Humangenetik für Biologen

3PRINGER ,EHRBUCH

7ERNERÈ"USELMAIER 'HOLAMALIÈ4ARIVERDIAN

(UMANGENETIKÈ FàRÈ"IOLOGEN -ITÈÈ!BBILDUNGEN



0ROFÈ$RÈ7ERNERÈ"USELMAIER 0ROFÈ$RÈ'HOLAMALIÈ4ARIVERDIAN Kd_l[hi_jj>[_Z[bX[h] ?dij_jkj\”h>kcWd][d[j_a ?cD[k[d^[_c[hkcWdX_ebe]_[$;_d[kd_l[hi_jh[LehX[h[_jkd]_ij^_[h][hWZ[_d>kcWd# ][d[j_aledWkœ[hehZ[djb_Y^[h8[Z[kjkd]$;djifh[Y^[dZ[i]_bjX[p”]b_Y^Z[h=hkdZbW# ][dWkiX_bZkd]\”h<WY^f[hiedWbled;_dh_Y^jkd][dZ[h8[^_dZ[hj[d^_b\[$ =b[_Y^me^b]WX[iX_i^[ha[_dB[^hXkY^Z[h>kcWd][d[j_a\”hIjkZ[dj[dZ[hl[h# iY^_[Z[d[dJ[_bX[h[_Y^[Z[h8_em_ii[diY^W\j[d$:_[i]_bjieme^b\”hZ[dkd_l[hi_jh[d 8[h[_Y^c_jZ[dIjkZ_[d]d][d8_ebe]_[c_jP_[bh_Y^jkd]:_fbec"IjWWji[nWc[d"CWi# j[he\IY_[dY[kdZ8_ej[Y^debe]_[WbiWkY^\”hZ_[[djifh[Y^[dZ[d8[h[_Y^[Wd<WY^# ^eY^iY^kb[d$:_[IjkZ[dj[dmWh[d_cM[i[djb_Y^[dWk\ZWi>kcWd][d[j_a#B[^hXkY^ \”hC[Z_p_dijkZ[dj[dZ[h7kjeh[dZ_[i[i8kY^[iWd][m_[i[deZ[hWk\ceb[akbWhX_ebe# ]_iY^[Kdj[hh_Y^jim[ha["X[_Z[d[d^kcWd][d[j_iY^[kcWd][d[j_a][dWkieX[^WdZ[bjm[hZ[dm_[Z_[Poje# ][d[j_a"Z_[\ehcWb[kdZab_d_iY^[=[d[j_a"Z_[FefkbWj_edi][d[j_aiem_[Z_[?dj[hWa# j_edled=[d[dkdZKcm[bj$M_Y^j_]mWhWkY^Z_[8[iY^h[_Xkd]Z[hfhWaj_iY^[d7d# m[dZkd]iX[h[_Y^[ kdZ Z[h m_ii[diY^W\jb_Y^[d 7if[aj[ \”h WdZ[h[ <WY^X[h[_Y^[ m_[ Z_[Ah[Xi\ehiY^kd]"Z_[[nf[h_c[dj[bb[;cXhoebe]_["Z_[;lebkj_edi\ehiY^kd]X_i^_d pkh\eh[di_iY^[dC[Z_p_d$ 8[_Z[hL[hc_jjbkd]Z[iIje\\[imkhZ[dWj”hb_Y^ceZ[hdij[dZ_ZWaj_iY^[d8[Z”h\# d_ii[dH[Y^dkd]][jhW][d$M[hj][b[]jmkhZ[WkY^Wk\[_dWki\”^hb_Y^[i=beiiWh_kc" ZW_cJ[njl_[b[<WY^WkiZh”Ya[L[hm[dZkd]\_dZ[dc”ii[d"Z_[WkiZ[hc[Z_p_d_iY^[d J[hc_debe]_[ijWcc[dkdZ\eb]b_Y^d_Y^jpkcWbb][c[_d[d?dl[djWhZ[h8_ebe][d][# ^h[d$ 7kjeh[dkdZL[hbW][h^e\\[di_Y^>_dm[_i[";cf\[^bkd][dkdZah_j_iY^[8[khj[_# bkd][d Z[i J[nj[i led ijkZ[dj_iY^[h I[_j[ kdZ led I[_j[d Z[h <WY^aebb[][d" Z_[ [dj# iY^[_Z[dZpkL[hX[ii[hkd][da”d\j_][h7k\bW][dX[_jhW][dadd[d$

6)))È

6ORWORT

>[hpb_Y^ZWda[dcY^j[dZ_[7kjeh[d_^h[dm_ii[diY^W\jb_Y^[dB[^h[hdkdZ^_[h lehWbb[c>[hhdFhe\$:h$c[Z$:h$^$Y$kcWd][d[j_a$$$$$$$$$$ * ;k][d_akdZFeb_j_a$$$$$$$$$$$$$$:_[;djm_Yabkd]Z[h c[Z_p_d_iY^[d=[d[j_a $$$$$$$$$$$ / :D7#j[Y^debe]_iY^[i P[_jWbj[hZ[h=[][dmWhj$$$$$$$$$$$'& -OLEKULAREÈ'RUNDLAGENÈÈ DERÈ(UMANGENETIKÈ ÈÈÈÈÈÈÈÈÈÈÈÈÈÈÈÈ Kd_l[hiWb_jjZ[h][d[j_iY^[d =hkdZbW][ $$$$$$$$$$$$$$$$$$$$$$ '* 7k\XWkkdZH[fb_aWj_edZ[h:D7 $$ '+ 7k\XWkkdZ:[\_d_j_edled=[d[d$$ () JhWdiah_fj_edZ[h:D7_d HD7kdZFheY[ii_d] $$$$$$$$$$$$$(=[d[nfh[ii_ed$$$$$$$$$$$$$$$$$$$ )+ Fhej[_dX_eiodj^[i[ÄJhWdibWj_ed$$$)/ Fhej[_dijhkajkh$$$$$$$$$$$$$$$$$$*) #HROMOSOMEN È-UTATIONENÈUNDÈÈ IHREÈ&OLGENÈFàRÈDIEÈ'ESUNDHEITÈÈÈÈÈÈ P[bbpoabkikdZP[bbj[_bkd]$$$$$$$$$ */ ?dj[hc_jei[poabki$$$$$$$$$$$$$$$$ */ C_jei[kdZ_^h[IjWZ_[d$$$$$$$$$$$ +( 7c_jej_iY^[L[hdZ[hkd][dZ[i 9^heceiec[diWjp[i $$$$$$$$$$$$$ ++ C[_ei[$$$$$$$$$$$$$$$$$$$$$$$$$$ +;djm_Yabkd]Z[h=[iY^b[Y^ji# p[bb[d$$$$$$$$$$$$$$$$$$$$$$$$$$$ +7XbWk\Z[hC[_ei[$$$$$$$$$$$$$$$$ +k\_][Iocfjec[X[_WkjeiecWb[d 9^heceiec[dWX[hhWj_ed[d$$$$$$ '() )$-$. IecWj_iY^[ 9^heceiec[dWX[hhWj_ed[d$$$$$$ '()

8È

)NHALTSVERZEICHNIS

)$.

=[dckjWj_ed[dkdZ_^h[ \kdaj_ed[bb[d<eb][d $$$$$$$$$$$$ '(* )$.$' >ce]beX_dceb[a”b $$$$$$$$$$$$ '(* )$.$( Ckbj_fb[7bb[b_[ $$$$$$$$$$$$$$$$$ '(/ )$.$) CkjWj_ed[dd_Y^j#][aeff[bj[h Bea_c_jl[hmWdZj[hkcWd# ][decikdZi[_d[8[]b[_jfhe`[aj[$(&+ :_[l[hiY^_[Z[d[d c[j^eZ_iY^[d7dijp[$$$$$$$$$$$ (&, =[d[j_iY^[AWhj_[hkd]c_j H[ijh_aj_edi#\hW]c[djbd][d# Febocehf^_ic[d $$$$$$$$$$$$$$$ (&, =[d[j_iY^[AWhj_[hkd]”X[h C_aheiWj[bb_j[d#CWha[h$$$$$$$$$$(&=[d[j_iY^[AWhj_[hkd]”X[h;_dp[b# dkab[ej_Z#Febocehf^_ic[dIDFi(&F^oi_aWb_iY^[AWhj_[hkd]iijhWj[]_[d dWY^abWii_iY^[c7diWjp$$$$$$$$$ (&. >eY^Wk\bi[dZ[f^oi_aWb_iY^[ AWhj_[hkd]ic[j^eZ[d$$$$$$$$$$$ (&/ Dec[dabWjkhc[diY^b_Y^[h=[d[ kdZ:D7#I[]c[dj[$$$$$$$$$$$$$('' =[decfhe`[aj[WdZ[h[h Eh]Wd_ic[d$$$$$$$$$$$$$$$$$$$$('' :[hWbb][c[_d[7k\XWk Z[ic[diY^b_Y^[d=[deci $$$$$$$ (') :WiA[hd][dec $$$$$$$$$$$$$$$$ ('* :_[L[hj[_bkd]Z[i9^hecWj_di kdZZ[h=[d[_c=[dec$$$$$$$$$ ('+ C[diY^b_Y^[HD7#=[d[$$$$$$$$$$ ('+ C_jeY^edZh_Wb[=[d[$$$$$$$$$$$$ (', :[hc_jeY^edZh_Wb[ =[d[j_iY^[9eZ[$$$$$$$$$$$$$$$$ ('. AeZ_[h[dZ[:D7$$$$$$$$$$$$$$$$ ('/ 7dj[_b[Wdh[f[j_j_l[h:D7$$$$$$$ ('/ :_[BW][led=[d[d c_jl[hmWdZj[hkcWd][d[j_a_ijledX[iedZ[h[c?d# j[h[ii[" m[_b Z_[ >kcWd][d[j_a" _c =[][diWjp pkl_[b[dWdZ[h[dDWjkhm_ii[diY^W\j[d_cc[h m_[Z[h iep_Wb[ kdZ feb_j_iY^[ ;h[_]d_ii[ X[# [_d\bkiij ^Wj$ Kc][a[^hj mWh i_[ _d _^h[h ;dj# m_Yabkd] Wbi M_ii[diY^W\j WkY^ kdj[hiY^_[Z# b_Y^[d feb_j_iY^[d :h”Ya[d Wki][i[jpj" Z_[ _^# h[^Y^ij[F[hl[hj_[hkd]_d:[kjiY^bWdZ_dZ[h Wbi×HWii[d^o]_[d[ÆX[p[_Y^d[j[d;k][d_aZ[i DWj_edWbiep_Wb_icki[hh[_Y^j[d$?d;hm[_j[hkd] Z[hWdZ[h[dB[X[dim_ii[diY^W\j[dX[iY^\j_]j i_Y^ Z_[ >kcWd][d[j_a c_j Z[d X_ebe]_iY^[d =hkdZbW][dkdi[h[h[_][d[d;n_ij[dpkdZc_j Z[hWWh[" D][b" L[d[d" 7hj[h_[d" I[^# d[dkdZAdeY^[d"kdi_Y^jXWh"m[_b_^h[J[_b[ie

ab[_d i[_[d$ M^h[dZ Z[i MWY^ijkci m”hZ[d i_[ i_Y^ ][jh[ddj led[_dWdZ[h [djm_Ya[bd kdZ [hfeijkb_[hj[×m_[addj[i_Y^>WWhWkiD_Y^j# >WWhkdZWhjie# [Ya[h ',--" ^_[bj i_Y^ deY^ Z_[ >ofej^[i[ Z[h <ehc_[hkd]" m[dd WkY^ [_d_][ ]bWkXj[d" ZWii ZWi ?dZ_l_Zkkc _d If[hc_[d lehWki][# X_bZ[jleh^WdZ[dmh[$:_[i[hIjh[_jZ[h×El_i#

È

È qÈ $IEÈ0ARADIGMENÈVONÈ'ALTONÈUNDÈ-ENDEL

j[dÆ ][][d Z_[ ×If[hcWj_ij[dÆ ^_[bj bWd][ Wd" X_iiY^b_[œb_Y^Meb\\'-+/X[_Z[I[_j[d_d_d# m[_i[ Wk\ Z_[ L[h[hXXWha[_j led AhWda^[_j[d$ Ie fkXb_p_[hj[ CWcf[hj_ki '-+( [_d[ <Wc_# b_[ c_j FeboZWajob_[ _d l_[h =[d[hWj_ed[d" me# X[_ [h ZkhY^ MW^hiY^[_db_Y^a[_jiX[h[Y^dkd# ][d[_d[;djij[^kd]Z[h\Wc_b_h[dAedp[djhW# j_edZkhY^Pk\WbbWkiiY^beii$IY^b_[œb_Y^l[h\# \[djb_Y^j[Z[hXh_j_iY^[7hpj7ZWci'-+,Ä'.'. '.'*[_d8kY^c_jZ[cJ_j[b×7Jh[Wj_i[edj^[ Ikffei[Z >[h[Z_jWho Fhef[hj_[i e\ :_i[Wi[iÆ$ ;iaWddWbi[hij[hLehbk\[hled;ha[ddjd_ii[d pkh ][d[j_iY^[d 8[hWjkd] Wd][i[^[d m[hZ[d" _dZ[c[iX[c[ha[dim[hj[8[\kdZ[X[iY^h[_Xj$ Iem[hZ[dX[h[_ji×h[p[ii_l[ÆkdZ×Zec_dWdj[Æ L[h[hXkd]iX[Z_d]kd][dWd][Z[kj[j$;im[hZ[d ^k\_][dW^[L[hmWdZjiY^W\jiX[p_[^kd][dled ;bj[hd X[_ \Wc_b_h[d ;hahWdakd][d X[iY^h_[# X[d$Kdj[hiY^_[Zb_Y^[CWd_\[ijWj_ediWbj[hm[h# Z[d [X[die Wk\][p[_]j" m_[ Z[h ;_d\bkii led Kcm[bj\Wajeh[dWk\Z_[FhZ_ifei_j_edled;h# ahWdakd][d kdZ Z[h[d M[_j[h]WX[" m[dd Z_[ FhZ_ifed_[hj[d d_Y^j i[bXij [hahWdaj[d$ :Wi 8kY^ ][^j [_d Wk\ Z_[ c]b_Y^[ kdj[hiY^_[Z# b_Y^[ ][d[j_iY^[ 8Wi_i led ;hahWdakd][d" _d# jhW\Wc_b_h[Aehh[bWj_ed[dX[_c;hahWdakd]i# Wbj[h" ^^[h[ _dm[_i Wk\ ZWi 7k\jh[j[dledd[k[dCkjWj_ed[d][m[hj[jm[h# Z[d$ Akhp dWY^ ;hiY^[_d[d Z_[i[i 8kY^[i \eb]# j['.(&ZkhY^Z[dZ[kjiY^[dC[Z_p_dfhe\[iieh DWii[ Z_[ ;djZ[Yakd] Z[i m_Y^j_]ij[d \ehcW# b[d 9^WhWaj[h_ij_akci N#Y^heceiecWb#h[p[i#

È



i_l[hL[h[hXkd]X[_>cef^_b_[$DWii[[haWdd# j[" ZWii Z_[ 8bkj[hahWda^[_j dkh X[_ cddb_# Y^[dF[hied[dcWd_\[ijm_hZkdZZ_[{X[hjhW# ]kd]ledJY^j[hd[hahWdaj[hCdd[hWk\Z[# h[d A_dZ[h [h\eb]j" i[bXij m[dd i_[ c_j [_d[c CWddl[h^[_hWj[ji_dZ"Z[ii[d<Wc_b_[d_Y^jX[# jhe\\[d_ij$;h\”^hj[m[_j[hWki"ZWiiZ_[7dbW# ][jh][hiY^W\j X[_ Z_[i[d k# cWd][d[j_a X[iWœ a[_d \”^h[dZ[i FWhWZ_]# cW$:_[;djm_Yabkd]pk[_d[hM_ii[diY^W\jX[# ]Wdd"m_[Z_[iLe][b'//,X[iY^h[_Xj"_c@W^# h['.,+ZkhY^pm[_lec7diWjp^[hi[^hkdj[h# iY^_[Zb_Y^[FWhWZ_]c[dled=WbjedkdZC[d# Z[b$M^h[dZC[dZ[bc_ji[_d[d;hXi[d#;nf[# h_c[dj[d7XX$'$'kdZ'$(WbiZ[h=h”dZ[hZ[h Wbb][c[_d[d=[d[j_a]_bj"\”^hj[=WbjedZWiX_e# c[jh_iY^[FWhWZ_]cWZkhY^pm[_akhp[IY^h_\# j[dc_jZ[cJ_j[b×>[h[Z_jWhoJWb[djWdZ9^W# hWYj[hÆ [_d JWX[bb[ '$'$ :khY^ Z_[ IWccbkd] kdZ X_ec[jh_iY^[7kim[hjkd] led 8_e]hWf^_# [d ^[hWkihW][dZ[h Cdd[h kdZ Z[h kcWd][d[j_a X[p[_Y^d[d aWdd$ 7kY^ _d Z[d [hij[d @W^hp[^dj[d Z[i (&$ @W^h# ^kdZ[hji mWh =Wbjedi 7diWjp [_d\bkiih[_Y^$ ;h l[hbeh[hijWd8[Z[kjkd]ZkhY^Z_[<ehjiY^h_j# j[Z[hceb[akbWh[d8_ebe]_["kdZC[dZ[bi=[# i[jp[ [hm_[i[d i_Y^ Wbi kdX[]h[dpj \hkY^jXWh kdZ led [dZ]”bj_][h" WdWboj_iY^[h AhW\j$ :Wi

+APITELÈÈqÈ$IEÈ'ESCHICHTEÈDERÈ(UMANGENETIK

È

!BBÈÈ -ENDELSÈ6ERSUCHSANSATZ





 4ABELLEÈ È $IEÈ ENTSCHEIDENDENÈ 0UBLI È KATIONEN È WELCHEÈ DIEÈ WISSENSCHAFTLICHEÈ 'ENETIKÈ GRàNDETENÈ -ENDELSÈ 0UBLIKATIONÈ ERSCHIENÈAUFÈDERÈ"ASISÈVONÈZWEIÈ6ORLESUNGENÈ AMÈ È &EBRUARÈ UNDÈ AMÈ È -ËRZÈ È IMÈ &OLGEJAHR 'REGORÈ-ENDELÈÈ 6ERSUCHEÈàBERÈ0FLANZENHYBRIDENÈ È)6ÈÈ "ANDÈDERÈ6ERHANDLUNGENÈDESÈNACHFORSCHEN DENÈ6EREINSÈINÈ"RàNN &RANCISÈ'ALTONÈÈ (EREDITARYÈ4ALENTÈANDÈ#HARACTERÈ È -ACMILLANSÈ-AGAZINEÈ

=[daedp[fjmkhZ[pkcp[djhWb[dAedp[fj\”h Z_[][iWcj[=[d[j_a$:[ddeY^"WkY^^[kj["_c P[_jWbj[h Z[h 7dWboi[ Z[i c[diY^b_Y^[d =[# deci"]_Xj[iaecfb[n["ceZ[hd[7dijp["m_[ p$8$_dZ[hL[h^Wbj[di#kdZIep_Wb][d[j_a"_dZ[# d[d[_d[Z_h[aj[=[dm_hakd]deY^d_Y^jkdj[h# ikY^j m[hZ[d aWdd kdZ Z[h X_ec[jh_iY^[7d# iWjpZ[h[_dp_]]Wd]XWh[_ij$

È

$IEÈFRàHEÈ(UMANGENETIKÈ

:Wi C[dZ[bÉiY^[ FWhWZ_]cW mkhZ[ _d Z_[ c[diY^b_Y^[ <ehiY^kd] ZkhY^ =WhheZ '/&( c_j i[_d[h FkXb_aWj_ed ×J^[ _dY_Z[dY[ e\ 7b#

aWfjedkh_W0 7 ijkZo _d 9^[c_YWb ?dZ_l_Zk# Wb_joÆ [_d][\”^hj$ DWY^ [_d][^[dZ[d <Wc_b_# [dkdj[hikY^kd][d kdZ Z[h 8[iY^h[_Xkd] Z[h WkiiY^b_[œb_Y^[d 7kiiY^[_Zkd] led >ece# ][dj_i_dikh[ ZkhY^ Jh][h Z_[i[i B[_Z[di [h# m^dj =WhheZ Z_[ C[dZ[bÉiY^[d =[i[jp[ kdZ Z_[AecfWj_X_b_jjZ[h:Wj[dc_j[_d[ch[p[i# i_l[d;hX]Wd]$:Wh”X[h^_dWki][^[dZ[hm^dj [h7bX_d_ickikdZPoij_dkh_[Wbim[_j[h[c]# b_Y^[8[_if_[b[\”h[_d[]b[_Y^Whj_][L[h[hXkd] kdZ Z_[i Wbi [_d Fh_dp_f m[_jl[hXh[_j[j[h" Y^[# c_iY^[h Kdj[hiY^_[Z[ pm_iY^[d C[diY^[d$ ;h p_[^j ZWhWki Z[d IY^bkii" ZWii ][h_d][ Y^[c_# iY^[Kdj[hiY^_[Z[pm_iY^[dC[diY^[die^k# \_]i_dZ"ZWiia[_dC[diY^Y^[c_iY^_Z[dj_iY^ pk[_d[cWdZ[h[d_ij$:_[imWhZ[h8[]_dd[_# d[i d[k[d <ehiY^kd]ipm[_][i" Z[h X_eY^[c_# iY^[d=[d[j_a$ ?dZ[d@W^hp[^dj[ddWY^C[dZ[bi>oXh_Z_# i_[hkd]i[nf[h_c[dj[d kdZ =Wbjedi X_ec[jh_# iY^[d 7dWboi[d [djm_Ya[bj[ i_Y^ Z_[ 9^hece# iec[d\ehiY^kd]$ C[dZ[b mkiij[ deY^ d_Y^ji ledikXijWdp_[bb[dJh][hdZ[h][d[j_iY^[d?d# \ehcWj_ed$8WbZZWhWk\\eb]j[`[ZeY^Z_[?Z[d# j_\_aWj_ed Z[h 9^heceiec[d kdZ Z_[ 7dWbo# i[ledC_jei[kdZC[_ei[$:_[i[Fhep[ii[mkh# Z[dWbi^eY^][ehZd[jkdZe\\[di_Y^jb_Y^][[_]# d[j\”hZ_[h[]kbh[L[hj[_bkd]Z[h][d[j_iY^[d ?d\ehcWj_ed[haWddj"ieZWiicWd'/&&Z_[FW# hWbb[b_jj pm_iY^[d C[dZ[bÉiY^[h I[]h[]Wj_ed kdZ Y^heceiecWb[hL[hj[_bkd] _d Z[h C[_ei[ [haWddj[$:_[9^heceiec[dmkhZ[dWbiJh][h Z[h][d[j_iY^[d?d\ehcWj_ed_Z[dj_\_p_[hj$

È qÈ $IEÈFRàHEÈ(UMANGENETIK

È

È



!BBÈ È &AKSIMILEÈ DESÈ HANDSCHRIFTLICHENÈ -ANUSKRIPTSÈ 'REGORÈ -ENDELSÈ È !BSCHNITT È MITÈ DEMÈ ERÈ SEINEÈ 6ERER BUNGSLEHREÈVERÚFFENTLICHTÈHATÈ$IEÈLINKEÈMITÈ"LEISCHRIFTÈGESCHRIEBENEÈ!NMERKUNGÈuÈ3EPARATAhÈSTAMMTÈVOMÈ2E DAKTEURÈDERÈ6ERHANDLUNGENÈDESÈNACHFORSCHENDENÈ6EREINS

+APITELÈÈqÈ$IEÈ'ESCHICHTEÈDERÈ(UMANGENETIK

È





 4ABELLEÈÈ (ERVORRAGENDEÈ-ËNNERÈUNDÈIHREÈ6ERWANDTSCHAFTSBEZIEHUNGENÈNACHÈ'!,4/.È :AHLÈÈ DERÈÈ &ËLLEÈ È

È È È È

6ORKOMMENÈÈ VONÈNAHENÈÈ MËNNLICHENÈ 6ERWANDTENÈ

È 0ROZENTSËTZEÈ "EDEUTENDERÈ6ATERÈ "EDEUTENDERÈ-ANNÈ HATTEÈBEDEUTENDENÈ HATTEÈBEDEUTENDEN 3OHNÈ È "RUDER

È È È È È

!LLEÈ-ËNNERÈVONÈ ÈuORIGINELLEMhÈ6ERSTANDÈÈ ORIGINALÈMIND ÈAUSÈALLENÈÈ "ERUFSSCHICHTENÈZWISCHENÈÈÈ UNDÈÈNÈ3IRÈ4È0(), ,)03

ÈVÈÈ&ËLLENÈ

ÈMALÈVÈÈ

ÈMALÈVÈÈ

È È È

,EBENDEÈ"ERàHMTHEITENÈNACHÈ 7!,&/2$3|Èu-ENÈOFÈTHEÈTIMEShÈ "UCHSTABEÈ!

ÈVÈÈÈ&ËLLENÈ ÈMALÈVÈÈ

ÈMALÈVÈÈ

È È

-ALERÈALLERÈ:EITENÈÈ "29!.|3È$ICTÈ!

ÈVÈÈ&ËLLENÈ

ÈMALÈVÈÈ

ÈMALÈVÈÈ

È

-USIKERÈ&%49|3È$ICTÈ! È

ÈVÈÈ&ËLLENÈ

ÈMALÈVÈÈ

ÈMALÈVÈ

È

,ORDKANZLERÈNÈ,/2$È#!-0"%,, È

ÈVÈÈ&ËLLENÈ

ÈMALÈVÈÈ

ÈMALÈVÈ

È È È

u3ENIORÈCLASSICShÈ"ESTEÈINÈÈ DENÈKLASSISCHENÈ3PRACHEN ÈÈ #AMBRIDGE

ÈVÈÈ&ËLLENÈ

ZUÈJUNG È

ÈMALÈVÈÈ

È

$URCHSCHNITTSWERTEÈ

ÈVÈÈ&ËLLENÈ

ÈMALÈVÈÈ

L_[b[M_ii[diY^W\jb[h i_dZ ^_[h pk d[dd[d$ >[hjm_] '.-+ X[eXWY^j[j[ Z_[ WhZo kdZ Z[h Z[kj# iY^[7hpjM[_dX[h]\ehckb_[hj[d[jmWpkh]b[_# Y^[d P[_j '/&. ZWi \kdZWc[djWb[ J^[eh[c Z[h FefkbWj_edi][d[j_a" m[bY^[i [habhj" mWh# kcZ_[_jb[h#:[kjiY^# bWdZ _ij [_d[i Z[h cWaWX[hij[d kdZ jhW]_iY^i# j[d AWf_j[bd _d Z[h =[iY^_Y^j[ c[diY^b_Y^[h ?d^kcWd_jj _c DWc[d [_d[i fi[kZem_ii[d# iY^W\jb_Y^[dDWj_edWbiep_Wb_icki$ ?d Z[h Iem`[jkd_ed mkhZ[ Z_[ ;k][d_a _d Z[d '/(&[h @W^h[d [jWXb_[hj ZkhY^ Z_[ =h”d# Zkd] [_d[i ;k][d_a#?dij_jkji" [_d[h [k][d_# iY^[d=[i[bbiY^W\jkdZ[_d[i[k][d_iY^[d@ekh# dWbi$ :_[ [k][d_iY^[d ?Z[Wb[ aWc[d `[ZeY^ iY^d[bb _d Aed\b_aj c_j Z[d e\\_p_[bb[d :eajh_# d[dZ[iCWhn_icki#B[d_d_icki"ieZWii_dZ[d ifj[d'/(&[h@W^h[dZ_[8[m[]kd]pkiWcc[d# XhWY^kdZi_Y^Z_[_dlebl_[hj[dM_ii[diY^W\jb[h _dWdZ[h[=[X_[j[pkh”Yape][d$:[ddeY^Xb_[X ZWi ?dj[h[ii[ Wd Z[h c[Z_p_d_iY^[d 7dm[d# Zkd] Z[h >kcWd][d[j_a X[ij[^[d$ ;_d ]heœ[i ?dij_jkj\”hc[Z_p_d_iY^[=[d[j_amkhZ[_dZ[d '/(&[h @W^h[d [jWXb_[hj" Wbb[hZ_d]i l[hiY^mWdZ i[_d:_h[ajeh_dZ[d'/)&[h@W^h[dkdZ>kcWd# ][d[j_a mkhZ[ e\\_p_[bb Wbi DWp_#M_ii[diY^W\j [habhj$:[hifj[h[;_d\bkiiBoii[daei[hij_Ya# j[ Wbb[ ][d[j_iY^[d 7hX[_j[d X_i _d Z_[ \h”^[d '/,&[h @W^h[" dWY^Z[c Boii[daei :ec_dWdp X[[dZ[j mWh$ :_[ M_[Z[h[_d\”^hkd] led >k# cWd][d[j_a _d Z_[ Iem`[jkd_ed \WdZ ”X[h Z_[ c[Z_p_d_iY^[=[d[j_aijWjj"kdZ[_dd[k[i?di# j_jkjmkhZ[_dCeiaWk'/,/kdj[hZ[cPoje][# d[j_a[h8eY^aelWbi7ki]Wd]iXWi_iZ[hceZ[h# d[d>kcWd][d[j_a][]h”dZ[j$

ÈÈ $IEÈ%NTWICKLUNGÈÈ È DERÈMEDIZINISCHENÈ'ENETIKÈ :_[ ;djm_Yabkd] Z[h c[Z_p_d_iY^[d =[d[j_a ^Wj _^h[d 7ki]Wd]ifkdaj _d [_d[h H[_^[ led XW^dXh[Y^[dZ[d ;djZ[Yakd][d kdZ F_ed_[h# WhX[_j[d$ '/*) ][b_d]j Z[c Xh_j_iY^[d 8_eY^[# c_a[h7ijXkh]Z_[[hij[Hdj][dWk\dW^c[Z[h :D7$ '/** X[m[_i[d 7l[ho kdZ C_jWhX[_j[h Wc D[m Oeha HeYa[\[bb[h H[i[WhY^ ?dij_jk# j[" ZWii i_Y^ ][d[j_iY^[ C[hacWb[ ZkhY^ :D7 led[_d[cEh]Wd_icki”X[hjhW][dbWii[d"me#

È

È



c_jX[m_[i[d_ij"ZWii:D7_dZ[d9^heceie# c[dZ[hJh][hZ[h;hXikXijWdp_ij$FWkb_d][h# a[ddj'/*/"ZWiiI_Y^[bp[bbWdc_[[_d[ceb[ak# bWh[;hahWdakd]_ij"kdZ_c]b[_Y^[d@W^hm[_ij Z[h KI#8_eY^[c_a[h 9^W]W\\ Z_[ 8Wi[daec# fb[c[djWh_jj Z[h :D7 dWY^$ Pm[_ @W^h[ if# j[h"'/+'][b_d][dHeiWb_d[j[he][d_jjkdZZ_[Ck# jWj_edihWj[d led l[hiY^_[Z[d[d [hXb_Y^[d ;h# ahWdakd][d$ DWY^ Z[h ;djZ[Yakd] Z[i ][d[# j_iY^[d 9eZ[i mkhZ[d l_[b[ CkjWj_ed[d X[_ c[diY^b_Y^[d AhWda^[_j[d Wbi [_dp[bd[ 7c_# deikh[ikXij_jkj_ed[d ][\kdZ[d" WdZ[h[ [dj# fkffj[d i_Y^ Wbi kdj[hiY^_[Zb_Y^[ :[b[j_ed[d eZ[h \hWc[i^_\j#CkjWj_ed[d" ^db_Y^ iebY^[d" m_[ cWd i_[ X[_ C_aheeh]Wd_ic[d [djZ[Yaj[$ :_[Dkab[ej_Zi[gk[dpZ[hc[diY^b_Y^[d>ce#

È



+APITELÈÈqÈ$IEÈ'ESCHICHTEÈDERÈ(UMANGENETIK



 4ABELLEÈÈ $IEÈENTSCHEIDENDENÈ-EILENSTEINEÈDERÈ-OLEKULARBIOLOGIEÈDERÈLETZTENÈÈ*AHRE È È È È È È È È È È È

7ERNERÈ!RBERÈENTDECKTÈDIEÈ2ESTRIKTIONSENDONUKLEASEN 0AULÈ"ERGÈGELINGTÈDIEÈ(ERSTELLUNGÈREKOMBINANTERÈ$.! (ERBERTÈ"OERÈUNDÈ3TANLEYÈ#OHENÈSCHLEUSENÈERSTMALSÈ&REMD $.!ÈINÈ%ÈCOLI +ARYÈ"È-ULLINSÈENTWICKELTÈDIEÈ0#2 -ETHODE 3TARTÈDESÈ(UMANÈ'ENOMÈ0ROJEKTS #RAIGÈ6ENTERÈUNDÈDASÈ(UMANÈ'ENOMÈ0ROJEKTÈGEBENÈEINEÈGROBEÈ+ARTEÈÈ DESÈMENSCHLICHENÈ'ENOMSÈBEKANNT :UMÈÈ*AHRESTAGÈDERÈ%NTDECKUNGÈDERÈ$OPPELHELIXSTRUKTURÈWIRDÈDIEÈ3EQUENZIERUNGÈÈ VONÈ ÈDESÈMENSCHLICHENÈ'ENOMSÈBEKANNTÈGEGEBEN $IEÈ:AHLÈDERÈPROTEINKODIERENDENÈ'ENEÈWIRDÈDURCHÈDASÈ)NTERNATIONALEÈ(UMANÈ'ENOMÈÈ 3EQUENZIERUNGSKONSORTIUMÈMITÈ ÈANGEGEBEN

]beX_d#=[d[mkhZ[Wk\][abhj$L_[b[Wd][Xeh[# d[#=hkff[[_d[h8Wi[7XX$ ($($ HD7 kdZ :D7 kdj[hiY^[_Z[d i_Y^ _d _^# h[d F[djei[d$ HD7#Dkab[ej_Z[ [h^Wbj[d [_d[ H_Xei[" :D7#Dkab[ej_Z[ [_d[ (É#:[ienoh_Xe# i[7XX$($)$Ieme^bX[_:D7WbiWkY^X[_HD7 \_dZ[d i_Y^ `[ * ij_Yaije\\^Wbj_][ 8Wi[d" kdZ pmWh`[pm[_Fkh_d#kdZFoh_c_Z_dWXaccb_d# ][ 7XX$ ($ * kdZ ($+$Led i[bj[d[d 8Wi[d WX# ][i[^[d" ]_Xj [i _d Z[d [_dp[bd[d Dkab[_dik# h[d`[m[_bidkh)l[hiY^_[Z[d[Foh_c_Z_dXWi[d" ZWX[_aeccjZ_[8Wi[J^oc_ddkh_d:D7leh" Z_[8Wi[KhWY_bdkh_dHD7$

ÈÈ !UFBAUÈUNDÈ2EPLIKATIONÈDERÈ$.!È "AUSTEINEÈDERÈ$.! 1XNOHLQVlXUHQVLQG0ROHNOHPLW0ROHNXODUJH ZLFKWHQ LQ GHU *U|‰HQRUGQXQJ YRQ 0LOOLRQHQ !BBÈÈ 3CHEMAÈZUMÈ!UFBAUÈUNDÈZURÈ.OMENKLATURÈ 'XUFKdkab[_dikh[ifWbj[dZ[;dpoc[Dkab[W# EINESÈ.UKLEOTIDS

!BBÈÈ :USAMMENSETZUNGÈVONÈ !DENOSINÈAUSÈ!DENINÈUNDÈ2IBOSE

È

+APITELÈÈqÈ-OLEKULAREÈ'RUNDLAGENÈDERÈ(UMANGENETIK

 !BBÈ È  $ESOXYRIBOSEÈ DERÈ $.!È UNDÈ2IBOSEÈDERÈ2.!

!BBÈÈ 0URINBASEN

!BBÈÈ 0YRIMIDINBASENÈ

!BBÈÈ 3CHEMATISCHERÈ!USSCHNITTÈ AUSÈEINEMÈ0OLYNUKLEOTIDSTRANGÈ NACHÈ"RESCHÈUÈ(AUSMANNÈ

È qÈ !UFBAUÈUNDÈ2EPLIKATIONÈDERÈ$.!

 Fkh_dXWi[ :D70 *XDQLQ$GHQLQ HD70 *XDQLQ$GHQLQ

Foh_c_Z_dXWi[ &\WRVLQ7K\PLQ &\WRVLQ8UDFLO

&KHPLVFKH XQG SK\VLNRFKHPLVFKH 'DWHQ ]HLJHQGDVV1XNOHLQVlXUHQDXVODQJHQXQGXQ YHU]ZHLJWHQ<WZ[dceb[a”b[dEHVWHKHQ+LHUEHL VLQGGLHHLQ]HOQHQ0RQRQXNOHRWLGHGXUFK3KRV SKRGLHVWHUELQGXQJHQ ]ZLVFKHQ &¶ XQG &¶ GHU 3HQWRVHQ PLWHLQDQGHU YHUNQSIW 'LH 0R OHNOH EHVLW]HQ DOVR ZHJHQ GHU ¶  ¶%LQGXQ JHQ]ZLVFKHQ=XFNHUXQG3KRVSKDWHLQHQH_Y^# jkd]ii_dd$EE  Dkab[_dikh[d X[ij[^[d Wbie Wki l_[b[d 8Wkij[_d[d" Z[d Dkab[ej_Z[d$ ;_d Dkab[ej_Z i[jpj i_Y^ Wki [_d[h ij_Yaije\\^Wbj_][d 8Wi[" [_# d[h F[djei[ kdZ [_d[h Ehj^ef^eif^Wj]hkff[ pkiWcc[d 7XX$ ($-$ :D7 [dj^bj Z_[ 8Wi[d 7Z[d_d7"=kWd_d="9ojei_d9kdZJ^o# c_d J kdZ Wbi F[djei[ [_d[ :[ienoh_Xei[$ HD7[dj^bj_dZ[hH[][bijWjjZ[h8Wi[J^oc_d KhWY_bKkdZ[_d[H_Xei[ijWjj:[ienoh_Xei[$

!BBÈÈ $.! .UKLEOTIDÈHIERÈ!DENINÈALSÈ"ASE







3TRUKTURMODELLÈDERÈ$.!È .ULVWDOORJUDSKLVFKH 8QWHUVXFKXQJHQ %HXJXQJ YRQ5|QWJHQVWUDKOHQ ]HLJHQGDVVGLH'1$HL QHIY^hWkX[dijhkajkhEHVLW]W:HLWHUOlVVWVLFK DXV GHQ 'DWHQ IU 'XUFKPHVVHU XQG *DQJK| KH GHU 6FKUDXEH HLQHUVHLWV XQG IU 0DVVH XQG /lQJH GHV 0ROHNOV DQGHUHUVHLWV EHOHJHQ GDVV HV VLFK XP HLQH :eff[biY^hWkX[:eff[b^[b_n KDQGHOQPXVV 9^W]W\\ [djZ[Yaj[ '/+&#'/+) [_d[ Wbb][# c[_d[=[i[jpcœ_]a[_j\”h:D7l[hiY^_[Z[di# j[h>[hakd\j0  ZWi ceb[akbWh[ L[h^bjd_i led 7Z[d_d pk J^oc_dkdZled=kWd_dpk9ojei_dX[jh]j ij[ji'0'$ 7k\Z_[i[d^_[hdkhakhpWd][Z[kj[j[d8[\kd# Z[dXWi_[hj_cM[i[djb_Y^[dZWi'/+)ledMWj# iedkdZ9h_YaWk\][ij[bbj[kdZifj[h_d;_dp[b# ^[_j[dledM_ba_dil[hX[ii[hj[:D7#Ijhkajkh# ceZ[bb$ :_[i[ Zh[_M_ii[diY^W\jb[h j[_bj[d i_Y^ '/,(Z[dDeX[bfh[_i\”hF^oi_ebe]_[kdZC[Z_# p_d\”h_^h[<ehiY^kd]pkhceb[akbWh[dIjhka# jkh Z[h :D7$ :WdWY^ X[ij[^j ZWi :D7#Ceb[# a”b Wki pm[_ Febodkab[ej_Zijhd][d" Z_[ [_d[ ][][dbk\_][ FebWh_jj X[i_jp[d kdZ pk [_d[h :eff[biY^hWkX[ kc[_dWdZ[h][mkdZ[d i_dZ$ :WX[_ X_bZ[d `[m[_bi pm[_ i_Y^ ][][d”X[hb_[# ][dZ[" pk[_dWdZ[h aecfb[c[djh[ kdZ i[da# h[Y^j pkh >WbXWY^i[ ij[^[dZ[ 8Wi[d c_j _^# h[dD[X[dlWb[dp[dMWii[hije\\Xh”Ya[d"kdZ[i fWWhj i_Y^7Z[d_d ij[ji c_j J^oc_d kdZ =kW# d_dij[jic_j9ojei_d$ :[h:h[^i_ddZ[hIf_hWb[X_bZ[j[_d[H[Y^ji# iY^hWkX[$ :_[ M_dZkd][d m[_i[d ZWX[_ [_# d[Xh[_j[kdZ[_d[iY^cWb[H_dd[Wk\$:[h7X# ijWdZ pm_iY^[d Z[d Wk\][ijeYaj[d 8Wi[d X[# jh]j &")* dc DWY^ `[m[_bi p[^d 8Wi[dfWWh[d" Wbie)"*dc"_ij[_d[lebb[KcZh[^kd][hh[_Y^j 7XX$($.$:_[][][dbk\_][FebWh_jjX[Z[kj[j" ZWii_d[_d[cFebodkab[ej_ZijhWd]Z_[I[gk[dp 9#)É#F^eif^Wj#9#+ÉWdij[_][dZ"_dZ[cWdZ[h[d WX\Wbb[dZ l[hbk\j$ :_[ IjWX_b_jj Z[h >[b_n X[# hk^jWk\IjWf[bah\j[d"Z_[pm_iY^[dZ[d^oZhe# f^eX[d I[_j[d [d] X[_[_dWdZ[hb_[][dZ[h 8W# i[dWk\jh[j[d"d_Y^j"m_[cWdWdd[^c[dadd# j[" Wk\ Z[d MWii[hije\\Xh”Ya[d aecfb[c[dj# h[h8Wi[d7XX$($/"JWX[bb[($($

È

+APITELÈÈqÈ-OLEKULAREÈ'RUNDLAGENÈDERÈ(UMANGENETIK

!BBÈÈ 3TRUKTURÈDERÈ $.!ÈNACHÈ+NIPPERSÈETÈALÈ 



&LEXIBILITËTÈDERÈ$.!È :_[:eff[b^[b_nZ[h7XX$($._ijZ_[IjWdZWhZ# ZWhij[bbkd]Z[h:D7kdZjWjiY^b_Y^[djifh_Y^j Z[hWbb[h]hœj[J[_bZ[hA[hd#:D7_db[X[dZ[d P[bb[d c[^h eZ[h m[d_][h ][dWk Z_[i[h :Wh# ij[bbkd]"Z_[cWdWbi8#<ehcX[p[_Y^d[j$D[k# [h[ ah_ijWbbe]hWf^_iY^[ :Wj[d p[_][d `[ZeY^" ZWii_dd[h^WbXZ[h8#<ehc#=[ec[jh_[_[h d_ccj ZWi PkYa[h#F^eif^WjZ_[ij[h#H”Ya]hWj [_d[ P_Ya# PWYa#<ehc[_d$CWd^WjZ_[i[<ehc_dBikd# ][dc_j^e^[cIWbp][^Wbj][\kdZ[d$:_[m_ha#







b_Y^[ X_ebe]_iY^[ ;n_ij[dp Z[h7# kdZ P#<ehc _ijkcijh_jj[d"c]b_Y^[hm[_i[i_dZi_[dkh[n# f[h_c[dj[bb [hp[k]XWh$ I_[ p[_][d WX[h" ZWii ]hkdZijpb_Y^ Z_[ :D7#Ijhkajkh \b[n_X[b _ij" kdZ jWjiY^b_Y^ aecc[d WkY^ X[_ =[d#Ijhka# jkh[d 7Xm[_Y^kd][d led Z[h Wbb][c[_d[d 8# <ehcleh$ :_[ ab[_dij[d :D7#Ceb[a”b[" Z_[ m_h led L_h[d a[dd[d" X[ij[^[d Wki [_d_][d JWki[dZ 8Wi[dfWWh[d" Z_[ ]hœj[d X[\_dZ[d i_Y^ _c 9^heceiec[d led J_[h[d kdZ F\bWdp[d kdZ add[d Wki c[^h[h[d ^kdZ[hj C_bb_ed[d 8W# i[dfWWh[d Wk\][XWkj i[_d$ :WX[_ _ij Z_[ =hœ[ pkc_dZ[ij_d[hij[hD^[hkd][_dCWœ\”hZ_[ C[d][Wd][d[j_iY^[h?d\ehcWj_ed$ ,INEAREÈUNDÈRINGFÚRMIGEÈ$.!È :_[ :D7 _d [kaWhoej_iY^[d 9^heceiec[d b_[]j b_d[Wh leh 7XX$ ($'&$ 8[_ Z[d c[_i# j[d 8Waj[h_[d" X[_ C_jeY^edZh_[d kdZ Z[d f\bWdpb_Y^[d9^behfbWij[d_iji_[h_d]\hc_]][# iY^beii[d$:_[i^Wjp$8$_dZ[hfhWaj_iY^[d7h#

!BBÈÈ $IEÈ0AARUNGÈKOMPLEMENTËRERÈ"ASENÈDURCHÈÈ BZWÈÈ7ASSERSTOFFBRàCKENÈ



 4ABELLEÈÈ 3TRUKTURELLERÈ!UFBAUÈDERÈ$.!ÈÈ $OPPELHELIXÈ È0OLYNUKLEOTIDSTRËNGEÈSINDÈZUÈEINERÈ $OPPELSCHRAUBEÈUMEINANDERÈGEWUNDEN 0OLARITËT "EIDEÈ3TRËNGEÈBESITZENÈEINEÈGEGENLËUFIGEÈ 0OLARITËT "ASENPAARUNG 3PEZIFISCHEÈ"ASENPAARUNGÈ!ÈMITÈ4ÈÈ'ÈMITÈ#È $REHSINN 'EGENÈDENÈ5HRZEIGERSINNÈAUFSTEIGENDERÈ $REHSINNÈ%INEÈVOLLEÈ5MDREHUNGÈISTÈNACHÈÈ "ASENPAARENÈERREICHTÈ 3TABILITËT (YDROPHOBEÈ"INDUNGENÈBEIEINANDERLIEGENDERÈ "ASENÈSCHAFFENÈDENÈ:USAMMENHALT

!BBÈ È ,INEAREÈ UNDÈ RINGFÚRMIGEÈ $.!È .ACHÈ +IPPERSÈ

È



+APITELÈÈqÈ-OLEKULAREÈ'RUNDLAGENÈDERÈ(UMANGENETIK

X[_j <eb][d \”h _^h[ IjWX_b_jj X[_ Z[h ;hij[b# bkd] led :D7#Fhe\_b[d pkh F[hied[d_Z[dj_\_# aWj_edi$AWf$''$:Wh”X[h^_dWki_ijh_d]\h# c_] ][iY^beii[d[ :D7 e\j l[hZh_bbj" mWi cWd WbiIkf[h^[b_nX[p[_Y^d[j"Z[ddZ_[L[hZh_bbkd# ][di_dZledZ[dM_dZkd][dZ[h:eff[b^[b_n ”X[hbW][hj$:_[PW^bZ[hL[hZh_bbkd][dikf[h# Ye_biaWddled:D7#pk:D7#Ceb[a”bkdj[h# iY^_[Zb_Y^i[_d$ 2EPLIKATIONÈDERÈ$.!È :[h L[hc[^hkd]ic[Y^Wd_icki Z[h :D7 m_hZ Wbi H[fb_aWj_ed X[p[_Y^d[j$ :_[ ]heœ[ X_ebe# ]_iY^[ 8[Z[kjkd] Z_[i[i Leh]Wd]i b_[]j ZW# h_d"ZWiiZkhY^_^dZ_[?d\ehcWj_edZ[i[bj[hb_# Y^[d;hX]kji=[decWk\Z_[DWY^\eb][][d[# hWj_ed”X[hjhW][dm_hZ$DWY^Z[cMWjied#kdZ 9h_Ya#CeZ[bb p[_]j Z_[ :D7 ][hWZ[ X[p”]b_Y^ Z[hH[fb_aWj_ed[_d[d]heœ[dLehj[_b$:khY^Z_[ Aecfb[c[djWh_jjZ[h8Wi[d_ijdcb_Y^Z_[?d# \ehcWj_ed_c:D7#Ceb[a”bZeff[bjkdZ_d`[# Z[c Febodkab[ej_ZijhWd] [_dcWb leh^WdZ[d$ =hkdZijpb_Y^_ijZ_[?d\ehcWj_ed[_d[iIjhWd]i Wkih[_Y^[dZ" kc Z_[ 8Wi[d\h[gk[dp Z[i WdZ[# h[dpm[_\[bi\h[_Wdpk][X[d$ !UFSPREIZUNGÈDERÈ$OPPELHELIXÈ C[^h[h[;dpoc[i_dZ_dZ[dLeh]Wd]Z[hH[f# b_aWj_ed[_d][XkdZ[d$I_[i_dZX[_FheaWhoej[d Wbi H[fb_aWj_ediaecfb[n Wd Z_[ P[bbc[cXhWd ][XkdZ[d$PkdY^ij\\d[ji_Y^ZWi:D7#Ceb[# a”bdWY^Z[h7hj[_d[iH[_œl[hiY^bkii[i$:WX[_ X[ij[^jZ[h[hij[IY^h_jjpkhz\\dkd]Z[i:D7# Ceb[a”bi _d Z[h 7k\m_dZkd] Z[h :eff[b^[# b_nZkhY^[_d[>[b_aWi[$PkhL[hc_dZ[hkd]Z[h IfWddkd]i[jpjZWX[_[_d[Jefe_iec[hWi[][b[# ][djb_Y^[ ;_dp[bijhWd]Xh”Y^[ _d Z_[ :D7$ :Wi z\\d[dZ[h:eff[b^[b_n[h\eb]jZkhY^[_dm[_j[# h[i ;dpoc" m[bY^[i Z_[ X[_Z[d Febodkab[ej_Z# ijhd][ieifh[_pj"ZWiii_Y^Z_[h[bWj_lb[_Y^jpk jh[dd[dZ[dMWii[hije\\Xh”Ya[dbi[d$IY^b_[œ# b_Y^ ijWX_b_i_[h[d :D7#8_dZkd]ifhej[_d[ Z_[ [_dp[bijhd]_][:D7kdZl[h^_dZ[hd[_d[d[k# [hb_Y^[Dkab[ej_ZfWWhkd]$ ?c =[][diWjp pk FheaWhoej[d ]_Xj [i X[_ ;kaWhoej[dc[^h[h[H[fb_aWj_edi#IjWhjfkdaj[" Z_[cWdWbieh_]_de\h[fb_YWj_edX[p[_Y^d[j$

2EPLIKATIONÈMITTELSÈ0OLYMERASENÈ DWY^ Z[h z\\dkd] Z[h :eff[b^[b_n [djij[^[d d[k[Ijhd][Z[hh_Y^j_][dI[gk[dp"_dZ[ci_Y^ `[Z[[_dp[bd[8Wi[Z[hX[_Z[d][jh[ddj[dIjhd# ][WkiZ[cLehhWjZ[hl[hiY^_[Z[d[dDkab[ej_# Z[Z[hP[bb[ZWiDkab[ej_Zc_jZ[hpk_^hfWi# i[dZ[d aecfb[c[djh[d 8Wi[ ikY^j$ :[h fW# h[djWb[ IjhWd] Z_[dj ]b[_Y^iWc Wbi CWjh_p[ \”h Z[dd[kpkiodj^[j_i_[h[dZ[d7XX$($''$:WX[_ fWWhji_Y^`[[_dIjhWd]Z[hfWh[djWb[d:D7c_j [_d[c d[k iodj^[j_i_[hj[d IjhWd]$ :_[i[hLeh# ]Wd]m_hZWbii[c_aedi[hlWj_l[H[fb_aWj_edX[# p[_Y^d[j$:_[FebWh_jjZ[hX[_Z[d;bj[hdijhd][ _ijZkhY^Z_[Fei_j_edZ[h+É#kdZZ[h)É#;dZ[d ][a[ddp[_Y^d[j$:_[H[fb_aWj_edf\bWdpji_Y^_d Z[h H[fb_aWj_edi]WX[b \ehj" meX[_ Z_[ Iodj^[# i[ Z[i b_da[d JeY^j[hijhWd]i B[_jijhWd]" b[W# Z_d]ijhWdZ aedj_dk_[hb_Y^ WXbWk\[d aWdd$ I_[ m_hZZkhY^Z_[:D7#Feboc[hWi[AX[_8Waj[# h_[dFeboc[hWi[???[hc]b_Y^j$ 7dZ[hi_ijZ_[iX[_Z[hIodj^[i[Z[ih[Y^j[d JeY^j[hijhWd]i$I_[l[hbk\jledeX[ddWY^kd# j[d"ZWX[_m[hZ[ddkhakhp[:D7#Ij”Ya[iod# j^[j_i_[hj Z_[ EaWpWa_#Ij”Ya[$ Iec_j ckii pmWd]ibk\_]Wbb[fWWh^kdZ[hjDkab[ej_Z[[_d d[k[i :D7#Ij”Ya Wd\Wd][d$ :_[i m_hZ ZWdd c_j Z[c leh^[h iodj^[j_i_[hj[d ZkhY^ B_]Wi[ l[had”f\j" Z_[ ZWi )É#;dZ[ [_d[i :D7#Ij”Yai c_j Z[c +É#;dZ[ [_d[i pm[_j[d :D7#Ij”Yai l[hX_dZ[d$ :_[ Feboc[hWi[d add[d _c M[i[djb_Y^[d dkh [_d :[ienodkab[ej_Z Wd ZWi )É#;dZ[ [_# d[h iY^ed X[ij[^[dZ[d A[jj[ Wd^d][d" Z_[ cWd Wbi Fh_c[h X[p[_Y^d[j$ :_[i[ Fh_c[h#Ij”# Ya[" led Z[d[d Wki Z_[ :D7#Iodj^[i[ WXbWk# \[daWdd"X[ij[^[dWkiHD7Z_[ledZ[h:D7# Feboc[hWi[Aiodj^[j_i_[hjm[hZ[d$I_[X[ij[^j Wki*Kdj[h[_d^[_j[d"ledZ[d[dZ_[=hœj[Z_[ :D7#feboc[h_i_[h[dZ[ 7aj_l_jj X[i_jpj$ :_[ X[_Z[d ab[_d[h[d Kdj[h[_d^[_j[d m_ha[d Wbi Fh_cWi[d kdZ iodj^[j_i_[h[d akhp[ HD7#Ij”# Ya["Fh_c[h"Z_[ledZ[h]hœ[h[dKdj[h[_d^[_j ZkhY^7d^[\jkd] led :[ienodkab[ej_Z[d l[h# bd][hjm[hZ[dadd[d$;_d[7k\]WX[Z[hc_jj# b[h[d Kdj[h[_d^[_j _ij Z_[M[Y^i[bm_hakd] c_j WdZ[h[dH[fb_aWj_edifhej[_d[d$

È qÈ !UFBAUÈUNDÈ2EPLIKATIONÈDERÈ$.!







!BBÈÈ 2EPLIKATIONSMODELLÈ DERÈ$.!

2EPARATURÈDURCHÈ0OLYMERASEÈ :D7#Feboc[hWi[d m_[Z[hkc" dcb_Y^ Z_[ :D7#Feboc[hWi[ B X[_ 8Waj[h_[d Feboc[hW# i[?^WX[dX[_Z[hH[fb_aWj_eddeY^[_d[WdZ[# h[if[p_\_iY^[eceiW# f_[di$ 8[_c C[diY^[d i_dZ Z_[i X_i pk '&&&$ :Wi FheXb[c Z[h H[fb_aWj_ed Z[h 9^hece# iec[d[dZ[d m_hZ ZWZkhY^ ][bij" ZWii Z[h B[_jijhWd] c_j >_b\[ [_d[i if[p_[bb[d ;dpoci" Z[h J[bec[hWi[ m[_j[hiodj^[j_i_[hj m_hZ$ :_[

È



+APITELÈÈqÈ-OLEKULAREÈ'RUNDLAGENÈDERÈ(UMANGENETIK

 4ABELLEÈÈ !BLAUFÈDERÈ2EPLIKATIONÈMITÈBETEILIGTENÈ0OLYMERASEN



%NZYM0ROTEINÈÈ

"IOLOGISCHERÈ3CHRITTÈ

(ELIKASEÈ

%NTWINDUNGÈDERÈ$OPPELHELIX

4OPOISOMERASEÈÈ È

%NTSPANNUNGÈDERÈVERDRILLTENÈ$OPPELHELIXÈUNDÈ3ETZUNGÈVONÈÈ %INZELSTRANGBRàCHEN ÈALSÈDIEÈ2OTATIONÈNICHTÈWEITERLEITENDEÈ'ELENKEÈ

$.! "INDUNGSPROTEINÈ

3TABILISIERUNGÈDERÈEINZELSTRËNGIGENÈ$.!

0RIMASEÈÈ

3YNTHESEÈKLEINERÈ0RIMER 2.!È

$.! 0OLYMERASEÈAÈ È

0RIMASE È3YNTHESEÈKURZERÈ$.! 3TàCKEÈZURÈ%INLEITUNGÈDERÈ2EPLIKATION ÈÈ 3YNTHESEÈDESÈ&OLGESTRANGS

$.! 0OLYMERASEÈBÈ

2EPARATURÈ

$.! 0OLYMERASEÈDÈ

3YNTHESEÈDESÈ,EITSTRANGSÈ

$.! 0OLYMERASEÈEÈ

+ETTENVERLËNGERUNG È2EPARATUR

$.! 0OLYMERASEÈGÈ

-ITOCHONDRIAL ÈMT $.! 2EPLIKATION

J[bec[hWi[_ij[_d_dj[h[iiWdj[i;dpoc"ZWiWki   [_d[cHD7#8[ijWdZj[_bkdZ[_d[cFhej[_d#8[# 4ABELLEÈ È "IOLOGISCHEÈ !UFGABENÈ DESÈ %RB MATERIALSÈ ijWdZj[_b Wk\][XWkj _ij$ :[h HD7#8[ijWdZj[_b aWddkdj[hiY^_[Zb_Y^bWd]i[_d"p$8$X[_Ik][# 2EPLIKATION j_[h[d [jmW (+& Dkab[ej_Z[ kdZ [dj^bj 8[h[_# 0RËZISEÈ6ERDOPPELUNGÈWËHRENDÈDERÈ:ELLTEILUNGÈ Y^["Z_[8Wi[dfWWhkd]c_jZ[dJ[bec[hi[gk[d# p[d [_d][^[d add[d$ 8[_ Z[c Wki c[^h[h[d 3PEICHERUNG Kdj[h[_d^[_j[d X[ij[^[dZ[d Fhej[_d#8[ijWdZ# 3PEICHERUNGÈDERÈGESAMTENÈNOTWENDIGENÈBIO j[_b _ij Z_[ ]hœj[ Kdj[h[_d^[_j Wc m_Y^j_]i# LOGISCHENÈ&UNKTION j[d$ I_[ jh]j Z_[ 8[p[_Y^dkd] J[bec[hWi[#H[# 7EITERGABE l[hi[#JhWdiah_fWi[J;HJ$ ;i _ij Wbie [_d ;d# 7EITERGABEÈDERÈGENETISCHENÈ)NFORMATIONÈANÈ poc"ZWiHD7_d:D7”X[hi[jpj$J;HJd_ccj DIEÈ:ELLEÈ Z[d HD7#J[_b Z[i ;dpoci Wbi X[m[]b_Y^[ CW# 3TABILITËT jh_p[kdZ^[\j[j[djifh[Y^[dZZ[hLeh]WX[Z[h !UFRECHTERHALTUNGÈDERÈ3TRUKTURSTABILITËT ÈUMÈ HD7#I[gk[dpd[k[Dkab[ej_Z[WdZWi)É#J[be# %RBËNDERUNGENÈ-UTATIONEN ÈZUÈMINIMIEREN c[h[dZ[ 7XX$ ($'($ ?ij [_d[ J[bec[h[_d^[_j \[hj_]" ifh_d]j i_[ Wd Z[h[d ;dZ[ kdZ X[]_ddj ledd[k[c$7dZWidkdl[hbd][hj[IjhWd][d# Z[aWdddkd[_dd[k[hHD7#IjWhj[hX_dZ[d"Wd m[bY^[cZ_[:D7#Feboc[hWi[Z_[Iodj^[i[Z[i <eb][ijhWd]i lebb[dZ[j$ 7d ;dZ[d e^d[ :ef# f[bijhWd] c_j ”X[h^d][dZ[c )É#;dZ[ aWdd CeZ[bb Wbb[ ;h\ehZ[hd_ii[ Wd ZWi ][d[j_iY^[ i_Y^ [_d[ >WWhdWZ[bijhkajkh pkh”Ya\Wbj[d kdZ CWj[h_Wb[h\”bbj$:_[:D7[hbWkXjZ_[?d\ehcW# ieZ_[J[bec[h[dZ[dl[hi_[][bd7XX$($')$ j_ediif[_Y^[hkd]" i_[ X[i_jpj Z_[ C]b_Y^a[_j Z[h _Z[dj_iY^[d H[fb_aWj_ed kdZ Z[h H[fWhW# ¯BERTRAGUNGÈDESÈ%RBGUTS jkh kdZ iec_j Z[hM[_j[h]WX[ Z[i ;hX]kji$7bi PkiWcc[d\Wii[dZ biij i_Y^ Wbie \[ijij[bb[d" =h[dp\Wbbadd[d][m_ii[_b\[ Z[i ;dpoci H[l[hi[ JhWdiah_fjWi[ Wki c#HD7[hij[bbjmkhZ[$:_[i[IY^b[_\[dmkhZ[d ZkhY^ ][dec_iY^[ :D7#H[]_ed[d l[hkhiWY^j" Z_[ e\\[di_Y^jb_Y^ _d Z[h Y#:D7 d_Y^j leh^Wd# Z[d mWh[d" eXme^b Wbi LehWkii[jpkd] Wd][# decc[dmkhZ["ZWiiZ_[Y#:D7jWjiY^b_Y^[_# d[_Z[dj_iY^[Aef_[Z[hc#HD7ZWhij[bbj$8[_c B#=beX_d#=[d\WdZcWdpm[_iebY^[hH[]_ed[d" Z_[_dd[h^WbXZ[haeZ_[h[dZ[dH[]_ed[dbW][d kdZ Zh[_ I[gk[dp[d Z[i pk][^h_][d Fhej[_di Xpm$Z[h[djifh[Y^[dZ[dc#HD7kdj[hXhWY^[d$ :_[i mWh Z_[ ;djZ[Yakd] Z[h kdj[hXheY^[d[d =[d[X[_;kaWhoej[d$ ?d Z[h Pm_iY^[dp[_j ^Wj cWd _d l_[b[d =[# d[d led ;kaWhoej[d iebY^[ Kdj[hXh[Y^kd][d [djZ[Yaj" Z_[ cWd `[ZeY^ X_i^[h d_[ X[_ jo# f_iY^[d FheaWhoej[d \WdZ$ 7bb[hZ_d]i aedd# j[cWd_dpm_iY^[dX[_[_d[cJ#F^W][dkdj[h# XheY^[d[ =[d[ dWY^m[_i[d$ :W^[h _ij [i d_Y^j kdmW^hiY^[_db_Y^" ZWii WkY^ _^h[ fheaWhoej_# iY^[d M_hj[ iebY^[ =[d[ [dj^Wbj[d" Z_[ cWd X_i^[h dkh deY^ d_Y^j [djZ[Yaj ^Wj" `[Z[d\Wbbi _ijZ_[i[h=[dWk\XWk\”hZ[dC[diY^[dZ_[H[# ][b$Dkhi[^hm[d_][c[diY^b_Y^[=[d[^WX[d a[_d[ Kdj[hXh[Y^kd][d" Z_[i[ i_dZ _d Z[h H[# ][b i[^h ab[_d JWX[bb[ ($+$ ?di][iWcj ]_Xj [i X[_c[diY^b_Y^[d=[d[d[h^[Xb_Y^[=hœ[dkd# j[hiY^_[Z[$ %XONSÈUNDÈ)NTRONS CWd^WjZ_[I[gk[dp[d"Z_[_dZ[hc#HD7leh# ^WdZ[di_dZ"Wbi;nediZ[\_d_[hjkdZiebY^["Z_[ Zehj \[^b[d" Wbi ?djhedi$ ;ned# kdZ ?djhedbd# ][di_dZi[^hkdj[hiY^_[Zb_Y^$?dc[diY^b_Y^[d =[d[di_dZ;nediZkhY^iY^d_jjb_Y^'((XfbWd] i$AWf$-$,$:WX[__ijZ_[;nedbd][kdWX^d# ]_]ledZ[hBd][Z[i=[di1iei_dZWkY^[_d_][ i[^h ]heœ[ ;nedi X[aWddj$ 8[_ ]heœ[d =[d[d



 4ABELLEÈ È -ENSCHLICHEÈ 'ENEÈ !USWAHL È DIEÈNICHTÈDURCHÈ)NTRONSÈUNTERBROCHENÈSINDÈ !LLEÈÈ-ITOCHONDRIENGENEÈÈ (ISTONGENEÈÈ 'ENEÈFàRÈKLEINEÈ2.!S ÈZÈ"ÈDIEÈMEISTENÈÈ T 2.! 'ENEÈ (ORMONREZEPTORGENEÈÈ 3 (4È3EROTONINREZEPTORÈÈ $OPAMINREZEPTORÈ$ÈUNDÈ$È !NGIOTENSIN )) 4YP  2EZEPTORÈ A ADRENERGERÈ2EZEPTORÈÈ &ORMYLPEPTIDREZEPTOR (ODENSPEZIFISCHEÈ%XPRESSIONSMUSTER 0HOSPHOGLYCERATKINASEÈ0+' È 'LYZERINKINASEÈ'+ È 'ENÈDERÈMYC &AMILIEÈ-9#, È 0YRUVATDEHYDROGENASEÈ%AÈ0$(! È 'LUTAMATDEHYDROGENASEÈ',5$

_ijZ[h;ned][^WbjZW][][di[^h][h_d]$_dZ[h H[][b ”X[hjh_\\j Z_[ Bd][ Z[h ?djhedi Z_[ Z[h ;nedikc[_dL_[b\WY^[iJWX[bb[($,$ 3PLICING 7k\Z[cM[][pm_iY^[d?d\ehcWj_edWk\:D7# ;X[d[kdZ=[d[nfh[ii_edckiiWbiedeY^[_d Fhep[iiZWpm_iY^[d][iY^Wbj[ji[_d"Z[dm_hpk# c_dZ[ij X_i ^[kj[ X[_ FheaWhoej[d d_Y^j X[# eXWY^j[d aeddj[d$ Led :D7 m_hZ [_d[ Aef_[ _d<ehcledHD7WX][b[i[d"Z_[][dWkZ_[I[# gk[dp _c =[dec m_[Z[h]_Xj$ CWd ^Wj Z_[i[ HD7 WkY^ Wbi ^[j[he][d[ dkab[h[ HD7 ^d# HD7 X[p[_Y^d[j$ :_[i[ ^d#HD7 aWdd Wbb[h# Z_d]i d_Y^j Z_h[aj \”h Z_[ Fhej[_dfheZkaj_ed ^[hWd][pe][d m[hZ[d0 I_[ _ij [_d He^b_d]" Z[h [hij deY^ ZkhY^ Z_[ ;np_i_ed Z[h ?djhedi pk# h[Y^j ][iY^d_jj[d m[hZ[d ckii$ CWd ^Wj Z_[# i[d Leh]Wd] Wbi ×ifb_Y_d]Æ :[kjiY^0 Ifb[_# œ[d X[p[_Y^d[j$ :Wi ;h][Xd_i Z[i Ifb[_œ[di _ijZWdd[_d[c#HD7"Z_[Wki[_d[hH[_^[d\eb# ][led;nedipkiWcc[d][i[jpj_ij$:WX[_m[h# Z[dZ_[;nedi_cc[h_dZ[hi[bX[dH[_^[d\eb][ ^_dj[h[_dWdZ[h][ehZd[j"_dZ[hi_[_dZ[h:D7 Wk\jh[j[d$



È qÈ !UFBAUÈUNDÈ$EFINITIONÈVONÈ'ENEN







 4ABELLEÈ È 'RڔENUNTERSCHIEDEÈ UNDÈ DURCHSCHNITTLICHEÈ %XON È UNDÈ )NTRONGRڔENÈ EINIGERÈ MENSCHLI CHERÈ'ENEÈ.UKLEOTIDEÈ8È 'ENPRODUKTÈ È

'ENGRڔEÈ È

M 2.! È 'RڔEÈ

!NZAHLÈDERÈ %XONSÈ

!NZAHLÈDERÈ )NTRONSÈ

$URCHSCHNITTLICHEÈ'RڔE %XONSBP È )NTRONSKB

B 'LOBINÈ

 È

 È

È

È

È

 

)NSULINÈ

 È

 È

È

È

È

 

&AKTORÈ6)))È

È

È

È

È

È

 

$YSTROPHINÈ

È

È

È

È

È

 

"EDEUTUNGÈDERÈUNTERBROCHENENÈ'ENE :eY^ m[bY^[d I_dd ^WX[d Z_[ ×kdj[hXheY^[# d[dÆ =[d[ Z[h ;kaWhoej[d c_j _^h[h _d ;nedi \hW]c[djWh_iY^Wd][ehZd[j[d?d\ehcWj_ed5 B[_Z[h_ijcWdZWX[_Wk\If[akbWj_ed[dWd# ][m_[i[d" ZW _d l_[b[d ehced[ Z_[d[d" Z_[ [_dp[bd[ =[d[ m^# h[dZX[ij_ccj[h;djm_Yabkd]if^Wi[dWaj_l_[# h[dkdZ_dWdZ[h[dF^Wi[dZ[Waj_l_[h[d$ :khY^ Z_[ I[fWh_[hkd] Z[h ;nedi \”h l_[# b[ l[hiY^_[Z[d[ Fhej[_d[ _d 7dj_ahf[h][d[d iY^W\\[d Z_[ ?djhedi Wki^Wbji# ][d["=[d["Z_[_dZ[hC[^hpW^bWbb[hP[bb[d[n# fh_c_[hjm[hZ[d"iem_[pW^bh[_Y^[WdZ[h[=[d# fhecejeh[dX[i_jp[da[_d[J7J7#8en$>_[h\_d# Z[j cWd ^k\_] [_d[ =9#8en$ I_[ [dj^bjLWh_# Wj_ed[d Z[h Aedi[dikii[gk[dp ===9==$ :_[ 977J#8en[jmWWdZ[hFei_j_ed#.&lecJhWd# iah_fj_ediijWhjfkdajWki_ij[X[d\WbbiX[_Fhe# cejeh[d m[_j l[hXh[_j[j kdZ _d Z[h H[][b Z[h \”h Z_[ M_haiWca[_j Z[i Fhecejehi X[ij_c# c[dZ[<WajehJWX[bb[($/$ :_[ HD7#Feboc[hWi[ m_hZ ZkhY^ Z_[ 8_d# Zkd] Wd Z_[ JhWdiah_fj_edi\Wajeh[d Waj_l_[hj







 4ABELLEÈ È +ONSENSUSSEQUENZÈ AUSGEWËHL TERÈ 0ROMOTORBOXEN È DIEÈ VONÈ 4RANSKRIPTIONS FAKTORENÈERKANNTÈWERDENÈ "OXÈ

+ONSENSUSSEQUENZÈDERÈ$.!

4!4!È

4!4!!!

'#È

'''#''

#!!4È

##!!4

kdZX[]_ddjWd[_d[hX[ij_ccj[dIj[bb[c_jZ[h HD7#Iodj^[i[ 7XX$ ($'-$ >k\_] _ij Z_[i [_d =#eZ[h7#Dkab[ej_Z_dZ[\_d_[hj[h;dj\[hdkd] lecIjWhjaeZed[_d[i=[di$ E\j i_dZ =[d[" Z_[ jhWdiah_X_[hj m[hZ[d" ZkhY^ie]$9f=#?di[bd][a[ddp[_Y^d[j$:_[i_ij [_d[ 7Xa”hpkd] \”h Z_[ Aeffbkd] led 9 c_j = ”X[h [_d[ )É#+É#F^eif^eZ_[ij[hX_dZkd]$ ;i ^WdZ[bji_Y^^_[hX[_kc:D7#8[h[_Y^[led'#( aX Bd][" _d Z[d[d Z_[i[i :_dkab[ej_Z ^k\_] l[hjh[j[d_ij"m^h[dZ[i_dZ[hh[ijb_Y^[d:D7 m[i[djb_Y^ i[bj[d[h pk \_dZ[d _ij$ :_[ 9ojei_d# h[ij[ _d Z[d 9f=#:_dkab[ej_Z[d add[d Wc Ae^b[dije\\Wjec+c[j^ob_[hjm[hZ[d$:_[C[# j^ob_[hkd]m_hZ_dZ[hH[][bWbiJhWdiah_fj_edi# l[hXejWd][i[^[d$?ijX[_[_d[cFhecejeh[_d[ 9f=#?di[bc[j^ob_[hj"ie_ijdehcWb[hm[_i[Z_[ =[d[nfh[ii_ed Z[i ZWpk][^h[dZ[d =[di kd# j[hZh”YajJWX[bb[($'&$ 0ROCESSINGÈUNDÈ3PLICINGÈDERÈ2.! :_[_cP[bba[hdiodj^[j_i_[hj[HD7_ijm[i[dj# b_Y^]hœ[hWbiZ_["Z_[cWd_cPojefbWicWWd Z[d H_Xeiec[d \_dZ[j$ ;i m_hZ [_d[ i[^h l_[b ]hœ[h[ Fhakhieh\ehc fheZkp_[hj" Z_[ ZWdd ZkhY^ZWiie]$FheY[ii_d]_cL[hbWk\Z[iJhWdi# fehjilecP[bba[hdpkcPojefbWicW"deY^_c A[hd"pkh[dZ]”bj_][dc#HD7pkh[Y^j][iY^d_j# j[dm_hZ7XX$($'.$ CWd X[p[_Y^d[j Z_[ Fhakhieh\ehc _d Z[d l[hiY^_[Z[d[dFheY[ii_d]ijWZ_[dWbi^[j[he][# d[dkab[h[HD7^d#HD7"m[_bZ_[HD7#Ce# b[a”b[_dZ[hBd][lWh__[h[d$LedZ[h^d#HD7 ijWccj WkY^ [_d[ ab[_d[ dkab[h[ HD7 WX0 :_[ id#HD7 i 3 icWbb _ij X[_ Z[h :khY^\”^# hkd] Z[i Ifb_Y_d] X[j[_b_]j" m[bY^[i m_h m[_#

È

+APITELÈÈqÈ-OLEKULAREÈ'RUNDLAGENÈDERÈ(UMANGENETIK



!BBÈ È 4RANSKRIPTIONSSTARTÈ -EHREREÈ 4RANSKRIPTIONSFAKTORENÈ BINDENÈ AMÈ 0ROMOTORÈ DIREKTÈ NEBENÈ EINEMÈ 'ENÈ UNDÈBRINGENÈDIEÈ2.! 0OLYMERASEÈINÈ3TARTPOSITIONÈZURÈ4RANSKRIBIERUNGÈEINESÈ'ENSÈ



 4ABELLEÈÈ !BLAUFÈDERÈ4RANSKRIPTIONÈ 4RANSKRIPTIONSGESCHWINDIGKEITÈ

 ÈKBMIN

2.! 0OLYMERASEN nÈ2.! 0OLYMERASEÈ) )))È nÈ2.! 0OLYMERASEÈ))ÈÈ

&àRÈDIEÈ4RANSKRIPTIONÈDERÈVERSCHIEDENENÈ2.! +LASSEN &àRÈDIEÈZELLULËRENÈ'ENE

4RANSKRIPTIONSREGULATORENÈ

0ROMOTOR È%NHANCER È3ILENCERÈUNDÈ4RANSKRIPTIONSFAKTOREN

0ROMOTORBOXENÈ È È

4!4! "OX '# "OX #!!4 "OX

4RANSKRIPTIONSUNTERDRàCKUNGÈ

-ETHYLIERUNGÈDERÈ$.! ÈBESONDERSÈ -ETHYLCYTOSIN



È qÈ 4RANSKRIPTIONÈDERÈ$.!ÈINÈ2.!ÈUNDÈ0ROCESSING





!BBÈÈ 4RANSKRIPTIONÈEINESÈ'ENSÈAUFÈHN 2.!ÈUNDÈ3PLICINGÈDERÈHN 2.!ÈZURÈTRANSLATIONSFËHIGENÈM 2.!È#APÈ UNDÈ0OLY ! 3CHWANZÈWERDENÈNICHTÈTRANSLATIERT È

j[h kdj[d a[dd[d b[hd[d m[hZ[d$ 8[_c C[d# iY^[d mkhZ[ cWd Wk\ Z_[i[ HD7 ZkhY^7kje# Wdj_ahf[h Wk\c[haiWc" Z_[ cWd X[_ Jh][hd ledioij[c_iY^[cBkfki[hoj^[cWjeZ[idWY^# m[_i[daWdd$



 4ABELLEÈÈ 0ROCESSINGÈDERÈM 2.! #APPING !NHEFTUNGÈVONÈ -ETHYL 'UANOSINÈANÈDASÈ @ %NDE ÈDIESÈERMÚGLICHTÈSPËTEREÈ&IXIERUNGÈDERÈ M 2.!ÈANÈDASÈ2IBOSOMÈ

!BLAUFÈDESÈ0ROCESSING :WiFheY[ii_d]JWX[bb[($''X[_d^Wbj[jieme^b 0OLYADENYLIERUNG [_d M[]iY^d[_Z[d Wbi WkY^ [_d 7d^[\j[d led !NHEFTUNGÈEINESÈ0OLY ! 3CHWANZESÈANÈDASÈ =hkff[d" Z_[ _c fh_ch[d JhWdiah_fj d_Y^j /( %NDE leh^WdZ[dmWh[d$8[h[_jiI[akdZ[ddWY^JhWd# 3PLICING iah_fj_ediX[]_dd m_hZ [_d if[p_[bb[i Dkab[e# 4RENNUNGÈUNDÈ:USAMMENFàGUNGÈVONÈDENÈ j_Z"ZWi-#C[j^ob#=kWdei_d”X[h[_d[Jh_f^ei# %XONSÈMITÈàBERSETZBARENÈ)NFORMATIONENÈVONÈ f^WjXh”Ya[WdZWi+È#;dZ[Wbi9Wf[_d[hd[k[d DENÈDAZWISCHENÈLIEGENDENÈ)NTRONS ÈDIEÈNICHTÈ c#HD7Wd][\”]j7XX$($'/$:Wi9WfZ_[djZ[h àBERSETZTÈWERDEN 7d^[\jkd]Z[hc#HD7WdZWiH_Xeiec$ :WdWY^ \eb]j Z_[ m[_j[h[ 7d^[\jkd] led Dkab[ej_Z[d Wd ZWi )È#;dZ[ Z[h A[jj[ c_j [_# d[h =[iY^m_dZ_]a[_j led )&#+& Dkab[ej_Z[d A[jj[ m_hZ [_d[ I[gk[dp led Dkab[ej_Z[d WX# fhe I[akdZ[$ :_h[aj dWY^ 8[[dZ_]kd] Z_[i[h ][ifWbj[d kdZ '&&#(&& 7CF m[hZ[d Wd ZWi

È

+APITELÈÈqÈ-OLEKULAREÈ'RUNDLAGENÈDERÈ(UMANGENETIK



!BBÈÈ #APPINGÈDESÈ %NDESÈEUKARYOTISCHERÈM 2.!SÈ$ASÈG 0HOSPATÈAMÈENDSTËNDIGENÈ .UKLEOTIDÈWIRDÈENT FERNTÈ%SÈWIRDÈVONÈEINEMÈ'40 6ORLËUFER ÈDERÈMITÈDEMÈURSPRàNGLICHENÈTERMINALENÈ .UKLEOTIDÈEINEÈSPEZIELLEÈ  4RIPHOSPHAT "INDUNGÈEINGEHT ÈEINÈNEUESÈ'-0ÈBEREITGESTELLTÈ7EITERÈWIRDÈDERÈ+OHLENSTOFFÈÈAMÈENDSTËNDIGENÈ'È SOWIEÈDASÈ +OHLENSTOFFATOMÈDERÈ2IBOSEÈANÈDENÈBEIDENÈBENACHBARTENÈ.UKLEOTIDENÈMETHYLIERTÈ.ACHÈ3TRACCHAN È 2EADÈ

)É#E>#;dZ[ Wd][^[\j[j$ :_[i[h Leh]Wd]" Z[d cWd Wbi FeboWZ[dob_[hkd] X[p[_Y^d[j" Z_[dj Z[c IY^kjp Z[i fh_ch[d JhWdiah_fji leh po# jefbWicWj_iY^[d ;dpoc[d$ DWY^ Wbb[d Kdj[h# ikY^kd][d\WdZcWdX_i^[kj[dkh[_d[[_dp_][ c#HD7"Z_[_cA[hdd_Y^jfeboWZ[dob_[hjkdZ e^d[ Febo#7#IY^mWdp _di PojefbWicW [djbWi# i[dm_hZ$:_[i_ijZ_[c#HD7\”h>_ijedfhej[_# d["Z_[dkh[_d[akhp[{X[hb[X[dip[_j_cPoje# fbWicW^WX[d$ :_[CeZ_\_aWj_edZ[ifh_ch[dJhWdiah_fji Z_[dje\\[dXWhZ[cbd][h[d{X[hb[X[dZ[hc# HD7 _c PojefbWicW$ DWY^ ][dWk[h 8[jhWY^# jkd] Z[i Fhakhiehceb[a”bi b_[œ i_Y^ p[_][d"

ZWii Z_[i[i _c P[bba[hd _c :khY^iY^d_jj YW$ +&&&Dkab[ej_Z[bWd]_ij"m^h[dZZ_[c#HD7 _c PojefbWicW dkh kd][\^h '&&& Dkab[ej_Z[ kc\Wiij$:Wc_jmWhabWh"ZWii"_c=[][diWjppk FheaWhoej[d" a[_d[ Z_h[aj[ 7X^d]_]a[_j pm_# iY^[d Z[h Bd][ Z[h :D7#I[gk[dp Z[i =[di kdZZ[hBd][Z[iFhej[_diX[ij[^j"\”hZWi[i aeZ_[hj$ :_[L[ha”hpkd] Z[i Fh_chjhWdiah_fji X[# Z_d]j[_dPkh[Y^jiY^d[_Z[dZ[hc#HD7lehZ[h JhWdibWj_ed$ :_[i[dLeh]Wd]" m[bY^[h Z[h ;dj# \[hdkd]Z[h?djhediZ_[dj"^WX[dm_hX[h[_jiWbi Ifb_Y_d]Ifb[_œ[dWd][ifheY^[d$

È qÈ 4RANSKRIPTIONÈDERÈ$.!ÈINÈ2.!ÈUNDÈ0ROCESSING

3PLICINGÈDERÈ2.! ?djhedi X[]_dd[d _cc[h c_j =J kdZ [dZ[d c_j 7=$ :_[i i_dZ Z_[ X[_Z[d Ij[bb[d" Wd Z[# d[dZWi?djhed^[hWki][iY^d_jj[dm_hZ$E\\[d# XWhp[_][di_[`[ZeY^d_Y^jWbb[_d[_d?djhedWd" Xpm$h[_Y^[di_[pkh?djhed[ha[ddkd]d_Y^jWki$ IemkhZ[deY^[_d[Zh_jj[m[i[djb_Y^[?djhed# i[gk[dp [djZ[Yaj" Z_[ \”h ZWi Ifb_Y_d] m_Y^# j_] _ij" Z_[ ×XhWdY^ i_j[Æ$ I_[ X[\_dZ[j i_Y^ dW# ^[Wc;dZ[Z[i?djhedi"cWn_cWb*&Dkab[ej_# Z[lecj[hc_dWb[d7=#;dZ[[dj\[hdj$:WiIfb_# Y_d]bk\jZ[cdWY^_d)IY^h_jj[dWX0 '$ IfWbjkd] Z[h +É#][b[][d[d#;ned#?djhed# =h[dp[:edWjehij[bb[$ ($ :Wi=#Dkab[ej_Z]h[_\jWdZ[h:edWjehij[bb[ dkab[eboj_iY^[_d7WdZ[h×XhWdY^i_j[ÆWd" [i\eb]j[_d[BWiieX_bZkd]$ )$ IfWbjkd] Z[h )É#][b[][d[d#;ned#?djhed# =h[dp[7ap[fjehij[bb["ZWi?djhedm_hZWbi BWiie \h[_][i[jpj kdZ Z_[ ;nedWdj[_b[ m[h# Z[d pkiWcc[d][ifb[_œj$ C[^h[h[ id#HD7# Aecfb[n[ \”^h[d ZWX[_ ZWi Ifb_Y_d] Wki$ :_[i[FWhj_a[bX[ij[^[dWkifhej[_d][XkdZ[# d[did#HD7#Ceb[a”b[dkdZX_bZ[dZ_[Ifb_# Y[eiec[d$:_[i[X_dZ[dWdZ_[:edWjehij[b# b[" Z_[ ×XhWdY^ i_j[Æ kdZ Z_[7ap[fjehij[bb[ kdZ\”^h[dZWiIfb_Y_d]ZkhY^7XX$($(&$

!BBÈÈ 3PLICINGÈDERÈHN 2.!







!LTERNATIVESÈ3PLEI”ENÈUNDÈ3PLEI”MUTATIONENÈ 8[_l_[b[dc[diY^b_Y^[d=[d[dm[hZ[dIfb[_œ# ij[bb[d Wbj[hdWj_l X[dkjpj$ :WZkhY^ [djij[^[d l[hiY^_[Z[d[ c#HD7#I[gk[dp[d \”h ][m[Xi# if[p_\_iY^[ Fhej[_d[$ :Wi 9WbY_jed_d][d _ij [_d 8[_if_[b ^_[h\”h$ ;_d[ AecX_dWj_ed Wki Wbj[h# dWj_l[cIfb[_œ[dkdZWbj[hdWj_l[hFeboWZ[do# b_[hkd]\”^hjpkkdj[hiY^_[Zb_Y^[d=[dfheZka# j[d$ ?d Z[h IY^_bZZh”i[ m_hZ 9WbY_jed_d ][X_b# Z[j"ZWi_c8bkjZ[d9W(!#If_[][baedijWdj^bj" _c>ofej^WbWckim_hZZW][][dZWiie]$YWbY_# jed_d][dl[hmWdZj[F[fj_Z][X_bZ[j"ZWid[khe# ceZkb_[h[dZkdZjhef^_iY^m_ha[daWdd$ 7kY^add[dIfb[_œckjWj_ed[dZ_[Ifb[_œ# ij[bb[d _dWaj_l_[h[d eZ[h pk [_d[h ahofj_iY^[d Ifb[_œij[bb[ Waj_l_[h[d$ ;_d 8[_if_[b ^_[h\”h _ij Z_[ B#=beX_d#CkjWj_ed :(,A _c >ce]be# X_d ;$ I_[ l[hkhiWY^j kd[hmWhj[j[h M[_i[ [_# d[ B#J^WbWiic_[$ :Wi 9eZed (, b_[]j _d Z[h :D7#I[gk[dp _d Z[h D^[ Z[h Ifb[_œZedWjeh# ij[bb[_c9eZed)&$:_[IkXij_jkj_ed=m7l[h# c_dZ[hjZ_[;\\[aj_l_jjZ[hIfb[_œh[Waj_ed$ 4RANSFER 2.! :_[ JhWdi\[h#HD7 j#HD7 cWY^j [jmW '& Z[h][iWcj[dHD7Z[hP[bb[Wki$I_[_ij\”hZ[d

È



+APITELÈÈqÈ-OLEKULAREÈ'RUNDLAGENÈDERÈ(UMANGENETIK

7c_deikh[jhWdifehj pkijdZ_]$ ?^h[ 7k\]WX[ HD7#If[p_[il[hiY^_[Z[d[8Wi[dWk\jh[j[d$ X[ij[^jiec_jZWh_d"WkiZ[cP[bbhWkc7c_de# 7d Z_[i[i )È#;dZ[ m_hZ Z_[ \”h `[Z[ j#HD7 ikh[d Wk\pkd[^c[d kdZ Wd Z[d Iodj^[i[ehj if[p_\_iY^[ 7c_deikh[ Wd][^[\j[j$ 7c +È# Z[h Febof[fj_Za[jj[d pk Xh_d][d" me i_[ ZWdd ;dZ[ij[^j_cc[h[_df=$ [djifh[Y^[dZ Z[h CWjh_p[dlehiY^h_\j Z[h c#  :_[ c_jjb[h[ Ab[[XbWjjiY^b[_\[ _ij ZkhY^ [_d HD7pkiWcc[d][XWkjm[hZ[d$ \”h Z_[ Wd][^[\j[j[ 7c_deikh[ Y^WhWa# j[h_ij_iY^[i 8Wi[djh_fb[jj ][a[ddp[_Y^d[j$ !UFBAUÈDERÈT 2.! :_[i[iWbi7dj_aeZedX[p[_Y^d[j[8Wi[djh_# j#HD7#Ceb[a”b[X[i_jp[d[jmWZ_[<ehc[_d[i fb[jj_ijaecfb[c[djhpkZ[cJh_fb[jj"ZWi Ab[[XbWjji 7XX$ ($('" i_dZ Wki -+#/& Dkab[e# Z_[ [djifh[Y^[dZ[7c_deikh[ Wk\ Z[h c# j_Z[d Wk\][XWkj kdZ ^WX[d [_d Ceb[akbWh][# HD7aeZ_[hj"kdZZ_[djpkc7Xb[i[dZ[hc# m_Y^j led [jmW )&$&&&$ 8[jhWY^j[j cWd j#HD7 HD7#CWjh_p[$ l[hiY^_[Z[d[h Eh]Wd_ic[d kdZ l[hiY^_[Z[d[h  ;_d[ m[_j[h[ =[c[_diWca[_j Wbb[h j#HD7# 7c_deikh[if[p_\_jj" ie \bbj X[_ Wbb[d X_i^[h Ceb[a”b[_ijZ_[;n_ij[dp[_d[h]heœ[d7d# X[aWddj[d j#HD7#If[p_[i [_d[ H[_^[ led =[# pW^b i[bj[d[h 8Wi[d d[X[d Z[d l_[h IjWd# c[_diWca[_j[dWk\0 ZWhZXWi[d$:WZ_[i[i[bj[d[d8Wi[da[_d[d  :[h Ij_[b Z[i Ab[[XbWjji ^Wj Wc )#;dZ[ aecfb[c[djh[d FWhjd[h \_dZ[d add[d" Z[h Dkab[ej_Za[jj[ ij[ji Z_[ 8Wi[di[gk[dp ]WhWdj_[h[d i_[ Z_[ ;_dp[bijhd]_]a[_j Z[h +$$$N997)É$:WX[_X[Z[kj[jNWd*$Fei_j_ed [djifh[Y^[dZ[dH[]_ed[d$;_d[i[bj[d[8W# lehZ[c;dZ["ZWii^_[h_dZ[d[_dp[bd[dj# i["dcb_Y^Y"b_[]j_dZ[hJY9#IY^b[_\["Z_[

!BBÈ È AÈ T 2.!È DERÈ !MINOSËUREÈ 3ERIN È BÈ -ODELLÈ DERÈ DREIDIMENSIONALENÈ 3TRUKTURÈ EINERÈ T 2.!È .ACHÈ 2ICHÈ 

È qÈ 'ENEXPRESSION

[_d[ m_Y^j_][ Hebb[ X[_ Z[h 7d^[\jkd] Z[h j#HD7WdZWiH_Xeiecif_[bj$7dZ[h:>K# IY^b[_\[ \_dZ[d m_h Z_[ i[bj[d[ 8Wi[ :_^o# Zhenokh_Z_d$ :_[i[ IY^b[_\[ _ij ^WkfjiY^# b_Y^ \”h Z_[ 7dbW][hkd] Z[h j#HD7 Wd Z_[ Iodj^[jWi[dl[hWdjmehjb_Y^$ 0ROCESSINGÈDERÈT 2.! ;_d ^db_Y^[i FheY[ii_d]" m_[ X[_ Z[h c#HD7 X[iY^h_[X[d" \_dZ[j WkY^ X[_ j#HD7#Ceb[a”# b[d ijWjj$ :Wi fh_ch[ JhWdiah_fj_edifheZkaj _ijWkY^^_[h]hœ[h$PkdY^ijm[hZ[dc[^h[h[ j#HD7i_d[_d[cCeb[a”biodj^[j_i_[hj$:_[i[i m_hZ ZWdd _d Z_[ [_dp[bd[d j#HD7i ][ifWbj[d" Z_[ +È#kdZ )É#j[hc_dWb[d I[gk[dp[d m[hZ[d ZkhY^ FheY[ii_d][dpoc[ [dj\[hdj$ 8[_c C[d# iY^[dm_hZZ_[j#HD7ledkd][\^h,&j#HD7# =[d[d jhWdiah_X_[hj$ :_[ i[bj[d[d eZ[h ceZ_# \_p_[hj[d 8Wi[d i_dZ d_Y^j _c khifh”d]b_Y^[d JhWdiah_fj_edifheZkaj leh^WdZ[d" i_[ m[hZ[d _c Pk][ Z[i FheY[ii_d] ZkhY^ KcmWdZbkd] Z[h]d]_][d8Wi[d][X_bZ[j$







2IBOSOMALEÈ2.! :[d]hœj[d7dj[_bWdZ[h][iWcj[dHD7Z[h P[bb[ ^Wj c_j .&#.+ Z_[ h_XeiecWb[ HD7 h# HD7$ I_[ _ij" m_[ Z[h DWc[ X[h[_ji iW]j" [_d 8[ijWdZj[_bZ[hH_Xeiec[d"Z_[WkiZ[hh#HD7 kdZ Wki Fhej[_d[d X[ij[^[d$ h#HD7 m_hZ Wd 9^heceiec[dWXiY^d_jj[diodj^[j_i_[hj"WdZ[# d[d [_d[ l_[b\WY^ m_[Z[h^ebj[ <eb][ led =[d# ehj[d \”h h#HD7 lehb_[]j$ :_[ ]heœ[ PW^b h[Z# kdZWdj[h=[d[\”hh#HD7_ijm[][dZ[h]heœ[d C[d][Z[hX[dj_]j[dh#HD7dejm[dZ_]$CWd X[p[_Y^d[j Z_[ 9^heceiec[dWXiY^d_jj[" Wk\ Z[d[d Z_[ =[d[ \”h h#HD7 beaWb_i_[hj i_dZ" Wbi Dkab[ebkieh]Wd_iWjeh[d$

0ROCESSINGÈDERÈR 2.! 7kY^ X[_ Z[h h#HD7 \_dZ[j [_d FheY[ii_d] WkiFhakhiehceb[a”b[dijWjj$8[_cC[diY^[d m_hZ[_dbWd][iFh_chjhWdiah_fjc_j[_d[h(.# I#[_d[h'.#I#kdZ[_d[h+".#I#;_d^[_j][X_bZ[j$ ?c[hij[dIY^h_jjZ[iFheY[ii_d]m_hZ"[dpocW# j_iY^l[hc_jj[bj"[_dIY^d_jjpm_iY^[dZ[h'.#I# kdZZ[h+".#I#;_d^[_jZkhY^][\”^hjkdZZWi?d# +OPPLUNGÈDERÈ!MINOSËURENÈANÈT 2.! jhed [dj\[hdj$ :Wdd m_hZ Z_[ +".#I#h#HD7 Wd M_[ [ha[ddj [_d[ X[ij_ccj[ 7c_deikh[ _^# Z_[(.#I#;_d^[_j][XkdZ[d"Z_[pkiWcc[dc_j h[ j#HD75 :[h [hij[ IY^h_jj _ij Z_[ 7aj_l_[# _^h"iem_[[_d[h+#I#h#HD7"Z_[i[fWhWjjhWdiah_# hkd]Z[h7c_deikh[c_j>_b\[led7Z[dei_d# X_[hjm_hZ"kdZ*/Fhej[_d[dZ_[]hœ[h[,&#I# jh_f^eif^Wj 7JF" l[hc_jj[bj ZkhY^ ZWi ;d# Kdj[h[_d^[_j [_d[i H_Xeieci X_bZ[j$ :_[ *&#I# poc7c_deWYob#j#HD7#Iodj^[jWi[$ oZheno]hkff[Z[h H_Xei[Z[i[dZijdZ_][d7Z[dei_di_dZ[d8[# 2EGULATIONÈDERÈ'ENEXPRESSIONÈ h[_Y^Z[i7c_deWYob#7CF][bWd]j$IY^b_[œb_Y^ 8[_ Z[h 8[iY^h[_Xkd] Z[h JhWdiah_fj_ed mkh# m_hZ Z[h 7c_deikh[h[ij Wk\ Z_[ H_Xei[ Z[i Z[d X[h[_ji Z_[ JhWdiah_fj_edi\Wajeh[d Wbi h[# 7Z[dei_di Z[h j#HD7 kdj[h _b\[Z[i7dj_aeZedih_Y^j_]_d[_dFebof[fj_Z X[h[_ji [hm^dj$ I_[ X_dZ[d Fhej[_d[" Z_[ Z[h [_d][XWkjm[hZ[d$ =[dh[]kbWj_edZ_[d[d$7kY^]_Xj[iKdj[hiY^_[# Z[ pm_iY^[d jhWdiah_fj_ed[bb Waj_l[d kdZ _d# Waj_l[dH[]_ed[d_dZ[h:D7"mWii_Y^_dZ[h

+APITELÈÈqÈ-OLEKULAREÈ'RUNDLAGENÈDERÈ(UMANGENETIK

È



!BBÈÈ 0ROCESSINGÈDERÈR 2.!ÈFàRÈ2IBOSOMENÈVONÈ%UKARYOTENÈ



 4ABELLEÈÈ %NTSTEHUNGÈDERÈVERSCHIEDENENÈ2.! !RTEN È

-ESSENGER 2.!È

4RANSFER 2.!È

2IBOSOMALEÈ2.!

'ENEBENEÈ È È È È

0RODUKTIONÈEINERÈGRڔE È RENÈ0RËKURSORFORMÈ È È È

0RODUKTIONÈMEHRERERÈ T 2.!SÈINÈEINEMÈ -OLEKàLÈ È È

0RODUKTIONÈEINERÈ  3 R 2.! ÈEINERÈÈ  3 R 2.! ÈEINERÈ   3 R 2.!ÈUNDÈEINERÈ  3 R 2.!

0ROCESSINGÈ È È È

#APPINGÈUNDÈ0OLY È ADENYLIERUNG È3PLICINGÈ VONÈ)NTRONSÈUNDÈ%XONSÈ È

3PALTUNGÈINÈEINZELNEÈÈ T 2.!S È%NTFERNUNGÈDERÈ TERMINALENÈ3EQUENZENÈUNDÈ "ILDUNGÈDERÈSELTENENÈ"ASEN

:USAMMENFàGEN ZURÈ 3 ÈUNDÈ 3 5NTEREINHEITÈ

Ijhkajkh Z[i 9^hecWj_di m_Z[hif_[][bj$ ?dWa# j_l[i 9^hecWj_d _ij ijha[h aedZ[di_[hj kdZ m_hZ ifj _d Z[h I#F^Wi[ Z[i P[bbpoabki h[fb_# p_[hj$7kœ[hZ[c _ij ZWi >_ijed >' \[ij ][Xkd# Z[d$ JhWdiah_fj_ed[bb Waj_l[ :D7 ^Wj [_d[ e\# \[d[Aed\ehcWj_edkdZm_hZ_dZ[hH[][b\h”^ _dZ[hI#F^Wi[h[fb_p_[hj$I_[X[i_jpj[_d[iY^mW# Y^[8_dZkd]led>_ijed#>'#Ceb[a”b[dkdZ[_# d[ijWha[7Y[job_[hkd]Z[hdkab[eiecWb[d>_i#

jed[$M[_j[h^_d[dj^Wbj[dZ_[Fhecejeh[da[_d[ c[j^ob_[hj[d9ojei_d[$ =[hWZ[ Z_[i[ C[j^ob_[hkd]" dcb_Y^ c[# j^ob_[hj[ 8Wi[d" X[iedZ[hi +#C[j^obYojei_d _ij [_d[ ]Wdp X[iedZ[h[ ;_][dWhj Z[i M_hX[bj_[h# ][deci$ :_[ :D7 [_d_][h WdZ[h[h ;kaWhoe# j[d" m_[ p$ 8$ Z_[ Z[h X7i[jpji_Y^pk/. Wki (A# kdZ (B#Febof[fj_Za[jj[d pkiWcc[d$ ;i m_hZ Wbi A(B( X[p[_Y^d[j$ 7bb[ ;hmWY^i[# d[d X[i_jp[d ZWh”X[h ^_dWki _d ab[_d[c Kc# \Wd][jmW(>X7($;iX[ij[^jWki`[(A#kdZ (D#A[jj[dkdZm_hZWbiA(D(X[p[_Y^d[j$:_[D# A[jj[kdj[hiY^[_Z[ji_Y^dkh_d'&7c_deikh[# fei_j_ed[dledZ[hB#A[jj[$:Wi\[jWb[>ce]# beX_d >XWkfjWdj[_bWdZ[h>ce# ]beX_dc[d][" m_hZ ZWdd WX[h pkd[^c[dZ [h# i[jpj"ieZWii[iX[h[_jidWY^[_d_][dCedWj[d dkhdeY^m[d_][Fhep[djWkicWY^j7XX$($()$ :EITLICHÈUNTERSCHIEDLICHEÈ'ENAKTIVITËT CWdaWddX[_>X_[haWddkdiZWi>ce]beX_dpkcL[hijdZ# [ii_dZZ_[i7Gc_j7bWd_dkdZ=Gc_j=bo# d_i Z[h =[dWaj_l_jj[d Wk\ ceb[akbWh[h ;X[d[ Y_d1JWX[bb[($'*$:_[G#A[jj[kdj[hiY^[_Z[ji_Y^ l[hiY^_[Z[d Z_\\[h[dp_[h[dZ[d P[bb[d m[hZ[d kdj[hiY^_[Zb_Y^[ =[d[ Waj_l_[hj Xpm$ _dWaj_# l_[hj$:WX[_l[h\”]jpmWhÄled7kidW^c[dm_[ Z[d Wdj_ahf[hiodj^[j_i_[h[dZ[d 8#Bocf^e# poj[dkdZFbWicWp[bb[diem_[J#Bocf^epoj[d WX][i[^[d" Z[h[d :_\\[h[dp_[hkd] ”X[h JhWdi# beaWj_ed[dkdZ:[b[j_ed[d[h\eb]jÄm[_j[h^_d `[Z[ P[bb[ ”X[h Z_[ ][iWcj[ ][d[j_iY^[ ?d\eh# cWj_ed"i_[aWddWX[hdkh[_d[dJ[_bZ_[i[h?d# \ehcWj_edWXhk\[d$:_[i[dLeh]Wd]X[p[_Y^d[j cWdWbiZ_\\[h[dp_[bb[JhWdiah_fj_ed$I_[_ijZ[h m_Y^j_]ij[C[Y^Wd_icki_dZ[hP[bbZ_\\[h[dp_[# hkd]$ I_dZ Z_[ :_\\[h[dp_[hkd]ifhep[ii[ [_d[i Eh]Wd_ickiWX][iY^beii[d"ie_ij[im_[Z[hkc Z_[Z_\\[h[dp_[bb[JhWdiah_fj_ed"Z_[_dl[hiY^_[# Z[d[d Eh]Wd[d pk hjb_Y^[d Kdj[hiY^_[Z[d _d Z[h=[dWaj_l_jj\”^hjkdZZWc_j\”hZ_[eh]Wd# if[p_\_iY^[7kifh]kd]kdZce]beX_d[leh$ ;i i_dZ Z_[i0 >X FehjbWdZ" m[bY^[i ZkhY^ (Z # A[jj[d Y^WhWaj[h_i_[hj _ij Z( G(" >X =em[h ' c_j (Z# kdZ (E#A[jj[d Z(E( kdZ >X =em[h ( c_j ( A# kdZ (E#A[jj[d A(E($ ?d Z[h 7c_de# ikh[pkiWcc[di[jpkd]]b[_Y^jZ_[Z#A[jj["Z[h A#A[jj["kdZZ_[E#A[jj[^Wju^db_Y^a[_jc_jZ[h B#A[jj[$:[hLehj[_bZ[h[cXhoedWb[dkdZ\[jW# b[d >ce]beX_d[ _ij _^h[ ^^[h[ IWk[hije\\W\# \_d_jj" mWi [_d[ l[hc[^hj[ E(#7X]WX[ Wd Z_[ =[m[X[[hc]b_Y^j$

Z[h[d=[m[X[ddWY^][m_[i[dm[hZ[d$:_[bWX_# b[Aecfed[dj[m_hZdkh_dB[X[hp[bb[d][\kd# Z[d"m_hZWbieWkiiY^b_[œb_Y^Zehjiodj^[j_i_[hj$ :_[FAK_ijdkh[_d8[_if_[bZW\”h"ZWiiieme^b ×dehcWb[Æ Wbi WkY^ Z[\[aj[ =[d[ dkh _d X[# ij_ccj[dEh]Wd[deZ[h=[m[X[dWaj_l_[hji[_d add[d$7dZ[h[=[dWaj_l_jj[dZW][][dbWii[d i_Y^Wdl_[b[dl[hiY^_[Z[d[dIj[bb[dZ[iEh]W# d_icki dWY^m[_i[d$ >_[hpk p^b[d Z_[×^eki[ a[[f_d]][d[iÆ"WbieZ_[=[d["Z_[\”hZ_[Wbb][# c[_d[d7k\]WX[dZ[iP[bbije\\m[Y^i[bil[hWdj# mehjb_Y^i_dZ$  :[hWaj_l[J[_bZ[i=[deci[_d[h`[Z[dP[b# b[i[jpji_Y^[_d[hi[_jiieme^bWki=[d[dpk# iWcc[d"Z_[_dl_[b[dP[bb[dWaj_lkdZZW# ^[h\”h[_d[dZ[\_d_[hj[d:_\\[h[dp_[hkd]i# ]hWZ m[d_][h if[p_\_iY^ i_dZ" kdZ WdZ[# «RTLICHÈUNTERSCHIEDLICHEÈ'ENAKTIVITËT h[hi[_ji Wki =[d[d" Z_[ ^eY^if[p_\_iY^ kdZ ;_d 8[_if_[b \”h eh]Wdif[p_\_iY^[ =[dWaj_l_jj \kdaj_ediWZWfj_[hj dkh _d X[ij_ccj[d Eh# _ij Z_[ ;nfh[ii_ed Z[h F^[dobWbWd_d^oZheno# ]Wd[dWX][b[i[dm[hZ[d$ bWi[$ :[h :[\[aj Z_[i[i ;dpoci \”^hj pk F^[# doba[jedkh_[ FAK$ :WX[_ _ij Z_[ >oZhenobW# È 0ROTEINBIOSYNTHESEÈnÈ4RANSLATIONÈ i[h[Waj_ed [_d IY^h_jj _d Z[h Ije\\m[Y^i[ba[jj[ ledF^[dobWbWd_dpkJ^ohei_d"_dZ[h[_d[H[_# :_[:D7_ijJh][hZ[h][d[j_iY^[d?d\ehcWj_# ^[WdZ[h[h][d[j_iY^[h8beYaic_jY^WhWaj[h_i# ed" kdZ Z_[i[ ?d\ehcWj_ed _ij _d Dkab[ej_Zjh_# j_iY^[d IodZhec[d X[aWddj i_dZ$ :_[ >oZhe# fb[jjid_[Z[h][b[]j7XX$($(*$:Wi_Y^Z_[][# nobWi[ X[ij[^j Wki pm[_ Fhej[_daecfed[dj[d" d[j_iY^[?d\ehcWj_ed_cP[bba[hdX[\_dZ[j"Z_[ [_d[hbWX_b[dkdZ[_d[hijWX_b[d$FAK_ijZkhY^ Fhej[_dX_eiodj^[i[ WX[h _c FbWicW ijWjj\_d# [_d[daecfb[jj[d7ki\WbbZ[hB[X[h#F^[dobWbW# Z[j" m_hZ [_d C_jjb[h _d <ehc Z[h C[ii[d][h# d_d^oZhenobWi[ ][a[ddp[_Y^d[j" meX[_ Z_[ bW# X_b[Aecfed[dj[Z[i;dpocioij[ciX[jhe\\[d _ij$:_[ijWX_b[Aecfed[dj[aWdd_dl_[b[dWd#



 4ABELLEÈ È -ENSCHLICHEÈ (ËMOGLOBINEÈ VONÈ DERÈ EMBRYONALENÈ BISÈ ZURÈ ADULTENÈ %NT WICKLUNG 3TADIUMÈ

(ËMOGLOBINÈ

3TRUKTUR

%MBRYONALPHASEÈ È È

(B'OWERÈÈ (B'OWERÈÈ (B0ORTLANDÈ

ZE AE ZG

&ETALPHASEÈ È

(B&È È

A'G A!G

!DULTPHASEÈ È

!È !È

AB AA

!BBÈ È #ODE 3ONNEÈ .ACHÈ "RESCHÈ UÈ (AUSMANNÈ 

È

+APITELÈÈqÈ-OLEKULAREÈ'RUNDLAGENÈDERÈ(UMANGENETIK

!BBÈÈ 3CHEMAÈDERÈ 4RANSKRIPTIONÈUNDÈDERÈ4RANS LATIONÈ$ASÈ0ROCESSINGÈDERÈ M 2.!ÈWURDEÈDERȯBERSICHTÈ HALBERÈNICHTÈMITGEZEICHNET



HD7X[dj_]j$:_[{X[hjhW]kd]Z[hDWY^h_Y^j led Z[h :D7 Wk\ Z_[ c#HD7 ^WX[d m_h Wbi JhWdiah_fj_ed X[p[_Y^d[j$M_h mebb[d dkd X[# iY^h[_X[d"m_[Z_[?d\ehcWj_edZ[hc#HD7_c P[bbfbWicW _d Fhej[_d[ kc][i[jpj m_hZ$ CWd X[p[_Y^d[j Z_[i[d Leh]Wd] _c =[][diWjp pkh JhWdiah_fj_edWbiJhWdibWj_ed7XX$($(+$ ;_d[ m[i[djb_Y^[ Hebb[ X[_ Z[h JhWdibWj_ed if_[b[d Z_[ H_Xeiec[d$ I_[ i_dZ ZWi X_dZ[dZ[ =b_[Z pm_iY^[d Z[h c#HD7 kdZ Z[h c_j7c_# deikh[d X[bWZ[d[d j#HD7$ CWd aWdd i_[ Wbi Z_[ ×kd_l[hi[bb[d :hkYacWiY^_d[dÆ Z[h P[bb[ X[p[_Y^d[d$

:[h Leh]Wd] X[]_ddj c_j Z[h 8_bZkd] Z[i ?d_j_Wj_ediaecfb[n[i$ :_[ h_XeiecWb[ *&I#Kd# j[h[_d^[_j[ha[ddjZWi+É#9Wfkdj[h8[j[_b_]kd] ledFhej[_d[d$I_[ikY^jZ_[c#HD7WX"X_ii_[ Wk\ZWiIjWhjaeZed7K=ijœj"m[bY^[i\”hC[# j^_ed_d aeZ_[hj$7K= ckii WX[h _d Z_[ h_Y^j_# ][I[gk[dp[_d][bW][hji[_d"kcWbi×IjWhjÆ[h# aWddjm[hZ[dpkadd[d$:_[^k\_]ij[;ha[d# dkd]ii[gk[dp _ij =997%=997K==$ :WX[_ _ij e\\[dXWhZWib[jpj[=kdZZWi)Dkab[ej_Z[leh 7K=b_[][dZ[=\”hZ_[A[ddkd][djiY^[_Z[dZ$ 7diY^b_[œ[dZ m[hZ[d Z_[ 7c_deikh[d dWY^# [_dWdZ[h _d Z_[ i_Y^ l[hbd][hdZ[ Febof[fj_Z#



È qÈ 0ROTEINBIOSYNTHESEÈnÈ4RANSLATION

a[jj[[_d][XWkj${X[h[_d[F[fj_ZX_dZkd]m_hZ `[m[_biZ_[7c_de]hkff[Z[hd[kWdZ[dJhWdi# bWj_ediaecfb[n ^[hWd][XhWY^j[d 7c_deik# h[ c_j Z[h 9WhXenob]hkff[ Z[h pkb[jpj [_d][# XWkj[d7c_deikh[l[had”f\j$:_[im_hZaWjW# boi_[hjZkhY^Z_[]heœ[Kdj[h[_d^[_jZ[iH_Xe# ieci c_j >_b\[ Z[i ;dpoci F[fj_ZobjhWdi\[hW# i["ZWi_dj[]hWb[h8[ijWdZj[_bZ[h]heœ[dKdj[h# [_d^[_j_ij7XX$($(,$:_[i[hLeh]Wd]m_hZie# bWd][\ehj][i[jpj"X_iZ_[Febof[fj_Za[jj[\[hj_]# ][ij[bbj_ijkdZi_Y^lecH_Xeiecjh[ddj7XX$ ($(-$  7biF[fj_ZX_dZkd]X[p[_Y^d[jcWd[_d[H[# Waj_edpm_iY^[d9WhXenob]hkff[kdZ7c_# de]hkff[ pm[_[h7c_deikh[d kdj[hMWi# i[hWXifWbjkd]$ ;i ]_Xj ,* AeZedi" WX[h dkh (& l[hiY^_[Z[# d[ 7c_deikh[d$ :[h ][d[j_iY^[ 9eZ[ _ij Wb# ieZ[][d[h_[hj$7kY^]_Xj[idkh[jmWic[^hWbi

!BBÈ È 0EPTIDBINDUNGÈ ZWISCHENÈ #ARBOXYLGRUPPEÈ UNDÈ!MINOGRUPPEÈZWEIERÈ!MINOSËUREN





)& j#HD7#Ceb[a”b[ _c PojefbWicW kdZ (( _d Z[d C_jeY^edZh_[d$ 8[_Z[ add[d Z_[ ,* Ae# Zedi [ha[dd[d$ :WX[_ i_dZ Z_[ [hij[d X[_Z[d Fei_j_ed[d X[_ Z[h FWWhkd] led AeZed#7dj_# aeZed[djiY^[_Z[dZ$?dZ[h)$Fei_j_edaWdd[i pkIY^mWdakd][daecc[d$DWY^Z[hMeXXb[# >ofej^[i[ i_dZ WkY^ =#K#FWWhkd][d ][ijWjj[j JWX[bb[($'+kdZ[im_hZledZ[h7#K#kdZ=# 9#H[][bWX][m_Y^[d$ M_[ [ha[ddj dkd Z_[ P[bb[" ZWii [_d Febo# f[fj_Z \[ij][ij[bbj _ij5 :Wi ;dZ[ Z[h Febof[f# j_Za[jj[ J[hc_dWj_ed m_hZ ZkhY^ Dedi[di# aeZed[d"WbieiebY^["Z_[IjefX[Z[kj[d"Wd][# p[_]j$ WbXm[hjip[_j[d5I_[i_dZ[_d[i[^h aedec_iY^[;_dh_Y^jkd]Z[hP[bb[$;_d[8Wa# j[h_[dp[bb[ p$8$ kdj[hb_[]j ^k\_] C_b_[kl[hd# Z[hkd][d" Z_[ [_d[ iY^d[bb[7ZWfj_ed Z[h P[b# b[ [h\ehZ[hd$ ;_d[ iY^d[bb[7ZWfj_ed [h\ehZ[hj WX[h[_d[diY^d[bb[dM[Y^i[bZ[hIodj^[i[b[_i# jkd][d$ Mh[ Z_[ c#HD7 bWd]b[X_]" ie m”h# Z[d ”X[h [_d[d bWd][d P[_jhWkc _cc[h Z_[# i[bX[d ;dpoc[ ][X_bZ[j p$8$ pkc 7XXWk Z[i Ije\\[i 7" Z_[ l_[bb[_Y^j Wk\]hkdZ [_d[i C_b_# [km[Y^i[bi d_Y^j c[^h ][XhWkY^j m[hZ[d$ :W# \”h addj[d WdZ[h[ b[X[didejm[dZ_][ ;dpo# c[p$8$pkc7XXWkZ[iIje\\[i8d_Y^j][X_b# Z[jm[hZ[d$?ijZ_[c#HD7`[ZeY^akhpb[X_]"ie m[hZ[dWdZ[h:D7iebWd][d[k[c#HD7#If[# p_[ipkc7XXWkled7jhWdiah_X_[hjkdZ_dZ_[ JhWdibWj_ed][][X[d"m_[Z[hIje\\7_cC_b_[k leh^WdZ[d _ij$ _ijed[kdZd_Y^jXWi_# iY^[dFhej[_d[pkhKciY^b_[œkd]Z[h:D7][# X_bZ[j$M[_j[h \_dZ[j [_d[ D[kX_bZkd]Z[hP[d# jh_eb[d ijWjj$ 7kY^ Z_[ HD7#Iodj^[i[ ij[_]j hWiY^Wd$:W][][d\_dZ[jpkdY^ij_dZ[dc[_i# j[d oZheboi[\h[_m_hZ"kcWdZ[dIf_dZ[b\W# i[hd[djbWd]pkmWdZ[hd$:_[L[hZeff[bkd]Z[h P[djh_eb[d\_dZ[jX[h[_jiakhplehZ[hI#F^Wi[ ijWjj$ :_[ 8_bZkd]iehj[ Z[h If_dZ[b\Wi[hd i_dZ Z_[ C_ahejkXkbkieh]Wd_iWj_edip[djh[d" Z[h[d C_jj[bfkdajZ_[_d[_d[ch[Y^j[dM_da[bpk[_d# WdZ[h b_[][dZ[d P[djh_eb[d ZWhij[bbj$ :_[ Fhe# f^Wi[ [hijh[Yaj i_Y^ ”X[h [_d[d P[_jhWkc led &"+#*"+^$

0ROPHASE :_[ Fhef^Wi[ X[h[_j[j Z_[ A[hdj[_bkd] leh" _d# Z[c i_Y^ Z_[ 9^heceiec[d ZkhY^ If_hWb_i_[# hkd]l[hZ_Y^j[d$7c;dZ[Z[hFhef^Wi[b_[][d Z_[9^heceiec[d_d[_d[hf^oi_ebe]_iY^_dWa# j_l[d ×JhWdifehj\ehcÆ leh" meX[_ `[Z[i 9^he# ceiec ^_[h Wki Z[d X[_Z[d _d Z[h ?dj[hc_je# i[ [djijWdZ[d[d JeY^j[hY^hecWj_Z[d X[ij[^j$ 7kœ[hZ[c mWdZ[hd Z_[ X[_Z[d P[djh_eb[d pk Z[dP[bbfeb[d"mWiZkhY^Bd][dpkdW^c[Z[h

0ROMETAPHASE ?d Z[h Fhec[jWf^Wi[ bij i_Y^ Z_[ A[hdc[c# XhWd Wk\" meZkhY^ Z[h If_dZ[bWffWhWj Wd Z[d 9^heceiec[d Wdi[jp[d aWdd$ :WX[_ X_bZ[d i_Y^ Z_[ A_d[jeY^eh#If_dZ[b\Wi[hd pm_iY^[d Z[d P[djhec[h[d Z[h 9^heceiec[d kdZ Z[d P[djh_eb[d Wki$ :_[ A_d[jeY^eh#If_dZ[b\Wi[hd i_dZledZ[dFeb#If_dZ[b\Wi[hdpkkdj[hiY^[_# Z[d" m[bY^[ Z_[ P[djh_eb[d pk Z[d Feb[d l[h# iY^eX[d^WX[d$

È

+APITELÈÈqÈ#HROMOSOMEN È-UTATIONENÈUNDÈIHREÈ&OLGENÈFàRÈDIEÈ'ESUNDHEIT

!BBÈÈA FÈ -ITOSEÈINÈ EINERÈ&ISCH "LASTULAÈÈ AÈ)NTERPHASE ÈBÈ0ROPHASE È CÈ-ETAPHASE ÈDÈFRàHEÈ !NAPHASE ÈEÈSPËTEÈ !NAPHASE ÈFÈ4ELOPHASEÈ .ACHÈ-ACLEODÈ



-ETAPHASE :_[9^heceiec[db_[][ddkd\h[_[jmW_dZ[h C_jj[ Z[i PojefbWicWi$ :_[ A_d[jeY^eh#If_d# Z[b\Wi[hd ^WX[d dkd Wbb[ 9^heceiec[d Wd Z[dP[djhec[h[d[h\Wiij$7kiZ[c8[h[_Y^Z[i If_dZ[bWffWhWji m[hZ[d Wbb[ ]hœ[h[d P[bbeh# ]Wd[bb[dl[hZhd]j$7kY^Z_[Dkab[eb[dm[hZ[d Wki Z[c If_dZ[bX[h[_Y^ [b_c_d_[hj kdZ ^WX[d i_Y^_c=hkdZfbWicWWk\][bij$?cL[hbWk\led m[d_][d C_dkj[d ][bWd][d Z_[ If_dZ[b\Wi[h# WdiWjpij[bb[d Z[h 9^heceiec[d _d Z_[ ugkW# jeh_Wb[X[d[ C[jWf^Wi[fbWjj[" Iocc[jh_[[X[#

d[ pm_iY^[d X[_Z[d If_dZ[bfeb[d kdZ m[h# Z[d ZkhY^ Z[d ][][di[_j_][d If_dZ[b\Wi[hpk] Zehj_dZ[hIY^m[X[][^Wbj[dZ_[i[ij[hdWhj_# ][ b\j[d][j[_bj"kdZiec_jm[hZ[dWkY^WdZ[h[ !NAPHASE P[bbaecfed[dj[dm_[C[cXhWd[d"Pojeia[b[jj" M_[ Z_[ C[jWf^Wi[ _ij WkY^ Z_[ ZWhWk\\eb][d# Eh]Wd[bb[dkdZbib_Y^[Fhej[_d[Wk\Z_[JeY^# Z[ 7dWf^Wi[ led h[bWj_l akhp[h :Wk[h (#(& j[hp[bb[dl[hj[_bj$:_[i][iY^_[^jc_j>_b\[[_d[i c_d$ 7bi [hij[i j[_b[d i_Y^ Z_[ P[djhec[h[d" aedjhWaj_b[dH_d][i"Z[hWki7aj_dkdZCoei_d Z_[ _d Z[h C[jWf^Wi[ Z_[ X[_Z[d 9^hecWj_# X[ij[^j$;hiY^d”hjZ_[P[bb[[_dkdZj[_bji_[_d Z[d [_d[i 9^heceieci deY^ pkiWcc[d^_[b# pm[_ JeY^j[hp[bb[d$ :khY^ :[febWh_iWj_ed Z[h j[d"_dZ[hBd]iWY^i[Z[h9^heceiec[dkdZ C_ahejkXkb_X_bZ[ji_Y^]b[_Y^p[_j_]"Wki][^[dZ ][X[d ZWc_j Z_[ 9^hecWj_Z[d \”h [_d[ Jh[d# lec P[djhec[h" m_[Z[h Z_[ ?dj[hf^Wi[WdehZ# dkd]\h[_"mWicWdWkY^Wbi;dZ[Z[hC[jWf^W# dkd]Z[hC_ahejkXkb_JWX[bb[)$($ i[X[p[_Y^d[daWdd$:Wdd[h\eb]jc_j>_b\[Z[h If_dZ[b\Wi[hd[_d[Jh[ddkd]Z[h9^hecWj_Z[d ÈÈ !MITOTISCHEÈ6ERËNDERUNGÈÈ DESÈ#HROMOSOMENSATZES kdZ _^h JhWdifehj pk Z[d [dj][][d][i[jpj[d È P[bbfeb[d"c_j[_d[h=[iY^m_dZ_]a[_jled'dc fhe C_dkj[$ :_[i ][iY^_[^j ZkhY^ A”hp[hm[h# %NDOMITOSE Z[d Z[h A_d[jeY^ehc_ahejkXkb_ kdZ m[_j[h[i ?d X[iedZ[hi if[p_Wb_i_[hj[d P[bb[d eZ[h WkY^ 7ki[_dWdZ[hh”Ya[dZ[hIf_dZ[bfeb[$:_[ZkhY^ kdj[h fWj^ebe]_iY^[d 8[Z_d]kd][d X[_if_[bi# Z_[ X[_Z[d 9^hecWj_Z[dijp[ ][X_bZ[j[d pm[_ m[_i[X[_Jkceh[daWdd[ipk[_d[hL[hc[^# ij[hdWhj_][d7dehZdkd][dm[hZ[dWkY^Wbi:_# hkd] Z[h 9^heceiec[d _dd[h^WbX Z[h _djWaj Wij[hX[p[_Y^d[j$ Xb[_X[dZ[d A[hdc[cXhWd e^d[ 7kiX_bZkd] [_d[h C_jei[if_dZ[b aecc[d$ CWd X[p[_Y^# 4ELOPHASE d[j Z_[i[d Leh]Wd] Wbi ;dZec_jei[$ :_[ <eb# :_[ b[jpj[ F^Wi[ Z[h A[hdj[_bkd]" Z_[ J[bef^W# ][ _ij [_d[ L[hl_[b\WY^kd] Z[i 9^heceiec[d# i["\bbj][m^db_Y^[c_jZ[hP[bbj[_bkd]pkiWc# iWjp[i" [_d[ Febofbe_Z_[$ {Xb_Y^[hm[_i[ m[hZ[d c[d$ C_j Z[h 8_bZkd] [_d[h d[k[d A[hd^”bb[ ZkhY^Febofbe_Z_i_[hkd]Wbb[9^heceiec[d[_#

È



+APITELÈÈqÈ#HROMOSOMEN È-UTATIONENÈUNDÈIHREÈ&OLGENÈFàRÈDIEÈ'ESUNDHEIT

d[h P[bb[ l[hZeff[bj" l[hl_[h\WY^j kim$ 7bb[h# Z_d]iadd[dWkY^dkh[_dp[bd[9^heceiec[d X[jhe\\[di[_dfWhj_[bb[;dZec_jei[$ 7bi 8[_if_[b[ \”h [_d[ iebY^[ L[hc[^hkd] Z[i 9^heceiec[diWjp[i i_dZ Eij[eabWij[d kdZ b\j[ h[Zkp_[hj m[hZ[d$;hijZWddadd[dZ_[^Wfbe_Z[;_p[bb[ 'dkdZZWi^Wfbe_Z[If[hc_kc'dpkhPo]e# j[l[hiY^c[bp[d"Z_[ZWc_jm_[Z[h[_d[dZ_fbe_# Z[d9^heceiec[diWjpX[i_jpj7XX$)$,$ :_[i[dLeh]Wd]X[p[_Y^d[jcWdWbiC[_ei[ H[_\[j[_bkd]$?dZ[hC[_ei[m[hZ[d_c=[][d# iWjp pkh C_jei[ ^ecebe][ 9^heceiec[d led# [_dWdZ[h ][jh[ddj kdZ ZWc_j Z[h 9^heceie# c[diWjp Wk\ Z_[ >b\j[ h[Zkp_[hj$ ?d Z[h C_je# i[m[hZ[dZW][][d9^hecWj_Z[d][jh[ddj"Z[h 9^heceiec[diWjpm_hZd_Y^jh[Zkp_[hj$ :_[;djm_Yabkd]Z[h=[iY^b[Y^jip[bb[dm_hZ Wbi If[hcWje][d[i[ kdZ Ee][d[i[ X[p[_Y^d[j$ 8[_Z[Leh]d][ ij_cc[d ^_di_Y^jb_Y^ Z[h J[_# bkd]i\eb][ kdZ L[hj[_bkd] Z[h 9^heceiec[d ]hkdZijpb_Y^”X[h[_d7XX$)$-$  :_[Kha[_cp[bb[di_dZm_[Ahf[hp[bb[dZ_# fbe_Z$I_[\”^h[dpkdY^ijpW^bh[_Y^[c_je# j_iY^[J[_bkd][dZkhY^kdZfheZkp_[h[d[_# d[]heœ[PW^bledIf[hcWje]ed_[dkdZEe# ]ed_[d$  :_[i[ [djm_Ya[bd i_Y^ m[_j[h pk If[hcWje# poj[d ?$ EhZdkd] kdZ Eepoj[d ?$ EhZdkd]" X[_Z[ideY^Z_fbe_Z[IjWZ_[d$  :_[i[IjWZ_[djh[j[ddkd_dZ_[H[Zkaj_edi# j[_bkd] [_d" Z_[ i_Y^ _d pm[_ H[_\[j[_bkd][d

3 0HASE 8[lehZ_[=[iY^b[Y^jip[bb[d_dZ_[C[_ei[[_d# jh[j[d" ZkhY^bWk\[d i_[ [_d[ ^db_Y^[ ;djm_Ya# bkd] m_[ ][m^db_Y^[ Ahf[hp[bb[d _d Z[h ?d# j[hf^Wi[leh[_d[hC_jei[$7kY^^_[h\_dZ[dm_h m^h[dZZ[hb[jpj[dfhc[_ej_iY^[d?dj[hf^W# i[[_d[I#F^Wi["_dZ[hZ_[H[fb_aWj_edZ[h:D7 ijWjj\_dZ[j$ :_[ ie lehX[h[_j[j[d P[bb[d jh[j[d dkd_dZ_[[hij[H[_\[j[_bkd][_d$ :_[L[hj[_bkd]Z[h9^heceiec[d_dZ[hC[_e# i[bk\j"m_[X[h[_ji[hm^dj"_dpm[_J[_biY^h_j# j[dWX0  ?d Z[h [hij[dH[_\[j[_bkd]H?m[hZ[d Z_[ ^ecebe][d 9^heceiec[d" Z_[ Wki pm[_

!BBÈÈ 3TARKÈVEREINFACHTESÈ3CHEMAÈZURÈ2EIFETEILUNGÈ UNDÈ"EFRUCHTUNG

È

+APITELÈÈqÈ#HROMOSOMEN È-UTATIONENÈUNDÈIHREÈ&OLGENÈFàRÈDIEÈ'ESUNDHEIT

!BBÈÈ 6ERGLEICHEN DESÈ3CHEMAÈVONÈ /OGENESEÈUNDÈ3PERMA TOGENESE



9^hecWj_Z[d X[ij[^[d" led[_dWdZ[h ][# Z_[9^hecWj_Z[d_ijdeY^d_Y^ji_Y^jXWh$@[# jh[ddj7XX$)$. Z[i9^heceiec_ijc_jX[_Z[d;dZ[d"Z[d  :_[ pm[_j[ H[_\[j[_bkd] H ?? [djifh_Y^j J[bec[h[d"WdZ[hA[hdc[cXhWd\_n_[hj$ fh_dp_f_[bb [_d[h C_jei[" _d Z[h Z_[ X[_Z[d  Po]ejd$ ?cPo]ejdX[]_dd[di_Y^Z_[^e# 9^hecWj_Z[dled[_dWdZ[h][jh[ddjm[hZ[d cebe][d 9^heceiec[d e\j led Z[d ;d# JWX[bb[)$*$ Z[d ^[h \ehjiY^h[_j[dZ fWhWbb[b Wd[_dWd# Z[hpkbW][hd$:_[i[hLeh]Wd]m_hZWbiIod# 6ERLAUFÈDERÈÈ2EIFETEILUNG Wfi_iX[p[_Y^d[jkdZij[bbjZ[d[djiY^[_Z[d# 0ROPHASEÈ) Z[dehZd[dZ[dLeh]Wd]_dZ[hC[_ei[ZWh$ :_[Fhef^Wi[?biiji_Y^m_[Z[hkc_dc[^h[h[ :_[9^heceiec[dfWWh[b_[][ddkdc_jZ[d J[_biY^h_jj[Wk\j[_b[d$ [_dWdZ[h [djifh[Y^[dZ[d =[dehj[d [nWaj  B[fjejd$ :_[ 9^heceiec[d if_hWb_i_[h[d d[X[d[_dWdZ[h$:_[im_hZZkhY^Z_[×IY^_[# i_Y^ kdZ m[hZ[d Wbi \[_d[ ehced[" Z_[ C[_ei[ m_[Z[h Wk\$ :Wh# Wk\ \eb][d Z_[ :_Wa_d[i[" m[bY^[ Z_[ Fhef^Wi[ ?Z[h[hij[dc[_ej_iY^[dJ[_bkd]X[[dZ[j"ZWdd Z_[C[jWf^Wi[?"Z_[7dWf^Wi[?"Z_[J[bef^Wi[? kdZ_c7XijWdZledm[d_][dC_dkj[dZ_[Fhe# f^Wi[??kdZC[jWf^Wi[??$?dZ_[i[cIjWZ_kc aeccjZ_[;djm_Yabkd][hd[kjpkcIj_bbijWdZ$ Pojebe]_iY^\_dZ[jcWd[_d[kd]b[_Y^[FbWicW# l[hj[_bkd] pm_iY^[d ;_p[bb[ kdZ '$ Febahf[h$ 8[_Z[ P[bb[d Xb[_X[d `[ZeY^ kciY^beii[d led [_d[hZ_Ya[dFhej[_d^”bb[PedWf[bbkY_ZW$ ;_d_][ IjkdZ[d dWY^ ;hh[_Y^[d Z[h C[jW# f^Wi[ ?? \_dZ[j" ZkhY^ >ehced[ _dZkp_[hj" Z_[ ElkbWj_ed Z[h ;_ifhkd] ijWjj$ {Xb_Y^[hm[_# i[l[hbiijdkh[_d[Eepoj[Z[d;_[hijeYakdZ m_hZlec;_b[_j[hWk\][\Wd][d$:_[WdZ[h[d_c ]b[_Y^[d Poabki ^[hWd][h[_\j[d Eepoj[d Z[][#

d[h_[h[d$?c;_b[_j[haWdddkdZWi;_dZh_d][d Z[i If[hc_kci kdZ ZWc_j Z_[ 8[iWckd] Z[h C[jWf^Wi[#??#Eepoj[ ijWjj\_dZ[d$ ;hij ZWdWY^ \”^hj Z_[ C[jWf^Wi[#??#Eepoj[ Z_[ C[_ei[ pk ;dZ["meX[_Z[h($Febahf[hWX][jh[ddjm_hZ$ :Wi`[jpjlehb_[][dZ[IjWZ_kcm_hZWbiFhedka# b[kiijWZ_kcX[p[_Y^d[j"ZWi_Y^`[m[_bikcZ_[ ^Wfbe_Z[d9^heceiec[dijp[Z[hEepoj[kdZ Z[i If[hc_kci [_d[ A[hdc[cXhWd WkiX_bZ[j kdZ ie `[m[_bi [_d Fhedkab[ki [djij[^j$ 7d# iY^b_[œ[dZl[hiY^c[bp[dZ_[X[_Z[dFhedkab[_ pkcZ_fbe_Z[dPo]ej[da[hd"Z[hi_Y^_diY^d[b# b[h<eb][c_jej_iY^m[_j[hj[_bj7XX$)$')$

ÈÈ !UFBAUÈEINESÈ#HROMOSOMS 9^heceiec[d"iem_[m_hi_[WkiB[^hX”Y^[hd a[dd[dkdZ\eb]b_Y^lehkdi[h[c][_ij_][d7k# ][ ][][dmhj_] ^WX[d" l[h\”^h[d kdi [^[h pk [_d[hj[_bm[_i[_hh_][dLehij[bbkd]"Z[ddi_[h[#

È qÈ !UFBAUÈEINESÈ#HROMOSOMS







!BBÈÈ "EFRUCHTETEÈ MENSCHLICHEÈ%IZELLEÈIMÈ6IER ZELLSTADIUM È:ONAÈPELLUCI DAÈUNDÈEINEÈGRڔEREÈ!NZAHLÈ VONÈ3PERMIENÈSINDÈGUTÈZUÈ ERKENNENÈ.ACHÈ%DWARDS

fhi[dj_[h[d dkh [_d akhp[i PkijWdZiX_bZ _c P[bbpoabki m^h[dZ [_d[h akhp[d F^Wi[" Z[h C[jWf^Wi[Z[hC_jei[_dLehX[h[_jkd]Wk\Z_[ P[bbj[_bkd]$=[dWk_dZ_[i[hF^Wi["dcb_Y^Z[h Z[h^Y^ij[dAedZ[diWj_ed"bWii[di_[i_Y^WX[h WdWboi_[hXWh fhfWh_[h[d kdZ ZWhij[bb[d" mWi WkjecWj_iY^kdi[h[X_bZb_Y^[Lehij[bbkd]fh]j$ ?d Z_[i[c IjWZ_kc i_dZ i_[ WX[h [_][djb_Y^ d_Y^jh[fhi[djWj_l"ZWZ_[[njh[c[L[hfWYakd] pk [_d[h 7XiY^Wbjkd] Z[h =[d[ \”^hj$ M[dd WkY^Z_[P[bbj[_bkd]Wdi_Y^ledWkœ[hehZ[djb_# Y^[h8[Z[kjkd]_ij"ZWdWj”hb_Y^[j[heY^hecWj_dd_ccj lehZ[hP[bbj[_bkd]X[_c{X[h]Wd]lec7h# X[_ji# _d Z[d J[_bkd]ia[hd ijWha pk$ ;dj# ifh[Y^[dZ_ijZ_[C[d][Z[i>[j[heY^hecW# j_di[_d7kiZhkYa\”hZ_[Ije\\m[Y^i[bWaj_# l_jj[_d[hP[bb[1iec_jkdj[hb_[]jZ[h7dj[_b Z[i >[j[heY^hecWj_di _d [_d[c P[bba[hd Z[kjb_Y^[d IY^mWdakd][d$ 8[_c >[j[he# Y^hecWj_d bWii[d i_Y^ m_[Z[hkc pm[_ <eh# c[dkdj[hiY^[_Z[d0 Ä Aedij_jkj_l[i >[j[heY^hecWj_d$ Fh_dp_# f_[bbaWddi_Y^`[Z[hJ[_b[_d[i9^hece# ieci aedZ[di_[h[d kdZ ^[j[heY^hecW# j_iY^ m[hZ[d" cWdY^[ J[_b[ b_[][d WX[h _cc[h_dZ_[i[h<ehcleh$CWdifh_Y^j ZWddledaedij_jkj_l[c>[j[heY^hecW# j_d$ :_[i[i 9^heceiec[dcWj[h_Wb m_hZ d_[cWbi_dFhej[_d”X[hi[jpj"[im_hZX[_ Z[h P[bbj[_bkd] ifj h[fb_p_[hj kdZ ][^j Wbi>[j[heY^hecWj_dWk\Z_[JeY^j[hp[b# b[d”X[h$;_d8[_if_[b_ijZ_[P[djhec[h# h[]_ed" Wd Z[h Z_[ X[_Z[d 9^hecWj_Z[d [_d[i 9^heceieci pkiWcc[d][^Wbj[d m[hZ[d$;X[diem_hZpkh:ei_iaecf[d# iWj_ed ][][d”X[h cddb_Y^[d P[bb[d _d `[Z[h m[_Xb_Y^[d P[bb[ [_d[i Z[h X[_Z[d N#9^heceiec[_dWaj_l_[hj0:_[i[iI[n# Y^hecWj_daWddZkhY^][[_]d[j[[j[heY^hecWj_d$ 7d i[_# d[hC[d][aWddcWdZ[d;djm_Yabkd]i# pkijWdZ eZ[h Z[d f^oi_ebe]_iY^[d Pk# ijWdZ[_d[hP[bb[[ha[dd[d$Ie\_dZ[ji_Y^ _d WkiZ_\\[h[dp_[hj[dP[bb[dl_[b>[j[he# Y^hecWj_d" m[_b [_d =heœj[_b Z[i Y^he# ceiecWb[d CWj[h_Wbi aedZ[di_[hj kdZ ZWc_jij_bb][b[]j_ij$Dkh[_d][h_d][hJ[_b Z[h ;hX_d\ehcWj_ed ckii deY^ WX][b[# i[dm[hZ[dkdZ_ij\eb]b_Y^d_Y^jaedZ[d# i_[hj$;cXhoedWb[P[bb[dZW][][d"X[_Z[# d[d [_d ]heœ[h J[_b Z[h ;hX_d\ehcWj_ed jWjiY^b_Y^ _d Fhej[_d ”X[hi[jpj m[hZ[d ckii"^WX[dm[d_]>[j[heY^hecWj_d$

#HROMATIN 8[jhWY^j[j cWd [_d[d \_n_[hj[d kdZ c_j XWi_# iY^[d <WhXije\\[d Wd][\hXj[d P[bba[hd kd# j[h Z[c B_Y^jc_aheiaef" ie [ha[ddj cWd [_d ×A[hd][h”ijÆ$ :_[i _ij ZWi 9^hecWj_d" ZWi Wki Z[h [_][djb_Y^[d ;hXikXijWdp" Z[d 9^heceie# c[d X[ij[^j$ :Wi 9^hecWj_d _ij [_d 7hj[\Waj kdZ[djifh_Y^jd_Y^jZ[cdWj”hb_Y^[dPkijWdZ Z[h9^heceiec[d$?dZ[hP[bb[b_[]j[i_dpm[_ <ehc[dleh0  ;kY^hecWj_d$ BeYa[h l[hj[_bj[i 9^hecWj_d _c7hX[_jia[hd$ :Wi ;kY^hecWj_d _ij m[_j# ][^[dZ[djif_hWb_i_[hjkdZm_hZWbiWaj_l[i #HROMOSOMEN =[dcWj[h_WbWd][i[^[d$  >[j[heY^hecWj_d$ :_Ya[ 9^hecWj_dcWi# ;_dp[bd[ 9^heceiec[d i_dZ _c ?dj[hf^Wi[# i[d" Z_[ ZWi A[hd][h”ij X_bZ[d$ :Wi >[j[# a[hd Z[h [kaWhoej[d P[bb[ b_Y^jc_aheiaef_iY^

È qÈ !UFBAUÈEINESÈ#HROMOSOMS

d_Y^j i_Y^jXWh$ :_[ :D7#(7">(8">)kdZ>*"  [_d[ ^[j[he][d[ =hkff[ led D_Y^j#>_ijed# Fhej[_d[d" Z_[ X[_if_[bim[_i[ l[hiY^_[Z[d[ ;dpoc[ZWhij[bb[d$ :_[>_ijed[i_dZ\”hZ_[ijhkajkh[bb[Eh]Wd_iW# j_edZ[h9^heceiec[dl[hWdjmehjb_Y^$I_[^W# X[dl_[b[XWi_iY^["fei_j_l][bWZ[d[7c_deik# h[d kdZ ZW^[h [_d[ ^e^[7\\_d_jj pkh d[]Wj_# l[d BWZkd] Z[h :D7$ :_[ >_ijed[ >(7" >(8" >) kdZ >* X_bZ[d Wd Z[d Feb[d WX][\bWY^j[ Fhej[_dak][bd"EajWc[h[WkiZ[d:_c[h[dZ[h l_[h l[hiY^_[Z[d[d >_ijed[$ @[Z[ Fhej[_dak][b 4ABELLEÈÈ 3TRUKTURÈDESÈ#HROMATINS







_ij led [_d[c :D7#<WZ[d c_j '"-+ B_daim_d# Zkd][d kcm_Ya[bj" mWi '*, 8Wi[dfWWh[d [dj# ifh_Y^j$ :_[i[h Aecfb[n _ij Z[h Dkab[eiec[d# Yeh[JWX[bb[)$,$ :Wi>_ijed>'b_[]jWkœ[h^WbXZ[iDkab[eie# c[dYeh[i kdZ _ij c_j :D7 lWh__[h[dZ[h Bd][ '+#'&& 8Wi[dfWWh[ Wiiep__[hj" Z_[ [_d Dkab[e# iec c_j Z[c WdZ[h[d l[hX_dZ[j" Z[h ×B_da[h# :D7Æ$Iem[hZ[d\ehjbWk\[dZ[dZ[;_d^[_j[dled YW$ (&& 8Wi[dfWWh[d ][X_bZ[j" Z_[ [_d[d <WZ[d c_j[_d[c:khY^c[ii[hled'&dc[hp[k][d$ :_[ >'#>_ijed[ l[ha”hp[d Z[d :D7#<W# Z[dm[_j[h"_dZ[cc_j_^h[h>_b\[c[^h[h[Dk# ab[eiec[d ^[b_aWb Wk\][Zh[^j m[hZ[d$ :_[i \”^hjpk[_d[h9^hecWj_d\Wi[hled[jmW)&dc :khY^c[ii[h$ I_[ m_hZ m_[Z[hkc _d IY^bWk# \[d][b[]j"meX[_`[Z[IY^bWk\[[jmW-+aX:D7 [dj^bj$ :_[IY^bWk\[di_dZWd[_dp[djhWb[i=[h”ij Wki iWkh[d D_Y^j#>_ijed#Fhej[_d[d ][^[\j[j$ :_[i[i=[h”ij[dj^bjZWi;dpocJefe_iec[hW# i[??"ZWi_dZ[hBW][_ij"Z_[X[_Z[d:D7#Ijhd# ][ Z[i :D7#:eff[bijhWd]i m_[Z[h pk [djm_d# Z[d$ :_[ Jefe_iec[hWi[ ?? kdZ WdZ[h[ Fhej[_# d[Z[i9^hecWj_diX_dZ[dWdX[ij_ccj[:D7# I[gk[dp[dc_j[_d[c^e^[d7dj[_b”X[h,+ Z[i8Wi[dfWWh[i7Z[d_dkdZJ^oc_d$:_[i[I[# gk[dp[dm[hZ[dWkY^Wbi=[h”ijaeff[bkd]iX[#

È



+APITELÈÈqÈ#HROMOSOMEN È-UTATIONENÈUNDÈIHREÈ&OLGENÈFàRÈDIEÈ'ESUNDHEIT

h[_Y^[×iYW\\ebZWjjWY^c[djh[]_ediÆ"I7HX[# p[_Y^d[j kdZ ij[bb[d c]b_Y^[hm[_i[ WkY^ Z_[ ;b[c[dj[ ZWh" Wd Z[d[d Z_[ 9^hecWj_diY^bWk# \[dWk\][^d]ji_dZ$ :_[ie_dIY^bWk\[dWk\][^d]j[9^hecWj_d# \Wi[h m_hZ ZkhY^ IY^b[_\[dX_bZkd] m[_j[h l[h# a”hpj$:_[i[m[_j[h[7k\m_dZkd]pkZ[d9^he# cWj_Z[d [_d[i C[jWf^Wi[Y^heceieci \”^hj iY^b_[œb_Y^pk[_d[h[jmW'&$&&&\WY^[dL[ha”h# pkd] Z[h khifh”d]b_Y^[d Bd][ Z[i :D7#<W# Z[di7XX$)$'*"7XX$)$'+ ÈÈ :ENTROMER È4ELOMERÈUNDÈÈ È /RIGINÈOFÈ2EPLICATION :ENTROMER ?d C[jWf^Wi[Y^heceiec[d _ij fhe 9^hece# iec[_dP[djhec[hWbifh_ch[Aedijh_aj_edWd Z[h FWWhkd]iij[bb[ Z[h IY^m[ij[hY^hecWj_Z[d i_Y^jXWh$ :khY^ 8hkY^[h[_]d_ii[ [djijWdZ[d[ Wp[djh_iY^[