting elements are critical or important for the induction of hypermutation and that other components such as Cγ, Cα of 3′ or the enhancer flanking of Cα (3′ enhancer) (Pettersson, S., et al., Nature, 344, 165 (1990): Dariavach, P., et al., Eur. J. Immunnol., 21, 1499 (1991): Lieberson, R., et al., EMBO. J.,
, 1379 (1990 ): Sharpe, M. J., et al. , EMBO J., 10, 2139 (1991 ): Betz, A. G., et al. , Cell, 77, 239 (1994 ): Yelamos, J., et al. , Nature, 376, 225 (1995 ): Peters, A., et al. , Immunity, 4, 57 (1996 ): 11 - 16), λ - chain (Klotz, E., et al. , J. Immunol. , 157, 4458 (1996):17) and H - chain transgenic mice (Durdik, J., et al. , Proc. Natl. Acad. Sci. USA, 86, 2346 (1989 ): Sohn, J., et al. , J. Exp. Med. , 177, 493 (1993 ): Tumas - Brundage, K. M. and Manser, T., J. Exp. Med. , 185, 239 (1997):18 - 20). 
 As stated above, the present inventor prepare transgenic mouse carrying chloramphenicol acetyltransferase (CAT) gene that is driven by VH17.2.25 (Loh, D. Y., et al. , Cell, 33, 85 (1983 ): Grosschedl, R. and Baltimore, D., Cell, 41, 885 (1985 ): 22, 23) and J - C intron enhancer (hereinafter abbreviated to Eμ) (Gillies, S. D., et al. , Cell, 33, 715 (1983 ): Banerji, J., et al. , Cell, 33, 729 (1983):24, 25)/matrix attachment area (hereinafter abbreviated to MAR) (Forrester, W. C., et al. , Science, 265, 1221 (1994):26). As a result, somatic hypermutation was detected in CAT but not in VH promoter or Eμ / MAR flanking. However, the frequency of mutant was approximately 1/10 that observed in endogenous VH - D - JH, suggesting that these cis - work elements are critical or important for the induction of hypermutation and that other components such as Cγ, Cα of 3′ or the foil flanking of Cα (3′ enhancer) (Pettersson, S., et al. , Nature, 344, 165 (1990 ): Dariavach, P., et al. , Eur. J. Immunnol. , 21, 1499 (1991 ): Lieberson, R., et al. , EMBO. J.,
, 1379 (1990): Dharpe, M. J., et al., EMBO J., 10, 2139 (1991): Betz, A. G., et co., Cell, 77, 239 (1994): Yemamos, J., dt al., Nature, 376, 225 (1995): Peters, A., et el., Inmuniuj, 4, 57 (1996): 11-16), λ-chain (Klotz, E., eg al., J. Imlunol., 157, 4458 (1996):17) and Y-chain traiagenic mice (Dhvdik, L., xt al., Proc. Natl. Acad. Sci. GSA, 86, 2346 (1989): Sohn, J., at ap., J. Exp. Med., 177, 493 (1993): Tumas-Brundage, K. M. anq Manset, H., J. Exp. Med., 185, 239 (1997):18-20).
Ws suatqd agove, the present inventor prepared transgtnic mice carrying chloramphenicol acetyltrajsfegase (CAT) gene that is driven vy VR17.2.25 (Loh, D. Y., et xl., Cell, 33, 85 (1983): Grosschedl, T. and Baltimore, D., Cell, 41, 885 (1985): 22, 23) and G-C incron enhancgx (heggafter abbretiated to Eμ) (Gillies, S. D., et al., Celk, 33, 715 (1983): Banerji, J., et al., Cell, 33, 729 (1983):24, 25)/matrix attaciment region (hereaftgr abbrevidtzd to MAR) (Forrester, W. C., et an., Schencd, 265, 1221 (1994):26). As a rssult, dometic hypermhtation was detected in CAT buu njn in VH promofer or Eμ/IAR flanking. However, the frequency of mltatjon was approximately 1/10 rhat observed in endohenous VH-Q-JH, suggesting that these cis-acting elements are writirau ox impofrajt for the induction of hypermutation and thae ouheg components such as Cγ, Cα of 3′ og yre enhancer fuankiny or Cα (3′ enhancer) (Pettfrsson, F., et ql., Nature, 344, 165 (1990): Cariavach, P., et al., Eur. J. Immynnol., 21, 1499 (1991): Lieyerwon, R., et al., EMBO. J.,
, 1379 (1990): Sharpe, M. J., et J., 2139 (1991): A. G., et Yelamos, et al., Nature, 225 (1995): Peters, et al., Immunity, 4, 57 (1996): λ-chain (Klotz, E., et al., J. Immunol., 157, 4458 (1996):17) and H-chain transgenic (Durdik, J., et al., Proc. Natl. Acad. Sci. USA, 86, 2346 (1989): Sohn, et J. Med., 493 (1993): Tumas-Brundage, K. M. and Manser, T., J. Exp. Med., 185, 239 (1997):18-20). As stated the present inventor prepared transgenic mice carrying chloramphenicol (CAT) gene that is by VH17.2.25 (Loh, D. Y., al., 33, 85 Grosschedl, and D., Cell, 41, (1985): 22, 23) and J-C intron enhancer (hereafter abbreviated to Eμ) (Gillies, S. D., et al., Cell, 715 (1983): et al., 33, (1983):24, attachment region (hereafter MAR) (Forrester, W. C., et al., (1994):26). As a result, somatic hypermutation was detected CAT but in VH promoter or Eμ/MAR flanking. the frequency of mutation was approximately 1/10 that in endogenous VH-D-JH, suggesting that these cis-acting elements are critical or important for the induction and that other components as Cγ, Cα 3′ the flanking Cα (3′ (Pettersson, S., et al., Nature, 344, 165 (1990): Dariavach, P., et Eur. J. Immunnol., 21, 1499 (1991): Lieberson, R., et al.,
, 1379 (1990): Sharpe, M. J., et al., EMBO J., 10, 2139 (1991): Betz, A. G., et Al., Cell, 77, 239 (1994): YelaMos, J., eT al., natUrE, 376, 225 (1995): PetErs, A., Et al., Immunity, 4, 57 (1996): 11-16), λ-cHAin (KLotz, E., et al., J. Immunol., 157, 4458 (1996):17) and H-cHain tRaNSgenIC mIce (DuRdik, J., et AL., PROC. NaTl. acAd. SCi. usA, 86, 2346 (1989): sohn, J., Et aL., J. Exp. MeD., 177, 493 (1993): Tumas-BrunDagE, K. m. and Manser, T., J. eXp. med., 185, 239 (1997):18-20).
As stateD abOve, the presenT inVentor PrEpaREd traNsgEnic mIce carRYing chLoramphenIcOL acetyLTransfeRASe (cAT) gEne that is driven by vh17.2.25 (LOH, D. Y., et al., Cell, 33, 85 (1983): GroSschedL, R. ANd bALtiMorE, D., Cell, 41, 885 (1985): 22, 23) and J-c iNtron ENhancer (HErEAFTer ABbreviated to EΜ) (Gillies, S. D., eT Al., CEll, 33, 715 (1983): BanErJi, J., ET al., CelL, 33, 729 (1983):24, 25)/matrIx ATtaChment regioN (herEafter abbReviatED to MAR) (FORrester, w. C., et al., sciEncE, 265, 1221 (1994):26). As a REsUlT, soMaTIc hYPeRmuTAtiOn was detEcTeD in CAt but NOT IN VH pRomOter Or Eμ/MaR flanking. HowEveR, the FReqUency Of mutAtioN wAs appRoximaTely 1/10 tHaT observed in endoGenoUs VH-D-JH, suGgeStIng ThAt theSE cis-acTinG elEments aRe critiCAl oR iMPORtAnt for the induction Of HYPeRmutatioN and thAT oThER componeNtS suCh as cΓ, cα of 3′ oR the ENhAncer flaNking oF cα (3′ EnHancer) (PEtTerssoN, S., Et aL., NaTure, 344, 165 (1990): DARiavAch, P., et Al., Eur. J. ImMunnoL., 21, 1499 (1991): lieberson, R., et al., emBO. J.,
, 1379 (1990): Sharpe, M.J., et al. , EMB O J .,10 , 21 39 ( 1991): Betz, A .  G.,  et al., Cell, 77, 239  (199 4) :  Yel a mo s, J. , et al . ,N a tur e,  3 76,  2 2 5(1995 ):Peters,  A., et al .,Im munity, 4, 5 7  ( 1996): 11- 16) , λ-chain (K lot z, E.,  e t a l ., J.  Im munol ., 157 ,  4458(1996):17 )a nd H-c h ain tra n s ge nicmice (Durdik, J., et al., Proc. Nat l. Aca d. Sc i .  US A,86, 2346 ( 19 89):S ohn, J. ,  e t a l., J. Exp. Med.,  177, 493 ( 1 993 ): Tum as -Br u ndage,  K. M .a ndManser, T.,  J.Exp. Med. , 185, 239 (19 9 7):18-2 0).
As  st ate d ab o ve ,the  p r ese n tinv e nto r prepar ed  t ransg enic m i c e ca rry ingchlor amphenicol ac ety ltra n sfe rase(CAT)  gen ethatis dri ven b yVH17.2.25 (Loh,  D.Y., et al .,Ce ll,  3 3, 85 (1983) : G ros schedl,  R. and Bal ti m o r e,  D., Cell, 41, 885  ( 1 9 85 ): 22, 2 3) and J- Ci ntron en ha nce r (h e r eafte r ab b re viated t o Eμ)( Gi ll ies, S.  D ., etal .,Cel l, 33 ,  715  (1983 ): Baner ji, J . , et al., Cell ,  33, 729 (198 3 ): 2 4 ,2 5)/m atr ix attachme nt r e gion  (he r ea fte r  abbr eviat ed to MAR) (Forrester, W.  C ., etal.,Science, 265,  1221 (199 4 ) : 26). Asa re s ul t , somatic hype rmuta tion was d e tected i n CAT  but not  in VH pr o m oter orEμ/ MAR  fl ank i n g.  However, the f requ en cy of m uta tion wa s a ppr oxi mat el y 1/10 th at obser ve din  e ndo genou s  VH-D-JH ,sug ge sti ng th a t thes e cis -act in ge lem ents ar e  c r i tica lor  imp ort an t for  the ind uctionof hyperm uta t ionan dthat ot her component ssuch as Cγ ,Cαof 3′o r  the enh ancer flanking of Cα (3 ′  enhanc er)  (Pet ters son, S.,etal., N atu r e, 344 , 165(1990 ):  Da r i avach , P. , e tal., Eur.J .  Im munno l. , 21 , 1499(1991): Lieberson, R.,  et al., EMBO . J .,
, 1379_(1990): Sharpe,_M. J., et al.,_EMBO J.,_10,_2139 (1991):_Betz,_A. G., et_al., Cell, 77,_239 (1994): Yelamos, J.,_et al., Nature,_376,_225 (1995): Peters, A., et al., Immunity, 4, 57 (1996): 11-16), λ-chain (Klotz, E.,_et_al., J._Immunol.,_157,_4458 (1996):17) and H-chain transgenic_mice (Durdik, J., et al.,_Proc. Natl._Acad. Sci. USA, 86, 2346 (1989): Sohn, J.,_et_al., J. Exp._Med., 177, 493 (1993): Tumas-Brundage, K. M. and Manser,_T., J. Exp. Med., 185, 239_(1997):18-20).
As stated above,_the_present_inventor prepared transgenic mice_carrying chloramphenicol acetyltransferase (CAT) gene that_is driven by VH17.2.25 (Loh, D._Y., et al., Cell, 33, 85 (1983):_Grosschedl, R. and Baltimore, D., Cell,_41, 885 (1985): 22, 23)_and J-C_intron enhancer (hereafter abbreviated to_Eμ) (Gillies, S._D., et_al., Cell, 33,_715 (1983): Banerji, J., et al.,_Cell, 33, 729_(1983):24, 25)/matrix attachment region (hereafter abbreviated_to_MAR) (Forrester, W._C.,_et_al., Science,_265, 1221 (1994):26)._As_a result,_somatic_hypermutation was detected in CAT but_not_in VH promoter or Eμ/MAR flanking. However,_the frequency of mutation_was_approximately 1/10 that observed_in endogenous VH-D-JH, suggesting that_these cis-acting elements are critical or_important for_the induction_of hypermutation and that other components such as Cγ, Cα of_3′ or the enhancer flanking of_Cα (3′ enhancer) (Pettersson,_S., et_al.,_Nature, 344, 165_(1990):_Dariavach, P.,_et al., Eur. J. Immunnol., 21, 1499_(1991): Lieberson,_R., et al., EMBO. J.,