Evolution of CONSTANS Transcriptional Regulation and Protein Function in the Brassicaceae Family

Transcription

1 Evouon o ONSNS nspon Rguon nd Pon Funon n h Bss Fmy InuguDsson zu Engung ds Dokogds d MhmshNuwssnshhn Fkuä d Unvsä zu Kön vogg von Smson Smon us Kön Kön, Novmb

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3 D vognd b wud m MxPnkInsu ü Pnznzühungsoshung n Kön n d bung ü Enwkungsboog d Pnzn (Dko Po D oupnd) ngg Bhs: Po D og oupnd Po D U Hök Püungsvosznd: Po D Mn Hüskmp g d Dspuon: Jnu

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5 BSR BSR Pns spond o sson hngs n dy ngh o ono dvopmn nsons suh s owng nd bud domny In h mod pn bdopss hn ( hn), ONSNS (O) vs h xpsson o FLOWERIN LOUS (F) spy und ong dys, nd F pon hn movs om h o h shoo p msm wh pomos h nson o owng O nspon s psy gud so h s mrn s pssd n h monng nd ss n h vnng o ong dy owng von o F ho, h dun pn o O nspon s n ssn omponn o h guon o owng m n hn h wo oss homoogs o O n hn, ONSNSk (OL) nd OL hv no unon n phoopod owng spons nd show dn mrn pns h gns vovd om ommon nso h s who gnom dupon (α) n h ng dng o hn h s bvd o hv oud ~ my h nspon pns o O nd OL onsvd n h bs Bss sps honm bum so h O homoog o hs sps bu no s OL homoog n ompmn h o muon n hn s h honm ng psns h s sp n h vouon o h Bss hs ndngs nd h O unon ws dy psn n y sg o Bss vouon nd s vy s ky onsvd houghou h my h pomo o O onns onsvd squn boks whh shd n ohoogs xmnd n n Bssn sps DOF bndng ss, EBoxs nd P bndng ss h mos bundn smns dnd n n O pomos Fuhmo, DOF nd P bndng ss songy nhd n h pomos o O gns ompd o OL gn pomos DOF bndng ss pod o nb bndng o pssv DF nspon os nd w mong h mos hghy onsvd mos n h pomos o O ohoogs EBoxs puv bndng ss o FLOWERIN bhlh (FBH) Fs h unon s nspon vos o O No o hs so bn ssgnd o P nspon os n guon o O nspon Pomo po suds n hn vd h h O pomo onns unon guoy squns up o kb om h S nd h sho onsvd guoy mo h ompss DOF bndng ss nd s psn boh dsy nd poxmy s sun o mrn pns hghy sm o ndognous O mod o h vouon o O pomo s poposd n whh downsm onsvd DOF bndng ss ppd dsy upsm o gu O h gn dupon dng o s dvson om OL ny hssn, mmb o h om my whh s ss o h Bss, hs ony on ohoog o O (hol) whh shs on s ommon ns gn wh O, OL nd OL hol pon squn s mos sm o OL homoogs om h Bss my I

6 BSR ddony mrn xpsson pn nd ow by o pomo y owng n hn ommon hss o hs gn wh OL nd OL bu no wh O Hn, h nspon guon o O s w s n ns n py o pomo owng whn ompd o s os homoogs OL nd OL vovd n h Bss my nd psns novy h os n hs my My vouony suds nd h O vovd by gn dupon h oo o h Bss my hs gn hn vovd unon n phoopod owng hough hngs o s nspon guon nd pon unon Suh hsoy onds h un vw h O hs n nn hsoy pdng h dvgn o monooydonous nd doydonous ngospms, bu h suggss h h o o O homoogous gns n onng phoopod owng mgh hv vovd ndpndny n dn ms o hgh pns II

7 ZUSMMENFSSUN ZUSMMENFSSUN Pnzn gn u sson Ändung d gsäng um Enwkungssh w ds Bühn od d Knospnuh zu konon In d Modpnz bdopss hn ( hn) kv ONSNS (O) d Expsson von FLOWERIN LOUS (F) m End ns Lnggs Duhn bwg sh F Pon vom B zum Sposspkmsm um do dn Whs zu podukvn Enwkung nzun D nskpon von O s päzs gu dm dssn mrn m Mogn undük wd und s m bnd ns Lnggs nsg, ws d kvung von F ub Ds von d gsz gu Po d O nskpon s som n ssn Komponn d Bühzguon n hn D zw ähnhsn Homoog von O n hn, ONSNSk (OL) und OL hbn kn Funkon n d phoopodshn Rguon d Bühz und wsn bwhnd mrn Po u d n smmn von nm zn gmnsmn Vogäng b und snd nh d zn nomdupkon (α) d zu hn Ln güh h, wh vo Monn Jhn snd, nsndn D nskponspo von O und OL snd n d bsn Bss Spzs honm bum konsv Ds O Homoog b nh ds OL Homoog von honm bum s n d Lg d o Muon n hn zu kompmnn W d honm Ln sh s ss von dn Bss bgnn h wsn ds Egbnss du hn, dss d O Funkon shon üh n d Bss Fm nsndn s und ds dssn kvä whshnh n d kompn Fm konsv s D Pomo von O nhä konsv Bök, d n zhn vshdnn Bss Spzs vokommn DOF Bndsn, EBoxn und P Bndsn snd d m häugsn vokommndn sbndsn d n dn O Pomoon dnz wdn konnn Whn snd DOF und P Bndsn übpäsn n dn Pomoon von O nn m Vgh zu dnn von OL nn DOF Bndsn wdn von undükndn DF nskponskon (Fs) gbundn und sn d m höhsn konsvn Mov d EBoxn snd mögh Bndsn ü FLOWERIN bhlh (FBH) Fs wh s nskpon kvon von O gn Fü P nskponskon wud noh kn Funkon n d Rguon von O sgs Pomo Rpo Unsuhungn n hn hbn gzg, dss O Pomo guosh Squnzn bs zu kb vom nskponss nhä und ds kuz konsv guosh Mov, d DOF Bndsn nhn und sowoh ds s uh poxm vokommn, ushnd snd um mrn Expssonsmus ähnh dm von ndognm O zu vmn En Mod ü d Evouon von dm O Pomo wud vogshgn n dm nhgnd konsv DOF Bndsn nh d ndupkon, d zu Dvskon von OL güh h, ds vognd uuhn um O zu gun III

8 ZUSMMENFSSUN ny hssn, n Mgd d Fm d om, n Shwsm d Bss, h nu n Ohoog von O (hol) whs nn zn gmnsmn Vogäng m O, OL und OL h hol Ponsqunz s d von OL Homoogn d Bss Fm m Ähnhsn Zusäzh s ds mrn Expssonspo und d gng Fähgk ühzgs Bühn n hn zu kvn gmnsm hkskn m OL und OL b nh m O so nsndn sowoh d nskpon Rguon von O so uh d höh Fähgk Bühn uszuösn n d Fm d Bss und sn som Nuhn d Mn vouonän Unsuhungn wsn du hn, dss O m Uspung d Bss Fm duh ndupkon nsndn s Dss n h dnn n Funkon n d phoopodshn Bühguon duh Ändungn n d nskponn Rguon sow d Ponunkon vov Ds Dsung wdsph d jzgn ussung nh d O vo d Enshung von monokoydonn und dkoydonn ngospmn shon vohndn w, sondn du n, dss d Ro von O s Rguo vom phoopodshm Bühn unbhängg n vshdnn Fmn d höhn Pnzn nsndn s IV

9 BLE OF ONENS BSR I ZUSMMENFSSUN III INRODUION Pmb Fowng m guon by dy ngh nspon gn guon Pn nspon gn guon nd h o o smns Phyogn shdowng dns sguoy modus n pns nspon guon o phoopod owng n hn O pon unons s nspon vo o FLOWERIN LOUS O pon suu nd unon n nspon guon h nun o phoopos on O pon sby h ONSNSk gn my shows dundny o O onsvon o O unon n oh sps Rguon o O nspon by xn ondn O mrn vs duny gud 9 FBHs v O nspon 9 DFs nspon pssos o O FKF nd I oodny dgd DFs nd v psson o O ddon guos mpd n O nspon guon Invovmn o Phoopos n O mrn guon onsvon o O mrn guon n oh sps h ss ms Bss nd om s sh oos IM OF HE SUDY MERIL ND MEHODS 9 Phyogn onshp nd unon dvson o O Homoogs n h Bss nd om 9 bum nd hssn ong dy pns 9 Subgoup I OL gns onsvd n h Bss nd hssn onns ony on suh gn h s osy d o OL Expsson pns o hn, bum nd hssn goup I OL gns onsvd Subgoup I OL gns om hn, bum nd hssn b o ompmn h o mun mno d squn hngs my xpn unon dns bwn O, OL, OL nd hol 9 Dsusson hp Phyogn Shdowng o ONSNS pomo nd unon s O pomos psn n Bssn sps nvsgd h pomo o O s onsvd n n Bssn Sps nd us unqu smn omposon V

10 Sgy o unon nyss o h hn O pomo nyss o hn O guon by pomo don onsus dns mnm pomo Dsson o O pomo by h gn o unon ppoh vs spb unons o submns n shpng mrn xpsson pns 9 nyss o onsvd guoy mos by gn o unon ppoh suppod ndngs om phyogn shdowng nd smn nyss ndm dupon dng o mgn o O usd ppn o guoy DOF bndng s us n h ds O pomo 9 Dsusson hp O pomo onsvon n h Bss h omposon o smns n h O pomo Funon nyss o h O pomo n hn h mod o O pomo vouon Rguon o O nspon by DFs s novy h os n h Bss DF nd DF bndng o h hn O pomo oud no b dd n pn DF nspon os gu O bu no OL nd OL n hn 9 Lgh downgus O mrn n h monng n h bsn o DF nspon os Lgh shps h xpsson pns o OL nd OL s w s hol n h monng h mrn o O, OL nd OL s hghy unsb Rd nd bu gh py sponsb o downgung O mrn n h monng n h bsn o DF nspon os Dsusson hp hip o DF nd DF o O nd F ous dd no d bndng Rguon o mrn vs by DFs s no onsvd bwn subgoup I OL gns Lgh downguon o subgoup I OL gns s onsvd nd dpnds on gh quy 9 ONLUSIONS ND PERSPEIVES 9 Insghs no nspon guon o O 9 mod o O pomo vouon 9 O s mod o pomo vouon 9 Inpy o O Funon nd nspon 9 h s ommon ns gn o O 9 Funon o O ohoogs byond h Bsss 9 LIERURE 9 PPENDIX 9 BBREVIIONS 9 KNOWLEDEMENS ERKLÄRUN LEBENSLUF VI

11 INRODUION INRODUION Pmb Pns sss ognsms h hghy dpd o h nvonmn o nsu opm suvv nd poduon n h hb Pns sns dy ngh nd onn n nn mkp, d h dn ok hs nomon s usd o mng o dvopmn posss, o whh h pogmmng om vgv o poduv phs, gny md owng, s ky sp Phoopod owng spons, whh nbs owng und voub nd nhbs und nppop dy ngh ondons ws s dsbd mos nuy go (n nd d, 9) Longdy ondons yp o spng nd summ owng n h mod ognsm bdopss hn Muns mpd n h phoopod owng phwy n bdopss hn w dnd s y s 9 Insngy ou o ou supv muns nvsgd h xhbd muons n gns o h phoopod owng phwy, nmy INE (I) nd ONSNS (O) (Réd, 9) I ws ony muh h hgh numb o owng muns ws dnd nd h gn onshp dnd (Koonn, 99) h h ky guos o phoopod owng n bdopss hn, I, O nd FLOWERIN LOUS (F) w hby pd n h sm phwy hs s h sg o nvsgng h mhnsm by whh bdopss hn s b o dsmn bwn dy nghs nd ng hs nomon no sgn h ggs owng n omponn n h gnon o owng spons s O, whh ngs nn sgns om h dn ok nd h xn sgn gh boh h nspon nd posnspon vs o v F xusvy und nduv LD ondons Fowng m guon by dy ngh h swh om vgv o poduv dvopmn n pns, d o s o nduon o owng, s u sp n h o ngospms s ns poduon Pns hv vovd mny guoy mhnsms o gg owng ony und voub ondons h sgns h ngd o gu owng m nud nn nd xn os Fowng n b dyd o mny ys n n g dpndn wy by n xndd juvn phs o xmp n s (Bohnus, ) Sson guon s mpon o mny pns nd s snsd by ngng dn sgns Pnn pns o xmp b o sns wn by spondng o od mpus o vod owng n uumn bu ow n h oowng spng (Wng, 9b) noh mpon sgn o dsmnng ssons s h msumn o dy ngh (n nd d, 9) Fowng n b nd n shody pns k Oyz sv (R) whn h dys shon n uumn ndng h h ho nd on dy summ s ov (Hym, ) Dy nu pns k Sonum yopsum (omo) do no ow n spons o dy ngh (Lshz nd Eshd,

12 INRODUION ) hs bhvou onds wh hs sps on ognng om gons wh dy ngh dos no subsny hng n on y Long dy (LD) pns on h oh hnd n owng n h spng o summ whn n dy ngh s xdd whh nds voub ondons n mp ms h pn mod ognsm bdopss hn ( hn) s LD pn (Koonn, 99) Fowng s d by LD ondons sung n h pn podung w vs bo owng nd nng owng s hn und SD ondons hn s uv ong dy pn mnng vnuy ows ndpndny o n nduv phoopod sgn und SD pn wh n obg qumn o n phoopod on h oh hnd dos no n owng und nonnduv ondons hn s mod o nduv phoopod owng nd nons bwn gns n h phoopod owng phwy h mou us o owng und nduv ondons (Koonn, 99) h gn podus o owng m guos p o ompx nspon nwoks h w b dsussd bow Nw nsghs n h vouon nd guon o n mpon hub n hs nwok, h gn ONSNS, w b psnd n hs sudy nspon gn guon nspon o DN no RN s h s sp n h n dogm o mou boogy (k, 9) h guon o nspon povds n mpon guoy sp nbng o ono h moun o pon h s podud om gn ny gvn m n guon ows muu ognsms o mk dn us o h sm gnom o dn yps nspon guon s ompx mhnsm n pokyos bu boms vn mo ompx n ukyo ognsms (bs, ) In gn nspon s d by h umn o g pon ompx, d RN poyms II (Po II), whh nsbs h mp DN snd o gns no mssng RN (mrn) nspon ws ound o ou ombnd n so d nspon os (ook, ; Osbon, ) h guon o h umn o Po II o h nspon s (S) s n gn s d by nspon os (Fs) Fs pons whh b o bnd DN nd gu nspon (bs, ) hy n b p o pon ompxs nd boh s vos o pssos dpndng on h mou onx (Bkmn nd Pvs, ) Sp DN squns, so d smns ognzd by Fs n guoy gons gny od o h odng gon bu n so b ound n nons, odng nd downsm gons h poxm guoy p s d h pomo o gn, wh mo ds guoy gons d nhns hs nhn gons n b ko bs ps (kb) wy om h odng gon (bs, ) noh mpon y o nspon guon nvovs pgn mhnsms hs hngs n h gnom h do no h DN squn bu gu gn xpsson h s ng om modon o sng o o g ps o homosoms h mos pomnn pgn hngs ou s posnspon modon o hsons (g yon) nd mhyon o DN squn (bs, ) In ons o h n pdgm o mou boogy ws ound mo

13 INRODUION ny h nspon s no sd o pon odng gns bu so ous n ngn sp In o xmp ~% o nsps dnd od n ngn sp (L, ) Suds n ys suggs n nvovmn o nonodng RNs os o h S o b nvovd n mhnsms o homn modng nd POL II umn nd hus nspon non (Duow, ; Ho, ) Pn nspon gn guon nd h o o smns bou 9% () o hn gns od o nspon os (Rhmnn, ), hghghng h mpon o nspon guon n pns Rguon o nspon s ognzd n ompx nspon nwoks, h ddony on nonnd (Hung, ; Kumnn, ) nspon os sso o DN v so d smns od n h guoy gon o pomo o gn (bs, ) smns gny sho squn shs Dn ms o Fs hv pns o n o smns, wh h bndng ss o ndvdu mmbs o gvn F my n vy In hn h bs hxoophx (bhlh) F my o xmp hs mmbs whh n b gozd by h DN bndng pn (odooz, ) Mos bhlh (9) w pdd o bnd h EBox (NN), wh h ohs h bnd vyng squns () o hv no pdd DN bndng py () O h EBox bndng pons, 9 bhlh hv pn o h Box (), sp vson o h EBox h pd smn o F n b dnd by dn mhods boh n vo usng mhods suh s pon bndng moys (PBM, H, ) nd n vvo wh uzng homn Immunoppon oowd by nx gnon squnng (hipsq, Kumnn, ) Nonhss nspon o bndng ss do no ou ndpndny bu usuy ognzd n so d sguoy modus (RMs) o ovy gu gn xpsson boh n pns nd nms (Mh, ; Nguyn nd Xu, 99; Znzn, 9) In nms RMs w dnd o b ~ bs ps (bp) ong nd y n o mo F bndng ss o s ou Fs (Lvn nd Dvdson, ) Phyogn shdowng dns sguoy modus n pns Evouon nds o onsv unony mpon DN squns, wh hngs n ss sgnn gons od hs mks squn ompsons o ohoogous gns o pons mong sps powu oo o dny unony mpon gons boh n Pons nd DN onsvon s n gn ow n nonodng gons ompd o pon odng gons whh omps h dnon o guoy gons o gn (Hudy, ) Howv, onsvd smns n pomos v phyogn oopn, mnng sho onsvd nd unony mpon mo h n b dnd n squn gnmns o guoy gons om homoogous gns (umuo, 99; g, 9) hs mhod ws dvnd o dny who sguoy modus, whh onn mny F bndng ss, by ompng nonodng gons o osy d sps om h sm my n mhod ond phyogn shdowng

14 INRODUION (Bo, ) In pns phyogn oopnng nd shdowng w usd o dny guoy gons n gns suh s h o homo gn MOUS (, Hong, ), h ok omponn LON ELONED HYPOOYL (LHY) (Spnsy, 9) nd h dn okssod PSEUDO RESPONSE REULOR 9 (PRR9, Ho, ) Rny phyogn shdowng ws ppd on who gnom v o h s m n pns nom squns o nn sps om h Bss my w mpoyd o dvop n s o onsvd nonodng gons whh svs s sou o xnsv dnon o sguoy gons n ngn sp (Hudy, ) nspon guon o phoopod owng n hn Rguon o owng non n hn s ognzd n sgnng sd sng om ppon o h nduv sgn n h vs o h nduon o suu hngs n h msm whh s pogmmd o podu ows Mos gns nvovd n hs dy ngh dpndn sd md nspon hngs o h downsm gs nd h od o Fs o pons nvovd n h guon o Fs (ndés nd oupnd, ) h LD phwy n hn s nspon nwok h vovd o sns hngs n dy ngh nd ggs h swh o poduv dvopmn n spons o hs nduv ondons ggng o owng ss wh O mrn vs sng n h phom ompnon s h nd o ong dy, mhnsm mdd by h dn ok nd gh (SuzLopz, ; Ynovsky nd Ky, ) O pon s subsquny sbzd by gh nd s s nspon vo o h o ngo F (dn, ; w, ; Vvd, ; Wgg, ) F nd s os homoog WIN SISER OF F (SF) p o h mob sgn ogn nd mov om h phom o h shoo p msm (SM) (Mhs, ; Ymguh, ; obs, ; Jg nd Wgg, ; Mhu, ), wh hy n wh h bzip nspon o FD (b, ; Wgg, ) hs ompx ws shown o nud pons n (ok, ) F, SF nd FD bvd o onbu o nspon hngs n h SM nudng von o h wo MDS Box gns SUPPRESSOR OF OVEREXPRESSION OF ONSNS (SO) (Bon, ; L, ; Smh, ) nd FRUIFULL (FUL) s w s h o msm dny gn PEL (P) (Shmd, ; pbmnok nd Smh, ; Wgg, ) SO n un ns wh noh MDS Box pon d L o v h nspon o LEFY (LFY), msm dny gn nvovd n h s sps o ow dvopmn (L, ) noh ss o Fs h boh mdos o owng spons nd d downsm gns o h FFD ompx nd SO n hn SQUMOS PROMOER BINDIN PROEINLIKE (SPL) gns, nmy SPL, SPL nd SPL (Jung, ) hs SPL os dy bnd o nd v nspon o SO, P, LFY nd FUL whh ds o h omon o ows (Wng, 9; Ymguh, 9)

15 INRODUION hus h nspon von o F n h vs by O ggs downsm nspon sd h vnuy ds o owng spons (ndés nd oupnd, ) Msgud O mrn nd pon vs d o dsupon o u owng spons n hn s shown by xpmns on mun nd ovxpsson ns (Onouh, ; Réd, 9) I s hus u o poduv suss o hn h O s ky snsoy gn n h LD phwy s gud ghy boh mrn vs s w s pon bundn O pon unons s nspon vo o FLOWERIN LOUS hn pns wh muons n h O gn xhb owng n LD wh owng m s und n SDs (Koonn, 99; Pu, 99; Réd, 9) Fowng m o o nu mun s ndsngushb n LD nd SD ondons (Lubng, ) Hn oss o O gn unon dsbs h by o hn o dsmn dy ngh dng o onsn owng m n ondons Oh phnoyps w no ssgnd o o muns h us o owng n o muns s h duon o xpsson o ogn gn F und nduv ongdy ondons (Smh, ) Ovxpsson o O om h ubquous uow Mos Vus (MV) S pomo s w s h vsuu sp SUROSE RNSPORER (SU) pomo ds o hgh F mrn vs nd y owng gdss o h phoopod (n, ; Imu, 999; SuzLopz, ) o nsu h owng s ony ggd und nduv ondons O pon s gud h posnspon v On ky mhnsm s h guon o O pon bundn nny by h dn ok nd by h xn sgn gh hs poss, d o s h xn ondn mod, nsus h O pon bundn dng o d von o F nspon ous h o m o h dy und nduv ondons (Sw, ; Song, ; Vvd, ) O pon suu nd unon n nspon guon O pon onsss o wo zn bndng BBox mos nd O, Ok, IMIN OF B EXPRESSION (O) () domn (Pu, 99; Robson, ) h BBox ndm mos show homoogy o zn ng mos n nm nspon os In nms BBox mos oou wh odo nd RIN ng domns (p mo) nd nvovd n ponpon nons bu do no on DN bndng pops (ook nd Ekn, ) h BBox my n hn s ompsd o mmbs onnng h on o wo BBox mos Muons n h BBox w shown o mp O pon unon (Fg, Robson, ) Expmns n ys usng h O BBox domn o L DN bndng domn nd h hs mo n md nspon von, whh mgh b s unon n O s bng p o DN bndng ompx n hn (BnNm, ) h domn s pn sp nd hs nu ozon sgn (Robson, ) Muon n hs domn mps O pon unon (Fg ) h domn s no ony ound n O nd

16 INRODUION Ok pons bu so n O, PSEUDEORESPONSE REULOR (PRR) pon (Sy, ) h domn o O nd oh PRR pons, whh sso wh homn n vvo, s sun o DN bndng n vo (ndon, ; Nkmh, ) Smy, d ssoon o O o F ous ws dnd nd h domn o O nbs o bnd DN n vo v sguoy mn psn n h F pomo (Song, ; w, ) ddony h domn ows phys non o O wh mmbs o h m bndng ompx (BF) so known s Nu Fo Y (NFY), whh ws md o b mpon o Omdd ggng o owng (Kummoo, ; BnNm, ; Wnk, ) hs non o O wh h NFY ompx nd h psn o Boxs n F pomo oud n hs sno pon nspon von (Loum, ; w, ) h nun o phoopos on O pon sby h guon o O pon bundn s u o phoopod owng ono n hn (Vvd, ) Inons wh dn pons ono h sby o O houghou h dy o nsu h O pon s xusvy sb h nd o gh pod n LD ondons h d gh phoopo phyohom B (phyb) ws shown o dsbz O n h monng (Vvd, ) h phoopos ypohom (y), y, phyohom (phy) nd FKF sbz O h nd o h dy (Song, ; Vvd, ) Ngh dgdon o O s mdd by SUPPRESSOR OF PHY (SP), SP, SP nd h nng E Ubqun Lgs ONSIUIVE PHOOMORPHOENESIS (OP) SP nd OP qu h domn o O o non (Jng, ; Lu, ; Wnk, ) h ONSNSk gn my shows dundny o O O s h oundng mmb o h mmb ONSNSk (OL) gn my n hn OL pons omposd o on o wo BBoxs nd domn h OL gn my s ognzd n h dn goups (I,II nd III) odng o h domn omposon nd onsvon (hs, ; Robson, ) oup I, onssng o O, OLOL, hsy hs wo BBoxs nd domn whh s spd by on non n h gnom onx oup II gns (OL, OL) n ons k on BBox oup III gns (OL9 OL) hv on BBox nd sond, dn zn ng mo, domn nd hsy h nons oup I n b uh subdvdd Subgoup I OL gns hv ou onsvd gons bwn s BBoxs nd domn In hn O, OL nd OL bong o hs submy nd mny oh pn sps hv s on subgoup I OL homoog (b ) hn OLOL w gozd no subgoup I bu hn hs no homoogs n subgoups Ib, Id nd I (hs, )

17 INRODUION S::OL ws shown o py ompmn o mun n SD ondons (Hssdm, 9) h wo oss homoogs o O n hn, OL nd OL, d o owng whn ovxpssd (Ldg, ) nd dd no ompmn o9 muon (Km, ) OL nd OL w mpd n dn ok guon bu no owng nd h unons hv no bn sovd (Km, ; Ldg, ) bdopss hn ONSNS o o o o o non o9 o o BBox BBox M M M M Fgu : Shm psnon o domns o subgoup OL gns usng O s n xmp O pon onsss o wo zn ng domns nmd BBoxs n h Nmn p (BBox nd BBox ) Fou onsvd gons n b dnd n h mdd p (MM) nd h ony non s od bwn M nd M h ONSNS,ONSNSk, O () domn s od os o h Nmnus h us gons o o muns ndd o nd o o o BBox wh o, o nd o n BBox h muons w dnd n h domn (o9, o nd o) h o nu mun o (os) s DN nson n nd hus s poson s no ndd Fgu modd om hs () onsvon o O unon n oh sps onsvon o O unon n o nduon s h subj o mny suds n h pn kngdom os homoogs o O w dnd n mny pn sps (b ) nd shown o ompmn o muns n hn usng S ovxpsson ns Suh suds w d ou wh Phbs n O (PnO), B vugs OL (BvOL) nd Popuus hop O (PO) (h, ; Hsu, ; Lu, ) In h mod gums Mdgo unu, Psum svum nd Lous jponus on h oh hnd ohoogs o O d OL w dnd, bu no nk o owng ws sbshd nd h gns w suggsd no o b unon O homoogs (Hh,, ; Ymshno, ) b : Sd nonbss subgoup I OL homoogs n nm Sps Fmy Pubon hol ny hssn om (Shnz nd MhOds, ) LjOL Lous jponus Fb (Ymshno, ) MOL Mdgo unu Fb (Hh,, ) PsOL Psum svum Fb (Hh, ) SO (onzázshn, ; Koosmn Sonum ubosum Son SO (SO), ; Nvo, ) VvO Vs vn V (md, 9) PnO Phbs n onvovu (Lu, ) PO PO Popuus hop S (Bohnus, ; Hsu, ) OsHD Oyz sv Po (Yno, ) HvO HvO Hodum vug Po (mpo, ; hs, )

18 INRODUION h o o O homoogs n owng m guon n h Po my on h oh hnd s w sbshd In h SD pn Oyz sv (R) OsI (I ohoog) ws pd upsm o HEDIN DE (Hd, homoog o O) whh n un gus Hd (F ohoog) In ons o hn guon o Hd by Hd showd unon nvson by supssng h F homoog n nonnduv LD ondons bu vng n SD ondons (Hym,, ) Hodum vug O (HvO), whh s os homoog o Hd, ws shown o owng n by whn ovxpssd bu d o ompmn o mun whn ovxpssd om h S pomo n hn (mpo, ) hs suggss h h IOF guon s onsvd n owng pns, bu gns no uy nhngb bwn sps h OF guon ws shown o b nvovd n oh phoopody gud dvopmn posss In Popuus spp (Pop) gn nk bwn PO nd PF ws ound PF s song owng ndu n Popuus nd ddony gus SD ndud bud omon n uumn In RN nn (RN) pns downgung h PF o PO bud omon ous suggsng boh gns wok n h sm phwy (Bohnus, ) Evn hough S::PO sud h o mun n hn, S::PO nd S::PO d o poduv ons n nsgn pop (Hsu, ) In Sonum ubosum L SO (so d SO) nd SO ngvy gu phoopod ubzon by upgung SSP (n F homoog) whh n un psss SSP (noh F homoog) xpsson n poo (onzáz Shn, ; Koosmn, ; Nvo, ) Insngy, S::SO ony py sus o mun n hn (onzázshn, ) hs xpmns suggs h h OF homoogs hv guoy unon byond owng m ono nd w mpoyd mny ms n vouon o gu dn phoopod sponss Ovxpsson o O homoog om h gn g hmydomons nhd (O) usng hoogous pomos (S, SU) ndud y owng nd/o ompmnd boh o (o) nd o (L) muns (Sno, 9) hs xpmns ddony nd h subgoup I OL gns mgh b onong phoopody gud mhnsms mo gny nd hv n nn vouony ogn Rguon o O nspon by xn ondn O pon unons s pon nspon vo o F nd h guon o pon bundn s u o h unon o O (dn, ; w, ; Vvd, ) Nonhss pos nspon guon o O pon s no sun o gu phoopod owng n hn, whh s ndd by y owng dyngh nsnsv phnoyps ndud by ovxpsson o O om hoogous pomos (n, ; Onouh, ) Hn guon o O mrn vs s ddony nssy o nsu o nduon ony und voub ondons O mrn vs und ompx nspon guon n hn nvovng mny nspon os nd s guos (Fon, 9; Io,

19 INRODUION ) h guon o O mrn nopos sgns om h dn ok nd h xn sgn gh (Imzum,, ; Sw, ; SuzLopz, ) h ps oupu o hs mhnsms nsus h O vs F xusvy und nduv ondons Hn, O mrn guon pys pvo o n h unony o h xn ondn mod o owng nduon n hn und nduv ong dy ondons O mrn vs duny gud O mrn s duny xpssd hough boh gh nd dn ok ono nd s mpo xpsson pn ws sudd n d (Fg,SuzLopz, ; Ynovsky nd Ky, ) In od o snddz dy ms o yng posss h m ZEIEBER IME (Z) ws nodud dnd s hous dwn o ghs on dpndng on h xpmn Und SD ondons o hous gh nd hous dknss O mrn s ony psn n h dk hous o h dy bu vy ow n h gh hous o h dy bwn Z nd Z In LD ondons o hous gh nd hous dknss O mrn s psn dwn bu hn quky dgdd h ough vs o O mrn bwn Z nd Z9 O s hn nsbd gn o om n vnng pk (Z o Z) whh s hough o b mpon o F von (SuzLopz, ; Ynovsky nd Ky, ) O mrn xhbs n ddon ngh pk o unknown unon O s h mjo vo o F nd ngs sgns om h pn dn ok nd dy ngh o nsu h owng s ony vd upon voub nduv ondons h gh guon o mrn bundn ws subj o mny suds n h ps nd vos nd pssos o O gn xpsson w dsovd nd nkd o boh h dn ok nd gh guon s dsbd bow (Fg, Fon, 9; Imzum, ; Io, ) FBHs v O nspon O nspon s vd by subss o dundn bs hxoophx (bhlh) Fs, d FLOWERIN bhlh (FBH, Io, ; odooz, ) Fou mmbs, nmy FBH, FBH, FBH nd FBH, bongng o h sm phyogn goup (bhlh, d IX) w shown o owng nd upgu O mrn whn xpssd om h S pomo h qudup xhbd ony md owng phnoyp boh n LD nd SD nd h ngh pk o O mrn ws mpd FBH nd FBH pons w shown o bnd spy o EBox (NN) mns bu no o Box () mn n h poxm O pomo n EMS suds s w s nsn LUIFERSE (LU) xpsson ssys FBH bnds o O pomo n vvo s shown by hip Songs bndng ws dnd os o h S o O bu ssoon ws so sn ds (kb) gon Insngy, S::FBH ovxpsson ns ndu O mrn up o od hgh hn wd yp vs bu h mpo xpsson pn n LD s unhngd hs s n gmn wh h ndng h FBH mrn vs do no y s O mrn dos bu h ubquousy xpssd houghou h dy ddony, h xpsson o βluoronidse (US) (Json, 9) dvn by pomo O (po) n FBH ovxpsson ns s sd 9

20 O mrn O mrn INRODUION Long Dy RFI? S ub ub ub I DF DFDF DF FKF DF DF DF DF FBH FBH FBH FBH Sho Dy Zgb m RFI? I FKF DF DF DF DF DNF? FBH FBH FBH FBH Fgu : nspon guon o O n LD nd SD O s nspony dny gud n nduv LD nd nonnduv SD ondons O mrn s downgud ny n h monng o LD by ss o dundn DOF Fs nmy DF, DF, DF nd DF In h p o h dy (ZZ) h bu gh dpndn ompx o FKF nd I pon oms n E ubqun gs o mk h DFs by poyubqunon (ub) o dgdon by h S posom (S) O s onsuvy vd by ss o dundn BHLH Fs d FBH, FBH, FBH nd FBH hy v O h nd o h gh pod n LD ddony ngh pk oms n LD ondons In SD ondons gh nd O xpsson do no ovp O mrn s ow bo ghs on nd sys ow un h nd o h gh pod hs psson s mdd dy by h DOFs nd puvy by DNF I nd FKF ompx dos no om n dknss, hus DOF pon vs sy hgh nd O vs do no om n vnng pk RFI s mpd n psson o O mrn boh n LD nd SD ondons by n unknown mhnsm Zgb m

21 INRODUION o ony w yps nudng som s, h oo p nd mpony vsu ssus o summz, FBH Fs n v O nspon bu nno xpn h u dun o sp pn ndng h O mrn guon s mo ompx boh spy nd mpoy, nd mus nvov oh vos DFs nspon pssos o O Dun xpsson o O mrn s d by ss o pssv Fs, d YLIN DOF FOR (DF) whh bong o h DNbndng wh on ng (DOF) F my (Fon, 9; Imzum, ; Sw, ; Ummu, ) Sx mmbs, DF, DF, DF, DF, O nd DF, w ssod wh guon o phoopod owng v psson o O nd F mrn (Fon, 9) DF mrn vs onod by h pn dn ok, showng pks o xpsson n h bgnnng o h dy whn O mrn s ow (Fon, 9; Imzum, ) Pomo US uson xpmns mpd h DF Fs xpssd n vsu ssu Ovxpsson o DFs om h S o SU pomo d o dy n owng und nduv LD ondons, spvy (Fon, 9; Imzum, ) h dr, d, d, d qudup mun (d) owd y und LD nd SD ondons nd hd vd O mrn vs houghou h dy nd mpony h downguon o O mrn dwn s mpd (Fon, 9) DF ws shown o bnd o h poxm O pomo (bp) n EMS suds s w s nsn LU xpsson ssys (Imzum, ) h DOF onsnsus bndng s s, wh () onbus o spy o DF s shown n EMS ompon ssys (Imzum, ; Yngsw nd Shmd, 999) hip xpmns nd h DF bnds o h O pomo os o h S s w s n ds p o h pomo (~kb) (Sw, ) FKF nd I oodny dgd DFs nd v psson o O odng o h un mod DF Fs oupy h O ous o pss s xpsson ompx npy o dn ok nd gh gud gns s nssy o s hs psson upon nduv LD ondons nd dv nspon o O h bu gh vd pons FLVIN BINDIN, KELH REPE, FBOX (FKF), nd LOV KELH REPE PROEIN (LKP) w shown o n wh DF, DF nd DF boh n Ys wo hybd (YH) nd pu down ssys FKF nd LKP ogh wh ZEILUPE (ZL) om sm pon my (Nson, ; Soms, ) hs pons onn LIH, OXYEN, VOLE (LOV) domn, whh nbs hm o sns bu gh, n FBox domn nd KELH p domn, whh ows hm o unon s E ubqun gss (vwd n Io, b) h k mun shows ow O mrn vs bwn Z9 nd Z (Imzum, ) In h vnng o ong dy FKF mds h dgdon o DF n bu gh dpndn mnn (Imzum, ) Bu gh s no sun o hs mhnsm: INE (I), pn sp pon o unknown bohm unon, ddony gus FKF pon bundn nd h IFKF ompx s

22 INRODUION sbzd spy by bu gh (Fon, 9; Fow, 999; Pk, 999; Sw, ) I s p o h pn dn ok nd s vnng sp xpsson (~Z) s hghy onsvd n owng pns (Fow, 999; Hym, ; Mzoguh,, ) Ony whn I nd FKF mrn xpsson nd bu gh ovp n hs pon ompx s n E pon gs o mk DF Fs o dgdon by h S posom nd s psson o O nspon (Fon, 9; Sw, ) ddon guos mpd n O nspon guon noh E Lgs, d DY NEURL FLOWERIN (DNF) ws dnd o gu O mrn vs ndpndny o I nd FKF bu downsm o h dn ok (Mos nd Jkson, ; Mos, ) Muons n dn d o nsd O mrn vs n h monng n SD ondons whh usd y owng noh pon h mgh gu O mrn dy s RED ND FRRED INSENSIIVE (RFI) (hn nd N, ) Muons n hs RINdomn zn ng pon d o hgh O mrn vs und LD, SD nd onsn gh ondons h muon uss y owng boh n LD nd SD ondons nd ws ps o o muon whou ng I xpsson o oh ps o h dn ok h d guoy mhnsm o O mrn guon ws no dnd bu RFI ws suggsd o unon downsm o h phoopos phy nd phyb (hn nd N, b) Invovmn o Phoopos n O mrn guon h nvovmn o bu gh snsng FKF nd s os homoogs LKP nd ZL n O mrn guon ws sudd n d Bu so muons n oh phoopos xhb ds n owng m guon h py du o hngs n O mrn vs Muons n h d gh phoopo phy ds o owng phnoyp n LD ondons (dán nd hoy, ) nd O ws dnd s p o h posud phygud nspon nwok (ppmn, ) odngy, O mrn vs dud n nndsn gh nhd LD ondons ompd o wd yp ono (Ynovsky nd Ky, ) h oppos ws obsvd n h phyb9 mun whh owd y n LD nd showd sghy vd vs o O mrn n LD (dán nd hoy, ) I s no known whh guoy mhnsms o nspon os md h md s o phy nd PhyB on O mrn vs onsvon o O mrn guon n oh sps O hs os homoogs n pobby owng pns nvsgd (b ) nd h dun guon o O s sm o ohoog HEDIN DE (HD) (Hym, ) ddon sms n xpsson o Pop PO d o h ssumpon h O mrn guon s onsvd n vouon (Song, ) In mny oh sps k Phbs n, Vs vn, B vugs nd Sonum ubosum on h oh hnd xpsson pns o O homoogs show

23 INRODUION monng phs o xpsson k LE ELONED HYPOOYL (LHY) nd IRDIN LOK REULED () (md, 9; h, ; Koosmn, ; Lu, ; Mzoguh, ) Insngy h monng xpsson s so shd by h oss homoogs o O n hn, OL nd OL (Ldg, ) h ss ms Bss nd om s sh oos hn s h bs sudd mod ognsm n h pn kngdom nd h s pn sps o whh h gnom ws sqund (h bdopss nom Inv, ) In od o dn mhnsms n hn nd undsnd h bod sgnn o dsovs md n hn ompson wh osy d sps s usu hn bongs o h musd my (Bss o u) hsy ows o Bssn sps hv ou ps whh ossshpd (uom, Bhn, ) Eonomy mpon mmbs o hs my h ops psd (Bss npus), bbg (Bss o) nd bk musd (Bss ng) h my ompss o 9 sps n gn nd pobby ognd n h Ino unn gon (ns, ; Fnzk, ) h my n b dvdd no wo mjo goups: h gnus honm s no dsn goup om h o o h my (owy, 99; Koh, ; Zunk, 999) Esms bou whn hs sp oud vy bwn my nd my (Fw, 9; Fnzk, 9; Koh, ; Shnz nd Mh Ods, ) Wh oh Bss sps ound ov h wod h gnus honm s md o gon ngng om Spn nd Mooo o ukmnsn (Fnzk, 9) h ogn o h Bss my suggss h ong dy phoopod owng spons s sn n hn mgh psn h ns s h Bss my undwn v ndpndn who gnom dupons (WD) o whh h wo mos nn dupons shd wh h sd pns nd ngospms, spvy (Jo, ) h γ psns h hd ods WD, wh h β oud ~my (ng, ) h α WD, whh hppnd ~my s sd o h Bss my nd shd wh honm bum ( bum, Fw, 9; Hudy, ) hus h dvgn m bwn h gnus bum nd h o Bss s ssumd o b ss hn my s h phyogny o h Bss my s w dvopd nd h mod hn s mmb, nw mod ognsms mg nd mov no sh ous bs pn ( pn) ws sbshd s mod o pnnsm (Wng, 9b) Eum pvuum (so known s hung pvu) s mod o pn dpon o xm hbs (Dssnyk, ) bdopss y ( y) s sudd bus s vy osy d o hn (my dvgn m) bu shows nsng dns n homosom numb (n= n hn; n= n y) nd n onss o hn s n ouossng sps (Hu, ) kn ogh h Bss my s o sp ns o sh dng o h vby o nn gnom squns un now

24 INRODUION (Hudy, ) Bssn sps h w usd o ompson n hs sudy nudd n Fg nd h phyogn onshp s shown v o ny hssn ( hssn) h s usd s ougoup bdopss hn bdopss y Lng I ps ub o Bss Nsuum on Nsuum o Eum pvuum bs pn Bss α WD Expndd Lng II Bα Bss p Bss npus Ssymbum o Ssymbum on honm bum ny hssn om hα WD Fgu : Shm psnon o phyogn onshps o sps om h od Bsss usd n hs sudy h Bss my n b dvdd n wo mjo ngs, h o Bss nd h honm ng, h psnd by honm bum h o Bss n b uh dvdd no Lng I psnd by bdopss, ps nd Nsuum sps, wh xpndd ng II onsss o bs pn, Eum pvuum, Bss nd Ssymbum sps ny hssn (omy om hssn) s h ony mmb o h om my dspyd, whh s h ss my o h Bss n h od Bsss Boh ms undwn ndpndn who gnom poypodzon vns h α s h s who gnom dupon (WD) vn dnd n bdopss hn nd s shd by ngs o h Bss bu no h om h hα gnom pon s ound n ny hssn I s o sm g ompd o h Bα, whh ws xusvy dnd n h gnus Bss = bdopss hn, h= ny hssn,b= Bss, Rd ss nd who gnom dupons (WD) Rns: (By, ; hng, ; Fnzk, ; Hudy, ) hssn (omy nmd om hssn) s mmb o h om my, ss my o h Bss n h od Bsss (H, ; Is nd ohn, ) Boh ms dvgd bwn 9my nd my (Bsn, ; Fnzk, 9) om s h gs gnus o h om my wh o sps (Sánhzbo, ) h gnus om s o sh ns o sudyng h vouony pogsson bwn nd phoosynhss (Msh, ) h spd ow hssn, whh s osy d o om spnos, hs s nu hb n souh m (hng, ) Fowng ws shown o

25 INRODUION b d n LD ondons, ndng h hssn s uv LD pn (Kovng, 9) hssn ws usd o dph h phyogn onshp o h ss ms h gnom o h hssn nso undwn popoypodzon vn ndpndn o h α dupon sung n pon o h gnom now d o s hα (omy sα) (Fg, (hng, ; Shnz nd MhOds, ) hs mks hssn o sp ns o hs sudy s h unon dvgn o O, OL nd OL oud h α nd h homoogs wh h on hssn ohoog dnd w b dsussd (Shnz nd MhOds, )

26

27 IM OF HE SUDY IM OF HE SUDY O pon s h ky vo o nspon o FLOWERIN LOUS n hn o LD ndud phoopod owng nspon o O s s hghy gud by gh nd h dn ok o nsu h mrn vs dng o sb O pon ony psn und voub LD ondons Suds o h mhnsm o O nspon guon n hn w so oussd on h gung nspon os (DFs nd FBHs) nd h posnson guos (I nd FKF) In hs sudy vouony ompsons o O pomo w b usd o dny onsvd gons, wh ous on known nd nw smns n h pomo h n hn b sd o unony usng po ns nd pomng ompmnon xpmns On m s o dny gons o O pomo gung nspon nd nyz h nun on owng m h unon onsvon o O nd s oss homoogs OL nd OL, whh mpd n ok unon h hn owng guon, w b nvsgd by ompson o h ohoogs n h bs Bss sps bum hssn om h om my hs xy on os O ohoog (hol) whh shs on ommon ns gn wh O, OL nd OL h unon nd mou hson o hol ms dmnng whh h nso o goup I OL gns n h Bsss ws unon owng m guo In summy, gn, mou nd phyogn suds w b usd o dn nd xpn vouony hngs n boh nspon guon nd unon o h phoopod owng m guo O n h Bss my

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29 MERIL ND MEHODS MERIL ND MEHODS Poyms hn on (PR) Sndd PR ons (gnoypng) w pomd wh nonpoodng PR odng o sndd b pooos onng PRs w pomd usng L q (KR) o ong gnom gmns o upm q DN Poyms Hgh Fdy (Invogn) o oh puposs odng o supps mnu PR gmns w pud h dy o om gos g usng NuoSpn Ex II (MhNg) nsomon o Eshh o Eshh o (E o) ws nsomd wh psmd DN usng h shok o opoon nd sd on ppop nbos odng o sndd b podus Fo ppons E o sn DHα (Invogn) ws usd xp o wy (W, Invogn) ompb g vos onnng h db gn whh w popgd n DB sn (Invogn) Psmd DN ws pud om qud uu usng NuoSpn Psmd (MhyNg) Psmd onsuon pdf::xh:w ws onsud bsd on S::xH:W (pgo) By, pomo o DF ws mpd wh ovhngs o HINDIII nd h Hg (b ) ompmny h H g ws mpd wh ovhngs o pdf on h nd nd MuI son s on h nd In sond PR boh gmns w ombnd p::xh ws movd om pgo by doub dgs wh HndIII nd MuI nd pdf::xh ws nsd by gon odng o supps mnu (Nw Engnd BoLbs) sung n pdf::xh::w h DN o DF ws psn s W onsu n pdonr nd ws ombnd usng LR on odng o supps mnu o obn pdf::xh::df s usd o hip b : onng pm o pdf::xh:w Nm Squn Pupos pdfhndiiifw pdf wh HndIII nd H pdfhrvlong ovhngs HpDFFw H g wh pdf nd MuI HMuIRv ovhngs po::xh:w ws onsud bsd on psu::xh:w hn (o) po ws xsd om po::w (pgo) usng doub son dgs (XbI nd XhoI) nd psu ws subsquny pd v gon wh po o obn po::xh:w 9

30 MERIL ND MEHODS onsus o o ompmnon xpmns w d by mpon o dsd odng squn (DS) om DN o bum (O nd OL) nd hssn (hol) nd subonng no pdonr v BP on (b ) DS o OL, OL n pdonr w vd om h soks onmon by Sng squnng DNs w ombnd no spv vos (pgo, b ) b : Psmds usd n hs sudy o onng Nm Bkbon B son Pn son Pupos pdonr pdonr nmyn () subonng o DNs pdonr pdonr nmyn () Subonng o po W::LU pn9 Knmyn BS LUIFERSE po W:pnos::LU pn9 Knmyn BS mnm pomo LUIFERSE po W::FP:ODN pn9 Knmyn BS O pomo ompmnon psu::xh:w pgo Spnomyn FP sd o Subgoup I OL ompmnon po::xh:w, pgo Spnomyn FP sd o Subgoup I OL ompmnon pdf::xh:w pgo Spnomyn FP sd o hip b : Pm o onng o subgoup I OL DS om bum nd hssn Nm Squn Pupos Fn onsu h_ow_fw (B) h_ow_rv (B) h_olw_fw (B) h_olw_rv (B) _OL_W_Fw (B) L_O_W_Rv (B) O DN psu::xh:o po::xh:o OL DN psu::xh:ol po::xh:ol hol DN psu::xh:hol po::xh:hol hn O pomo ompmnon xpmns nd po ns w d usng h W hnoogy By, h O pomo gmns w mpd om gnom DN (L) ngng B nd B W ss (b ) nd subond no pdonr v BP on Dsd onsus w ombnd by LR on no dsnon vo n h onx o FP:O, pnos:lu nd LU, spvy (b ) b : Pm o O pomo onsus Nm Squn Pupos Fn onsu OpomW (B) kb Fw; kb::lu;kb::fp:o DFw D:pnos::LU W_O RV (B) D_Rv D:pnos::LU O_b_FW_W (B) _Fw :pnos::lu

31 MERIL ND MEHODS O_b_RV_W (B) _Rv :pnos::lu O_b_FW_W (B) B_Fw B:pnos::LU O_9_RV_W (B) B_Rv B:pnos::LU W_O_9_FW (B) /kb_fw :pnos::lu;::lu kb::fp:o ow (B) Rv (bp om po::fp:o S) nd po::lu OpomW (B) kb Fw kb::fp:o kb::lu W_O FW (B) kb Fw kb::fp:o M_FW (B) DM Fw DM:pnos::LU M_RV (B) DM Rv DM:pnos::LU M_FW (B) MM Fw MM:pnos::LU M_RV (B) MM Rv MM:pnos::LU M_FW (B) PM Fw PM:pnos::LU M_RV (B) PM Rv PM:pnos::LU M_Myb_FW DMbs Fw PMbs:pnos::LU M_Myb_RV DMbs Rv PMbs:pnos::LU M_Myb_Rv (B) PMbs Rv PMbs/gbox:pnos::LU M_Myb Rv (B) PMbs gbox Rv PMbs/gbox:pnos::LU Pn nsomon Bny vos w nsomd no gobum umns sn V whh s ssn o mpn Hp psmds psoup (yn) o pn bsd onsus nd pmp9rk (gnmn nd knmyn) o pgo bsd onsus w usd o sbsh sb nsgn B (Hns,, b) B w gown o OD o nd gowh md ws pd by Suos souon [%] suppmnd wh Sv L [µ/] Fo dp ws usd o nsom onsus no hn ssons nd gnoyps ndd (ough nd Bn, 99) BS son (pn) o FP sgn n h sd o (pgo) ws usd o s o nsomns, s sggon o onm sng nsons nd homozygosy n h oowng gnon Psn o h nsgn ws sd v PR on gnom DN usng sndd podus (Edwds, 99) Pn m hn ssons o nd L w usd n hs sudy hn mun ns usd n hs sudy pubshd s ndd n h x bum nd hssn sds w kndy povdd by E Shnz (Wgnngn, Nhnds)

32 MERIL ND MEHODS non o dphyb9 h phyb9 mun ws ossd o h d mun by Fbo Fon (Unvs dg sud d mno, Iy) ppoxmy F pns w snd o y owng n SD ondons Homozygosy o muons ws onmd by PR on gnom DN (b ) n h h s pns nd homozygosy o h DFR nsgn ws onmd n h F gnon Fo gnoypng h phyb9 muon PR ws oowd by dgson o h podu wh BsI sung n bp gmn o phyb9 bu bp nd bp o o b : Pm o gnoypng Nm Squn Pupos PhyB9dPup phyb9 Fw PhyB9dPw phyb9 Rv F9SFo DFR Fw FDFR DFR Rv L DF Fw L9 DF d Rv F9KLB d d Fw FO DF Fw FO DF d Rv LH9R DF d Fw FDFR DF Rv FO LB d Rv Pn gowh ondons nd owng m msumn Sd w sd on so o h dys n dknss Pn w gown n m onod ondons on so n gowh hmbs (Pv o obnk; LF pn ms) dy nd ngh mpus und oo wh gh (ppoxmy µe) suppmnd wh nndsn gh Fowng m o hn ws msud s o numb (os numb bong + un numb) n LD (h gh, h dk) nd SD (h gh, h dk) o numb bong ws dmnd o bum n gowh hmbs nd o hssn n mpu nd gh onod gss hous ondons LU xpsson nyss wh OP OUN Don sysm n dy od sdngs (n=) o homozygo ns gown on ½MS n gowh hmbs (Pv) und oo wh gh (ppoxmy µe) w nsd o 9 w ps d wh µ ½MS + suos [%] nd µ Dun [,mm] ws ppd Lgh msson ws msud n op oun mhn (PknEm In; Whm, Msshuss, US) und LD LED ondons (bu + d gh, hous gh, hous dknss) ov v dys Lgh msson o sdngs h

33 MERIL ND MEHODS ndd Z ws vgd nd uh nomzd o h mn o h ov xpsson n h xpmn o h ospondng n (nomzd gh msson) Expsson nyss o mrn vs Pns w gown on so n gowh hmbs (Pv) und h sm ondons owng m ws msud Fo sh xpmns o d nd bu gh ondons pns w gown on ps (½MS nd %suos) o n dys nd shd o LED bu gh, LED d gh o dknss, spvy n dy od sdngs ( o hn, o bum nd o hssn) gown n h ndd gh ondons w od no qud nogn h gvn ZEIEBER IME (Z) RN ws xd om hn, bum nd hssn usng RNsy Pn Mn K (Qgn) odng o mnu Smps w d wh mbon DNs ( hnoogs) odng o mnu nd µg o RN ws usd o DN synhss (SupSp II Rvs nsps; Invogn) R m PR ws pomd usng IQ SYBR n Supmx (BoRd) on Lghy (Roh) usng h oowng ondons o h gns ndd (b ) oowd by xmnon o h mng uv: 9 mn 9 s x s s D w nomzd gns by duon ss o nomz PR ny On DN smp om h sm xon ws dud :, :, : nd : nd bon uv ws uomy ud sung n v onnons nvy onnons w ud s (y numb) Vus psnd s os o h houskpng gn PP o hn nd IN o bum nd hssn o o o dng DN onnons bwn smps Fo ompson o xpsson pn smps w ddony nomzd o h mn o h ds onssng o gh Z vus houghou on dy Mn nd sndd o o h hn ps om on m PR on w ud omng om h sm p I no sd ohws psnv xpmn o s wo boog ps s dspyd b : Pm ps o dmnon o mrn vs n (gn dn) Nm Squn PP FPP FW (99) FPP RV n F 9 R FP 9 9

34 MERIL ND MEHODS LU F () O () OL () OL () ho O OL LURw LURv F9FqRF F9FqRR F9OqRF F9OqRR o_r_fw o_r_rv OL_DS_Fw OL_DS_Rv _O_R_FW _O_R_RV S_O_R_FW _O_R_RV h_ol_fw h_ol_rv h xpsson vs o pn homoogs o O (_9), OL (_) nd OL (_) w hkd n nx gnon squnng o DN om LD mous (kndy povdd by EvM Wng, MPIPZ, oogn) By, d pod psns squn ds h w mppd o h n gnom nd nomzd boh o gn ngh nd by sz hm mn (odypn) dy od sdngs gown on ps (½MS nd %suos) n gowh hmbs (Pv) und LD ondons w nsd o ddho wh mm n onnon o doxydnosn (odypn, Sgm) o mok mn Sdngs w vuum nd o mn nd nsd bk o gowh hmbs nd hvsd n qud nogn h ndd mpons dyng h sdngs (Yk, ) homn Immunoppon In o h pvousy dsbd hip pooos w pomd (Bow, ; nd, ; S, ) Bndng o H:DF nd H:DF o DN ws sd usng h dn αh nbods (b ) ddony αdf nbody (b, Fon, 9) ws usd o hip n o nd d muns (d no shown) h hip sus dspyd w obnd usng h mhod mpoyd by Sw, (), whh s bsd on Bow () wh mno modons By, n dy od sdngs gown n LD w hvsd Z nd ossnkd wh omdhyd [% n PBS] (w mn vuum) Ron ws soppd by ddng gyn [M n onnon] M ws dd nd ozn n qud nogn Nu w xd by mxng pn ssu wh Exon Bu [M Suos, mm sh ph, mm Mg, mm BME, omp bs /m] nd ng hough moh P ws dssovd n

35 MERIL ND MEHODS Exon Bu [M Suos, mm sh ph, mm Mg, % on X, mm BME, omp mn/m] nd spun u spd P ws gn dssovd n Exon Bu [M Suos, mm sh ph, % on X, mm Mg, mm BME, omp mn/m] nd nd by gdn nugon n h sm bu Nu w ysd n Nu Lyss Bu [mm sh ph, mm ED, % SDS, omp mn/m] DN s shd wh Boupo (dgnod) w o mn (s on/ s o poson H) Dynbds (µ) w nubd n hip duon bu [% on X, mm ED, mm sh ph, mm N] wh αh nbody om (b ) o s hous nd subsquny wshd h ms n hip duon bu Smp ws dud / n hip duon bu o ow SDS onnon o % % npu ws kn nd smps w nubd ovngh wh pd bds nd wshd on h nx dy wh Low S Wsh Bu (w) [mm N, % SDS, mm ED, % on X, mmsh ph], Hgh S Wsh Bu (on) [mm N, % SDS, mm ED, % on X, mmsh ph], L Wsh Bu (on) [M L, % NP, % sodum doxyho, mm ED, mm sh ph] nd E Bu (w) ubs w hngd bo h s wsh sp DN ws ud usng uon bu (w µ) [%SDS, M NHO ] b : nbods usd o hip xpmns nbody Supp ogu numb / n αh bb bm b αh Roh F / αh mous Roh αh bb bm b9 αdf (Fon, 9) PonDN ossnkng ws vd by ddng N [n M] nd nubon ovngh (so o npu) Pon ws movd by nubon wh ED [n mm], s ph [n mm] nd pons K [µg/m] o hou DN ws ovd by phno/hooom xon n wo sps usng phs spon k/ubs Ppon ws don ovngh s h psn o gyogn [n µg/m], sodum [n M] nd wo voums o EOH [%] P ws wshd n EOH [%] nd ud n µ H O R PR ws pomd wh µ smp n µ o on voum usng IQ SYBR n Supmx (BIORD) on Lghy (Roh) (b 9) o d mmunoppd DN Ppd DN ws nomzd gns npu smp nomzon o n by duon ss s dsbd o mrn don

36 MERIL ND MEHODS b 9: Pm o hip RPR bbvon Nm Squn M M_hIP_Fw M_hIP_Rv mp_fw mp_rv F F mp Fw F mp Rv Wsn Bo hip nu x ws usd o don o xh:df pon xpssd om pdf Wsn bo ws pomd usng αh nbody (, b ) s dsbd bo (Smon, 9) Isoon o O pomos O pomo squns o bdopss hn, Bss npus, Bss p, Ssymbum o, om spnos, ppy, Popuus hop, Sonum ubosum nd Mdgo unu w dnd by BLS sh on NBI (hp://bsnbnmnhgov/bsg) h hvs son ws usd o onsu h O pomo om bdopss y bo h gnom ws ssmbd pn O pomo ws ssmbd om sho ds dnd by BLS sh o h pmny gnom ssmby (MPIPZ, oogn) Squns w ssmbd usng SqMn Po (DNSR Lsgn Vson ) b : Lngh o O homoogous pomos nudng s odon o O nd UR o h upsm gn OL Sps Pomo ngh [bp] bdopss hn 9 bdopss y ps ub Nsuum on 9 bs pn Bss npus 9 Bss o Ssymbum o Ssymbum on honm bum 9 O Pomos om ps ub, Nsuum on nd Ssymbum on w obnd by onng nd squnng o h ngn gon bwn OL nd O ohoogs om gnom DN (kndy povdd by Mkus Bns, MPIPZ, oogn) o dsgn pms n onsvd gons o OL nd O gns, spvy, squns o boh gns om hn, bdopss y,

37 MERIL ND MEHODS Bss npus, Bss p nd pn w gnd nd pm s ws pkd whh mps bou kb squn n hn (b ) mpon o ~kb gon nudng h who ngn gon bwn OL nd O ws sussu o bdopss bnnnss, ps ub Nsuum on nd Ssymbum on usng L q (KR) odng o supps mnu wh h oowng pogm: 9 mn; *(9 s; s; mn), mn usng gnom DN (µg p on) DN podu o xpd sz ws xsd om gos g nd subond odng o supps mnu (pem k; Pomg) no Eo DHα Pud vos w sqund by Sng squnng (MPIPZ nom n, oogn) h O pomo o h bum ohoog ws dnd by B sn pob o B by sn ws mpd om hn DN (~bp, b ) usng sndd PR hnqu B by ws snd by Sn Wöz (Wöz, ) B vo puon ws pomd wh Psmd Md K (Qgn) odng o hndbook ( m sud B n LB) Lyss sps nudng bu P, P (ppd sh) nd P w sd up ms Mdd gon o O ws mpd usng sndd PR ondons om h B DN, pud nd sqund Obnd squn om B nd N ws usd o subsqun pm wk b : Pms o mpon o Bss O pomos nd bum B sn pob Nm Squn Pupos OL_FW o O M onsvd OL Fw O_RV o OL R onsvd O Rv O_MR_Fw B pob Fw O_MR_Rv B pob Rv Bonoms d nyss oos Pd nd nx gnon squnng ds o bum gnom squn (hp://vgsmg/pubd/wd/ssymbum) w d novo gnd usng L noms Wokbnh (L Bo) wh sndd pms Dsd gns w subsquny shd n h bum gnom unnng BLS on o dbs Phyogn o onshp o subgoup I OL pon squns ws nd usng h NghboJonng mhod n ME wh boosp vus om ps (Sou nd N, 9; mu, ) Subsuon s w ud om odon gnmn o h spv odng squns oowd by uon o subsuon s usng SNP v (Rodgo nd Ln,, hp, pgs ) Pomo nd ous gnmns w pomd usng LN gohm on mvis (Budno, ; Myo, ) Oupu s dspyd s onsvon n p n n bp sdng wndows o h ospondng n squn Fo mo dnon dss w submd o MEME mo dnon oo (Vson,By nd Ekn, 99) wo dn sng w usd

38 MERIL ND MEHODS Du sngs dny mos wh mxmum mo wdh o bp nd mxmum mo numb o h nvy sho mos w dnd (bp o bp) h n ou n ny numb gnmns dspyd usng usx (Lkn, ) WbLogo ws usd o psn onsvd mos (Vson, ooks, ) Phyogn o pomo ompson ws d usng Phyogny (Dp, ) smns w ound usng usomzd P sp (o Vkkkm Jms, MPIPZ, oogn) Squns w shud ms by h gohm shu (Vson, Pss,, p) On Wy NOV nd uky s w pomd usng SgmS (Sys Sow)

39 HPER Phyogn onshp nd unon dvson o O Homoogs n h Bss nd om Poypodzon s ommon houghou h vouon o hgh pns (Sos, 9; ng, ) h Bss nd s ss my om n h od Bsss undwn ndpndn popoypodzon vns, α nd hα, spvy (Bk, 9) Sng gn dupon s noh ommon nd mpon vouony mhnsm (Wng, ) Fo nsn hn O, OL nd OL os hough h α WD (OL nd O/OL) oowd by sng gn dupon (O nd OL) (Bows, ) In hssn ony on subgoup I OL gn ws dnd (Shnz nd MhOds, ), whh shs on ommon ns gn wh s h hn ohoogs H h onsvon o subgoup I OL gns n h Bss s nvsgd by ompson o h ohoogs n h bs Bssn sps bum (By, ) wh h m o ssgnng guoy nd unon us o h hssn OL ohoog o dn h unon nd guon o h s ommon ns gn o O bum nd hssn ong dy pns Phoopod owng spons dpnds on O unon n hn (Pu, 99) owng m spons o ong dys s hus n ndon o h psn o hs phwy nd O n d sps Hn owng m o h bs Bss sps bum gvs nsghs whh ong dy on o owng s onsvd n h Bss hssn bongs o h nw wod goup o h om my whh s ss o h Bss my hssn s psn n Souh m nd shows md owng m spons o LD ondons (Kovng, 9; Sánhzbo, ) h phoopod owng spons o bum ws sd I owd mn o dys wh vs bong und LD ondons o h gh nd h dk (Fg,b) In onod ondons pns dd no ow und SD ondons (h gh / h dk) hus bum psns n obg ong dy qung pn hssn owng m ws xmnd by numb bong und dn dy ngh n gsshous ondons h s xpmn ws pomd n uumn nd wn nd hssn owd wh ound vs boh n LD (h gh) nd SD (h gh) (Fg,d) h sond xpmn ws pomd n summ nd wh SD gown pns s owd wh ~ vs h LD gown pns owd wh ound vs hssn sms o b h dynu o uv LD pn wh sgh on o owng und nduv ondons, whh s n gmn wh s puv ogn n dy nu ondons h wk phoopod owng 9

40 HPER spons so nds h h LD phwy s known om hn mgh b mpd n hs sps Dys o Bong NF honm bum n= b NF L Numb honm bum n= LD SD LD SD ny hssn d ny hssn n= L Numb n= n= L Numb LD SD LD SD Fgu : Fowng m o bum nd hssn Mn owng m s dys o bong () o numb bong (b) o bum n LD (h gh/h dk) nd SD (h gh / h dk) ondons n=; NF = No owng Mn owng m o hssn pod s numb ppn o s ows msud und onod gnhous ondons und ghs n wn () nd summ (d) Pns sd ndd by n Eo bs psn sndd o Subgoup I OL gns onsvd n h Bss nd hssn onns ony on suh gn h s osy d o OL hn O hs wo os homoogs (OL nd OL) wh ony on subgoup I OL gn (hol) ws dnd n hssn y (Shnz nd MhOds, ) In od o xmn whh h h subgoup I OL gns onsvd n h Bss h psn ws hkd n h o Bss sps pn s w s n h mo dsy d sps bum om h gnus honm, whh sp om h o o h Bss my y dung s don h go o hs sudy s o dn whh h nso o subgoup I OL gns

41 HPER n hn ws unon O ohoog nd squn nomon om hol n povd n ndon Fo hn h squn nomon o h dsd h o ws vd om pub dbss (IR O=, OL=, OL=) Fo pn h pmny gnmn o h gnom squn vb h MPIPZ oogn ws usd h gns w dnd by BLS sh nd mosynny o h hs ws hkd (d no shown), whh onmd h nghboung gns n pn show homoogy o h ospondng gns n hn hn h (kb) g g kb bum ong (kb) hn h (kb) O L g O g bum ong (kb) hn h (kb) g g O L g g b OL OL 9 OL hol OL OL O O O Fgu : Phyogn Ronshp o OL goup pons n hn, pn, bum nd hssn Synn onshp bwn hn nd bum O, OL nd OL homoogous gns ws hkd n h homosom onx () No u ohoog o OL s psn du o ngmn Nghbojonng (b) o mno d squn om subgoup I OL pons om hn (), pn (), bum () nd hssn (h) Numbs nd boosp vus o ons h gnom squn o bum s now puby vb (Hudy, ) Howv, h nx gnon squnng ds om pub dbs w vb nd w usd o ough ssmby o h gnom usng L wokbnh (L Bo) D om ou nx gnon pd nd squnng uns wh n ns sz o bp w gnd h ssmby hd N vu o ~9kb wh h gs ong bng ~kb Usng hs ds wo ongs onnng BLS hs o O nd OL w dnd ong (~kb) onnd squn homoogous o OL nd mosynny ws onsvd wh hn (Fg ) ong (kb) nudd homoog o O h downsm squn o O ws dnd o b homoogous onmng h

42 HPER mosynny h who ngn gon bwn O nd OL ws dnd s w bu ony h ds 9bp o h odng gon o h OL homoog psn n h ssmby h mnng upsm gon sms o hv undgon homosom ngmn In p O ws dnd by B sn (hp ) nd sqund by SNER squnng Boh squns, spnnng h ngn gon om OL o O s w s O odng gon w gnd whou msmh onmng h h su s no n o h h snng o B by o bum gnom DN o h nx gnon squnng ppoh h gon psn h OL homoog n bum s homoogous o dn p o h n hn (Fg ) h poxm p o OL n hn ws no dnd by BLS sh n bum Fo ompson o hssn h squn om B s OL homoog s dnd n pvous sudy ws usd (Shnz nd MhOds, ) I ws so onmd by BLS sh h no OL ohoogs oud b dnd on h wo oh B squns om ohoogous gons o h oh OLs n hn s nvsgd n Shnz nd MhOds () h pon squns o subgoup I OL gns dnd w gnd nd phyogn ws onsud usng h nghboujonng mhod (Fg b) Rmkby ony on pogous gn s psn n hssn, h d o s hol nd no ohoogous gn o OL s psn n bum O, OL nd OL ohoogs goup ogh wh % boosp suppo hol goups wh OL ohoogs wh boosp suppo o 9%, bu OL ohoogs om h Bss my os d o h oh hn o hol h dd no sov h onshp bwn h gn subms hmsvs kn ogh h hol pon hs os phyogn onshp o OL ompd o O o OL ohoogs s hol hs n qu vouony dsn o oh gns s unxpd h s mo osy d o on goup unss shs unony wh hs gn h ndngs hus nd h hol mgh b unon homoog o OL nd no O o OL h nuod subsuon s o O, OL, OL nd hol w ompd n odon gnmn o h ospondng DS (b ) h ompson o nonsynonymous nd synonymous subsuon s (dn/ds) gvs n ndon o h sv pssu h s on odng squns h ompsons o hn subgoup I gns wh hol showd dn/ds vus bow ndng sbzng son hol nd OL pons, whh phyogny os d ompd o OL nd O (Fg b), ddony xhbd ows o () nd od () numb o nonsynonymous subsuons n h spv DN squns hs sud n h ows dn/ds () o OL ompd o hol ndng h hs wo gns und sbzng son nd ddony hghghng h smy h numb o subsuons n so b usd o sm h v m whn h vouony sp bwn squns oud nd wo ssumpons n b sd n hs ds Fs, h d h h

43 HPER h subgoup I gns n hn nd hol hv on s ommon ns gn s suppod by h ndng h h ompson o O, OL nd OL o hol d o h hghs o synonymous subsuons obsvd (>) Sond, ows numb o o () nd synonymous hngs (9) ws obsvd o O nd OL suppong h un hypohss h h ndm dupon o O nd OL oud h α WD nd hus h sp om OL b : Nonsynonymous nd synonymous subsuon n hn nd hssn subgoup I OL gns h numb o obsvd synonymous subsuons (Sd) nd h numb o obsvd nonsynonymous subsuons (Sn) s w s o subsuon numb (o) s dspyd n pws ompson h vus w od usng Juksno mhod o synonymous (ds) nd nonsynonymous (dn) subsuons nd o (dn/ds) ws ud Lows vus n h ss mkd n d n nm Sd Sn o ds dn dn/ds O hol 9 OL hol 9 OL hol 9 O OL 9 9 O OL 9 9 OL OL Expsson pns o hn, bum nd hssn goup I OL gns onsvd h xpsson pn o O s mpon o s unon s dy ngh snso nd s dsn om hos o OL nd OL n hn (Fon, 9; Ldg, ) h xpsson pns o pn nd bum w hkd o onm onsvon o xpsson pns ound n hn homoogs Exmnng xpsson pn o hol gvs ndons o how h s ommon nso o Bss subgoup I OL gns ws xpssd Expsson pn o subgoup I OL gns w xmnd n sdngs gown und LD nd SD ondons mrn vs xmnd n hn n hs sudy w nomzd o h houskpng gn PROEIN PHOSPHSE (PP, Esnbg nd Lvnon, ; Wssmn, 99) Fo ompson o xpsson pns h vus w nomzd o h mn o h xpmn (nomzd xpsson) hn O (O) mrn vs hngd ov h ous o dy nd w dn n LD nd SD Rpd downguon o mrn dwn (bwn Z nd Z) nd h s o mrn vs sng Z9 hs o xpsson n sdngs gown o n dys und LD ondons Und LD ondons n so gown sdngs song ngh pk (Z o Z) ompd o vnng pk (Z9 Z) ws obsvd (Fg ) In SD ondons h pk xpsson ws sm h vnng pk ws mo ponound hn h ngh pk n SD ompd o LD Impony, O mrn ws no psn Z und SD ondons wh und LD ondons mrn ws dd (Z ws hvsd xy ghs on n hs sudy)

44 HPER h xpsson o hn OL (OL) showd hghs xpsson h bgnnng o h dy n boh LD nd SD h mrn vs w dud bu y db Z nd Z n ons o O h ough xpsson ws hd bwn Z9Z OL xpsson sd sng gn wds No mjo dns bwn LD nd SD w obsvd, hn O mrn b hn OL mrn nomzd xpsson,,,, LD SD nomzd xpsson LD SD, 9 Zgb m 9 Zgb m hn OL mrn d, bum O mrn nomzd xpsson LD SD nomzd xpsson,,,,, LD SD 9 Zgb m, 9 Zgb m bum OL mrn hssn OL mrn nomzd xpsson LD SD nomzd xpsson LD SD 9 Zgb m 9 Zgb m Fgu : Nomzd mrn vs o subgoup I OL gns n hn, bum nd hssn m ous xpmn dmnng mrn vs o O (), OL(b), OL() O (d) OL () nd hol () n dy od hn, bum o hssn sdngs h ndd Zgb m n ong dy (LD) o sho dy (SD) ondons DN onnons w nomzd o PP ( hn) o IN ( bum nd hssn) oowd by nomzon o h vg o h xpmn (nomzd xpsson) Dk gy nd gh gy s nd dknss n LD nd SD, spvy h mn o h hn ps o h sm DN s dspyd wh o bs ndng sndd dvon

45 HPER h xpsson pns o hn OL (OL) w sm o OL (Fg ) Is mrn vs syd hgh Z nd Z n LD ompd o SD bu xpsson os n LD Z nd Z ompd o SD hs pn ndd h h xpsson mgh b djusd o h bgnnng o h ngh (dwn kng) In ons o OL h mrn o OL ony ss Z bum O (O, Fg d) mrn ws xpssd n boh LD nd SD ondons n n dy od sdngs Is xpsson shd ky us wh O bu no wh OL nd OL In LD ondons s mrn ws ny downgud upon ghs on nd s ough o xpsson ws hd Z nd Z h mrn sd o ns gn wds nd h vnng nd ngh pks w dnd In SD ondons ony on bod pk ws dnd bwn Z nd Z Impony h ough o xpsson sd Z nd onnus un Z spnnng h omp gh pod, pn sm o xpsson o O wh s mpon o gn guon h ov mrn xpsson pn o bum OL (OL, Fg ) showd hgh smy o xpsson o OL nd OL boh n SD nd LD s sn o OL h pk o xpsson ws shd bwn LD nd SD sm o OL Lvs o mrn os n h nd o h SD nd so n h bgnnng o h dy, mnng h ough o mrn ws hd Z n SD bu ony Z9 o Z n LD, whh ws vn mo ponound hn h obsvd n OL ddony h xpsson o pn subgoup I OL gns ws hkd n ong dy mous RN sq d (kndy povdd by EvM Wng, MPIPZ, oogn) showd h O s downgud n h monng upon ghs on nd hs boh h vnng nd h ngh pk (Fg ) OL nd OL show monng xpsson, pkng Z (Z) (Fg b) OL hs s ough xpsson bwn Z nd Z wh OL mrn s ows bwn Z nd Z O mrn n LD b OL nd OL mrn n LD OL OL mrn mrn Zgb m Zgb m Fgu : mrn Lvs o subgoup I ohoogs om pn mrn vs o pn () O (), OL (b) nd OL (b) ohoogs s dmnd by RNsq n LD ondons y s spy hous n h dk

46 HPER s dns w nd onsvd bwn O, OL nd OL os ohoogs n hn, pn nd bum ws o ns o s h xpsson pn o h ony mmb o subgoup I OLs n hssn, s hs ky psns h xpsson pn o h s ommon ns gn hssn OL (hol) mrn ws dd n sdngs (Fg ) nd vs o owng pns (d no shown) h mrn pn y shd h ky us dsbd so o Bss OL o OL ohoog nd no o O Expsson o hol ws hghs ound Z nd hd s ough Z9 Expsson sgnny os Z bu mrn vs ns und SD ompd o LD, u dsbd o boh OL nd OL xpsson In gn h xpsson pns o subgoup I OL gns n h Bss n b ssgnd o wo sss on bng sm o O wh h oh s sm o OL/OL h ngh pk s ommon bwn boh pns bu dns k h pd monng downguon o O no shd h phyogn onshps bwn ohoogs ospond o h onsvon o xpsson pns o gns nvsgd hol xpsson goups wh OL/OL xpsson onmng pvous ndngs h hol pon s mos osy d o OL ohoogs ompd o OL nd O ohoogs In summy hs suggss h h OL/OL xpsson pns psn h nn s nd h O mrn pn vovd n h Bss Subgoup I OL gns om hn, bum nd hssn b o ompmn h o mun Phyogn nyss nd xpsson suds nd h hol s no unon homoog o O In od o s hs hypohss s w s onm onsvon o O unon n h Bss ompmnon xpmns usng O nd hol DS w pomd OL nd OL s w s OL w nudd s ngv ono s ovxpsson o OL o OL om h MV S pomo ws shown o hv no on owng m guon n hn (Km, ; Ldg, ) ompmnon xpmns w pomd wh xh (H) ggd vsons o DSs xpssd om h nv O pomo (kb) o h phom sp SU pomo (psu) n hn o bkgound (os) (Imu, 999; Lubng, ) Fowng m o pns ws sod n LD ondons Fowng m xpmns o psu dvn OL ns dvd om o mun w pomd n h gsshous n LD ondons o pns owd wh mn o 9 vs wh o ono owd wh mn o vs (Fg ) homozygous psu::h:o (n o) n ws sd s posv ono nd pns owd ompd o wd yp wh mn o vs h owng m o psu::h:o ws s pdd hn o wh mn o 9 vs Insngy OL nd OL s w s OL nd hol bhvd n sm wy Fowng m ngd bwn mn o vs o OL nd vs o hol on wy NOV oowd by uky s (pws ompson) ws pomd o dny

47 HPER ss sgnn In hs s o, o nd psu:h:o pns no ssy dsn goups (p<) Insngy h ony n h ws ssy no dsngushb om psu::h:o ws psu::h:o h su so onmd h oh onsus w b o s su h owng phnoyp o o o wd yp vs Fowng m o psu::h:ol ws ssy hn o bu hn psu::h:o hus ovxpsson o subgoup I OL gns n h phom ompnon s sud h owng phnoyp o o mun ndng h h OL gns sd hv h by o pomo owng n hn h owng m o ompmnon ns dvn by h nv hn O pomo (po) ws sd n gowh hmbs (Fg b) In hs xpmn h ono o owd wh mn o numb o wh o owd wh mn o homozygous ono n yng po::h:o n o bkgound ws usd s posv ono nd owd wh mn o numb o vs h mn o numb o ns yng po::h:o ws vs Fowng m o po dvn OL nd OL ws mn o nd vs, spvy Lns yng OL owd smy wh mn o vs po::h:ho ns owd wh mn o vs On Wy NOV nd uky s ws pomd o hs xpmn s w nd ndd h O ns sgnny (p<) owng hn o ono bu no ssy dn om h O ono n Insngy oh gnoyps no on goup bng ssy hn o bu so ssy hn o, xp hol whh s ndsngushb om o In summy, ompmnon wh O ydd sm owng m ompd o h O ns sd, whh onmd h hypohss h O unon s onsvd down o h bs Bss sps bum h hssn ohoog d o gv h sm su h py o subsung O unon n hn ws ompb o h oh subgoup I OL gns sd Insngy h us o dn pomos nmy po nd psu povdd dn sus om pvous pubons usng h MV S pomo I s possb o ompmn h o muon usng subgoup I OL gns sd whn dvn by h SU pomo p ompmnon ws vn obsvd usng po hs s n gmn wh pvous sudy n whh hmydomons nhd O homoog ws usd o ompmn o muon h uhos obsvd n owng phnoyp whn usng h psu pomo s w s h ps (Sno, 9) h xpsson o O (n, ) s w s s g F (dn, ) nd s upsm guos, DFs (Fon, 9; Sw, ) nd FBHs (Io, ), s md o h vsuu wh psu s v Usng h SU pomo hus s suon n whh h nsgn s hghy xpssd n h ppop yp h sm s u o h nv O pomo Howv whn xpssd om h nv pomo mrn vs ow hn whn xpssd und h ono o psu bu sgnny hgh hn o wd yp O (Song,

48 HPER Fg S) In summy OL gns sd hv h py o pomo owng bu nonhss Bssn O ohoogs unony mo v ogh wh h phyogn hsoy hs d nd h O, OL nd OL hv h py o pomo owng n hn bu O bm unony mo pon dung h y vouon o h Bss b Fowng m n LD (psu) o L Numb,d n= d, n=, n=,d, n=,d n= b o o O OL OL O OL hol psu::xh n o b Fowng m n LD (po) o L Numb d n= d n= d n=,d n= n= Fgu : Fowng m o ompmnon ns usng DN om subgoup I OL gns gns om hn, bum nd hssn hn o nu mun ws ompmnd wh DN o OL, OL, O, OL nd hol xpssd om psu () o po (b) Fowng m ws sd usng pns sd by FP sgn n h sd o o ndd numb (n) und LD ondons n h gsshous (psu) o m hmb (po) w, o nd homozygous po::h:o nd psu::h:o shown s onos (n=) Eo bs psn Sndd dvon Ss sgnn ws ud usng On Wy NOV oowd by uky s (pws ompson) p<,, gnoyps showng ssy sm owng phnoyps goupd (sm s: d) o o O OL OL O OL hol po::xh n o

49 HPER mno d squn hngs my xpn unon dns bwn O, OL, OL nd hol h bov sus suggs h hol s mo sm o OL hn o O o OL n phyogny bsd on mno d squn, mrn xpsson pns nd unon hus h mno d gnmn o subgoup I OL pons ws xmnd o dny dns h oud xpn why O ohoogs h mos v h squn gnmn bwn OL, OL nd O ohoogs (Fg 9) vs hgh onsvon h wo BBoxs nd h domn (Robson, ) hghy onsvd ov ong shs (Fg 9) Whn ompng h O homoogs o oh pons s nn mno d posons onsvd n OLs bu hngd n O ohoogs (s ows n Fg 9) O hs, ou ound nsd h onsvd BBox nd domns On subsuon om sn n O o nn n OLs s ound n BBox I (O,S9) Hvng sn hs poson sms o b h dvd s, s g OL, Phbs n O (PnO) nd OsHD y n nn hs poson (hs, ) hs xhng ws dy sd n nsgn ppoh nd no ws obsvd whn hs mno d ws hngd n O (Km, ) h sm s u o h s subsuon n BBox II (O, D9), wh no ony OL nd OL ohoogs hv n nn bu so oh subgoup OL pons OL, PnO nd OsHD (hs, ) h sond subsuon n BBox II s hng om Isoun o vn (O, I9V) In hs s OL y n Isoun, mnng h Isoun oud psn h nn s (hs, ) h mno d subsuon n h domn (O, NK) wh O ohoogs hv n spgn (N) bu ohs y Lysn (K) yng Lysn hs poson s h nn s s OL, PnO, OsHD hv h sm mno d on h poson onsvon gos uh n vouon s d domn pons k PRR, PRR, PRR9 nd O so hv onsvd Lysn sdu h poson (ndon, ) onsvd mno d hngs obsvd bwn O nd h oh OLs No onsvd mno d hngs ommon bwn hol nd Bssn O ndng h hol pon mgh no unon s O ohoog bu h s OL/ ohoog In gmn wh boh xpsson nd ompmnon d hol s mo osy d o OL ohoogs n h phyogn onsuon bu h so mno d hngs h shd wh h OL o OL suppong h d h subgoup I gns n h Bss nd hol dvd om on s ommon ns gn nd mgh hv undgon sub unonzon n vouon In onuson mno d dns bwn O nd osy d OL pons w dnd h mgh b us o h unon hng om h puv ns pon 9

50 HPER OL OL OL hol OL OL O O O OL OL OL hol OL OL O O O OL OL OL hol OL OL O O O OL OL OL hol OL OL O O O * * * * : * * * * : * * * * * * * * * * * * * * : * * : : : * : * * : : * * * * : * * * * : * * * * * * * : * : * * MLKEESNES WRDRSVYEDSYLDRVHNRVSRHERVRVQSESPFLKD MLKEESNES WRDRSVYEDSYLDRI HNRVSRHERVRVQQESPFLKD MLKEESNESR ENSWRDRSVYEDSYLSDQVHNRVSRHERVRVESEPFLKD MLKEERSEENNWRI DRSVYRDSYLSDRVHNHVSRHERVWVESERPFLKD MLKVESN WQDRSVYRDSYLSSDQVHNRLSRHERVRVQSERPFFKD MMKQESN WQDRSVYRDSYLSDQVHNRVSRHERVRVESERPFFKD MLKQESNDI S ENNRRPDRSNVYHDSYLMSDQVHSNRVSRHKRVRVESERPFLEDD MLKQENDI S NNRRDQSVYHDSYLSDQVHSNRVSRHKRVRVESERPFLEDD MSKEESNDRS ENRRDQSVYQDSYLSDQVHSNRVSRHERVQVESERPFLKDN 9 9 * * * * : * * : * : * * * * * * * * * * : * : * * * * * * * : SLDEI HSNPLRRHQRVPI LPLSNSSSM PSEDDN DEDDREVSWLLPN SLI DEI HSNPLRRHQRVPI HQSN PSEDDN DEDDQEVSWLLLN SLDEI HSNPLRRHQRVPI LPI SHSSSMHHPPSEVDDNMMMQEEEDEDEDDREVSWLLLN SLDEI HSNPLRRHHRVPI LPI SSMSPMNHHP SEMDENDMVVREEEDEDEDDEESWLLLN SLDSEI HSNPLRRHQRVPI LPI SEYSYSSNHS EV DPENRLVL QEEEDEDEESWLLPN SLDSEI HSNPLRRHQRVPI LPI SNSYSSMPNNHS SEVDPENRLVVS QEEE EDEESWLLPN SLDSEVHSNPLRRHQRVPI LPI SNSFSSMHHQSEKMDPEKRLVVDQE EEEDKDKEVSWLFPN SLI DSEVHSNPLRRHQRVPI LPI SNSYSSK QHKSEMNPENRLVVQ EDE DHKEPWLFN SLSDSEVHSNPLRRHQRI PI QPI SNSSSMVHQQR ENRLVVSKEVEDDNEDDRVSWLPD 9 : * : * : * * : * : * : * * * * * * : : PKN I NQNNFLF VEYLDLVDYS SSMDNQFEDN QYHYQRSFDVVPLQVEESS PK NQNNFLF VEYLDLVDYN SMENQYED QYNRYQRSFDVVPLQVEESN PKN SNNNNNPNNFLF VEYLDLVDYN SNLDNQFDQY QRDVPQRNFDVVPLQVEESN PKN SNNN NQNNFFFDEDEYLDLVEYN SSMENQFSDQYSQYHQDVPQKSFDVVPLQVEESR SKN S NNN FSI DEFLNLVDY SSSDKQFDQSNQYQLDNVPQRSYEDVVPLQI EVSK SKN N NNNSQNNFSI DEYLDLVDY SSMDKQFDQSNQYQQDYNVPQRSYDVVPLQVEELK SD KNNNNQNNLLFS DEYLNLVDYNS SMDYKFEYSQHQQNSVPQSYDRVVPLKLEESR SDKI SHNHNNNNHNNELLFS DEYLDLVDYN YKFQYNQQQHDSVPQSYDRVVPLQLKESR ER NSDNNNNQNNEFLY EEYLDLVDYNSSMDYKSSMDYSSQYNQHQQDVPQSYDVVPLQFEESK < < < BBox BBox : * : * * : * : * HLQQSQQN FQLI NYFSSHYNNN SLKDLNHSSVSSMD I SVVPESSDI VQHPRKEI DQLSPPQVV HLQQNQHDDFQLI NFYNN YN SLKNLNHSVSI SSMDNI SVVPES VQENSRI KEI DQVSP LV HLHHNQQN FQSI NYSSQYNYNSSLKDLNHNVSI LSMD I SVVPESSDI VPHPRPKDQLSPPQMM QLHHEQQS FQLI YSPLYSYN SMNHSVSMSSMD I VVVPESSDMVVSQLRPKDLLI PPI QMM MYQEQQN FQLSI NSWLRSSN SLSHMVNVSSMD LVVPESSD VSNPRSPKVDQPPYPP HMHHEQHD FQFFHSSHQSSI SLSH I VVPESPSDI SHPRSPKVDQLLEPP HQHNQQN FQFNI KYSSHYNDN SI NHNYI SSME VVPESV SHPRPKVEQQPDPSQMI HLHKQHN FQSI NFSHYSDN SSSHPRMPKE I DQQPDPPI QI I QLSPMD REQPDPPI QI I PLRHEQQN FQLDI YSSRNQYSYYD SLNHNRI LSME VVPEP PHPRPKI DQLP I QMI < < < < OL OL OL hol OL OL O O O * : * : * * * : : * * * * * : * * * * : * * * * * * * * * * * * * * * * : : * * * * * : : : : : * * * * * * * : Q QLPMERERVLRYREKKKRKFDKI RYSRKYEI RPRI KRFKRI EE EEEI FSSLMSEYI VPSF Q QLSPMDRERVMRYREKKKRKFEKI RYSRKYEI RPRI KRFKREEVDDEQLFSR YI VPSL H QLPMDRERVLRYREKKKRKFEKI RYSRKYEI RPRI KRFKRDI E EEQLFSLMSDYI VPSF P QLSPMDRERVLRYREKKKRKFEKI RYSRKYERPRI KRFKRDI E EVDQFSLMQESYI VPSF Q MLSPRDRERVLRYREKKKMRKFEKI RYSRKYEKRPRI KRFKKKDVDE ENQFSMI FDYI VPSF Q VLSPMDRERVLRYREKKKRKFEKI RYSRKYERPRI KRFKRKEVD EDQPFSMI MFDYI VPSF VQLSPMDRERVLRYREKRKRKFEKI RYSRKYEI RPRVNRFKR EI E EEQFNMLMYNYI VPSF QLSPMDRERVLRYREKKKRKFEKI RYSRKYERRPRI NRFKRREI E EDQVFNMLMNDYI VPSF QLPMDRERLLRYREKKKRKFEKI RYSRKYEI RPRI NRFKRRE ENQLLMSEYI VPSF Fgu 9: Squn gnmn om subgoup I OL gns n hn, pn, bum nd hssn Squn gnmn (mno ds) om O, OL nd OL ohoogs hn (), pn (), bum () n ompson wh OL gn om hssn (h) Rd ms mk BBoxs nd domn, spvy < nds mno ds h onsvd n OL ohoogs bu dn n O ohoogs ssks nd onsvd mno ds Dsusson hp h owng m o bum ws sd n onod ondons bum s n obg LD pn n gnhous ondons h dd no ow n SD hs s n ons o h uv LD pn hn h spons o od xposu (vnzon) ws no hkd bu bum owd ~ dys n LD dy, nd ho s unky o show song spons o vnzon wo dn bhvous w obsvd o hssn n h wo boog ps psnd h s xpmn ound no sgnn dns n numb bong bwn LD nd SD < <

51 HPER ondons s sn o dy nu pns h sond xpmn pomd n summ ondons vd owng n LD ompd o SD ndng h hssn s uv LD pn hs ndng s suppod by pvous sudy n whh hssn s dsbd s uv LD pn (Kovng, 9) Sm o hs sudy mn numbs o n LD nd n SD owng w obsvd hssn whh s ound n Souh m (Sánhzbo, ) shows spons o ong phoopods Idnon o subgoup I OL gns vd h k o OL ohoog n bum I mgh b ound n noh poson n h gnom bu w ky b nonunon s h s 9bp mn djn o O Hn, h O/OL dupon ky xsd nd OL ws os n bum hus bum s pobby b o suvv nd dvop whou unon OL ohoog, phps bus s gy dundn o OL hs s so suppod by h ndng h hssn ony s on subgoup I OL ohoog vn hough hs undgon n ndpndn gnom pon (hng, ; Shnz nd MhOds, ) h oh wo ops mus hv bn os h pon vn I s possb h h pon o h ns gn n h Bss d o subunonzon Hn h ogn unon oud b mnnd by on opy pobby OL, wh h wo oh ops, n hs s OL nd O hngd unon h phyogn onsuon vd h hol pon s mo osy d o OL ohoogs ompd o O nd OL ohoogs, spvy mon o hs nyss s h s ony bsd on sm numb o gns Insng h numb o gns nudd n h nyss, spy ohoogs om oh om sps woud ns h souon o h so pvous nyss w pomd ony o h BBoxs o h domn, xudng h onsvd mdd p (MM, Fg ) hs oud b sd s w, vn hough h mgh b oo w dns n mno d squn o obn hgh souon n h phyogn h nyss o nuod subsuon s (dn/ds) ndd h sbzng son s ng on subgoup I gns n ompsons sd Insngy dn/ds vus o ompsons o O w h hghs obsvd (b ) hs nds h son poss mgh b ng on O gn whh s mskd by h ov vouony o o kp h gn unon nspon guo Sp ps o O gn om dn Bss sps oud b sd o dny gons h mgh b und posv son h xpsson o hn, pn, bum nd hssn subgoup I OL ohoogs gv sus, whh suppo h phyogn onshps dsussd bov O mrn guon vovd n h Bss h α who gnom dupon nd s onsvd down o h bs sps bum hs sudy md ndng h sms bwn d gns bu s so o ns o dny dns bwn sps Fo xmp h xpsson o

52 HPER O oud b nysd n bum n nmd dy ngh suh s h gh nd h dk o nd dns h xpsson pn o hol suggss h h gn s no nvovd n dsmnon bwn phoopods s mrn vs hgh n h monng boh n LD nd SD whh s shown o bosh dy ngh dsmnon by O (Fon, 9) hs s suppod by h ndng h on o owng n hssn und LD ondons s md I woud b o ns o omp h sp xpsson pn o h gns OL nd OL w gny xpssd mo hghy hn O n hn (>od, d no shown), whh ws onmd by h pn RN sq d (Fg ) I OL nd OL w xpssd hghy n h vsuu hs woud d o y owng n boh LD nd SD, whh s no obsvd n hn hus h dns n xpsson w mos ky nvov hngs n h sp xpsson o xmn h sp xpsson usons o dn pomos k pol, pol, pol nd phol o US gn w b nysd n nsgn hn h unon nvsgon o hs osy d ohoogs n ompmnon o o mun vd unxpd sus gns nvsgd ompmn h o muon o n dg h song psu nbs mo ompmnon ompd o po O ous hs owng m xpmns nd o b pd wh homozygous pns o psnv ns In pvous suds us o h MV S pomo d o dn onusons (Km, ; Ldg, ) h on o owng s obsvd usng h psu pomo s n suon h dos no h wd yp ondon Smy DF uss owng whn xpssd om h psu pomo (Fon, 9) bu no nssy whn dvn by h MV S pomo (Imzum, ) Nvhss usng psu snghns h un mod s DF s ssumd o b d psso o O nd oss o unon d s nsd O xpsson (Fon, 9) nyss o h psu dvn ns mgh hus nb mo u pdons bou h unon o vsu xpssd gns h xpmns usng po suppo hs ndngs I ws unxpd o obsv p ompmnon o h o muon whn usng po dvn OL bus MV S dvn OLs d o owng o ompmn o muns (Km, ; Ldg, ) I n so no b xudd h hol s n vo o n F homoog n hssn nd dos hs s ny s O vs F n hn Evouony hngs mos ky dd no ony ou n O nd s ohoogs bu so s mny nos, whh mgh b dn n hssn nd hn ompd o h s ommon ns gns Fuhmo, hs xpmns md ompng OL homoogs n h by o p O Unouny nno b sd whh hol s b o p h OL nd OL bus h unon s no dsbd n d nd doub muns hv no bn sod (Km, ; Ldg, )

53 HPER Funony O ohoogs nd OL/OL ohoogs nudng hol no dsn goups s shown n h po ompmnon xpmns hs d o h dd nyss o dns bwn O nd oh OL ohoogs h ous ws on dns n ou sdus n h onsvd BBoxs nd domns o h pons h sdus w onsvd n h goups bu dn bwn goups h o hs hngs (O, S9, D9 nd NK) suggs h O s h dvd s O sms o psn h nn s ony n on hng n BBox II (O, I9V), wh mno ds wh h sm pops (nonpo) xhngd Dvng mno d hngs ddony onsvd n O, O nd O, mnng hy oud b o mpon, spy whn kng no oun h h bum nd o Bss sp oud h α dupon mnng up o ~ my go (Fw, 9) hs hngs oud nun unon, whh ow sub unonzon o O Evn hough on poson (S9) ws dy xudd by muon nyss (Km ), h oh hngs o vn n non o dn mno ds oud b sponsb o h dns bwn OL, OL nd O

54

55 HPER Phyogn Shdowng o ONSNS pomo nd unon s nspon s gud by non o Fs wh DN squn mos h ous o h gn o ns O mrn s dny gud n hngng dy ngh nd ys dung h dy suggsng ompx nspon guon E suds vd h n hn kb upsm o O s odon s sun o ompmn h o muon whn dvng nspon o O DN (n, ) Sp xpsson suds usng h US po gn so h bsd on kb pomo suds o gnom onsus o O ous (n, ; kd nd oo, ) Evn hough bndng o O guos ws shown o ou mo ds ps o O pomo (Io, ; Sw, ) mos suds ous on smns n h poxm p o h pomo (up o kb) hs nud DOF bndng ss (Imzum, ) nd EBoxs (Io, ) ddony h ndng h h O gn s ony psn n h Bss nd h s nspon guon vovd n hs my (hp ) n b usd o dny onsvd mos hus h O pomo squns om dn Bss sps usd o dny onsvd guoy squn h m o hs sudy s o dn mnm pomo o O, dsb s guoy gons nd omp smn hngs bwn O nd s osy d pogs O pomos psn n Bssn sps nvsgd Phyogn oopnng nd shdowng powu hnqus o dny onsvd squns n ngn gons h n subsquny b sd o h unon mp n boog ssys In od o dny mpon guoy squns by phyogn shdowng h ngn sp bwn O nd s upsm pog OL ws od om dn Bss sps In hn h ngn gon spns ~kb By shng dbss usng h BLS gohm h squns o Bss npus, Bss p nd Ssymbum o w vd ddony h squn om bdopss y ws ssmbd usng sho ds om h NBI hvs pn squn ws dnd by shng h pmny gnom gnmn by BLS (MPIPZ, oogn, unpubshd) o dny O pomo squns om sps wh squn nomon ws no vb onsvd pm s ws nhod n O nd s upsm pog OL o obn onsvd gon sub o nhong pms h odng squns o O nd OL ohoogs om hn, bdopss y, Bss npus, Bss o nd pn w gnd Pms w hosn os o h mnus o OL nd n h s xon o O o mnmz PR gmn sz Fg b shows p o h gnmn usd o s h pm s h sung PR podu hs ngh o ~kb n hn (Fg ) mpon o h dsd gmn ws sussu o v o svn sps sd (gnom DN povdd by Mkus Bns, MPIPZ, oogn), nudng hn s posv ono (Fg ) PR gmns o h dsd ngh w subond nd sqund om Boh s, Ssymbum on, ps ub nd

56 HPER Nsuum on No squn oud b mpd om hssn, Rsd uo (Fg ) nd bum (d no shown) ONSNSk ~kb ONSNS b gnmn OL [kb] M Bs So h No R M gnmn O d B on O ohoog B on O ohoog No F No N No Ys N Ys K No 9P No F No N 9P N + M [kb] Fgu : Isoon o O ohoogous pomo squns om dn Bsss sps hn O nd OL od n ndm on homosom () Pms w pd n onsvd squns o OL nd O o mpy ngn gons om oh sps n h od Bsss gnmn o OL nd O ohoogous DN squns (b) om v Bssn sps ws usd o h dsgn o pms ndd n PR podus () usng onsvd pms (,b) Ingn gons w onmd by squnng (mkd wh ssks) M Mk; hn; Bs Boh s; So Ssymbum on; h hssn; ps ub; No Nsuum on; R Rsd uo ( ) w ono bum B sn (xmp n d) usng n hn O DN pob (9bp) spnnng h onsvd mdd gon sung n Bs sd () wo djn spos nd sm b on n squ (d) Idn bum O ohoog ws dnd n N nd s onmd by PR () usng hn gnom DN s posv ono (+ mps bp), wh no podu ws mpd n w ono () o obn h O pomo o bum B sn ws pomd usng h n gon o O s pob hs gon ws hosn s s onsvd n O ohoogs nd oh subgoup I OL gns (MM) bu vs n oh mmbs o h OL my (hs, ) h pms usd mpd 9bp o O gn om DN bu bp om gnom DN s h pms spn h non s non squn s n gn mo vb ompd o odng gon h pob ws gnd om DN, whh xuds h non h B sn (Fg d) ydd gh ndd Bs (Fg ) O hs wo w onmd o onn O ohoog by mpon, subonng nd squnng h ngn gon bwn O nd OL ws sqund usng pm wk (M nd Mhods) nd boh Bs (N nd ) d dn squn h ngn gon spns ~kb n bum bu ony 9bp o OL ohoog oud b sqund nd h

57 HPER upsm gon ws homoogous o noh gon on h o hn (s hp ) hs su ws onmd by nyss o who gnom squnng d hs ngmn xpnd why mpon usng OL nhod pm ws no sussu o bum h oh sx Bs w no nvsgd uh bu hy mgh onn oh mmbs o h subgoup I OL gns OL ohoog ws dnd n h bum gnom (hp ) O homoog o hssn ws dnd by Shnz nd MhOds () h ndng h no OL/O ohoogous gmn oud b mpd om hssn suppos dsovs, h hol s h ony mmb o subgoup I OL gns n hs sps ddony, no O pomo oud b mpd om Rsd uo, mmb o h Rsd, my n h od Bsss h O pomo mgh hus no b psn n oh ms o h od Bsss In summy ohoogous O pomos w dnd n Bssn sps nvsgd nd n O pomos w sod o uh suds h pomo o O s onsvd n n Bssn Sps nd us unqu smn omposon o dny onsvd squn gons n h pomos o O ohoogs, h pomos sod om h Bss sps w usd o mup squn gnmn (ppndx) h squns om n Bssn O pomos w gnd usng h LN gohm n h mvis su (m nd mhods) Fo h gnmn h ngn gon bwn O nd OL ohoogs ws usd nudng boh O UR s w s OL UR h VIS po psnon s shown usng hn (Fg ) s w s bum (Fg b) s bs gnom h onsvon o h spv bs gnom s shown n pn o dn bs ps n sdng wndow o bp Vus bov % onsvon w mkd n gh d Fom h ompson o squns wh hn n b obsvd h h ov onsvon s hgh whn squns om osy d sps ompd o hn Whn ompng o mo dsny d squns om o xmp Bss, pn o Ssymbum, sng boks o onsvon bwn ~bp nd kb mg om h nyss ompson o h hn O pomo o h o bum, whh s onsdd o b h mos bs Bss sps usd n hs sudy (By ), s vs onsvd boks phyogn ws onsud om h ds (Fg ) In hs hn, ps nd Nsuum sps goup ogh wh Bss, Ssymbum nd pn sps om sond subgoup bum s od s n ougoup hs s h phyogny o h spv sps n h Bss my nd dsngushs bum s mmb o dsn ng ousd h o Bss (omp Fg, By, ) bum O pomo shows sm onsvon o oh ohoogous squns nvsgd (Fg b), bus h don o oh sps (o Bss) oud h sp om h bum ng nd shs on s ommon nso wh o hm (By, ; Fnzk, ) On h oh hnd hn nd ps ngs o xmp sp hn

58 HPER bdopss y ps ub Nsuum on Ssymbum o Ssymbum on bs pn Bss npus Bss o honm bum Bs: bdopss hn kb kb kb kb kb kb bp bp DM MM PM b bdopss hn bdopss y ps ub Nsuum on Ssymbum o Ssymbum on bs pn Bss npus Bss o kb Bs: honm bum onsvd Mo kb kb kb kb kb kb 9bp bp bp DM MM PM DOF DOF DOF onsvd Mo d DOF (x) EBox (x) DOF P 9 9 ps ub Nsuum on bdopss hn bdopss y Bss npus Bss o Ssymbum o Ssymbum on bs pn honm bum P (x) Fgu : onsvon o O pomo n h Bss O homoogous pomos (ngn gon bwn OL nd O nudng UR) om n Bss sps w usd o ompson gnmn (LN) s dspyd s mvis po wh h bs gnom hn () o bum (b) Sdng wndow dspys onsvon bwn % n bp sdng wndow onsvon bov % s hghghd n gh d oo UR o O n uquos s nnod n IR h ppoxm posons o onsvd Poxm Mo (PM), onsvd Mdd Mo (MM) nd onsvd Ds Mo (DM) s dsbd n Fg ndd wo hghs onsvd pomo ps (bp) s dnd by MEME mo dnon (), Rd nd Bu s psn poson n b DOF () nd P () bndng ss undnd h hghs onsvd sho mos (bp o bp) dspyd s dnd by MEME (d) mo dnon oo, whh ou wh hgh numb o pons ( o ms) n h n pomos onsnsus F bndng ss undnd Nghbou jonng () s h phyogn onshp bwn O pomos om n Bssn sps, d numbs nd boosp vu

59 HPER hn nd pn, hus hn shs mo squn smy wh ps hn wh pn (Fg ) ddony von mong onsvd gons s obsvd Fo xmp sm onsvd bok ound bp nd 9bp (Fg b) ws ony psn n h bdopss/ps ngs bu bsn n oh squns wh bok bwn bp nd bp ws bsn ony n h Bss ng bu psn n oh squns hs boks mgh b nsng o uh nyss o puv dns n h guon o O ohoogs n hs sp sps onsvon o h O pomo ws sussuy dd bwn Bssn sps o dny unon guoy squns h pomo s ws uh nysd wh ous on RMs nd spy h smn omposon Fo hs pupos h who s o ohoogous O pomos ws nysd usng h MEME mo dnon oo (By, 9) Fg shows h songs wo hs whn shng o onsvd mo wh mxmum ngh o bp h s ound n squns In hs psnon h hgh o h Bs psns s quny, wh u psns % onsvon h onsvd Mos nd mhs wh h o o h bods pks dnd (Fg b) onsvd Mo onns h DOF bndng ss (), wh onsvd Mo onns on DOF bndng s nd on P bndng s (, s bow) Insngy h hghs onsvd RMs w no dnd n h poxm p o h pomo bu ~kb nd ~kb upsm o h S, ndng h hs gons mgh b o mpon o guon o O mrn vs n hn nd d sps Rnyss o h ds wh pm o sho mos (bp), whh oud ou ny numb, dnd h hghy ovpsnd sho squn shs n h who pomo (Fg d) Evn hough h gohm ws no ookng o known smn h bs h hs onnd known smns h s mn, bng psn ms n n pomos, onnd h DOF bndng s () h mo ws dsbd s h o DOF bndng s (Yngsw nd Shmd 999), wh h ddon sdus, ompng h hxm, w ound o gv ddon spy o DF (Imzum, ) nd puvy o DF, DF nd DF s hy bong o h sm subgoup o h DOF my (goup II, Fon, 9) hs ddon spy mgh b mpon o g dsmnon s h DOF nspon o my onns mmbs (Yngsw, ; Yngsw nd Shmd, 999) h sond mn (N) ws dnd ms nd onns h EBox onsnsus (NN) whh s bhlh bndng s (odooz, ) goup o bhlh nspon os d FBHs w pvousy dnd s vos o O nspon (Io, ) FBHs w so shown o n n vo nd n vvo wh O pomo squn (Io, ), hus dnyng hs mo n h pomo s suppos h un mod o O mrn guon h hd mo dsovd hs hxm s s o squn, whh ws ound o b psn ms ( ms p squn) n h ds hs mo ws shown o b EOSINE BRNHED/YLOIDE/PF (P) F 9

60 HPER bndng s by n vo suds (Shomm, ) h o mo ws ndpndny dnd by shng o ovpsnd mos n gns h msgud n p mun o P ovxpsso (Shomm, ) hus, h MEME mo dnon ppoh ws sussu n dnyng h so unnkd ss o P nspon os (ubs, 999) s puv O nspon guos Hn, hs nyss suppos h d non o O nspon vos (FBHs) nd pssos (DFs) wh O ous no ony n hn bu so n h who Bss my Whh h smn omposon o h pomos s d o xpsson pn dns bwn O ohoogs nd OL/OL ohoogs ws hn sd o xmn dns h bundn o smns n h dn pomos ws dmnd h m ws o dny smns h w ssy ovpsnd n O ohoogous pomos ompd o h oh subgoup I OL gns, whh do no sh h mrn xpsson pn Fo hs pupos ony sps w nudd wh squn nomon bou h subgoup I OL gns ws vb n h Bss h nyss ws md wh hn, pn (gnom squn unpubshd: MPIPZ, oogn), Bss p (Wng, ), Eum pvuum (hung pvu, Dssnyk, ) nd bum (Hudy, ) Ps no h no OL ohoog s psn n bum Fo Bss p wo OL nd OL ohoogs bu ony on O ohoog w dnd by BLS sh nd squn ompson hs sus n v O, v OL nd sx OL ohoogous pomos vb o nyss Fo ompson ousd h Bss OL homoogs bongng o subgoup I w usd (Pomo squns nd sson numbs n h ppndx) In sv ss, h gn xpsson ws sd nd shown o b dn gud wh song monng pk k OL/OL (Fg ) hssn OL s mmb o h om my ws nudd (Shnz nd MhOds, ) bus s h ony mmb o goup I OL gns dnd nd monng xpsson s dsbd n hs sudy n d (Fg ) h Mdgo unu homoog MOL ws nvsgd s phyogny goups wh subgoup I OL gns om hn (Hh, ) Vs vn O homoog (VvO), wo homoogs om Popuus hop, PO nd PO, nd noh wo homoogs om Sonum ubosum, nmy SO nd SO, w ssd s subgoup I OL gns nd ddony sh monng mrn xpsson (md, 9; Hsu, ) SO mrn ws shown o b gud by SDF, poo DF ohoog (Koosmn, ) In od o mnmz bs h kb squn om h s odon o hs gns ws sd o nyss h m ws o xmn h quny o smns dnd by MEME mo dnon n h pomo o O nd omp hs o h oh OL subgoup I pomo n od o h hng n nspon pn o hngs n smns h mo smns w nudd n h nyss h Box () ws nudd s s psn n h hn pomo wo posons on os o h S (Io, ) nd h oh ound ~kb upsm (Fg ) MYB

61 HPER bndng ss (W) psn n O pomo wh wo bng n os poxmy o h Boxs dsbd bov (Fg, ) hs sp MYB bndng s s nvovd n h ssoon o h vnng ompx (E, Nusnow, ) o DN by povdng bndng s o h LUX RRHYHMO (LUX) F (H, ) h ndng h O pomo hs h LUX bndng ss (LBS) n h s bp o s pomo (how, ) nd h I ns wh mmb o h E (ELF, Yu, ) mks n nsng puv guoy mn o O nspon guon h Box () mo ws so nvsgd s mgh b nvovd n sng nspon o vsu s (Ss, ; Wnk, ) How ovxpsson ns k S::FBH nd S::FBH us vd O xpsson (po::us) sd o h vsuu (s w s som n vs nd h oo p) mns un (Io, ) sm phnomnon s obsvd wh S::O nhnd xpsson o pf::us (dn ) In o sx mns w nvsgd whh mgh gu O mrn xpsson n n ohsd wy smns w ound o pomos nd h mn nd sndd dvon ws ud (Fg ) h ndom oun o suh sho mos hngs wh h onn o boh h mo s nd h squn nvsgd Fo xmp n hn h onn dvs om %, bng ~% n odng squn nd doppng n h ngn sp o % (h bdopss nom Inv, ) ddony onn so vs bwn dn pn sps (Šmd, ) In od o o o hs bs n pdng h ndom oun o h smn h pomo squns w shud ms nd nysd o onm sgnn dns On Wy NOV oowd by uky s ws pomd nd sgnny dn goups wh p< w dnd In hs nyss h mn oun o DOF bndng ss n O pomos ws (Fg ) h mn oun n h oh pomos ws ssy ow (OL), (OL) nd (non Bssn OL) h vus o h ndomzd ds ngd bwn nd whh s no ssy dn om h OL, OL nd OL pomos hs onms h O ohoogous pomos hv ssy mo DOF bndng ss hn h OL homoogs, nd hs oud onbu o h hngs n O nspon h oud dung vouon (hp ) ddony h ov oun o DOF bndng ss n hn pomos (kb squn om S) ws hkd nd h O pomo ong wh on oh gn () shows h hghs numb o DOF bndng ss (x, K Nodsöm, MPIPZ, oogn) n h n gnom P bndng ss () w dnd by MEME mo dnon ppoh h mn bundn p O pomo ws hgh ( bndng ss) hn ound n OL (), OL () nd nonbssn OL () (Fg b) Evn ow numbs w obsvd o h shu ono () h ss s vd h P bndng ss sgnny nhd n O ohoogous pomos ompd o h oh subgoup I OL pomos nd h shu ono No

62 HPER ss dn bwn h numb o P bndng ss n OL pomos nd h shu ono ws obsvd Mn bundn b DOF bndng s b b b b b b b Mn bundn b P bndng s b b b b b b O OL OL OL O OL OL OL O OL OL OL O OL OL OL Expmn Shu ono Pomo Expmn Shu ono Pomo EBox d,, Box Mn bundn,b b b b b b Mn bundn,,,,,b b,b b b b b O OL OL OL O OL OL OL, O OL OL OL O OL OL OL Expmn Shu ono Pomo Expmn Shu ono Pomo Mn bundn LBS Mn bundn Box O OL OL OL O OL OL OL O OL OL OL O OL OL OL Expmn Shu ono Pomo Expmn Shu ono Pomo Fgu : Ss nyss o F bndng ss n subgoup I OL gns Mn bundn o smns () n h kb upsm gon o Bssn O, OL nd OL s w s non Bssn OL ohoogs (OL) s ndd (Expmn) Sm nyss ws pomd ms wh shud dss s ngv ono (Shu ono) OnWynov oowd by uky s ws pomd o s o sgnn Ls,b nd h d ss no sgnny dn goups (p<,), wh o bs psn sndd dvon Bssn squns nud homoogs om hn, pn, Eum pvuum, Bss p (xo, xol nd xol) nd bum (no OL) Upsm squns om nonbssn sps nud hssn (hol), Mdgo unu (MOL), Popuus hop (PO; PO), Sonum ubosum (SO; SO) nd Vs vn (VvO) ) DOF=, b) P=, ) EBox= NN, d) Box=, ) LBS=W nd ) Box=

63 HPER Nx h oun o EBoxs ws nvsgd (Fg ) s hs mn hs ony ou xd posons nd wo nonsp bss (NN, odooz, ) hgh numb o EBoxs ws xpd p pomo ompd o hxms h mn numb n O pomos ws ound o b OL pomos showd vuy h sm numb (), wh OL wh nd OL pomos wh ss p pomo showd ow mn bundn h shud d s showd ow mn numbs bwn 9 nd Ssy, h numb o EBoxs n O nd OL pomos s hgh ompd o nonbssn OL nd h shu onos OL pomos dd no show sgnn dns wh O/OL o oh dss sd h mn numb o Boxs () n O pomos s, wh h mn s o OL, o OL nd o OL pomos, spvy (Fg d) h ndom oun o hs mo ngd bwn nd n hs ds O pomos hv sgnny mo Boxs hn OL pomos bu no s mny s OL nd nonbssn OL pomos Insngy O pomos h ony goup h shows sgnny mo Boxs ompd o s ospondng shu ono h nun o smn poson n pomo ws no ddssd, bu o n mn h ony ous on o w poson my b mpon Boxs ound os o h S nd nvovd n nspon guon (vwd n zgh nd shmo, 99) Mos Boxs dnd n hs sudy so posond os o h S Insngy h sond Box n O pomos n b ound mosy n os poxmy wh onsvd Mo (Fg,, ) nd s o w b dsussd n hs hp nyss o LBSs (W) vd no sgnn dn n bundn n h O pomo nd h oh pomos o h shu ono wh mn numb o nd bndng ss p pomo (Fg ) hs dos no xud o o hs smn s s psn n O ohoogous pomos nvsgd, bu unon woud nd o b sbshd by xpmn nyss mn o Boxs () ws ound o O pomos (Fg ) hs numb ws no sgnny dn n oh pomos nd shu onos nvsgd s o h LBSs boog o nno b ud ou In summy hs xpmn vd h dm ns n DOF bndng ss nd sm ns n P bndng ss h mjo vouony hngs n smn numb bwn pomos o O nd s os vs, wh dns o LBS nd Boxs w no ound h numb o EBoxs s hgh hn ssy xpd n O pomos bu hs s so u o OL pomos hy mgh py guoy o h s shd wh OL nd myb vn OL Sms w obsvd o Boxs, whh ovpsnd n O ompd o shu ono bu no ovpsnd ompd o OL nd OL, suggsng h hy oud py o n h pomos In hs s oh pms k poson onsvon woud nd o b

64 HPER onsdd n vung h sgnn In gn whh hng n bundn o smns n pomo hs nun on h nspon guon o h ssod gn nds o b xmnd by xpmnon Sgy o unon nyss o h hn O pomo h dn ppohs w kn o dn guoy gons n pomo o hn O Pomo don onsus w sd n ompmnon xpmns usng O DN nd h y LUIFERSE (LU) po (M, 99) In sond gn o unon ppoh O pomo ws dvdd no ou ps nd gmns w usd o h NOPLINE SYNHSE (NOS) mnm pomo (pnos, Pun, 99; Shw, 9) nd LU h pnos mnm pomo povds nspon s s h nbs sng h py o upsm pomo gons o nhn nspon non h hd ppoh ombns phyogn shdowng wh h gn o unon ppoh So O pomo gons h onsvd bwn Bss sps w usd o pnos::lu o s h unony OL DOF P Box LBS kb EBox Box b kb bp DM:pnos::LU kb kb MM:pnos::LU PM:pnos::LU + kb D:mn::LU bp (kb) 9bp :mn::lu bp (kb) bp (kb) ONSNS Fgu : Mod o O ous n hn ndng poson o smns n h onx o po ns Mod o O ous s psnd om h sond xon o OL o s xon o O In ong h onsvon o bum O pomo s dspyd s psnd n Fg Eh smn s symbozd ndng s ppoxm poson n h ous DOF=, P=, EBox=NN, Box=, LBS=W nd Box= ppoxm posons o onsvd squn shs usd o pomo nyss (pnos::lu) ndd () DM= onsvd Ds Mo, MM= onsvd Mdd Mo, PM= onsvd Poxm Mo ppoxm poson o ~bp gmns (D) nysd (pnos::lu) dspyd (b) Poson v o S, D nuds bp UR o O Rv poson o pomo don onsus usd o ompmnon xpmns nd LU po ssys shown () UR s nudd n onsus hus ngh (bp o kb) s o upsm gon om h h poson o h onsus s ddony ndd n h mod kb 9bp B:mn::LU bp (kb) bp :mn::lu bp (kb) +bp nyss o hn O guon by pomo don onsus dns mnm pomo In od o dn h mnm pomo o O, dn nghs o O pomos w usd o FP:O DN nd nsomd no Lndsbg (L) o mun (Mk Rüh, Umå unvs, Swdn) h u ngh pomo ws dsbd o b ~kb om h S n hn (n, ) hus, kb onsu ws sd s posv ono nd sho gmns o kb, kb, kb nd kb nudng h UR o O w dsgnd usng L gnom DN s mp ddony h kb nd h kb O onsus w usd o LU nd nodud no o wd yp pns Fg uss h sou o hs gmns Noby, on smn

65 HPER h gon h s uh upsm o kb, d o onsvd Ds Mo, s bsn n h kb nd kb onsus h owng m o homozygous ompmnon ns ws xmnd n LD nd SD ondons (Fg ) L ono owd wh 9 nd o mun ono wh vs n LD Pns yng h u ngh pomo dvn nsgn (kb) owd wh ~ vs (h ndpndn ns, Fg ) FP:O dvn by kb pomo s owng n LD o, 9, 9 nd vs, spvy h ns yng h kb gmn owd wh, 9 nd vs n LD, spvy ho n LD ondons h kb po dvn ompmnon ns owd sgnny ompd o kb po dvn onsus h su o h kb gmn ws mo hognous Wh on y n (#) ws no sgnny dn om h kb ns h owng m o noh n (#) smbd kb po ompmnon ns wo oh ns showd n nmd (# nd #) owng m phnoyp ompd o kb nd kb hs su suggsd h ong pomo gmns sud n gdu ns n pomo vy Fowng m ws so sd n SD ondons xp h sd ns owd sm o L nd o ono pns wh ound nd 9 vs, spvy h ns hough (kb #9 nd, kb #) showd y owng n SD ondons wh numb bwn nd hs ns w mong h s n LD ondons s w In summy, kb po s sun o ompmn o muon bu upsm squns up o kb ddony owng n LD ondons nd hus nud mpon guoy squn Indpndny, h owng m o nsgn ns xpssng FP:O om kb nd kb pomo O onsus w sd (Fg b) In LD ondons ony md on o owng ompd o o mun (9 vs) ws obsvd o kb po ( vs) wo ndpndn ns mpoyng kb po gmn owd wh nd vs, spvy L nd kb po onos showd sm owng ms ompd o h oh xpmns (Fg ) hus O pomo gmns o kb o sho no sun o ompmn h o muon, whn usd o xpss FP:O I bnds o O pomo s wo posons n hn nd on o owng by I s mny hough von o O nspon (Mzoguh, ; Sw, ; Suz Lopz, ) Insngy on bndng s spns h onsvd gon dnd n hs sudy upsm o kb, d o s onsvd Ds Mo hs gon s xudd n h kb onsu bu nudd n h kb In od o s h non o I wh h ds p o O pomo h kb nd kb ns w ossd o S::I n o mun nd owng m ws xmnd n boh LD nd SD ondons (Fg ) L ono owd wh vs n LD nd vs n SD Wh S::I owd n LD (9) nd SD (), S::I n o mun owd n LD () bu n SD (9) ompd o L h owng m o nsgn

66 HPER ompmnon ns ws vy onssn o h kb onsus ou ns owd wh o vs boh n LD nd SD ondons kb onsus showd owng n LD wh 9, 9 nd n LD nd sghy owng n SD wh, nd vs, spvy hs xpmn nds h S::I s owng v hs O pomo onsus nd h boh h kb O pomo s w s h kb O pomo und h ono o S::I n= Fowng m Long Dy Sho Dy o L Numb L o # #9 # # # # # # #9 #9 kb::fp:o o kb::fp:o o kb::fp:o o b n= Fowng m Long Dy n= Fowng m Long Dy Sho Dy o L Numb o L Numb L o kb #9 kb # kb # po::fp:o o kb # Fgu : Fowng m o O pomo ompmnon ns Mn owng m (o numb) o po::fp:o ns nsomd no L o mun Fowng m ws dmnd n ong dy (bk) o sho dy (gy) ondons L, o nd S::I n o shown s onos, spvy Fowng m o kb, kb nd kb po::fp:o ns () s ndd (n=) Fowng m o kb nd kb po::fp:o nsgn ns n LD (b, n=) Fowng m o kb nd kb po::fp:o ns ossd o S::I n o n LD nd SD (, n=) vus dspyd s mn nd sndd o # nds ndpndn nsgn homozygous n L S::I S::I o # # # # # # #9 kb::fp:o S::I o kb::fp:o S::I o

67 HPER h mrn vs o FP:O nd F w xmnd n h kb, kb nd kb po ompmnon ns o dny dns n mpo mrn guon Sdngs w gown o dys nd mrn om on psnv n o h onsu ws smpd vy h hous n LD nd SD ondons (Fg ) F mrn vs n LD (Fg ) nd SD (Fg ) w hghs n h kb po ompmnon n, oowd by h kb nd ows n h kb n In LD ondons F mrn showd wo pks, on sm monng pk Z nd h mjo vnng pk Z (Fg ) Dns n mrn vs o FP:O nsgn w no s, hus wo boog ps shown (Fg,b) h pn o xpsson o O smbd xpd pn o wd yp O (omp Fg ) In h s boog p h vnng pk (Z) ws mo ponound n h kb n ompd o kb nd kb (Fg ) nd so mrn vs w hgh n h monng (Z) In h sond p h xpsson o FP:O ws hgh n h kb n ompd o kb nd kb Z (Fg b) ddony h xpsson o po::lu (kb nd kb) nodud no o nd mrn vs w xmnd n m ous xpmn o on psnv n o h onsu (Fg d) Ony sm dns n xpsson Z nd Z w obsvd bwn nsgn ns sd onssn wh h ndngs n ompmnon ns h F mrn n SD ondons showd ony on pk h ous bwn Z nd Z9 (Fg ) Dns n o F mrn vs y h owng m o hs ns wh h kb po n hvng hghs vs oowd by h kb nd kb ns h FP:O mrn vs show ows vs n h s h m pons o h SD s xpd (Fg ) h mrn vs s bwn Z nd Z9 n h kb nd kb wh h xpsson sys ow n h kb n hs s onssn wh h s n F vs (Fg ) ound hs m o h dy Dns n F mrn nd owng m w on mo ponound n hs m hn dns n FP:O mrn Possby, FP:O mrn vs h gv s o dns n F mrn oud hv oud n dvopmn hn F mrn vs nd ho w no obsvd n h xpmn (obs, ) o s hs mrn vs o FP:O nsgn nd F n kb nd kb nsgn ns w xmnd n dvopmn m ous ss Z,, nd 9 ong dys (Fg g,h) Dns n F mrn bwn h ns w dy obvous LDs nd go mo ponound wh h ong dy (Fg h, obs, )

68 HPER, FP:O mrn n LD b, FP:O mrn n LD,, FP / PP,,, kb::fp:o #9 kb::fp:o # kb::fp:o # FP / PP,,,, kb::fp:o #9 kb::fp:o # kb::fp:o #9,,,,, 9 Zgb m, 9 Zgb m, F mrn n LD d, LU n LD F / PP,,, kb::fp:o #9 kb::fp:o # kb::fp:o #9 LU/PP,,,, kb::lu #9 kb::lu #,,,,, 9 Zgb m FP:O mrn n SD, 9 Zgb m F mrn n SD FP / PP,,,,, kb::fp:o #9 kb::fp:o # kb::fp:o #9 F / PP kb::fp:o #9 kb::fp:o # kb::fp:o #9,,, 9 Zgb m 9 Zgb m g, FP::O n LD Z h,, F n LD Z FP /PP,,, kb FP::O kb FP::O F /PP,,,,, kb FP:O kb FP:O,,,, 9 Dys, 9 Dys Fgu : nyss o mrn vs n O pomo ompmnon nd po ns mrn vs o FP:O (,b,), F (,g) nd LU (d) nomzd o PP n psnv kb, kb nd kb po::fp:o o po::lu nsgn ns ws xmnd n LD nd SD n mous xpmns vy h hous s ndd Sdngs w gown o n dys on so ddony, mrn vs o FP::O (h) nd F () nomzd o PP n,, nd 9 dy od sdngs Z gown on ps ws xmnd h mn o h hn ps o h sm DN s dspyd wh o bs ndng sndd dvon y s spy dk hous o h dy

69 HPER h FP:O mrn vs nsd ov m s w bu no sgnn dn ws obsvd bwn h ns Indd mrn vs o h FP:O nsgn ppd o b vn ow n h kb n ompd o h kb n Possby F s vd ony n subs o s xpssng O, nd n hs s h kb pomo s ss v hn h kb In summy, O pomo dos no psn sghowd swh bu ws shown o hv mny unon ps dng o pogssv ns n vy wh nsng ngh s psnd by on o owng s w s ospondng F mrn vs h xmnon o O:FP mrn vs d o mbguous sus nd no dn n mrn pn ws dd h mos ky sno s h mpud s ow n sho pomo gmns n hn O pomo ong hn kb s nssy o uy ompmn h o muon Dsson o O pomo by h gn o unon ppoh vs spb unons o submns n shpng mrn xpsson pns o dsb h onbuon o dn pomo ps o O mrn guon h ~kb squn ws dvdd no ou ps o ~bp n ngh (Fg b) h sho mns (bp o +bp om h S), B (9 o ), (9 o 9bp) nd D (bp o 9bp) w usd o h pnos mnm pomo nd usd o dv xpsson o h LU gn h u ngh pomo s w s mn usd o LU whou h pnos mnm pomo w usd s ono ns Emn onns h UR o O nd hus dos no nssy qu h ddon S o h pnos pomo onsus w nodud no o pns ::LU # :pnos::lu # B:pnos::LU # :pnos::lu # D:pnos::LU# D:mn::LU # Fgu : Sp xpsson o hn po gn o unon onsus Lgh msson (LU sgn) n sdngs onnng ~bp gmns o O pomo (D, Fg b) usd o pnos::lu s dd by D m Fo h onsu on psnv n s shown h sp xpsson ond by, B, nd D usd o pnos::lu ws xmnd by mgng gh msson n LD gown sdngs Lgh sgn ws obsvd n h vsuu o oydons nd s wo u vs o onsus sd (Fg ) No sp dn ws obsvd bwn ::LU nd ::pnos:lu Dns n nnsy o h sgn w obsvd bwn nsgn ns (d no shown) nd bwn onsus onsus nd gv song gh sgns wh B nd D showd wk sgns, ndng h hs dn ps o h pomo d o dn vs o mrn poduon n pn onsus w so usd o pnos::us nd sb nsgn ns w sbshd bu no sgn ws dd o onsus sd (d no shown) o onud, 9

70 HPER hough xpsson mpuds w dn ou onsus ond nomon o h xpd sp xpsson pn, ompb o h o ndognous O mrn In od o nvsg h mpo xpsson pns, vy o h pnos::lu onsus ws oowd ov m o dny sms nd dns o ndognous O mrn vs Lgh msson ws msud ov mous xpmn n LD ondons (Fg,,,g) Boh :pnos::lu nd D:pnos::LU showd dun gh msson pn n LD ondons Lgh msson n :pnos::lu ws hgh h bgnnng o h dy nd hd ough sgn ound Z nd hn os un Z (Fg ) D::pnos:LU gh msson dsd upon ghs on nd sd o s om ound Z o h pu Z, sm o xpsson o h ndognous gn (Fg d) h nomzd gh sgn o B:pnos::LU dd no vy ov h ous o dy, wh h sgn o :pnos::lu sowy dsd wh m (Fg,) Bus h gh msson n opoun xpmns ws os o h don m o som ns nd onsus (g B:pnos::LU, d no shown), LU mrn vs w so xmnd hough m ous xpmn o ou onsus wo homozygous ns w sd o h onsu nd on psnv boog p s shown o h (Fg b,d,,h) h xpsson o :pnos::lu mrn dd om h gh sgn obsvd o h sm onsu (Fg,b) yng o xpsson ws onmd by qrpr bu mrn vs mmdy upon ghs on n h monng nd sy ow un Z nd hn om n vnng pk Z h xpsson pn o B:pnos::LU so yd houghou h dy, bu B:pnos::LU mrn vs hd ony % (LU/PP=) o mxmum vs obsvd o ::pnos:lu (LU/PP=), ndng h gmn B on s own ons vy ow o no xpsson (Fg b,d) h mrn vs o :pnos::lu yd mo songy hn suggsd by h umnsn d (Fg,) LU mrn dss om Z o h ough Z nd ss sowy un Z Upon dknss :pnos::lu mrn vs os spy o h n vnng pk Z (Fg ) Ov LU xpsson hd mxmum v o (LU/PP), whh s ow bu s ompb o :pnos::lu vs h downguon n h monng nd upguon ngh ond by gmn so us o ndognous O mrn vs h mrn vs o D:pnos::LU w n gmn wh h ndngs n h opoun umnsn xpmns (Fg g,h) Downguon n h monng wh ough Z nd Z, hn upguon hng pu Z9 o Z dpndng on h n xmnd Insngy n hs onsu h ngh pk dd no domn h dun pn, whh dsmnd om h oh ns nvsgd

71 HPER, :pnos::lu n LD b, :pnos::lu mrn n LD, nomzd gh msson,,, LU/PP,,,, # #,,, 9 Zgb m 9 Zgb m nomzd gh msson,,, B:pnos::LU n LD d LU/PP,,,, B:pnos::LU mrn n LD # #,, 9 Zgb m 9 Zgb m, :pnos::lu n LD, :pnos::lu mrn n LD nomzd gh msson,,, LU/PP,,,, # #, 9 Zgb m, 9 Zgb m nomzd gh msson g,,, D:pnos::LU n LD h LU/PP,,,,, D:pnos::LU mrn n LD # #, 9 Zgb m 9 Zgb m Fgu : mpo xpsson o po gmns usd o pnos::lu n LD ondons op oun xpmn showng nomzd (), B (), (), nd D (g) pnos::lu xpsson n LD ondons (LED) o n dy od sdng gown on ps mrn vs o LU nomzd o PP o,(b), B (d), (), nd D (h) pnos::lu (wo ndpndn ns) n LD ondons h ndd Z n n dy od sdngs gown on so psnd h mn o h hn ps o h sm DN s dspyd wh o bs ndng sndd dvon y s spy hous n h dk,

72 HPER Nomzd LU mrn vs dvn by h ~bp gmns usd o pnos::lu w ompd o ndognous O mrn vs (Fg ) In hs xpmn O mrn ws downgud bwn Z nd Z so h h ough n xpsson xndd un Z so O mrn showd n vnng pu nd pk Z hs ompsons dmonsd h h dn ps o O pomo on dn sps o O mrn pn :pnos::lu (Fg ) shows n downguon n h monng nd h ngh pk Z Howv n hs onsu vnng von bwn Z9 nd Z s kng B:pnos::LU nd :pnos::lu xpsson pns sm (Fg b,) h ompson o hs onsus wh O mrn showd h h downguon o LU n h monng s no n nd ough xpsson s ony hd Z (:pnos::lu) o Z9 (B:pnos::LU), spvy h xpsson o LU nd O ovps Z9 D:pnos::LU hd s ough o xpsson om Z o Z9 (Fg d) nd mrn vs hn os I ws h ony onsu wh xpsson n h vnng (Z nd Z) ws hgh hn obsvd n nomzd O xpsson :pnos::lu # mrn n LD b, B:pnos::LU # mrn n LD nomzd LU / PP O / PP nomzd,,, LU / PP O / PP, 9 Zgb m, 9 Zgb m, :pnos::lu # mrn n LD d, D:pnos::LU # mrn n LD nomzd,,, LU / PP O / PP nomzd,,, LU / PP O / PP,,, 9 Zgb m 9 Zgb m Fgu : ompson o LU mrn dvn by bp O pomo gmns usd o pnos::lu o ndognous O mrn vs Expsson vs o (), B (b), () nd D (d) usd o pnos::lu w ompd o ndognous O mrn vs n n dy od sdngs gown on so n mous xpmns n LD ondons mrn vs o LU nd O dspyd s os o PP oowd by nomzon o h vg o h xpmn (nomzd xpsson) On psnv n s dspyd h mn o h hn ps o h sm DN s dspyd wh o bs ndng sndd dvon y s spy hous n h dk,

73 HPER Expsson vs ond by h pomo gmns w so ompd o po kb::lu ono n (Fg 9) h mrn vs o h pnos::lu onsus w sgnny ow ompd o h u ngh onsu hs su ws suppod by h ndng h kb () po::fp:o nno ompmn h o mun (Fg b) pomo gmn onsus podud vy ow mrn vs n h ondons sd h kb gmn () ws so usd o LU whou h pnos mnm pomo o xmn whh h pomo nodud bs wo ndpndn ns w sd o ::LU (Fg 9b) nd ::pnos:lu (Fg b), spvy h dn onsus podud sm mrn pns nd n ov vs w sm s w hs onms suds showng h h pnos mnm pomo povds nspon s s bu dos no nun nspon vs by uonomousy vng nspon (Hm nd Ky, ; Pun, 99) LU mrn n LD b, ::LU mrn n LD LU/PP kb::lu # :pnos::lu # B:pnos::LU # :pnos::lu # D:pnos::LU # LU/PP,,,, # #,, 9 Zgb m, 9 Zgb m, :pnos::lu mrn n SD d, D:pnos::LU mrn n SD,, # #, # # LU/PP,, LU/PP,,,,,, 9 Zgb m 9 Zgb m Fgu 9: ompson o LU mrn vs dvn by bp O pomo gmns usd o pnos::lu o kb::lu nd kb::lu nd xpsson nyss n SD LU mrn vs o, B, nd D usd o pnos::lu w ompd o po::lu (kb::lu) n LDs () ddony, xpsson o poxm kb O pomo usd o LU (:LU) n LD o wo psnv ns s dspyd (b) mrn vs o :pnos::lu () nd D:pnos::LU (d) w xmnd n SD ondons sdngs w gown on so n h ndd dy ngh o n dys h mn o h hn ps o h sm DN s dspyd wh o bs ndng sndd dvon y s spy hous n h dk s ndognous O s xpssd dny n dn dy ngh ondons mrn o :pnos::lu nd D:pnos::LU ws sd n SD (Fg 9,d) :pnos::lu showd ough Z nd pk Z bu no s ponound s n LD ondons Sm o ndognous O mrn,

74 HPER (Fg ) h LU mrn ws ow Z h bod pu dung h dk pod nd vy ow vs n h gh pod obsvd o O mrn w no podud, bu hs oud b du o ow ov vs n SD (d no shown) h mrn o D:pnos::LU vd n h wo ns sd (Fg 9d) bu h pn ws sm h xpsson ws ow dy upon ghs on (Z) nd syd ow un Z9 nd hn os o h pu bwn Z nd Z hs smbs ndognous O n SD ondons nd woud pobby ow psson o O vy und SDs s LU mrn ws ony psn n h dk hous o h dy (ZZ) whn O pon s dsbzd h dsson o h pomo pomd by usng ~bp gmns o pnos::lu nd nysng h unon n o onmd h dundn o o dn pomo ps h poxm kb () sms o povd h bkgound pn, whh ks h vnng pk, bu shows song ngh pk Emn B povds hyhm bu ow xpsson vs hs s onssn wh h ndng h h no sgnn dns n owng m o o mun yng h kb o kb pomo usons Rgon povds xpsson whn h vnng nd ngh pks ou bu h monng downguon s no n Rgon D on h oh hnd s ny downgud n h monng nd ons n vnng nd ngh pk ddony gmns povd h xpd sp nomon Summzng h ndngs s possb h ddv s o h ndpndn O pomo ps on nspon gn h ndognous O xpsson pn wd yp vs, spy whn syngs o h mns s ssumd Eh o h O pomo gmns povds wo o h h ky guoy us o ndognous O mrn nyss o onsvd guoy mos by gn o unon ppoh suppod ndngs om phyogn shdowng nd smn nyss In od o n h pomo gons h on xpsson pns mmkng ndognous O mrn, h sho onsvd pomo gons w sd (Fg, ) h h sho mos nmd onsvd Ds Mo (DM, 9bp), onsvd Mdd Mo (MM, bp) nd onsvd Poxm Mo (PM, bp) w usd o pnos::lu nd nodud no o (Fg ) In hs ppoh no ony onsvon bu so h smn omposon ws kn no oun o dsgn o h onsus DM hs on Box, on LBS, on Box nd h onsvd DOF bndng ss n 9bp (Fg ) I so ovps wh h bndng gon o I, FKF nd DF o O pomo s dnd by hip (Sw ) h MM mo hs, o smns nvsgd n hs sudy, Box, wo DOF bndng ss nd on P bndng s h PM onsss o h DOF bndng ss, on Box, on Box nd on LBS, bu shows ss onsvon mong sps (Fg ) I shs s smn onn wh DM bu h od nd dsn bwn h mns vs bwn h wo mos h LBS nd Box ound boh n DM nd PM, h n n mpon guoy gon o h pomo ogh wh pssv DOF bndng ss o n os poxmy o h S, spvy Boh LBSs w hngd by s dd mugnss n h

75 HPER onsvd Ds Mo 9bp ( o ): DM:pnos::LU LBS* Box DOF DOF * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * _hn _y _ub N_on _pn B_npus B_o S_o S_on _bum _hn _y _ub N_on _pn B_npus B_o S_o S_on _bum onsvd Mdd Mo bp ( o 9): MM:pnos::LU * * * * * * * * * * _hn _y _ub N_on _pn B_npus B_o S_o S_on _bum * * * * * * * * * * * * * * * * * * * * * * * _hn _y _ub N_on _pn B_npus B_o S_o S_on _bum _hn _y _ub N_on _pn B_npus B_o S_o S_on _bum DOF * * * * * * * * DOF P * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * onsvd Poxm Mo bp ( o ): PM:pnos::LU DOF _hn _y _ub N_on _pn B_npus B_o S_o S_on _bum bp Box* LBS* * * * * * * * * * * * * * _hn _y _ub N_on _pn B_npus B_o S_o S_on _bum Fgu : Squn gnmn psnng h onsvd gons n O pomo gnmn o homoogous gons o O pomo s dspyd n Fg n h ndd sps onsvd Poxm Mo (PM), onsvd Mdd Mo (MM) nd onsvd Ds Mo (DM) w ddud om hs gnmn (Fg ) Lngh nd poson o h Mos s ndd Idnd smns n hn psnd (Box, LBS, Box, DOF, P) Rd ssks nd smns h w hngd by s dd mugnss n h ospondng onsus Bk ssks nd % bs p onsvon bwn n Bssn O pomos DOF DOF DOF

76 HPER spv onsus h muon o h Box n h onx o h who pomo dd no hv n obvous on gn xpsson (d no shown), hus ws mud n h onx o PMbs h bp usons o pnos::lu onsus dsbd pvousy sud n ow gh msson n opoun xpmns (Fg ) h DM, MM nd PM usons o pnos::lu w ho dy nysd by xng mrn o n dy od sdng vy h hous o h h ompson wh po kb::lu showd h hs onsus do on xpsson bu ow hn h u ngh O pomo (Fg ) Insngy h mrn vs podud by PM nd DM w ow bu ompb o hos usd by :pnos::lu wh mn MM xpsson ppd undb whn pod on h sm s (Fg b) LU/PP LU mrn n LD kb LU # DM:pnos::LU # MM:pnos::LU # PM:pnos::LU # b LU/PP,,,,, LU mrn n LD :pnos::lu # DM:pnos::LU # MM:pnos::LU # PM:pnos::LU #,, 9 Zgb m, 9 Zgb m, mrn n LD nomzd xpsson (O/PP o LU/PP),,,,, ONSNS DM:pnos::LU # PM:pnos::LU #,, 9 Zgb m Fgu : h LU mrn vs ond by sho onsvd O pomo mos usd o pnos::lu ompd o kb::lu, :pnos::lu nd ndognous O LU mrn vs o PM, MM nd DM usd o pnos::lu w ompd o mrn vs o po::lu (kb::lu) () nd :pnos::lu (b) n LDs, spvy ddony ndognous O nd LU mrn vs w ompd n PM:pnos::LU nd DM:pnos::LU Vus dspyd s os o PP oowd by nomzon o h vg o h xpmn (nomzd xpsson) Sdngs w gown o n dys on so n LD ondons h mn o h hn ps o h sm DN s dspyd wh o bs ndng sndd dvon y s spy hous n h dk m ous xpmns o wo ndpndn ns w ompd, o xmn h xpsson pn ond by hs sho pomo squns h mrn vs o LU w nomzd gns

77 HPER PP o omp h v xpsson vs nd ddony nomzd o h ds o b b o omp gn xpsson pns mrn vs o DM:pnos::LU nd PM:pnos::LU w vy sm o ndognous O xpsson pn (Fg ) h pn s hsd by song downguon dwn oowd by ough xpsson h mrn oms n vnng pk bwn Z nd Z nd ss gn o xhb ngh pk ound Z nd Z whh s usuy hgh ompd o h vnng pk (Fg,,b,g,h) h xpsson ws ow n h ngh ompd o :pnos::lu (Fg b) h pn o xpsson o MM:pnos::LU ws hsd by ow vs n h gh pod (Z o Z) nd s by bou h od ghs o Z nd Z (Fg,d) h muon o h LBS n h onx o DM (DMbs) nd PM (PMbs) dd no us sgnn dns n xpsson vs o pn (Fg,b,,,) Expsson vs vy bwn ns nd xpmns bu nd ws no obsvd Wh on wd yp PM n xhbd hgh vs ompd o wo DMbs ns sm vs w dd o noh wd yp n (Fg ) ddon ndon h h s no sgnn dn oms om h PMbs ns In hs xpmns on wd yp n showd dud mpud ndng opposng s n boh ns wh h sm smn omposon (Fg ) h pn o xpsson ws so no hngd o PMbs nd DMbs ompd o h spv onos s ndd by ompson o nomzd vus (Fg b,h) Mung h Box n PMbs (PMbsg/box) on h oh hnd sud n sgnny ow mrn vs (Fg g) wh h xpsson pn ws unhngd (Fg h) Evn hough von n xpsson vs ws obsvd o hs ns xpmns suggsd h h Box onbus o n von n ov mrn poduon n hs onx Noby xpsson pns h ndognous O mnnd vn whou h Box nd h LBS hs xpmns show h h Box mgh py n vng unon n guon o O mrn Bu s suggsd bo (Io ), h pn mgh b shpd by h pssos o O, h DFs, nd hus von hough EBoxs s shown bo o h Box, s suggsd n hs sudy, mgh ony hng mpud o xpsson In onuson sho onsvd squn shs n O pomo sun o md n mrn pn h mms ndognous O h mos pomnn smn n hs nyss mns h DOF bndng ss wh no ws ssgnd o h LBS h Box os o h S n O pomo mgh onbu mpud o O mrn n hn

78 HPER, DM:pnos::LU mrn n LD b DM:pnos::LU mrn n LD LU/PP,,,, DM # DM # DMbs # DMbs # nomzd DM # DM # DMbs # DMbs #,,, 9 Zgb m 9 Zgb m,, MM:pnos::LU mrn n LD MM # MM # d,,, MM:pnos::LU mrn n LD MM # MM # LU/PP,, nomzd,,,,,, 9 Zgb m, 9 Zgb m, PM:pnos::LU mrn n LD, PM:pnos::LU mrn n LD LU/PP,,,, PM # PM # PMbs # PMbs # nomzd,,,, PM # PM # PMbs # PMbs #,,, 9 Zgb m, 9 Zgb m g, PM:pnos::LU mrn n LD h, PM:pnos::LU mrn n LD LU/PP,, PM # PM # PMbs/gbox # PMbs/gbox # nomzd,,,, PM # PM # PMbs/gbox # PMbs/gbox #,,, 9 Zgb m, 9 Zgb m Fgu : LU mrn vs n PM, MM nd DM pnos::lu po ns LU mrn vs n n dy od sdng gown n LD o DM::pnos:LU nudng bs muon (,b), MM::pnos:LU (,d), PM::pnos:LU nudng bs muon (,) nd PM::pnos:LU nudng bs/gbox muon (g,h) Expsson ws h nomzd o PP (,,,g) o ddony oowd by nomzon o h vg o h xpmn (nomzd xpsson) (b,d,,h), spvy h mn o h hn ps o h sm DN s dspyd wh o bs ndng sndd dvon y s spy hous n h dk

79 HPER ndm dupon dng o mgn o O usd ppn o guoy DOF bndng s us n h ds O pomo hs sudy shows h h pomo o O s onsvd n h Bss h onsvd gons o O pomo w shown o onn unony mpon guoy squn n hn h pomo o O s ony psn n h Bss nd mos ky vovd h ndm dupon o OL nd O nso Wh h OL xpsson pn mnd sm o OL dupon h O nspon pn hngd h onsvon bwn pomo O nd pol om hssn ws ow (Fg ), whh onmd obsvd hngs n smn omposon (Fg ) Smy onsvon bwn h pomo o hol nd hos o oh subgoup I OL gns n hn nd bum ws ow (Fg b) downsm onsvd gon ws dnd n subgoup I OL gns om hn, bum nd hssn hs gon ovps wh h onsvd Ds Mo (DM) o h O pomo Dd nyss vd h h DOF bndng ss psn n h downsm gon o hol nd bwn on nd h DOF ss n oh O nd OL o nysd (Fg b,) hs gon s vouony onsvd nd psn n h nso o hssn nd Bssn subgoup I OL gns D om hs sudy mps h hs onsvd squn sh mgh b mpon o pop O guon n hn (Fg ), bng nvovd n onbuon o O mrn pn bu no OL/OL pn (Fg ) ddony hs p on s own s sun o on n xpsson pn hghy sm o ndognous O n LU po ssy (Fg ) In onuson hs onsvd ngn gon bwn O nd OL mos ky gus O bu no OL nspon h o o hs squn sh n h downsm gon o h oh OL gn mns unnvsgd Dung h ndm dupon h d o O nd OL h downsm gon bm dupd s w nd on opy ws subsquny od upsm o wh bm O (Fg d) hs mhnsm nodud DOF bndng ss no h upsm guoy gon o O, whh ddony nsd n oh posons o h pomo hus hs dupon no ony owd h unon dvson o h wo gns bu so povdd h s sp n vouon o O nspon pn by nodung n smns h hng n xpsson pn psumby vovd o du ov xpsson o O nd bosh xpsson n h s p o h dy, whh oud boh b mdd by DF nspon os Suh psson ws ssn o h phoopod unon o O h o psson n h vnng by h FKFI modu mgh hv vovd o nhn von und LDs 9

80 HPER Pomo ompson % bum po % % hssn pol kb Bs gn: hn po kb kb kb % +bp b Lous ompson n hn O % hn OL % % hn OL bum O bum OL Bs gn: hssn OL kb bp +kb +kb +kb % % % % % % % MEME mo dnon x d Mod o OL ndm dupon DOF kb + OL nso Lous [ds kb] # o DOF ss O OL OL O OL OL hol +kb ONSNSk dupon DM + ONSNS Fgu : Evouon o O pomo n h Bss mvis psnon o gnmn o O o O nd hol pomo s dspyd () Lgh d oo psns gons o mo hn % bp onsvon n sdng wndow o bp uquos nds UR o O n s nnod n IR mvis psnon o gnmn o subgoup OL gns (kb o +kb) s psnd (b) O, OL nd OL s w s O nd OL ompd o h bs squn hol nds psn o onsvd DOF bndng ss () n h squn onsnsus sho mo dnd by MEME mo dnon oo () n h downsm gon (ds, kb) o gns ndd n b nd h bundn n h spv ds Bu oo nds pon odng gon o O n s nnod n IR Mod o h vouon o OL ndm dupon s dspyd (d) O/OL gn bm dupd nudng ppoxmy kb upsm nd kb downsm squn (up o +kb) h dupon d o h ppn o DOF bndng ss ( ) n h ds pomo (DM) o h nso gn o Bss O ohoogs

81 HPER Dsusson hp O pomo onsvon n h Bss hs sudy hghghs h onsvon o h O pomo bwn dsny d Bssn sps hs ppoh ssums h mpon squns onsvd mong sps, nd hus ony dns sms Evn hough h ov xpsson pn s onsvd, mos ky oh dns n h guon o O vovd Evy O ohoog s pobby gud n sghy dn wy, hus h phyogn shdowng ppoh n ony gv sng pon o uh, mo dd nyss ddony ony dnyng squns h onsvd bwn sps sus n guoy gons h sp o som sps nd nw vouony nvnons bng ovookd On gon mnond o b ony onsvd bwn bdops, ps nd bum ws no nudd n h nyss bu oud b usd o nvsg puv dns n guon n hs sps ompd o ohs mssng hs onsvd pomo p noh mon o hs ppoh s h souon bwn sps In h Bss hs ppoh ws sussu bu d o d ny onsvd gons whn pomos w ompd o hssn (Fg ) hssn s s osy d sps s s bongs o ss goup o h Bss n h od Bsss (Fnzk, ) I ws xpd h O nd hol do no sh ommon pomo gons s h guon s dn Bu s h xpsson o hol smbs OL nd OL xpsson pomo onsvon woud b xpd n hs sps h ng o h phyogn shdowng ppoh s hus md nd vs bwn gns h Phyogn shdowng n ons o h d ppoh o phyogn oopnng s nndd o nd sguoy mos bwn osy d sps (Bo, ), nd s suss dpnds on dn os On son s h odng gons nd sguoy gons vov n dn wys h x poson o smn mgh no b s u o unon s s o n mno d In h hn O pomo o xmp Box s od os o h S nd s gny onsvd bum so onns hs Box bu n upsm oon On o h EBoxs nby vovd no Box, wh h Box n h poxm p bm n EBox hs hngs mnnd h smn omposon bu hngd h posons, whh mgh hv on O guon, bu mks dnon by squn ompson hd noh o nunng h ny o phyogn shdowng s h unon mpon o h squns I guoy modu s dundn hngs n b ompnsd o nd obvous unon onsvon dos no o wh d squn onsvon h hol pomo o xmp s no mo sm o OL nd OL pomos ompd o po (Fg ) bu h nspon guon s ompb (Fg ) hs mons d o h sond ppoh kn, wh smns w dnd dsgdng h d poson bu pung wgh on h ov oun o sng mn

82 HPER Pomo onsvon ws pvousy sudd o oh hn gns nd dng dgs o onsvon w obsvd h pomo o F s ong hn h O pomo bu ompson o pn dy d o d hghy onsvd gons nd F pomo n hus b gdd s ss onsvd (dn, ) ompson o I pomo om hn nd pn hghghd h hs wo sps hv sub vouony dsn o dny onsvd bok n hs gn (Bns, ) h O pomo s vn mo hghy onsvd oss s who ngh bwn hn nd pn ompd o I h pomo o PRR9 on h oh hnd showd sm onsvon bwn hn nd pn ompd o O pomo (Ho, ) h numb o gns nvsgd s pobby oo ow o dw ny onusons bou unon onsvon o hs guoy mhnsms oss h who Bss my h omposon o smns n h O pomo Pvousy ony wo smns n h O pomo, h EBox nd h DOF bndng s w shown o gu O nspon bsd on nyss o h ogn Fs (Imzum, ; Io, ) hs sudy vd by MEME mo dnon h noh my o nspon os, h P my mgh so gu O nspon hs smn ognzd by P Fs ws hghy ovpsnd n h pomos o O ohoogs bu no n h pomos o h oh subgoup I OL gns nvsgd Ins n smn numb n ony mpy guoy unon, whh nds o b onmd n boog xpmns I n ony b spud whh o h pdd P pons n hn (Kosug nd Ohsh, ) mgh b nvovd n h guon o O, bu wo dn suds ound onnon bwn P Fs nd owng m h p sng mun, h p/p/p p mun s w s h jwd n, mun n whh m9 s ovxpssd dng o downguon o P mrn vs, ws shown o ow sgnny n LD ondons (Shomm, ) I pd hs xpmn nd ound h und ou ondons h p/p/p p mun owd wh vs n LD (n=) wh h o ono owd wh vs (n=) h p p mun ws no gnoypd bu showd h obvous mophoogy phnoyp s dsbd (Shomm, ) noh po obsvd sgnn owng phnoyp o h p//// qunup mun (Koym, ), vn hough h dn o ~ vs s mo md hn obsvd by Shomm () onssn wh my obsvons Howv, h dn n owng m msud n dys ws mo ponound mnng h pns dvop sow, whh mgh suggs n nd on numb bong s su o noh dvopmn ddony, ws ound h O s downgud n moy xpmn usng hm P pon h s nspon psso domn nd ws xpssd om n ndub pomo o dny d gs (Koym ) In hs xpmn O ws pssd whn h hm P pon ws ndud Whh P nspon os gu owng m v O nspon guon oud b uh sd by o xmp dsupng P bndng ss n O pomo by s dd mugnss nd sng h on nspon n nsgn ppoh o by nysng

83 HPER h dun O xpsson pn n h vous sng o hgh od muns vb (g p o p) h nyss o smns h puvy gu O nspon ws bodnd o sx mns DOF nd P bndng ss show ovpsnon, wh LBSs nd Boxs dd no Boxs nd EBoxs sgnny mo qun n O ompd o h ndom oun bu oh subgoup I OL gns show sm numbs mon n hs ppoh s k o bonoms ppn, s w s h knowdg o h dny o smns o s h DOF onsnsus o xmp s dsbd s (Ummu, ), bu o DF h pps o b x spy o (Imzum, ) Suh s pobby hod u o mos Fs nd hus h o bndng s s on sy ound bu Fs psn hgh spy o ddon Bss ound h o gon Smy s du o s possb ombnons, spy dn mmbs o h sm my gu h sm gn bu show sghy dn smn pn Funon nyss o h O pomo n hn Funon nyss o h O pomo vd mpon gons o h guon o owng m nd h h u pomo o kb s nssy nd sun o dv O xpsson onsus onnng kb o ss d o ompmn h o muon hs nsgn ppoh usng pomo gmn o O o ggd vson o O DN v EWY onng uss unosn dus h owng m o nsgn o ns yng O usd o pomos ong hn kb ws hn wd yp, so h h onsus d o ovompmnon o h o mun I povd du o pnpon xy whh dns n O mrn vs d o dns n F mrn nd owng m s obsvd In hs nsgn ppoh h gnom ous o O ws no ony sod om s onx n h gnom o hn bu so nsd n bny vo, whh mgh ddony nun h guon o h gn h FP g, whh ws usd o dn FP:O om ndognous O mrn, md possb h posnson modon o h pon n pn mgh so b d I nno b xudd, h FP:O uson pon s mo sb ompd o ndognous O pon nd h hs mgh xpn h y owng Pvousy po::h:o n wh kb pomo ws shown o xpss O mrn hgh ompd o wd yp nd d n (Song, ) Possby guoy squns qud o du O xpsson mssng n hs sudy h nuns o h non nd h downsm squns o O on s mrn guon w so no nvsgd In summy, h ds pomo gmn, whh hs hgh dnsy o smns nd s onsvd (Fg, ), hs n on owng m nd F vs vn hough h us hngs n O xpsson oud no b dnd h O pomo ws ddony nvsgd by uson o gmns o LU djn o h pnos mnm pomo In gn hs xpmns hpd o dn guoy ps o hn O pomo nd suppo h sus om phyogn ompsons h LU po sysm hs

84 HPER hn mons In gn h LU po sysm ws dvopd n hn o nvsg m nspon hngs o ok gud gns h gv obus hyhms xhbng hug dns ov h ous o dy (M, 99) Howv, h sysm s subopm o ow xpsson vs, s ound o O Pushng h ms o h sysm d o unny ho I usd LU mrn msumns o suppo h us vy d I ws no nvsgd so how xpsson bhvs on h mrn v n mpy vo onos (LU nd pnos::lu) hus n mpon ngv ono s s mssng onsus nvsgd n hs sudy xhb hyhm xpsson (Fg, 9), whh oud ho s b n o h sysm On h oh hnd onsus d om om h duny gud gn O nd nno b xudd h ps o h pomo onbu o h dun pn n on o h oh wy, vn mpon smns (g Box) mud nsgn pns yng h mpy vo onos w ny d nd n b ssssd n h uu h xpsson pns o ::LU nd :pnos::lu w vy sm suggsng h h pnos mnm pomo dos no bs bu ons ony h nspon s s Nonhss wo nspon ss psn n :pnos::lu I ws no nvsgd whh S s usd n pn I h O S s usd n boh ::LU nd :pnos::lu h ono s o xud bs by h mnm pomo hs nds o b xmnd n h uu o vd hs ono h subdvson o h O pomo no ou ps ws usu o ssss unons o h pomo p On h oh hnd s o d oss k bwn mns s w s syngs s o pomo ps In h uu dn ps o h pomo suh s nd D whh yd nsng mrn pns ndvduy oud b usd ogh Emn on h oh hnd sms o ony hv wk on xpsson vs nd oud b xudd o hp dn mnm pomo o O Invsgng h xpsson ond by h onsvd sho mos (DM, MM nd PM) d o ddon onusons sho mo sh s sun o gv xpsson h smbs ndognous O I ws so shown h h LBSs dd no onbu o xpsson bu h Box nd LBS muon ombnd w mpon o mpud n hs po sysm hs s o xpmns suggss h sho shs, whh nhd n DOF bndng ss, sun o on n xpsson pn k O Whn h kb, kb nd kb onsus w dsgnd ws un whh hs gons woud onbu o von o psson o nspon h xpmns pomd suggs h DOF bndng ss mgh so s ss o von by mup us o h sm bndng s Fuh xpmns, k mung DOF bndng ss n O pomo, nd o b pomd hs woud so undn h mpon o hs mns n h vouon o O pomo, bu s ompd by h hgh quny wh whh hs mn ous h mod o O pomo vouon mhnsm by whh h dupon o h OL/O nso bough O mrn vs und h ono o DOF bndng ss ws suggsd hs hypohss s uny suppod by d om

85 HPER hn O pomo suds ddony h nun o downsm gons om oh subgoup I OL gns on h xpsson pns n b sd n po ssys nvy po onsus vb n b xpndd by usons o h nd o h DN By suh ppohs h nun o downsm gons o OL o O oud b sd n h onx o dn pomos hs woud so hp o dn h o o hs onsvd sh n h downsm gon o subgoup I OL gns hs sudy povds h s d on dd nyss o O pomo nd mo wok s nssy o uy undsnd h nspon guon o hs mpon owng m guo n vouony ppoh ws kn whh povd powu s O ws h g o n dupon nd sub unonzon vns Mo unon nyss s nssy o omp ou undsndng o h O pomo Fo xmp smns oud b mud n h onx o h pomo o undsnd h on O mrn guon ddony nw nos oud b dnd by YH o so o xmp sp Ps h gu O boog o o nwy dnd Fs n b xmnd by nyss o mun o ovxpsso ns EMS nd hip xpmns n b pomd o onm bndng h O pomo ws so ound o b gud by ds onsvd s In od o nvsg how nspon guon s d by hs p o h pomo phys non wh h S oud n h uu b dnd by sd by usng mhods suh s homosom onmon pu (Dkk, )

86

87 HPER Rguon o O nspon by DFs s novy h os n h Bss O nspon s gud by ss o dundn nspon os d YLIN DN BINDIN WIH ONE FINER (DF) (Imzum, ) Fou mmbs, nmy DF, DF, DF nd DF, o hs submy o DOF Fs w dnd s mjo guos o O by pssng s nspon (Fon, 9) Muons n DFs d o upguon o O s w s F mrn usng h hgh od dr, d, d nd d (d) qudup mun o ow y n boh LD nd SD ondons (Fon, 9) DF bnds o O pomo s wo posons s w s o F pomo (Sw, ; Song, ) ddony, h ns n DOF bndng ss n O pomo s suggsd o b n mpon vouony hng h dsmns om oh subgoup I OL gns (hp ) h m o hs sudy s o xmn subgoup I OL mrn guon n h bsn o DFs n hn nd mk ompsons o oh subgoup I OL gns n bum nd hssn DF nd DF bndng o h hn O pomo oud no b dd n pn Evn hough ou mmbs o h DF my w shown o gu O nspon ony DF ws onmd o physy n wh h O pomo n pn (Sw, ) homn Immunoppon (hip) xpmns w pomd o onm bndng o DF o O pomo usng n pop ggd vson o DF dvn by s own pomo (pdf::xh:df, Sw, ) ddony h bndng o DF o O ous ws sd usng pdf::xh:df onsu nodud no h d mun n sbshd n o pop ggd nd ovxpssd ERMINL FLOWER (FL) pon (S::FL:H), whh ws shown o sso wh F ous ws usd s posv ono (uk, ) Fo hip xpmns h bndng gons w sd by qpr h pms nd pm M ov onsvd poxm (PM) nd ds (DM) bndng ss n h O pomo nd ovp wh pms h gv posv sus n hip xpmns (Fg, Sw, ) h hd pm p ws od n h poxm pomo p o h F pomo (F), shown o b bound by DF (Song, ) Enhmn ws pod s h o o DN n h smp vsus h npu o xpmns shown Bndng o FL:H o F pomo ws sd o onm h h hip xpmns wokd hny nd ws sussuy dd (Fg,d) No o ony md nhmn ompd o pm s F ws obsvd o FL on O pomo (Fg,d), whh s n gmn wh h ndng h O ous s nh FL (uk,, MPIPZ gnom bows) no HK mhyon g (Zhng, )

88 HPER No nhmn ws dd o xh:df o h pms sd ompd o ngv ono (o) nd no nbody ono (Fg ), ndng no bndng o DF o h O o h F pomo oud b dd () M () kb kb + DM MM PM ONSNS b M 9 pdf::xh::df () d # # #, hip pm, hip pm M, hip pm F, H (), H () H () Smp/Inpu,, Smp/Inpu,, Smp/Inpu,,,,, o pdf::h:df S::FL:H, o pdf::h:df S::FL:H, o pdf::h:df S::FL:H d hip pm H () hip pm M H (),, hip pm F H () Smp/Inpu Smp/Inpu Smp/Inpu,,, d pdf::h:df S::FL:H d d pdf::h:df S::FL:H d, d pdf::h:df S::FL:H d Fgu : homn Immunoppon xpmns dmons no bndng o H:DF nd H:DF o h O nd h F pomo Shm psnon o pm oon n O ous () wh pm oon, () nd () nd mpon numb (Sw, ) Lgh d oo vsuzs DN onsvon ompd o h bum O pomo h ppoxm posons o onsvd Poxm Mo (PM), onsvd Mdd Mo (MM) nd onsvd Ds Mo (DM) s dsbd n Fg ndd Wsn bo (b) o nu xs om sdngs xpssng pdf::xh:df usd o hip xpmns h ndpndn nsgn ns (#, # nd #) n h d mun w sd usng αh nbody, d () mun svd s ngv ono M=mk, sz ndon n kd hip xpmn () wh pdf::xh:df nbody d smp (αh) s ompd o no nbody ono () o nsgn n (pdf::h:df), ngv ono (o) nd posv ono o F (S::FL:H) Bndng s hkd o wo pms n h O pomo ( nd M, ) s w s on n h F pomo (F, Song, ) Rpsnv xpmn o wo boog ps s dspyd Ro o Smp o npu s shown wh o bs psnng h sndd dvon o h hn ps om h sm qpr hip xpmn pomd wh pdf::xh:df (#) (d) n ds n, bu nd d s ngv ono ddony pdf::xh:df ns w d o s o bndng o DF o h O nd F pomo h onsu ws nsomd no d qudup mun nd sud h y owng phnoyp o h mun (d no shown) h ndpndn nsgn ns sd

89 HPER showd sm vs o DF pon n nu xs usd o hip (Fg b) wo bnds w dd n Wsn bo nyss ound kd wh no bnd ws dd o h d ngv ono h sz o h dd pons s n gmn wh pvous xpmns nd wo bnds n b xpnd by pvous ndng h DF pon s pobby g o phosphoyon (Smon, 9) Rpodub sus w obsvd o hip n h pdf::h:df ns sd nd ony on psnv n nd xpmn s shown (Fg d): No nhmn ws obsvd o hip o xh::df o h O o h F pomo ompd o no nbody nd d ngv ono, spvy In summy bndng o DF nd DF o O nd F o oud no b dd n h ondons sd DF nspon os gu O bu no OL nd OL n hn DFs mpon nspon guos o O, bu O mrn guon vovd n h Bss nd ns o DOF bndng ss ws suggsd s mjo hng dsmnng h O pomo om hos o s os homoogs, OL nd OL (hp ) Hn h nyss ws xpndd o s h nun o DOFs on h oh subgoup I OL gns n hn h xpsson o OL nd OL n h d mun ws sd n LD nd SD ondons (Fg ) LD d s ony vb om ZZ In LD ondons O xpsson s hgh n h d mun ompd o o ono (Fg ) o mpons, s shown pvousy (Fon, 9) By ons h xpsson o OL (Fg ) nd OL (Fg ) dd no hng n h qudup mun In SD ondons O xpsson ws hgh n h d mun ompd o o (Fg b, Fon, 9) ddony hngs n mrn pn w obsvd n h d mun ompd o o O mrn n o n SD s vy ow bwn Z nd Z nd ony xpssd n h dk hous o h dy (Z9Z) h mrn vs n h d on h oh hnd dspyd hghs xpsson Z nd Z nd ow xpsson oh mpons (Z Z) ompb o monng pks obsvd o OL nd OL s n LD no dns bwn o nd d w obsvd o OL nd OL xpsson n SD Z9 n SD (Fg d) xpsson o OL n o s hgh ompd o Z hs ws no obsvd o oh xpmns n SD nd mgh psn hn pobm wh hs p h xpsson nyss psnd songy suggss h OL nd OL gns no und nspon ono o DF, DF, DF o DF 9

90 HPER O mrn n LD b, O mrn n SD o d, o d O/PP O/PP,, 9 Zgb m OL mrn n LD d, 9 Zgb m OL mrn n SD o d o d OL/PP OL/PP 9 Zgb m OL mrn n LD, 9 Zgb m OL mrn n SD OL/PP o d OL/PP,,,, o d,, 9 Zgb m, 9 Zgb m Fgu : Expsson o O bu no OL nd OL s d n h d qudup mun n LD nd SD Expsson o O (,b), OL (,d) nd OL (,) nomzd o PP n n dy od sdng nnd n LD (,,) o SD (b,d,) ondons h mn o h hn ps o h sm DN s dspyd wh o bs ndng sndd dvon LD d s dspyd o ZZ, SD d o ZZ Wh s nd gh pods wh y s nd dk pods Lgh downgus O mrn n h monng n h bsn o DF nspon os O mrn vs vd n h d mun ompd o wd yp (Fg, Fon, 9) En downguon o O mrn upon ghs on s mpd, whh onbus songy o h y owng phnoyp o h d mun hus h guon o O mrn by gh

91 HPER h bgnnng o h dy ws xmnd O mrn ws sd n boh o nd d n LD nd dk ondons On h dy o hvs pns w nsd o dk bo ghs w swhd on nd mrn vs w ompd o gh ono h O mrn vs w hgh n h d mun ompd o wd yp mpons (Fg ) h sh o dknss dd no hng O mrn n o smps ompd o gh ono O mrn ws downgud ny nd syd ow un Z n o sgh upguon n LD ompd o dk ws obsvd Z In h d mun O mrn vs w dn n gh nd dk d smps O xpsson ws ound o b hgh n h dk n mpons obsvd ompd o LD ono (Fg ) hs xpmn suggss h xposu o gh downgus O mrn n h monng n h d mun O mrn b, O mrn o O/PP o Lgh o Dk d Lgh d Dk O/PP,,, Wh Lgh Dk Rd Lgh Bu Lgh,,, 9 Zgb m O mrn d d,, Zgb m O mrn dg,,, O/PP, O/PP,,,,, Wh Lgh Dk Rd Lgh Bu Lgh Zgb m,, Wh Lgh Dk Rd Lgh Bu Lgh Zgb m Fgu : Wh, d nd bu gh supss O mrn n d nd dg muns n h monng ) O mrn o n dy od sdng n LD ondons n o nd d Pns w h kp n Lgh (LD) o nsd o dknss bo Z E o wh gh, dknss, d gh nd bu gh (LED) on O mrn n o (b), d () nd dg (dg) (d) ws sd h mn o h hn ps o h sm DN s dspyd wh o bs ndng sndd dvon y s spy dk hous o h dy Lgh shps h xpsson pns o OL nd OL s w s hol n h monng h o gh on O mrn s db n h d mun bu no n o Evn hough OL nd OL no gud by DFs boh mgh s sh h dk phnoyp obsvd o s hs hypohss h o gh vsus dknss on mrn vs o subgoup I OL gns

92 HPER n h monng ws xmnd I h downguon o mrn vs by gh n h monng s onsvd bwn subgoup I OL gns shoud b possb o d n n wd yp sdngs s OL nd OL no gud by h DFs, whh msk hs n O ho, OL nd OL mrn vs w dmnd n dk sh xpmn (Fg,b) Boh gns w xpssd dny n h dk ompd o gh h bgnnng o h dy In boh LD nd SD ondons h xpsson o OL nd OL ws hgh Z ompd o Z (Fg ) In h dk shd smps n boh o nd d h mrn xpsson o OL nd OL hd pk Z nsd o Z (Fg,b) hs nds h gh mdd downguon o mrn vs n h monng ous o h subgoup I OL gns n hn Expsson pns o subgoup I OL gns onsvd n h Bss I ws ho o ns whh h downguon o mrn vs n h monng s onsvd u o h nspon guon Hn, h xpsson o bum O nd bum OL ws sd n dk sh xpmns boh n LD nd SD ondons In hs xpmn h o gh on O mrn ws vsd ompd o hn gns sd (Fg,d): h xpsson vs o O mrn n LD nd SD ondons w ow n h dk smps ompd o gh smps Ony on boog p o h xpmn ws pomd, so mns o b sd whh hs ndng n b onmd OL xpsson xhbd spons o dk sh Wh OL xpsson ws dsng om Z o Z n h gh n ns n xpsson ws obsvd n h dk d smp (Fg ) h ws vn song n SD ondons (Fg ) Z h dn bwn gh nd dk d smp ppd o b ~od h o gh on mrn vs o h ony subgoup I OL gn n hssn, hol ws so sd von o hol mrn vs n dk vsus gh d smps ws obsvd n sdngs gown n LD ondons (Fg g) In ons o ndngs n hn nd bum OL gn xpsson ws hgh Z ompd o Z n h dk d smps n LD In SD on h oh hnd xpsson o hol (Fg h) ws vy sm o OL nd OL s w s OL wh hgh mrn vs obsvd bwn dk nd gh boh Z nd Z hs xpmns suggs h gh dwn nd y monng psss subgoup I OL gns o shp h monng pk xpsson obsvd ddony hs guon s onsvd n h subgoup I OL gns n hn, bum nd hssn

93 HPER OL mrn b OL mrn OL/PP o Lgh o Dk d Lgh d Dk OL/PP o Lgh o Dk d Lgh d Dk 9 Zgb m 9 Zgb m, O mrn LD d O mrn SD O/IN,, Lgh Dk O/IN Lgh Dk,,, Zgb m OL mrn LD, Zgb m OL mrn SD OL/IN,,,, Lgh Dk OL/IN,,,, Lgh Dk,, g,, Zgb m ho mrn LD h, Zgb m ho mrn SD hol/in,, Lgh Dk hol/in Lgh Dk,, Zgb m Zgb m Fgu : Lgh psson o mrn s onsvd n subgoup OL gns om hn, bum nd hssn Expsson OL () nd OL (b) xpsson n LD gown sdngs h kp n wh gh o shd o dk n o nd d mun bkgound h mn o h hn ps o h sm DN nomzd o PP s dspyd wh o bs ndng sndd dvon O (,d), OL (,) nd hol (g,h) xpsson n LD (,,g) nd SD (d,,h) s w s h spv shs o dk bum nd hssn xpmns w pomd on; xpsson s nomzd o IN gn Eo bs show sndd dvon om s h hn ps o h sm DN xpmns w pomd on so y s spy dk hous o h dy

94 HPER h mrn o O, OL nd OL s hghy unsb subgoup I OL nsp vs sd gud by gh n h monng (xp O) I s possb h hs s no ssod wh nspon guon bu su o mrn sby o xmn possb o mrn sby h nun o h hm ompound odypn on hn O, OL nd OL mrn ws hkd odypn s n dnosn dv h nopoon o hs Doxydnosn by RN Po II no n vy synhszd mrn ds o h mnon o nspon By hs mhnsm odypn boks mrn synhss vsby n s d wh h ompound (Sv, 99) nd ws pvousy shown o wok n hn (uéz,, Yk, ), O mrn sby ssy b, OL mrn sby ssy O / PP,,,, Mok odypn OL / PP,,,,,, Mok odypn,, Mnus mn Mnus mn, OL mrn sby ssy d onnon o PP mrn OL / PP,,,, Mok odypn PP mrn Mok odypn, Mnus mn Mnus mn Fgu : mrn sby ssy o hn subgoup I OL gns nspon ws bokd by mn wh odypn n dy od hn o sdngs Z bo ghs on mrn vs o O (), OL (b) nd OL () w dmnd,, nd mn mn DN onnons w nomzd o PP onnons o PP (d) nomzd o n by sndd uv s shown s ngv ono h mn o h hn ps o h sm DN s dspyd wh o bs ndng sndd dvon In hs xpmn h houskpng gn PP mrn vs ws usd s ngv ono (Fg d) PP vs w nomzd gns n by sndd uv (duon ss o hghy onnd DN smp gnd om h sm m) nd pod o xud mjo s on

95 HPER h sby o hs mrn sps In smps (odypn nd mok d) h onnon o PP vd n h ng o wo od (bwn wo nd ou by uns; Fg d) h bggs dn (wood) ws xhbd mn o mn hus PP mgh hv vy sb mrn (uéz, ) nd s good ono o hs xpmn O, OL nd OL mrn vs w dmnd (Fg ) nd nomzd gns PP mrn nyss o h subgoup I OL mrn vs vd h h mrn sps unsb h nomzon showd bwn nd od duons n mrn dy mn mn mos o h mrn ws dgdd hs xpmn ws pomd on dy sng Z n h dk nsps w pvousy ssumd o b unsb whn psnng h o ss hn mn (uéz, ) hs mpon o O bok o nspon by DF, DF, DF nd DF ws pdd by Fon (9) mnng h mrn vs o O woud dy b dud ov m h o h odypn mn ws muh mo dm, vng h possby h O mrn s dgdd quky whou onnuous d novo synhss In gn h sm s u o OL nd OL s dsbd n hp h moun o OL nd OL mrn hd s hghs vs ound Z nd dsd n h s hous o dy h nsby o h mrn sps suggsd h h downguon o O mrn n h monng oud b sbshd by bokng nspon o O wh h sow dn o OL nd OL mrn ky nvovs v nspon, ohws mrn vs woud ds s hn obsvd n Fg Rd nd bu gh py sponsb o downgung O mrn n h monng n h bsn o DF nspon os Downguon o O mrn n d ws mdd by wh gh I ws hus xmnd whh gh qus md h nspon psson o O h bgnnng o h dy Pns w gown n LD nd h shd o dk, bu gh, d gh o kp n wh gh h mrn vs o O dd no hng n o n gh gms sd, onmng obsvons n wh gh (Fg b) In h d mun O mrn vs w mo hn wo od hgh n h dk shd sdngs ompd o gh shd sdngs Z nd Z (Fg ) Boh d gh nd bu gh mn sud n nmd phnoyps: n boh ondons O mrn vs w hgh ompd o wh gh bu ow ompd o dk d smps No dn bwn bu nd d gh ws obsvd I s nvovd n h bu gh mdd dgdon o DFs n h vnng n ong dy ondons I s hn possb h I gus gh mdd O mrn guon oh ms o h dy I ws hus sd whh h g muon nuns O psson n h monng In h d g (dg) qunup mun O xpsson s hgh ompd o o bu ow ompd o d on (Fon, 9) Hgh vs o O mrn n dk d sdngs ompd o gh d sdngs ws obsvd n h d g qunup mun, ompb o

96 HPER h d mun (Fg d) so xposu o d nd bu gh d o nmd phnoyps n h qunup mun h g mun ws no sd on s own s s known o xhb vy ow O mrn vs dy (Fon, 9; SuzLopz, ) hus gh downguon o O xpsson n h d mun ws mdd by boh bu nd d gh nd ws ndpndn o I vy o d phyb9 d phyb9 b Fowng m LD,, O mrn o L numb O/PP,,,, o Lgh o Dk phyb9 Lgh phyb9 Dk, o d phyb9 d phyb9, Zgb m d,, O mrn,, O mrn,,, O/PP,, O/PP,,,, d Lgh d Dk dphyb9 Lgh dphyb9 Dk,,, d Lgh d Dk dphyb9 Lgh dphyb9 Dk, Zgb m, Zgb m Fgu 9: h d gh phoopo phyb s no sponsb o gh dpndn O mrn psson n h monng n h d mun Pu o o, d, phyb9 nd dphyb9 pns gown n LD ondons o ~dys () Mn owng m (b) n LD ondons s o numb (n=, xp dphyb9 n=9), o bs dspy sndd o mrn vs o O nomzd o PP n n dy od sdng gown n LD o o nd phyb9 () s w s d nd dphyb9 (d,) n gh nd dk h mn o h hn ps o h sm DN s dspyd wh o bs ndng sndd dvon Eo bs show sndd dvon om s h hn ps o h sm DN y s spy dk hous o h dy phyb s h mjo phoopo n d gh nd ws dy suggsd o b nvovd n O mrn guon (ukmn, 99; dán nd hoy, ; Robson, 99) o dny o o d gh n O mrn guon n h monng nd upsm sgnng h phyb9 nu muon

97 HPER ws nodud no h d (Rd, 99) Boh phyb9 nd d mun pns xhb y owng phnoyps whn ompd o o (Fg 9,b) h owng m o h dphyb9 mun ws sd n LD ondons h s on owng m w ound o b ddv s h dphyb9 mun owd ~ vs ompd o h d qudup mun (~ vs) nd phyb9 mun (~ vs), spvy (Fg 9b) O xpsson ws sd n h phyb9 mun ompd o o hs xpmn showd ow O vs Z n phyb9 mun bu no obvous dns bwn dk nd wh gh (Fg 9) sng h d mun vsus dphyb d o onng sus In h s xpmn no dn bwn gnoyps ws obsvd n dk o wh gh (Fg 9d) h sond xpmn showd sghy ow O mrn vs n h dphyb mun ompd o d ono sh o dknss (Fg 9) O mrn ws downgud n h monng n h dphyb mun ompd o d n boh xpmns h d gh phoopo PhyB s mos ky ho no soy sponsb o h downguon o O mrn upon xposu o wh gh n h monng ndpndn o h DFs Dsusson hp hip o DF nd DF o O nd F ous dd no d bndng Unxpdy h hip xpmns whh show bndng o DF o h O nd F o oud no b pd (Sw, ; Song, ) h xpmns shown oow osy h mhod o h pubshd xpmn ommunon wh h Imzum b (Fnzsk uk, MPIPZ, oogn, pson ommunon) In o h dn pooos w sd (m nd mhods), whh wokd o h posv ono (S::FL:H o Hson, no shown) bu d o show nhmn o DF nd DF o O ous Dn H nbods w usd o pom h mmunoppon sp (m nd mhods) h nv DF nbody (Fon, 9) ws so sd nd no nhmn ws ound (d no shown) h oowng gn hn dus w nound n h hip xpmns psnd: h quy o nbods (g nv DF nbody) s w s o omm bhs vs whh n nun h mmunoppon sp dng o hgh bkgound vs h puy nd ow mouns o DN dmnd by qpr n d o hn os h d o vby nd pvn don o nhmn hs pobms n b sovd by usng g h n b mo by mmunoppd FP uson o DF dvn by s nv pomo (pdf::fp:df) ws onsud nd nsomd n h o bkgound hs onsu s h sg nd n b usd o hip xpmns usng FP nbody, whh hs povn mo v o hip wh oh Fs (gs, ; Kumnn, ) h DFs mny xpssd n h vsuu wh hy pss O xpsson (Fon, 9) hus h xpsson domns o DF nd DF pons und h nv pomos mny hs ssu hs mgh du nhmn by hip s DN om oh yps s

98 HPER ovpsnd bu dos no gv hip sgn, hs ws dy suggsd o us pobms n pomng hip o O pon on F ous (Fnzsk uk nd Lyngu Lu, MPIPZ, oogn, pson ommunon) Enhmn o g s by Fuosnvd song (FS, IyPsuzz nd Bny, ) oud d o don o DF bndng o O ous ddony uu hn dvns mgh d o s dnon o n vvo bndng o pons o DN h xpmns psnd suggs h DF nd DF do no bnd o h O o h F pomo n pn By ons d bndng o DF o h O pomo ws dd by hip xpmns nd so n EMS suds nd nsn LU von ssys (Imzum, ; Sw, ) h ndng o n ns n DOF bndng ss dung h vouon o h O pomo nd s onsvon n h Bss my (hp ) ddony suppos d bndng o DFs o O ous h nv possby h DF guon o O nd F s nd oud b sd by snng d gs o DFs by hipsq, nd usng hs s posv onos n h nyss o O Rguon o mrn vs by DFs s no onsvd bwn subgoup I OL gns OL nd OL n ons o O w no msgud n h d mun ompd o o wd yp hs ws unxpd s onsvd DOF bndng ss w ound downsm n os poxmy o h odng gons o boh gns (Fg ) Ony wo ondons (LD nd SD) w sd nd s possb h h DFs gu OL nd OL n oh ondons suh s hgh o ow mpu ddony no DF ovxpsson n ws sd Moov h nun o oh DOF nspon os on OL nd OL mrn vs oud b sd s h my onsss o mmbs (Fon, 9; Yngsw, ) o s onsvon o O guon by DFs n bum nw ms nd o b d bum DF, DF, DF nd DF ohoogs w dnd by BLS sh (d no shown) nd oud b g usng n RN ppoh, pn nsomon ssy s dvopd o hs sps In hssn on h oh hnd pn nsomon pooo s vb (s, ) hus n RN ppoh knokng down DFs oud b sbshd n hssn dnon o DF homoogs n h ny pubshd gnom squn (hng, ) kn ogh xpmns suggs h guon o O nspon by DFs n h Bss s mhnsm h hs vovd whn h my nd s sp o O mong OL I gns Opposng ndngs om om Poo: SO ws shown o b downgud s su o ovxpsson o DF homoog (SDF), suggsng h h guon o subgoup I OL by DF nspon os mgh b onsvd n mny pn ms (Koosmn, ) I s so possb h oh mmbs o h DOF nspon o my gu gns suh s OL nd OL nd h guoy mhnsm hngd dung vouon nvy, h guon o O nd SO by DFs oud b h su o onvgn vouon

99 HPER Lgh downguon o subgoup I OL gns s onsvd nd dpnds on gh quy h downguon o O nspon n h s hous o h dy s u o s unon s dy ngh snso (Fon, 9) hs downguon s mpd n h d mun ns o d pns o dknss dwn dnd DFndpndn mhnsm h psss O xpsson hs phnoyp ws no obsvd n h w ono, mos ky bus s py dundn wh h vy o DF Fs (Fon, 9) h psson o O mrn ws dnd n h hgh od d mun bu ws y dd n wd yp pns o h oh subgoup I OL gns hs guon ws no ony ound n hn bu so n bum nd hssn Lgh psson o O mrn n h monng ws no dd n w bum sdngs, pobby bus s onsvon o O mpo nspon pn suggss, DFs pss O mrn ndpndny o gh (hp nd ) Loss o unon muns o DFs n bum oud onm hs hypohss (s bov) O, OL nd OL mrn ws obsvd o b unsb whn ompd o PP Hn whou nspon, mrn vs vy pdy hs xpmn ws ony pomd h bgnnng o h dy nd sby kns oud vy w hng ov h ous o dy Fuh xpmns oud b pomd o hk o hs possby Nonhss hs xpmns suggs h subgoup I OL gns vy nsbd n h monng so h mrn vs do no pdy nd h gh psss nspon sung n duon o mrn vs s obsvd h dk sh phnoyp ws ddony sd n wo gh ondons (d nd bu) nd nmd phnoyps w obsvd ompd o wh gh n h d mun s w s h dg qunup mun hus boh d nd bu gh nd possby gh o oh wvnghs onbus o hs guon n so unnvsgd wy Rd nd Bu gh xpmns w pomd wh LEDs hs LEDs povd ss gh whn ompd o wh gh povdd by uosn ubs nd bubs Hn, h o gh nnsy shoud b sd n dn wh gh nnss n h uu h o h d gh po phyb ws sd n h onx o h phyb 9 mun Ony md o no dns w obsvd bwn d nd dphyb qunup mun n wh gh h vs o O n h phyb9 mun w sghy hngd bu whou on h gh phnoyp h sm ws u o h ompson o d nd dphyb h mous n dn dy ngh gms s nssy o xmn h o dphyb9 muon on O mrn n h ondons sd Nonhss h gh downguon s no mdd by phyb on I s s possb h h d gh phoopos dundny nd h oh d gh snsng phyohoms (Phy, PhyD, PhyE) py n mpon o n h guon o hs phwy (Bsubmnn, ; Fnkn, ) h o oh gh ondons on h phnoyp n b sd n dn phoopo muns suh s y nd y o bu gh 9

100 HPER h unon o h dk sh phnoyp n nu s unknown bu s o physoog mpon o pns o kp k o h m o dy by h dn ok (Dodd, ) Pns o xmp b o k dusk nd dwn (Edwds, ) hus ok gns suh s I xhb sh n pk xpsson bwn LD nd SD (Fow, 999) sm phnoyp ws obsvd o OL, OL s w s hol (Fg ) s h xpsson os n SD ompd o LD In gmn wh hs ndng mrn ws so dud n h monng n SD dng o sh n pk m h sus psnd suggs h gh s n mpon sgn o gung OL gns nvsgd In OL nd OL ohoogs gh mgh b usd o k dwn n h monng nd downgu h mrn upon hs sgn In gmn wh hs ovxpsson o OL s h dn ok n gh un dpndn mnn (Ldg, ) hs suggss h OL s mpd n o gud by h dn ok Myb hs gn hs o n h gh npu o h dn ok Expsson o OL ws sd n DD nd LL nd h gn s msgud n boh ondons (Ldg, ) h pk o xpsson s shd n DD by ou hous o Z nd xpsson sys hgh n onsn dknss houghou h dy, whh s n gmn wh h sus psnd h (Fg ) OL xpsson s hgh n DD ompd o LD ound h s dwn bu hn nus n DD nd oud no b dd n h oowng dusk (Z, Ldg, ) hs suggsd dn guon o OL nd OL n DD, so h OL xpsson s psn und hs ondons wh OL xpsson s bsn In summy, dsbng h so un unons o OL nd OL w hp o ssgn o o hs dwn kng mhnsm (Km, ; Ldg, ) In O ohoogs h mnng o gh gud downguon s no obvous s h phnoyp s mskd by DF nspon os n wd yp I n b spud h hs phnoyp psns n vouony nn mhnsm whh gud h nso o subgoup I OL gns n h Bss nd om nd ws no os n vouon o O Rpsson o O mrn n h monng by gh s oo ky o O o pom s phoopod snsng modu Hn h guon o O mrn by DFs vovd s n ddon y o nsu O mrn dos no ovp wh gh n h monng 9

101 ONLUSIONS ND PERSPEIVES ONLUSIONS ND PERSPEIVES O s h mjo vo o F n h phoopod owng phwy n hn In hs sudy sysm vouony ppoh ws kn o nvsg h vouon o boh h unon nd h nspon guon o O n ompson o s oss homoogs n hn OL nd OL h vouony hsoy o hs h gns s nkd o h gnom oon O nd OL od n ndm on homosom wh OL s sng gn on homosom hs wo homosom gons os om h s who gnom dupon dd n hn (α) Phyogn nyss songy suggss h h ndm dupon dng o oun o O nd OL oud h α onsvon o O unon ws hkd by ompmnon o o mun by bum O ohoog bum, n obg ong dy pn s mmb o h nn honm ng n h Bss my, whh sp om h o Bss y n h vouon o h my hs xpmns nd h O unon nd s o n phoopod owng onsvd n h who Bss my Insghs no nspon guon o O h nspon pn o O s unqu nd mpon o s unon s owng m guo Ky us o O mrn guon n LD k pd downguon n h monng nd pk vs o xpsson n vnng nd ngh w dnd n xpsson nyss o O h os homoogs o O n hn nmy OL nd OL bu so OL om bum dny xpssd h mrn vs hgh ompd o O nd om monng pk, whh onds puv unon s dy ngh snso h onsvon o O xpsson pn s d by h onsvon o guoy squns n h pomo o O n Bssn sps nvsgd nudng h bs ng honm h pomo o O s py dundn nd onsss o guoy gons up o kb upsm om h S mpon o mdng u owng spons h hghs onsvd smns dnd n Bssn O pomos DOF bndng ss hs DOF bndng ss w ound o b sgnny nhd n h pomo o O ompd o h pomos o s os pogs o o ndom squns wh dn bs omposon ddony hy unon n onvyng O mrn xpsson pn s ps o onsvd guoy modus, puvy shpng h mpo pn o O ndpndny o oh guoy gons In summy h ns n DOF bndng ss h O ous shps h xpsson o O o unon s ong dy snso In h uu possb du unon o DOF bndng ss n psson nd von o O nspon oud b xmnd 9

102 ONLUSIONS ND PERSPEIVES I h unon o DFs s mpd O xpsson shs ddon us wh OL nd OL In h hgh od d mun O xpsson vs hgh n mpons bu spy monng downguon s mpd, onssn wh h hgh xpsson vs o h DF gns n h monng ddony gh downgus O mrn xusvy n h d mun bu no n w OL nd OL, whh no gud by DFs, sh hs sp, ndng h mgh b nn nd shd bwn pogs h guon o O by DFs hus pps o b n ddon y o guon h vovd on op o xsng nd onsvd guoy mhnsms, whh suggss pn o guon o h s ommon nso o h gns wo sss o smns w pvousy shown o b nvovd n guon o O mrn n hn, h DOF bndng s nd h EBox (Imzum, ; Io, ; Sw, ) hs sudy ddony suggss uh sss o smns o b nvovd n O mrn guon nmy P bndng ss nd Boxs uu go s o dny h Fs ssod wh hs puv guoy gons Fuhmo nspon guon s no mdd by sng Fs bu by ompxs ssod o homn I ws shown dy h DF nd s nos FKF nd I ooupy h sm posons on h O ous (Sw, ) Mo xpmns ndd no ony o dny non o smns n O mrn guon bu so how hs nons mdd on h pon v h npy bwn guoy os s psumby muh mo ompx nd hus gos byond h sop o hs sudy mod o O pomo vouon mod o h vouon o h O pomo ws poposd wh ous o how DOF bndng ss ppd s nov guos o O nspon h ndm dupon h d o O nd OL sud n onsvd DF bndng ss h w psn n h downsm squn o h nso o pp dsy upsm o O omng onsvd us d o s onsvd Ds Mo (DM) I n b mgnd h hs DM svd s bupn o h smn hngs h oud os o h S dng o sm F bndng s omposon h nso o O hus bm sndwhd bwn DOF uss h ndm dupon h dd nyss o upsm guoy gons so vd h h pomo o O s ky n nsgn pns, dng o ovompmnon phnoyps obsvd pvousy nd so n hs sudy (Song, ) In h uu n non o upsm nd downsm guoy gons oud b xmnd, whh mgh nd o o boh n h guon o O In gn h phys nons o homn h O ous bwn dsn guoy mos mgh v nw guoy gons O s mod o pomo vouon O psns sub mod o sudyng h vouon o pomo s s vouony sp om OL n b dd h α WD bu bo h sp o h honm ng om h o 9

103 ONLUSIONS ND PERSPEIVES Bss ddony OL n b ssumd o psn h nn onsvd s o xpsson wh O s h dvd nov s In uu xpmns h dns n guon whh w od wh hngs n smn omposon n hs sudy oud b sd n pomo po suds o o vn onsu h vouony sps dng o sbshmn o h pomo o O Inpy o O Funon nd nspon In ons o pvous pos OL nd OL n p h unon o O s dsovd by ovxpsson om h SU pomo Howv h unon s wk s boh o uy ompmn h o mun whn xpssd om h O pomo h unons o OL nd OL no d n hn y, bu h gns s py unony dundn Pobby h mmbs gu nspon nd h dsnon s usd by w dns n mno d pobby dng o hngs n posnson modon s w s non pns h ndng h OL nd OL n uy ompmn O unon whn bng hghy xpssd n h vsuu mps h hgh vs o OL nd OL n ovom pon dns whn ompd o O ddony n b onudd h guoy dns do no ony mpo xpsson bu nvby mus sp xpsson, bus hgh xpsson o OL nd OL s obsvd n w woud unvodby d o y owng psn n h xpsson domn o O In summy h hgh xpsson vs o OL nd OL pobby su om g sp xpsson domn ompd o O hus dmnng mhnsms o mpo xpsson h mhnsm mdng sp xpsson o h gns hs o b nvsgd h s ommon ns gn o O h subgoup I OL gns sh on ommon ns gn wh h ony homoog psn n hssn hus us h shd bwn hol nd O o OL/OL n b ssgnd s nn wh dns shoud b ssgnd s nw o dvd hol s monng xpssd k OL nd OL ndng h xpsson o O mrn vovd n h Bss nd s vouony young hs s suppod by h ndng h novs k smn hngs h ou n h Bss o O no shd wh hol Funony hol bhvd smy o OL nd OL n nsgn ompmnon ssys hus hs o b sd h h song owng non mdd by O homoogs n h Bss s novy h nso o O ony psnd mod by o pomo owng v h phoopod owng phwy hs mgh suggs h h dn unons o O, OL nd OL mdd by hol nd subunonzon ony oud n h Bss 9

104 ONLUSIONS ND PERSPEIVES Funon o O ohoogs byond h Bsss O hs homoogs n mny pn sps h s ddony vdn h h OF guon s onsvd n owng pns nd ws mpoyd o sns dy ngh nd gu downsm mhnsms boh n owng m ono nd oh mhnsms k ubzon hn O nd R HD xpsson s vy sm bu vovd hough onvgn vouon hs s no ony h su o hs sudy bu uhmo suppod by h ndng h O ohoogs om mny sps h vouony pd bwn h Bss nd h Po show ss monng xpsson pn k OL/OL O s song nspon guo n hn h ompmnon xpmns psnd n hs sudy oud n uu b usd o dny h us dns o h ns n unon o u O homoogs n h Bss my ompd o s pogs s w s O ohoogs om oh pn ms In summy O s pon vo o phoopod owng h vovd n h Bss pobby dung dpon o voub ong dy phoopods Impony h nspon guon o O dpd o ow nsd O mrn spy n LDs nd ho von o owng und voub ondons hs mhnsms mgh b nkd o h spd o h Bss my no mp ms owng dpon o song dns bwn ssons 9

105 LIERURE LIERURE b, M, Kobysh, Y, Ymmoo, S, Dmon, J, Ymguh,, Ikd, I, Ihnok, H, Noguh, M, oo, K, nd k, () FD, bzip Pon Mdng Sgns om h Fo Phwy Ingo F h Shoo px Sn 9, dn, J, Fon, S, Rm, JJ, bn, M, oupnd,, nd uk, F () srguoy Emns nd homn S oodny ono mpo nd Sp Expsson o FLOWERIN LOUS n bdopss Pn Onn, bs, B, Johnson,, W, P, Lws, J, R, M, nd Kh, R () Mou boogy o h (Nw Yok: nd Sn) md, R, b, N, so, J, RuzL, S, nd onzáz Vnuv, E (9) VvO nd VvOL, wo ONSNS homoogous gns, gud dung ow nduon nd domny n gpvn buds Pn Rp, 9 n, H, Rousso,, SuzLopz, P, obs, L, Vnn,, Pno, M, Hpwoh, SR, Moudov,, Jusn, S, unbu,, () ONSNS s n h phom o gu sysm sgn h ndus phoopod owng o bdopss Dvopmn, ndés, F, nd oupnd, () h gn bss o owng sponss o sson us N Rv n, 9 ns, SW, Snon, HK, undmnn, M, Russ, SJ, Koh, M, Shnd, H, nd Vog, J () h mpon o non mounns s h d o gob dvsy n bs pn, ky pn sps nn Bo, ukmn, MJ, Hshd, M, Ws, L, Wv, M, k,, msno, RM, nd Shok, R (99) don n h PHYD gn o h bdopss Wsswskj oyp dns o o phyohom D n d/d gh snsng Pn Onn 9, By, L, nd Ekn, (99) Fng mxu mod by xpon mxmzon o dsov mos n bopoyms Po In on In Sys Mo Bo, By, D, Koh, M, My, M, Mummnho, K, O Kn J, SL, Wwk, SI, Wndhm, MD, nd Shhbz, I () owd ob Phyogny o h Bss Mo Bo Evo, By, L, Bodn, M, Busk, F, Fh, M, n, E, mn, L, Rn, J, L, WW, nd Nob, WS (9) MEME SUIE: oos o mo dsovy nd shng Nu ds Rs, W W Bsubmnn, S, Sushkum, S, gw, M, Mh, P, Wssng,, Moo, JN, k, R, Whmnn, N, hoy, J, nd Wg, D () h PHYOHROME phoopo gn mds nu von n owng nd gowh sponss o bdopss hn N n, Bk, MS, Vog, H, nd Shnz, ME (9) Popoypody n h Bsss: nyss o h om nspom Eud h Hsoy o nom Dupons n bdopss nd Oh Bsss nom Bo Evo, 9 99 Bkmn, R, nd Pvs, () nspon Rguon by P od Spng Hb Psp Bo, 9 9

106 LIERURE Bsn, M, Ngngum, NS, mns, MD, Mnhs, SR, nd Mhws, S () Dd mou phyogns nd Mon ogn o bdopss hn Po N d S, Bns, M () nspon guon o h bdopss hn owngm gn INE Bo, D, Mu, J, Ovhnko, D, Lws, KD, Ovhnko, I, Ph, L, nd Rubn, EM () Phyogn Shdowng o Pm Squns o Fnd Funon Rgons o h Humn nom Sn 99, 9 9 Bohnus, H, Hung,, hbonnmp, L, Bunn, M, Jnsson, S, Suss, SH, nd Nsson, O () O/F Rguoy Modu onos mng o Fowng nd Sson owh sson n s Sn, Bon, R, Kmpmnn,, hnd, J, ssn, R, Wsmn, E, p, K, nd Mz, S () MDS domn gn nvovd n h nson o owng n bdopss Pn J Mo Bo, 9 99 Bows, JE, hpmn, B, Rong, J, nd Pson, H () Unvng ngospm gnom vouon by phyogn nyss o homosom dupon vns Nu, Bow,, Bnvnuo,, Lmm, P, Mono, D, Pobs, V, q, M, nd Pszkowsk, J () homn hnqus o pn s Pn J 9, 9 Bhn, E () Kompkxkon d Boog (Hdbg; Bn: Spkum, kd V) Budno, M, Do, B, oop, M, Km, MF, Dvydov, E, n, ED, Sdow,, nd Bzogou, S () LN nd MuLN: n oos o gs mup gnmn o gnom DN nom Rs, mpo,, Doss, B, S, I, oupnd,, nd von Ko, M () Funon hson o HvO, h by (Hodum vug) owng m ohoog o ONSNS: Funon hson o HvO n by Pn J 9, dán, PD, nd hoy, J () Rguon o owng m by gh quy Nu, hn, M, nd N, M () RFI, RINdomn zn ng pon, ngvy gus ONSNS xpsson nd phoopod owng Pn J, hn, M, nd N, M (b) RED ND FRRED INSENSIIVE, RINDomn Zn Fng Pon, Mds Phyohomonod Sdng Doon Rsponss PLN Physo, hng, S, vn dn Bgh, E, Zng, P, Zhong, X, Xu, J, Lu, X, Hobg, J, d Bujn, S, Bhd, S, Kuhogu,, () h ny hssn nom Povds Insgh no Rpoduv nd nom Evouon o us Pn, h, YP, Mu,, Jung,, nd Musogns, ES () Sug b onns g ONSNSLIKE gn my nudng O homoogu h s ndpndn o h ybong (B) gn ous J Exp Bo 9, how, BY, H,, Nusnow, D, nd Ky, S () ELF umn o h PRR9 pomo qus oh Evnng ompx mmbs n h bdopss dn ok Pn Sgn Bhv, 9

107 LIERURE ough, SJ, nd Bn, F (99) Fo dp: smpd mhod ogobummdd nsomon obdopss hn Pn J, ook, PR () Mod o noms: h Ro o nspon Fos J Mo Bo 9, obs, L, Vnn,, Jng, S, Fon, F, Fn, Q, S, I, kouns,, Fon, S, sso, L, unbu,, () F Pon Movmn onbus o LongDsn Sgnng n Fo Induon o bdopss Sn, k, F (9) n dogm o mou boogy Nu, ooks, E, Hon,, hndon, JM, nd Bnn, SE () WbLogo: squn ogo gno nom Rs, 9 ubs, P, Lu, N, Doby, J, nd on, E (999) h P domn: mo ound n pons gung pn gowh nd dvopmn Pn J, Dssnyk, M, Oh, DH, Hs, JS, Hnndz,, Hong, H,, S, Yun, DJ, Bssn, R, Zhu, JK, Bohn, HJ, () h gnom o h xmoph u hung pvu N n, 9 9 Dkk, J, Rpp, K, Dkk, M, nd Kkn, N () pung homosom onomon Sn 9, Dp,, ugnon, V, Bn,, ud, S, Bu, S, hvn, F, Duyd, JF, undon, S, Lo, V, Lso, M, () Phyogny: obus phyogn nyss o h nonsps Nu ds Rs, W W9 Dodd, N, Sh, N, H,, Kv, E, oh, R, Ngy, F, Hbbd, JM, M, J, nd Wbb, () Pn dn oks Ins Phoosynhss, owh, Suvv, nd ompv dvng Sn 9, Duow, N, Nx, D, Ho, D, Msh, B, Dy, B, Wsbok, E, Pn, J, nd ns, BR () Dynm nspom o Shzoshomys pomb shown by RNDN hybd mppng N n, 9 9 Edwds, K, Johnson,, nd hompson, (99) smp nd pd mhod o h ppon o pn gnom DN o PR nyss Nu ds Rs 9, 9 Edwds, KD, kmn, OE, Knox, K, Lumsdn, PJ, homson, W, Bown, PE, Pokhko,, KozmBogn, L, Ngy, F, Rnd, D, () Qunv nyss o guoy xby und hngng nvonmn ondons Mo Sys Bo Esnbg, E, nd Lvnon, EY () Humn houskpng gns omp nds n 9, Fw, J, M, S, nd Vn d P, Y (9) Pns wh doub gnoms mgh hv hd b hn o suvv h ous y xnon vn Po N d S, Fon, F, Pngh, KS, sso, L, Subunn, N, Rüh, M, Jo, J, nd oupnd, (9) bdopss DOF nspon Fos Rdundny o Rdu ONSNS Expsson nd Essn o Phoopod Fowng Rspons Dv, Fow, S, L, K, Onouh, H, Smh,, Rhdson, K, Mos, B, oupnd,, nd Pu, J (999) INE: dn okonod gn h gus phoopod owng n 9

108 LIERURE bdopss nd nods pon wh sv possb mmbnspnnng domns EMBO J, 9 Fnkn, K, Pk,, U, Sodd,, WM, Bnghm,, OE, Hdy,, KJ, nd Whm, () Phyohoms B, D, nd E Rdundny o ono Mup Physoog Rsponss n bdopss PLN Physo, Fnzk,, mn, D, Shhbz, I, nd Mummnho, K (9) bdopss my s: mou phyogny nd g sms n Bss xon Fnzk,, Lysk, M, Shhbz, I, Koh, M, nd Mummnho, K () bbg my s: h vouony hsoy o Bss nds Pn S, owy, L, Mmbg, RL, nd P, R (99) Phyogn uy o h nu gn gnn dboxys: n xmp om Bss Mo Bo Evo, n, WW, nd d, H (9) E o h v ngh o dy nd ngh nd oh os o h nvonmn on gowh nd poduon n pns J g Rs, nd, V, Lppmn, Z, Yodn,, oo, V, nd Mnssn, R () Dpndn o Hohom Hson H Mhyon Pns on h bdopss n DDM Sn 9, ndon, JM, PundPz, JL, Dohy, J, oss, M, Kng, SE, nd Ky, S () bdopss dn ok pon, O, s DNbndng nspon o Po N d S 9, onzázshn, ND, DízMndoz, M, Żuzk, M, nd SuázLópz, P () Poo ONSNS s nvovd n phoopod ubzon n gnsmssb mnn: Rguon o ubzon by poo ONSNS Pn J, 9 gs, V, ndés, F, Sss,, u, RF, Smonn, S, Mos, JL, o, S, Zmb, F, Pzzo, M, Bjkn, KN, () Idnon o phwys dy gud by SHOR VEEIVE PHSE dung vgv nd poduv dvopmn n bdopss nom Bo, R hs, S, Dunod,, RP, oupnd,, nd Lu,, D () h Evouon o ONSNS Lk n Fms n By, R, nd bdopss PLN Physo, umuo, DL, HsdWmson, H, y,,, S, Shon, D, g, D, Sghom, JL, oodmn, M, nd ons, FS (99) Phyogn oopnng vs nu pon whh bnds o sn squns n h humn gmm nd pson gobn gns Mo Bo, uéz, R, Ewng, RM, hy, JM, nd n, PJ () Idnon o unsb nsps n bdopss by DN moy nyss: pd dy s ssod wh goup o ouhnd sp okonod gns Po N d S 99, H, J, Sysm, KJ, nd Is, HH () Phyogny o pp nd Bss bsd on hoops squn d m J Bo 9, Hm, SL, nd Ky, S () Posv nd Ngv Fos on PhsSp dn Rguon o nspon n bdopss Pn Onn, 9 9 Hssdm, M, H, Y, Yk, E, Kon, I, nd n, RM (9) Ovxpsson o ONSNSLIKE n ndu owng n shody gown bdopss Pn, 9 9

109 LIERURE Hudy,, Ps, E, Vo, E, Hon, DR, Lq, M, Wmson, RJ, Fozk, E, Joy Lopz, Z, Sn, J, Hzzou, KM, () n s o ov 9, onsvd nonodng squns povds nsgh no u guoy gons N n, 9 9 Hym, R, Izw,, nd Shmmoo, K () Isoon o gns possby nvovd n h phoopod ono o owng by uosn dn dspy mhod Pn Physo, 9 Hym, R, Yoko, S, mk, S, Yno, M, nd Shmmoo, K () dpon o phoopod ono phwys podus shody owng n Nu, 9 Hh, V, Fouh, F, Fndz,, Mkngh, R, Nvo,, Mon, J, Vdy, ME, Es, N, Bn, JP, Rmu,, () onsvon o bdopss Fowng ns n Mod Lgums PLN Physo, Hh, V, Knows, L, Vnd Shoo, JK, Lw, L, Jons, SE, Lmb, MJM, nd W, JL () P LE BLOOMER Is INE Ohoog wh Ros n Phoopod Fowng, Doon, nd nspon Rguon o dn ok n Homoogs PLN Physo, H,, Nusnow, D, how, BY, hk, R, Buyk, ML, nd Ky, S () LUX RRHYHMO Enods Nghm Rpsso o dn n Expsson n h bdopss o ok u Bo, Hns, R, Munux, P, nd K, H () hn Fous: gud o gobum bny vos nds Pn S, Hns, RP, Edwds, E, Lynd, NR, Bn, S, nd Munux, PM (b) pn: vs nd xb bny vo o gobummdd pn nsomon Pn Mo Bo, 9 Ho, E, Komos, E, Bujdoso, N, Yun, Y, Wng, M, Bns, M, Uhwom, H, oupnd,, Sn, R, Jskosk, M, () ERLY FLOWERIN Rumn o ERLY FLOWERIN n h Nuus Susns h bdopss dn ok Pn Onn, Ho, K, Myosh,, Kugou, K, Homn, S, Shb,, nd Oh, K () Spws homn modng by sd o nspon non o nonodng RNs Nu, Hong, RL, Hmguh,, L, Bush,, M, nd Wg, D () Rguoy Emns o h Fo Homo n MOUS Idnd by Phyogn Foopnng nd Shdowng Pn Onn, 9 9 Hsu, Y, dms, JP, No, K, Lng, H, Mn, R, Phnov, O, Bk,, son, JE, Pg, P, nd Yu, () Ovxpsson o onsns Homoogs O nd O Fs o Nom Rpoduv Ons nd F Bud S n Woody Pnn Pop PLoS ONE, Hu,, Pyn, P, Bkk, E, o, J, hng, JF, k, RM, Fhgn, N, Fw, J, mwood, J, undh, H, () h bdopss y gnom squn nd h bss o pd gnom sz hng N n, Hung, W, Pz, P, Pokhko,, M, J, noshhkn, I, Rhmnn, JL, nd Ms, P () Mppng h o o h bdopss dn ok Dns h Nwok Suu o h Oso Sn, 9 99

110 LIERURE Is, HH, nd ohn, S () Suds n h om V: Nw nus nd n Nw ombnons o h Fo o Noh m Novon J Bo Nomn, Imzum,, n, H, Swz, E, Bggs, WR, nd Ky, S () FKF s ssn o phoopodsp gh sgnng n bdopss Nu, Imzum,, Shuz, F, Hmon, F, Ho, L, nd Ky, S () FKF FBox Pon Mds y Dgdon o Rpsso o ONSNS n bdopss Sn 9, 9 9 Imu,, un, E, nd Su, N (999) o nd ongdsn kng o h gn uosn pon n h phom nd symps unodng o h pon no snk ssus Pn Onn, 9 Io, S, Song, YH, JosphsonDy, R, M, RJ, Bon,, Omsd, R, nd Imzum, () FLOWERIN BHLH nspon vos ono xpsson o h phoopod owng guo ONSNS n bdopss Po N d S 9, Io, S, Song, YH, nd Imzum, (b) LOV Domnonnng FBox Pons: Lgh Dpndn Pon Dgdon Modus n bdopss Mo Pn, IyPsuzz, S, nd Bny, PN () Fuosnvd song n pn dvopmn boogy Mhods Mo Bo on NJ, 9 Jg, KE, nd Wgg, P () F Pon s s LongRng Sgn n bdopss u Bo, Jng, S, Mh, V, Pngh, K, Wnk, S, Sopp, W, Dng, XW, Vvd, F, nd oupnd, () bdopss OP shps h mpo pn o O umuon onng phoopod owng spons EMBO J, Json, R, Kvngh,, nd Bvn, MW (9) US usons: bguuonds s snsv nd vs gn uson mk n hgh pns EMBO J, 9 Jo, Y, Wk, NJ, yympym, S, hndb, S, Lndh, L, Rph, PE, omsho, LP, Hu, Y, Lng, H, Sos, PS, () ns poypody n sd pns nd ngospms Nu, 9 Jung, JH, Ju, Y, So, PJ, L, JH, nd Pk, M () h SOSPL modu ngs phoopod nd gbb d sgns o ono owng m n bdopss Pn J Mo Bo 9, Kumnn, K, Wm, F, Muno, JM, F,, Wus, SE, Kum, V, SnoMs,, Mduno, F, Kjwsk, P, Myowz, EM, () Ohson o Fo Inon by PEL Sn, 9 Km, SK, Pk, HY, Jng, YH, L, JH, nd Km, JK () h squn von sponsb o h unon dn bwn h ONSNS pon, nd h ONSNSk (OL) nd OL pons, sds mosy n h gon nodd by h s xons Pn S 99, Koosmn, B, bnd, J, omz, M d M, Oowjn, M, d Bo, JM, Kowwnh, K, Hovh, BM, vn Ek, HJ, Smznk,, P, S, () Nuy oung dvsy ows poo uvon n nohn uds Nu 9, Koh, M, Hubod, B, nd MhOds, () ompv vouony nyss o hon synhs nd oho dhydogns o n bdopss, bs, nd d gn (Bss) Mo Bo Evo, 9

111 LIERURE Kovng, JL (9) Fo Dvopmn nd Smn Fmn Eongon n om hssn m J Bo, Koonn, M, Hnh, J, nd Vn d Vn, JH (99) gn nd physoog nyss o owng muns n bdopss hn Mo n n M 9, Kosug, S, nd Ohsh, Y () DN bndng nd dmzon spy nd pon gs o h P pon my Pn J, Koym,, Msud, N, Sk, M, Shnozk, K, nd Ohmkg, M () P nspon Fos Rgu h vs o SYMMERI LEVES nd mr, s W s h uxn Rspons, dung Dnon o Lvs n bdopss Pn Onn, Kummoo, RW, Zhng, Y, Ss, N, nd Ho, BF () NFY, NFY nd NFY9 qud o ONSNSmdd, phoopoddpndn owng n bdopss hn: NF Y unon n owng m Pn J, 9 9 Loum,, D M, S, ms, P, Budn, M, nd Nb, () box bndng nspon os n pns: Y so mny? nds Pn S, Lkn, M, Bkshds,, Bown, NP, hnn, R, Mgn, P, MWm, H, Vnn, F, W, IM, Wm,, Lopz, R, () us W nd us X vson Bonoms, 9 9 Lubng, S, Mh, M, L ou, J, Wnk, S, dn, J, Jng, S, Kuj,, Bun, H, oupnd,, nd Hok, U () bdopss SP pons gu phoopod owng nd n wh h o ndu ONSNS o gu s sby Dvopmn, Ldg, S, Sy,, shon, F, Ky, S, nd Pu, J () nyss o h unon o wo dngud ONSNSLIKE gns Pn J, L, H () h MOUSLIKE MDS domn pon ngs o nduv phwys n bdopss ns Dv, L, J, Oh, M, Pk, H, nd L, I () SO nsod o h nuus by non wh L dy gus LEFY Pn J, Lvn, M, nd Dvdson, EH () n guoy nwoks o dvopmn Po N d S U S, 9 9 L, L, Wng, X, So, V, L, X, Zhng, D, Su, N, ongps, W, L, S, hng, Z, Wng, J, () nomwd nspon nyss n usng ng moys N n, 9 Lshz, E, nd Eshd, Y () Unvs ogn sgns ggd by F homoogus gu gowh nd owng ys n pnn dynu omo J Exp Bo, Lu, J, Yu, J, MInosh, L, Knd, H, nd Zv, J () Isoon o ONSNS ohoog om Phbs n nd s o n owng Pn Physo, Lu, LJ, Zhng, Y, L, QH, Sng, Y, Mo, J, Ln, HL, Wng, L, nd Yng, HQ () OPMdd Ubqunon o ONSNS Is Impd n ypohom Rguon o Fowng n bdopss Pn Onn, 9 Msh, DM, Muhd, R, Bown, NJ, Lu, Z, Sny, S, hs, H, Sg, RF, nd Hbbd, JM () om, gnus osy d o bdopss, onns sps spnnng

112 LIERURE dvopmn pogsson om o phoosynhss: phoosynhss n om Pn J, 9 Mhu, J, Whmnn, N, Kün, F, nd Shmd, M () Expo o F Pon om Phom ompnon s Is Sun o Fo Induon n bdopss u Bo, Myo,, Budno, M, Shwz, JR, Pokov,, Rubn, EM, Fz, K, Ph, LS, nd Dubhk, I () VIS : vsuzng gob DN squn gnmns o by ngh Bonom Ox Eng, Mh, P, Mok,, Bon,, MEn,, By,, ou, JD, Hzn, SP, Shn, R, Ps, HD, Suvn, M, () Nwok Dsovy Ppn Euds onsvd mo Dy Sp srguoy Modus PLoS n, Mhs, SD () Ingon o Fowng Sgns n Wnnnu bdopss PLN Physo, 9 M, J, Sho, SR, hu, NH, nd Ky, S (99) nov dn phnoyp bsd on y us xpsson n nsgn pns Pn Onn, Mzoguh,, Why, K, Hnzw, Y, Wgh, L, Mzoguh, M, Song, HR, é, I, nd oupnd, () LHY nd Py Rdundn ns Rqud o Mnn dn Rhyhms n bdopss Dv, 9 Mzoguh,, Wgh, L, Fujw, S, m, F, L, K, Onouh, H, Moudov,, Fow, S, Kmd, H, Pu, J, () Dsn Ros o INE n Pomong Fowng nd Rgung dn Rhyhms n bdopss Pn Onn, Mos, K, nd Jkson, SP () DY NEURL FLOWERIN dos no hough INE nd FKF o gu ONSNS xpsson nd owng m Pn Sgn Bhv, Mos, K, honb, S, od, L, Rhdson,, g,, Sdnndom,, homs, B, nd Jkson, S () DY NEURL FLOWERIN Rpsss ONSNS o Pvn bdopss Fowng Ey n Sho Dys Pn, BnNm, O, Eshd, R, Pns,, pbmnok, P, Sh,, oupnd,, Smh,, nd Lshz, E () h bndng o n md nons bwn ONSNSk pons nd DN Pn J, Nkmh, N, Kb,, Hnqus, R, Mzuno,, hu, NH, nd Skkb, H () PSEUDORESPONSE REULORS 9,, nd nspon Rpssos n h bdopss dn ok Pn, 9 Nvo,, bnd, J, uzoó, E, ué,, mk, S, Sv, J, Shmmoo, K, nd P, S () ono o owng nd sog ogn omon n poo by FLOWERIN LOUS Nu, 9 Nson, D, Lssw, J, Rogg, LE, ohn, M, nd B, B () < > FKF</>, ok onod n h Rgus h nson o Fowng n< > bdopss</>, Nguyn, H, nd Xu, X (99) Dosoph m xpsson dung msodm dvopmn s onod by ompx y o sng guoy modus Dv Bo, Nusnow, D, H,, Hmon, EE, Kng, JJ, Imzum,, Shuz, F, Fé, EM, nd Ky, S () h ELF ELF LUX ompx nks h dn ok o dun ono o hypooy gowh Nu, 9

113 LIERURE Onouh, H, Igño, MI, Péux,, vs, K, nd oupnd, () Mugnss o pns ovxpssng ONSNS dmonss nov nons mong bdopss owngm gns Pn Onn, 9 Osbon, S, hkov, L, Bown, KE,, D, Hoon,, Dbnd, E, oynh, B, Mh, J, Lops, S, Rk, W, () v gns dynmy ooz o shd ss o ongong nspon N n, Pk, DH, Soms, DE, Km, YS, hoy, YH, Lm, HK, Soh, MS, Km, HJ, Ky, S, nd Nm, H (999) ono o dn Rhyhms nd Phoopod Fowng by h bdopss INE n Sn, 9 Pss, WH, ukosky, S, Vng, W, nd Fnny, BP () Num ps: h o sn ompung (mbdg, UK ; Nw Yok: mbdg Unvsy Pss) Pun, P, W, N, nd Dng, XW (99) ombno npy o pomo mns onsus h mnm dmnns o gh nd dvopmn ono o gn xpsson n bdopss EMBO J, Pu, J, Robson, F, L, K, Smon, R, nd oupnd, (99) h ONSNS gn o bdopss pomos owng nd nods pon showng sms o zn ng nspon os, Réd, P (9) Supv muns o bdopss ns, Rd, JW, Ngp, P, Poo, DS, Fuuy, M, nd hoy, J (99) Muons n h gn o h d/d gh po phyohom B ongon nd physoog sponss houghou bdopss dvopmn Pn Onn, Rhmnn, JL, Hd, J, Mn,, Rub, L, Jng,, Kdd, J, dm, L, Pnd, O, R, OJ, Smh, RR, () bdopss nspon os: gnomwd ompv nyss mong ukyos Sn 9, Robson, F, os, MMR, Hpwoh, SR, Vz, I, Rvs, PH, Pu, J, nd oupnd, () Funon mpon o onsvd domns n h owngm gn ONSNS dmonsd by nyss o mun s nd nsgn pns Pn J, 9 Robson, PR, Whm,, nd Smh, H (99) Sd omponns o h shdvodn syndom dspyd n nom mnn n muns o bdopss hn nd Bss p dn n phyohom B Pn Physo, 9 Rodgo,, nd Ln, H () ompuon nd vouony nyss o HIV mou squns (Boson, M: Kuw dm Pubshs) Sou, N, nd N, M (9) h nghbojonng mhod: nw mhod o onsung phyogn s Mo Bo Evo, Smh,, Onouh, H, od, SE, D, S, ShwzSomm, Z, Ynosky, MF, nd oupnd, () Dsn Ros o ONSNS g ns n Rpoduv Dvopmn o bdopss Sn, Sánhzbo, L () phyogn sudy o h nw wod om (Bss, omod) nn Mo Bo d 9 Sw, M, Nusnow, D, Ky, S, nd Imzum, () FKF nd INE ompx Fomon Is Rqud o DyLngh Msumn n bdopss Sn,

114 LIERURE Shmd, M, Uhnhu, NH, odd, F, Dm, M, Bssn, R, Wg, D, nd Lohmnn, JU () Dsson o o nduon phwys usng gob xpsson nyss Dvopmn, Shomm,, Pnk, JF, ggw, P, hé,, ubs, P, Fm, EE, Nh, U, nd Wg, D () ono o Jsmon Bosynhss nd Snsn by mr9 gs PLoS Bo, Shnz, ME, nd MhOds, () Indpndn nn Poypody Evns n h Ss Fms Bss nd om Pn Onn, S, I, H, Y, uk, F, Vnn,, Fon, F, Köb, S, msno, R, nd oupnd, () h nspon o FL ons owng spons o vnzon by pssng msm ompn nd sysm sgnng n bdopss ns Dv, 9 9 Sno,, HPu, R, Romo, JM, Sno,, oupnd,, nd Vvd, F (9) hmydomons ONSNS nd h Evouon o Pn Phoopod Sgnng u Bo 9, 9 Shw, H,, H, nd Wson, MD (9) unon mp o h nopn synhs pomo Nu ds Rs, Ss, N, Dng, KK, Kummoo, RW, Bynum, WE, yos,, nd Ho, BF () ssu Sp Expsson Pns o bdopss NFY nspon Fos Suggs Pon o Exnsv ombno ompxy PLN Physo 9, Sv, M, Wnbg, R, nd Pnmn, S (99) h sv nupon o nuo RN synhss n HL s by odypn J Bo, Smon, S (9) nspon guon o h owngm gn ONSNS n bdopss hn Šmd, P, Buš, P, Šmd, J, nd Hoová, L () Msumns o gnom onn n pn gnoms wh ow yomy: s o by Nw Phyo 9, Sos, DE, b, V, LbnsMk, J, B, D, Pson, H, Zhng,, Snko, D, dpmphs, W, W, PK, nd Sos, PS (9) Poypody nd ngospm dvson m J Bo 9, Soms, DE, Shuz, F, Mnmow, M, nd Ky, S () < > ZEILUPE</> Enods Nov okssod PS Pon om< > bdopss</>, 9 9 Song, YH, Io, S, nd Imzum, () Sms n h dn ok nd phoopodsm n pns u Opn Pn Bo, 9 Song, YH, Smh, RW, o, BJ, M, J, nd Imzum, () FKF onvys mng Inomon o ONSNS Sbzon n Phoopod Fowng Sn, 9 Spnsy, M, Km, JY, Po, E, Rd, J, O, S, Hw,, nd, I (9) Evouony onsvd Rguoy Mos n h Pomo o h bdopss ok n LE ELONED HYPOOYL Pn Onn, Sy,, Oym,, Shuz, F, Rmn, R, Soms, DE, Ms, P, Shdnnd, P, Kps, J, nd Ky, S () onng o h bdopss ok n O, n uoguoy Rspons Rguo Homoog Sn 9,

115 LIERURE SuzLopz, P, Why, Robson, Onouh, H, Vvd, F, nd oupnd, () ONSNS mds bwn h dn ok nd h ono o owng n bdopss Nu, g, D, Koop, BF, oodmn, M, Sghom, JL, Hss, DL, nd Jons, R (9) Embyon ε nd γ gobn gns o posmn pm (go ssudus): Nuod nd mno d squns, dvopmn guon nd phyogn oopns J Mo Bo, 9 kd, S, nd oo, K () ERMINL FLOWER, n bdopss Homoog o HEEROHROMIN PROEIN, ouns h von o FLOWERIN LOUS by ONSNS n h Vsu ssus o Lvs o Rgu Fowng m Pn Onn, mu, K, Dudy, J, N, M, nd Kum, S () ME: Mou Evouony ns nyss (ME) Sow Vson Mo Bo Evo, 9 99 ng, H, Bows, JE, Wng, X, Mng, R, m, M, nd Pson, H () Synny nd ony n Pn noms Sn, ok, K, Ohk, I, suj, H, Fuu, K, Hysh, K, Yns,, Ymguh, M, Nkshm,, Puws, Y, mk, S, () pons s nu pos o Hd ogn Nu, pbmnok, P, nd Smh, () h Fowng Ingo F Rgus SEPLL nd FRUIFULL umuon n bdopss Lvs Pn Onn, ppmn, JM, Zhu,, hng, HS, Wng, X, nd Qu, PH () Mup nspono gns y gs o phyohom sgnng Po N d S 9, 9 9 zgh, WB, nd shmo, R (99) Lghgud nspon nnu Rv Pn Bo, h bdopss nom Inv () nyss o h gnom squn o h owng pn bdopss hn Nu, 9 w, SB, Shn, Y, hng, H, Hou, Y, Hs,, M, SF, MPnd, M, Hymus, J, dm, L, Mon,, () h owng m guo ONSNS s ud o h FLOWERIN LOUS pomo v unqu smn Nw Phyo, odooz, () h bdopss Bs/HxLoopHx nspon Fo Fmy Pn Onn, 9 ook, M, nd Ekn, LD () wo B o no wo B? Ovvw o h pdy xpndng Bbox my o pons D Rs Bo Dvs, s, Y, hn, PY, nd o, KY () Pn gnon nd sb nsomon n h ouu pn om spnos, ₃ pn osy d o h ₄ pn gynnd Pn Rp, 9 9 uk, F, Roud, F, Fon, S, MnMgn, ML, uum, E, Busn, N, gno, S, Mnssn, R, oupnd,, nd oo, V () bdopss FL/LHP Spy ssos wh ns Mkd by mhyon o Hson H Lysn PLoS n, Ummu, Y, Ishduk,, Ymmoo, R, nd Esk, M () h Do domn, zn ng DNbndng domn onsvd ony n hgh pns, uy unons s ys/ys Zn ng domn Pn J, 9

116 LIERURE Vvd, F, Moudov,, Sopp, W, Rvnso, D, Smh,, nd oupnd, () Phoopo Rguon o ONSNS Pon n Phoopod Fowng Sn, Wng, JW, zh, B, nd Wg, D (9) mrrgud SPL nspon Fos Dn n Endognous Fowng Phwy n bdopss hn, 9 Wng, R, Fon, S, Vnn,, Jok,, Shoo, H, uk, F, onsobno,, oupnd,, nd bn, M (9b) PEP gus pnn owng n bs pn Nu 9, Wng, X, Wng, H, Wng, J, Sun, R, Wu, J, Lu, S, B, Y, Mun, JH, Bno, I, hng, F, () h gnom o h msopoypod op sps Bss p N n, 9 Wng, Y, n, X, nd Pson, H () Dn pns o gn suu dvgn oowng gn dupon n bdopss BM noms, Wssmn, D, Soomon, NM, hng, H, Km, FD, hn, M, nd Rubn, M (99) Pon phosphs posvy nd ngvy gus Rsmdd phoopo dvopmn n Dosoph ns Dv, Wnk, S, uk, F, Sng, K, sso, L, L ou, J, Smh,, nd oupnd, () ONSNS nd h Box Bndng ompx Sh Funony Impon Domn nd In o Rgu Fowng o bdopss Pn Onn, 9 9 Wgg, P, Km, M, Jg, KE, Bush, W, Shmd, M, Lohmnn, JU, nd Wg, D () Ingon o Sp nd mpo Inomon Dung Fo Induon n bdopss Sn 9, 9 Wöz, S () nyss o owngm gns n Bss sps hzon o SHOR VEEIVE PHSE homoog n bs pn Yk, E, Hmn, D, Hssdm, M, nd n, RM () IRDIN LOK SSOIED nsp Sby nd h Ennmn o h dn ok n bdopss PLN Physo, 9 9 Ymguh, () WIN SISER OF F (SF) s s Fo Phwy Ingo Rdundny wh F Pn Physo, 9 Ymguh,, Wu, MF, Yng, L, Wu,, Pohg, RS, nd Wgn, D (9) h MoRN Rgud SBPBox nspon Fo SPL Is D Upsm vo o LEFY, FRUIFULL, nd PEL Dv, Ymshno,, Ymwk, S, Hgu, E, UokNknsh, H, Nkmh, N, Io, S, nd Mzuno, () okonod nd FLOWERIN LOUS Dpndn Phoopod Phwy n Lous jponus I Von o h Fowngssod Funon o n F Homoog ymshno pd Yngsw, S () h Do my o pn nspon os nds Pn S, Yngsw, S, nd Shmd, RJ (999) Dvsy nd smy mong ognon squns o Do nspon os Pn J, 9 Yno, M, Kyos, Y, shk, M, Ymnouh, U, Monn, M, Fus,, Bb,, Ymmoo, K, Umh, Y, Ngmu,, Y, () Hd, Mjo Phoopod Snsvy Qunv Lous n R, Is osy Rd o h bdopss Fowng m n ONSNS Pn Onn,

117 LIERURE Ynovsky, MJ, nd Ky, S () Mou bss o sson m msumn n bdopss Nu 9, Yu, JW, Rubo, V, L, NY, B, S, L, SY, Km, SS, Lu, L, Zhng, Y, Igoyn, ML, Suvn, J, () OP nd ELF ono dn Funon nd Phoopod Fowng by Rgung I Sby Mo, Zhng, X, nz, O, okus, S, Bnvhu, YV, Pgn, M, oodh, J, nd Jobsn, SE () Whonom nyss o Hson H Lysn mhyon n bdopss PLoS Bo, 9 Znzn, RP, do,, gnu, J, Bun, M, nd Fuong, EEM (9) ombno bndng pds spompo sguoy vy Nu, Zunk, K, Mummnho, K, nd Huk, H (999) Phyogn onshps n b Lpd (Bss) bsd on hoops DN son s von n J Bo,

118

119 PPENDIX PPENDIX Pomo squns om Bss O usd o phyogn shdowng >honm_bum gggggggggggggggggggg ggggggggggggggggggggg gggggggggggggggggggggggg gggggggggggggggg gggggggggggggggg gggggggggggggggggggggg gggggggggggggggggggggg gggggggggggggggggggg gggggggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggggggggg ggggggggggggggggg gggggggggggg gggggggggggggggggggggggggggg gggggggggggggggggggg ggggggggggggggggggggg gggggggggggggggggggggggggggggg ggggggggggggggggggg gggggggggggggggg gggggggggggggggggggggggggg gggggggggggggggggggggggg ggggggggggggggggggggg ggggggggg >bdopss_hn gggggggggggggggggggggggggg gggggggggggggggggggggg ggggggggggggggggggg gggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggggggggggg gggggggggggggggggggg gggggggggggggggggggggggggggggg ggggggggggggggggggggggggg gggggggggggggggggggggggg ggggggggggggggg ggggggggggggggg gggggggggggggggggggggggg ggggggggggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggggggggggggggggg gggggggggggggggggggggg gggggggggggggggggggg ggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggggggggg ggggggggggggggggggggggggggg gggggggggggggggggggggggggggg ggggggggggg >bdopss_y gggggggggggggggggggggggggggg ggggggggggggggggg gggggggggggggggggg gggggggggggggggggg ggggggggggggggggggggggggggggg ggggggggggggggggggggg gggggggggggggggggggggggg ggggggggggggggggggggg 9

120 PPENDIX gggggggggggggggggggggggggg gggggggggggggggggggggggggggg gggggggggggggggggggg gggggggggggggggggggg gggggggggggggggg ggggggggggggggggg gggggggggggggggggggggggg ggggggggggggggggggggggggg ggggggggggggggggggggggg gggggggggggggggggggggggggg gggggggggggggggggggg gggggggggggggggggggggg gggggggggggggggggggggg ggggggggggggggggggggggggg gggggggggggggggggggg gggggggggggggggggggggggggggggg ggggggggggggggggggg ggggggg >bs_pn gggggggggggggggggggggg ggggggggggggggggg gggggggggggggggggggggg ggggggggggggggggggg gggggggggggggggggggg gggggggggggggggggggggggg gggggggggggggggggggggg ggggggggggggggggggggggggg ggggggggggggggggggggggggg ggggggggggggggggggggggggggg gggggggggggggggggggggg gggggggggggggggg ggggggggggggggggggggggg ggggggggggggggg gggggggggggggg gggggggggggggggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggggggggggggggg ggggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggg ggggggggggggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggg >Bss_npus gggggggggggggggggggg gggggggggggggggggggggggggggggg ggggggggggggggggggggggggggggg ggggggggggggggggggggggggggggggggggg ggggggggggggggggggg gggggggggggggggggggg ggggggggggggggggggg ggggggggggggggggggggggggg gggggggggggggggggggggggggg ggggggggggggggggggggg gggggggggggggggggggggg gggggggggggggggggggggggggggggg ggggggggggggggggggggggg gggggggggggggggggg gggggggggggggggggggggggg gggggggggggg ggggggggggggggggggggggggggggg gggggggggggggggggggggggggg gggggggggggggggggggggg gggggggggggggggggggggggggg

121 PPENDIX ggggggggggggggggggg gggggggggggggggggggggg ggggggggggggggggggggggggggggggggg ggggggggggggggggggggggggggg ggggggggggggggggggg g >Bss_o ggggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggggg gggggggggggggggggg gggggggggggggggggggg ggggggggggggggggggggggggggg gggggggggggggggggggggggg gggggggggggggggggggggg ggggggggggggggggggggggggg ggggggggggggggggggggggggg ggggggggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggg ggggggggggggggggggg gggggggggggggggggggggggggggggggg ggggggggggggggggggg ggggggggggggggggggggggggg gggggggggggggggggggg ggggggggggggggggg ggggggggggggggggggggggggggggggggg gggggggggggggggggg gggggggggggggggg gggggggggggggggggggg ggggggggggggggggggg ggggggggggggggggggg gggggggggggggggg ggggggggggg gggggggggggggggggggg gggggggggggggggggggggg gggggggggggggggggggggggggggggggggggggggg gggggggggggggggggggggg ggggggggggggggggggggggggggggg gggggggg >ps_ub gggggggggggggggggggggggggg ggggggggggggggggggggg gggggggggggggggggggg gggggggggggggggggg gggggggggggggggggggg ggggggggggggggggggggggggg gggggggggggggggggggg ggggggggggggggggggggggggggg gggggggggggggggggggggggg ggggggggggggggggggggggggggggggg gggggggggggggggggggggg ggggggggggggggggggggg ggggggggggggggggggggg gggggggggggggg ggggggggggggggg ggggggggggggggggggggggg gggggggggggggggggggggggggggggg gggggggggggggggggggggggg ggggggggggggggggggggggggggg ggggggggggggggggg ggggggggggggggggggggg gggggggggggggggggggggggg

122 PPENDIX gggggggggggggggggggggg gggggggggggggggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggggggggggggggggg ggggggggggggggggg >Ssymbum_o ggggggggggggggggggggggggg ggggggggggggg ggggggggggggggggggggg ggggggggggggggggggggg ggggggggggggggggggggggggggg ggggggggggggggggg ggggggggggggggggggggggggg gggggggggggggggggggggggg ggggggggggggggggggggggg gggggggggggggggggggggggggg gggggggggggggggggggggggg gggggggggggggggggggg ggggggggggggggggggggg ggggggggggggggg ggggggggggggggg gggggggggggggggggggggggggggggggggg ggggggggggggggggg ggggggggggggggggggggggggg gggggggggggggggggggggggg ggggggggggggggggg gggggggggggggggggggggggggg ggggggggggggggggggggggg gggggggggggggggggggggggggggggggg ggggggggggggggggggg ggggg >Ssymbum_on ggggggggggggggggggg gggggggggggggg gggggggggggggggggggg ggggggggggggsggggggg gggkggggggggggkgggggg ggggggggggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggggggggggggg gggggggggggggggggggggggg gggggggggggggggggggggggggggggg ggggggggggggggggggggggggg ggggggggggggggggggg ggggggggggggggggg ggggggggggggggggggg ggggggggggggggggggggggg gggggggggggggggggggggggggggg gggggggggggggggg gggggggggggggggggggggggg gggggggggggggggggggggggggg ggggggggggggggggggggg ggggggggggggggggggggggggggggggg ggggggggggggggggggggggg gggggggggggggggggggggggggggggg gggggggggggg >Nsuum_on gggggggggggggggggggggggg gggggggggggggggggg gggggggggggggggggggg gggggggggggggggggggggggg gggggggggggggggggggggg gggggggggggggggggggg gggggggggggggggggg

123 PPENDIX ggggggggggggggggggggggggg gggggggggggggggggggggggg ggggggggggggggggggggg gggggggggggggggggg gggggxxxgggggggngggg gggggggggggggggggggggggggggg gggggggggggggggggggggggggg ggggggggggggggggggggg gggggggggggggggggggg ggggggggggggggg gggggggggggggggggggggggggggg ggggggggggggggggggggggg gggggggggggggggggggggggggggg gggggggggggggggggg gg Squns o subgoup I gns s usd o ous ompson >bddopss hn O ggggggggggggggggggggggggggg gggggggggggggggggggggg gggggggggggggggggggggggggggggg ggggggggggggggggggggg ggggggggggggggggggggggg gggggggggggggggg gggggggggggggggggggggggg ggggggggggggggggggggg gggggggggggggggggggggggggggg gggggggggggggggggggggg gggggggggggggggggggggggggg gggggggggggggggggggggggggggggggggggg gggggggggggggggggggggggggggg ggggggggggggggggggggggggggggggggggggggg gggggggggggggggggggggg ggggggggggggggggggggggggggggggg gggggggggggggggggg ggggggggggggggggggggggggggg gggggggggggggggggggggggggggg gggggggggggggggggggggggggggggggggggggggggg gggggggggggggggggggggggggggggggg gggggggggggggggggggggggg ggggggggggggggggggggg ggggggggggggggggggg gggggggggggggggggggggggggggg gggggggggggggg ggggggggggggggggggggggg gggggggggggggggg ggggggggggg ggggggggggggggggggggggggggg gggggggggggggggggggggggggg ggggggggggggggggggggggggggggggg ggggggggggggggggggg ggggggggggggggggggg ggggggggggggggg >bdopss hn OL gggggggggggggggggggggggg gggggggggggggggggggggggggggg gggggggggggggggggggggggggggggggggg gggggggggggggggggggg gggggggggggggggggggggggg gggggggggggggggggggggggggg gggggggggggggggggggggggg gggggggggggggggggggggggg gggggggggggggggggggggggggggggg gggggggggggggggggggggggggggg ggggggggggggg

124 PPENDIX gggggggggggggggggggggggggggggg ggggggggggggggggggggggggggggggggg gggggggggggggggggggggg ggggggggggggggggggggggggggggggggggggggggg ggggggggggggggggggggggggggggggg gggggggggggggggggggggggggggg ggggggggggggggggggggggggggggg gggggggggggggggggggggggggggggggggg gggggggggggggggggggggggggggggggg ggggggggggggggggggggggggggg gggggggggggggggggggggg ggggggggggggggggggg gggggggggggggggggggg gggggggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggggggggggg gggggggggggggggggggg gggggggggggggggggggggggggggggggg gggggggggggggggggggggggg gggggggggggggggggggggggg ggggggggggggggg ggggggggggggggg gggggggggggggggggggggggg ggggggggg >bdopss hn OL ggggggggggggggggggggggggggggggggg ggggggggggggggggggggggggggggggggggggggg gggggggggggggggggggggggggggggggggg gggggggggggggggggggggg gggggggggggggggggggggg ggggggggggggggg gggggggggggggggg gggggggggggggg gggggggggggggggggggggggg ggggggggggggggggggg gggggggggggggggg gggggggggggggggggggggggggggggggggg gggggggggggggggggggggggggggggggggg ggggggggggggggggggggggggggggggggg ggggggggggggggggggggggggggggggggggg ggggggggggggggggggg gggggggggggggggggggggggggg ggggggggggggggggggggggggggggggg ggggggggggggggggggggggggggggggggggg ggggggggggggggggggggggggggg gggggggggggggggggggggggggg ggggggggggggggggggggggggggg ggggggggggggggggggggg ggggggggggggggggggggggg gggggggggggggggggggggggg ggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggggggggg ggggggggggggggggggggggggg gggggggggggggggggggggggg gggggggggggggggggggggggggggg gggggggggggggggggggggggg gggggggggg >honm bum O ggggggggggggggggg gggggggggggggggggggg gggggggggggggggggggggggggg ggggggggggggggggggg ggggggggggggggggggggggggggg

125 PPENDIX ggggggggggggggggg gggggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggggggggggggggg ggggggggggggggggggg gggggggggggggggggg ggggggggggggggggggggggggggggggggggggg ggggggggggggggggggggggggggggggggggg gggggggggggggggggggggggggggggggggg gggggggggggggggggggggggggggggggggg ggggggggggggggggggggggggggggg gggggggggggggggggggggg ggggggggggggggggggg gggggggggggggggggggggggg gggggggggggggggggggggggggggggggggggggggg gggggggggggggggggggggggggg gggggggggggggggggggggggg ggggggggggggggggggg ggggggggggggggggggggggggg ggggggggggg ggggggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggggggggg gggggggggggggggggggggggg gggggggggggggggggggggggg ggggggggggggggggggggg gggggggggggggggggggggggggg gggggggggggggggggg ggggggggggggggggggggg ggggggggggggggggggggggg g >honm bum OL ggggggggggggggggggggggggggggg gggggggggggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggg gggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggg gggggggggggggggggg gggggggggggggggggggggggggggg gggggggggggggggggggggggggg gggggggggggggg gggggggggggggggggggggggggggggggggggggg gggggggggggggggggggggggggggggggggggggggg ggggggggggggggggggggggg gggggggggggggggggggggggggggggggggggggggg ggggggggggggggggggggggggggggggggggggggg gggggggggggggggggg ggggggggggggggggggggggggg ggggggggggggggggggggggggggggggggg gggggggggggggggggggggggggggggggggg ggggggggggggggggggggggggggg ggggggggggggggggggggg gggggggggggggggggggggg ggggggggggggggggggg gggggggggggggggggggggggggggg gggggggggggggggggggggggg gggggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggggggg gggggggggggggggggg gggggggggggggggggggg gggggggggggggggggggggg ggggggggggggggggg ggggggggggggggggggg

126 PPENDIX gggggggggggggggggg gggggggggggggggggggggggggggggg gggggggggggggggggggggg ggggggggggggggggggg >ny hssn OL (B s n Bnk ID: DQ9) ggggggggggggggggggggggggggggggggggg gggggggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggggggggg ggggggggggggggggggggggggggggggg ggggggggggggggggggggggggggg ggggggggggggg ggggggggggggggggggggggggggggggggggg ggggggggggggggggggggggggggg ggggggggggggggggggggg gggggggggggggggggggggggg gggggggggggggggggggggggggggggggggggggggg ggggggggggggggggggggggggggggggggggggggg gggggggggggggggggggggggggggggggggg gggggggggggggggggggggggggggggggggggggggggg gggggggggggggggggggggggggggggggggggg gggggggggggggggggggggggggg ggggggggggggggggggggggggg ggggggggggggggggggggggggggggggggg gggggggggggggggggggggggggggggggggggggggg ggggggggggggggggggggggggggg ggggggggggggggggggg ggggggggggggggggggggggggggggggg ggggggggggggggggggggggggggg ggggggggggggggggggggggggg ggggggggggggggggggggggggggggg gggggggggggggggggggggggg ggggggggggggggggggggggggg gggggggggggggggggg gggggggggggggggggggggggg ggggggggggggggggggggggggggg gggggggggggggggggggggggg gggggggggggggggggg ggggggggggggggggggggggg ggggggwysgggggggggggggggggggg ggggggggggggggggggggggggg gggggggggggggggggggg gggggggggggggggggggggggg gggggggggggggggggggggggggg g Pomo squns usd o smn ompson (kb): >Mdgo unu pol (9) ggggggggggggggggggg gggggggggggggggggggggggggggg gggggggggggggggggggggggggggg ggggggggggggggggggggggg gggggggggggggggggggg gggggg ggggggggggggggggggg gggggggggggggggggggggggggg gggggggggggggggggggg gggggggggggggggggggggggggg ggggggggggggggg ggggggggggggggggggggg ggggggggggggggggggg gggggggggggggggggg ggggggggggggggggg gggggggggggggggggggggggggg gggggggggggggggggggggggggggg

127 PPENDIX ggggggggggggggggggg ggggggggggggggggggg ggggggggggggggggggggggggg ggggggggggggggggggg gggggggggggggggggggggg ggggggggggggggggggggg ggggggggggggggggggggggggg ggggggggggggggggggggggggg ggggggggggggggggg ggggggggggggg gggggggggggg g >ny hssn pol (B s n Bnk ID: DQ9) ggggggggggggggggggggg gggggggggggggggggggg ggggggggggggggggggggggggggggggggggggggg ggggggggggggggggggggggggggg ggggggggggggggggggggggggggg ggggggggggggggggggggggggggggggggg gggggggggggggggggggggggggggggggg ggggggggggggggggggggggggggggggg ggggggggggggggggg ggggggggggggggggggggggg gggggggggggggggggggggggggggg gggggggggggggggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggggggggggggggggggggg gggggggggggggggggggggggggggggg ggggggggggggggggggggggggggggggg ggggggggggggggggggggggggggggggggg gggggggggggggggggggggggggggg gggggggggggggggggggggggggggggggggg gggggggggggggggggggggggggg ggggggggggggggggggggg ggggggggggggggggggggggg gggggggggggggggggggggggggggggg gggggggggggggggggggggggggggg ggggggggggggg ggggggggggggggggggggggggggggggggggg ggggggggggggggggggggggggggg ggggggggggggggggggggg ggggggggggggggggg >Popuus hop po (POPR s) gggggggggggg gggggggggggggggg gggggggggggggggggggggggggggg ggggggggggggggggggggg gggggggggggggggggggggg ggggggggggg ggggggggggggggggggg gggggggggggggggg gggggggggggggggggg ggggggggggggggggggggggggggggggg ggggggggggggg ggggggggg ggggggggggggg ggggggggggggggggggg ggggggggggggggggggggggggg gggggggggggggggggg ggggggggggggggg ggggggggggggggggggg gggggggggggggggggggg ggggggggggggggggg ggggggggggggggggg ggggggggggggggggg

128 PPENDIX ggg ggggggggggggggg ggggggggggggggggggggggggggg gggggggggggggggggg ggggggggggggggggggggggggg >Popuushop po (POPR s) gggggggggggggggggggggg ggggggggggggggggggggggggggg ggggggggggggggggggggg ggggggggggggggggggggggggg gggggggggggggggggg gggggggggggggggg gggggggggggggggggggggggg gggggggggggggggggggggggggggggggggggggggggg ggggggggggggggggggg gggggggggggggggggggggggggggggggggg ggggggggggggggggggggggggg gggggggg gggggggggg gggggggggggggggg ggggggggggggggggggg ggggggggggggggg ggggggggggggggggggggggggggggg gggggggggggggggggggggggggggggg gggggggggggggggggg gggggggggggggggggg gggggggggggggggg ggggggggg ggggggggggg ggggggggggggggggggggg ggggggggggggggggg ggg gggggggggggggggg ggggggggggggggggg >Sonum ubosum po (n ID: PSDM) ggggggggggggggggggggggggggggggg gggggggggggggggggggggggggg gggggggggggggggggggggggggg gggggggggggggggggggggggggggg ggggggggggggggggg ggggggggggggggggggggggggggggg ggggggggggggggggggggggg gggggggggggggggggggggggggg ggggggggggggggggggggggggg gggggggggggggggggggggggg ggggggggggggggggggggggg gggggggggggggggggggggggg ggggggggggggggggggggggggg ggggggggggggggggggggggggggggggg gggggggggggggggggggggg ggggggggggggggggg ggggggggggggggggg gggggggggggggg gggggggggggggggg ggggggggggggggg ggggggggggggggggggggg ggggggggggggggggg gggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggggg gggggggggggggggggggg gggggggggggggggggggg gggggggggggggg ggggggggggggg

129 PPENDIX >Sonum ubosum po (po) (n ID: PSDM) ggggggggggggggggggggggggg gggggggggggggggggg gggggggggggggggggggggggggggg ggggggggggggggggggggggg gggggggggggggggggggggg ggggggggggggggg gggggggggggggggggggggg ggggggggggggggggg ggggggggggggggggggggg gggggggggggggggggggggggg gggggggggggggggggggggggggggg ggggggggg gggggggggggggggggggggggggggg gggggggggggggggggggggggggggggg gggggggggggggggggggggggggg gggggggggggggggggggggggggggggggg ggggggggggggggggg gggggggggggggggggg gggggggggggggggggggggggggggggggggggg ggggggggggggggggggggg ggggggggggg gggggggggggggggg ggggggggggggggggggggg gggggggggggggggggggg gggggggggggggggggggggggg ggggggggggggggggggg gggggggggggggggggggg ggggggggggggggggggg ggggg >Vs Vn po (O9) gggggggggggggggg ggggggggggggggggg ggggggggggggggggggggggggggggggggg ggggggggggggggggggggggggg ggggggggggggg gggggggggggggggg ggggggggggggggggggggggggggggg ggggggggggggggggggggg ggggggggggggggggggggggggg ggggggggggggggggggg gggggggggggggggggggg ggggggggggggggggggg gggggggggggggggggggggg ggggggggggggggggggggggggggg ggggggggggggggggg gggggggggggggg gggggggg ggggggggggggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggggggggggg ggggggggggggggggggggggggggggggg gggggggggggggggggggggggggggggggggggggggggg gggggggggggggggggggggggggggggggggggg gggggggggggggggggggggggg ggggggggggggggggggg ggggggggggggggggg ggggggggggggggggggggggggg gggggggggggggggggggggg 9

130 PPENDIX O Pomo gnmn om n Bss sps s dspyd n Fg : * * * * * * * * * * * * * n h y 9 u b n o N 9 n p p u s n B o B o S n o S u m b 9 n h y u b n o N n p 9 p u s n B o B o S 9 n o S u m b * * * * * * * * * * * * * * * * n h 9 y 9 u b 9 n o N n p p u s n B o B 9 o S n o S 9 u m b n h 9 y 9 u b 9 n o N n p p u s n B o B 9 o S n o S 9 u m b * * * * * * n h y u b 9 9 n o N n p p u s n B o B 9 o S n o S u m b

131 PPENDIX * n h y u b n o N n p p u s n B o B o S n o S u m b * * * * * * * * * * * n h y u b n o N n p 9 p u s n B o B o S n o S u m b * * * * * * * * * * * * * * * * * * n h y u b n o N 9 n p p u s n B o B o S n o S N N u m b * * * * * * * * * * * * * * * * * * * * * * * * * * * * n h y 9 u b n o N n p p u s n B 9 o B o S n o S N N u m b * * * * * * * * * * * * * * * * n h y u b n o N n p p u s n B o B o S n o S u m b 9

132 PPENDIX * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * n h 9 y u b 9 n o N n p 9 p u s n B o B 9 9 o S 9 n o S 9 u m b 9 * * * * * * * * * * * * * * n h y u b 9 n o N n p p u s n B 9 o B o S n o S u m b 9 * * * * * * * * * * * * * * * * * * * n h y u b n o N 9 n p p u s n B o B o S n o S u m b * * n h 9 y u b n o N 9 n p p u s n B o B o S n o S u m b * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * n h y u b n o N n p 9 p u s n B o B o S 9 n o S u m b

133 PPENDIX * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * n h y u b n o N 9 n p p u s n B 9 o B o S 9 n o S u m b * * * * * * * * * * * * * * * n h y u b n o N n p p u s n B o B o S n o S u m b n h 9 y u b n o N n p p u s n B 9 o B 9 o S n o S 9 u m b * * * * * * * * * * * * n h y u b 9 n o N n p p u s n B o B o S 9 n o S u m b * * * * n h y u b 9 n o N 9 n p 9 p u s n B o B o S 9 n o S u m b

134 PPENDIX * * * * * * * * * * * * n h 9 y 9 u b 9 n o N N N N N n p p u s n B o B o S n o S 9 9 u m b 9 * * * * * * * * * * * * * * * * * * * * * * * n h y u b n o N n p p u s n B o B o S n o S u m b * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * n h y u b n o N 9 n p p u s n B o B o S n o S 9 u m b 9 9 * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * n h 9 y 9 u b n o N n p p u s n B o B 9 o S 9 n o S u m b * * * * * * * * * n h y u b n o N n p p u s n B 9 o B o S n o S u m b

135 PPENDIX n h y u b 9 n o N n p p u s n B o B o S 9 n o S u m b n h y u b 9 n o N n p p u s n B 9 o B o S n o S u m b n h y u b 9 n o N 9 n p p u s n B o B 9 o S n o S u m b 9 n h y u b n o N n p p u s n B 9 o B o S n o S u m b n h y u b n o N n p p u s n B 9 o B o S n o S u m b

136 PPENDIX n h y u b n o N n p p u s n B 9 o B o S n o S u m b n h y u b n o N n p p u s n B 9 o B o S n o S u m b n h y u b n o N n p p u s n B 9 o B o S n o S u m b n h y u b n o N n p p u s n B 9 o B o S n o S u m b n h y u b n o N n p p u s n B 9 o B 9 o S n o S u m b

137 PPENDIX n h y u b n o N n p p u s n B 9 o B o S n o S u m b n h y 9 u b n o N n p 9 p u s n B 9 o B o S n o S u m b n h y u b n o N n p 9 p u s n B o B o S 9 n o S u m b * * * * * * * * * * * * * * * * * * * * * * * * * * n h y u b n o N 9 9 n p p u s n B 9 o B o S 9 n o S 9 u m b 9 * * * * * * * * * * * * * * * * * * * * * * * * n h y u b 9 n o N n p p u s n B o B o S n o S 9 9 u m b

138 PPENDIX * * * * * * * * * * * * * * * * * * * * * * * * * * n h y u b n o N n p p u s n B o B 9 o S n o S u m b n h y u b n o N n p 9 p u s n B o B 9 o S n o S u m b 9 * * * * * * * * * * * * * * * * * * * * * * n h y 9 u b 9 n o N n p p u s n B o B o S 9 n o S u m b * * * * * * * * * * * * * * * * * * * * * * * * * * * * * n h 9 y u b n o N 9 n p p u s n B 9 o B o S n o S u m b 9

139 BBREVIIONS BBREVIIONS n dg sus µ mo ', ' pm, pm mno,,zo xh h ms Hmggunn g dnn mp mpn B b homosom bhlh bs hxoophx BLS bs o gnmn sh oo bp bsp yosn um hod MV uow mos vus ONSNS, ONSNSk, O DM onsvd ds mo DN ompmny DN DS odng squn hip homn Immunoppon h homosom MM onsvd mdd mo o oumb PM onsvd poxm mo RM onsvd guoy mo DD dknss ddh O on xhng pud nd szd w DMSO Dmhysuoxd DN dsoxybonu d dnp doxybonu phosph DOF DNbndng wh on ng ED hyndmn d EMS opho moby sh ssy EBR hdum bomd EOH hno g gm gunn gn gnmn W wy h hou H ninunz, Hmggunn H hydogn hod Hs hsdn Kn knmyn kb kobs kd kodon mm mm bu LB u boh LBS LUX bndng s LD ong dy LED ghmng dod L Lndsbg Lu un 9

140 BBREVIIONS L LOV m M mg mn Mn mo mrn MS MBS N NF NOH O/N OD ORF PBM po PR ph PI pnos POL II R RN R SM SD SDS SNP P q EMED F s S UR w YH Z mno ds nn ysn sp d um d Phnynn yn Hsdn Isoun Lysn Lun Mhonn hum LIH, OXYEN, VOLE m mo (mo/) mgm mnu mngns(ii) hod mo mssng RN Mushg nd Skoog s bud sn suppmnd wh mk powd ny bs sodum uod sodum hydoxd ov ngh op dnsy nm opn dng m pon bndng moys pomo o ONSNS poyms hn on ngv oghm o h poon onnon pos nhbo ok mnm pomo o NOPLINE SYNHSE RN poyms II Rmpn bonu d oom mpu shoo p msm sho dy sodum dodysu sng nuod poymophsm hymn ndm ny puon q poyms N,N,N',N' mhynhyndmn nspon o shydoxymhymnomhn nspon s unnsd gon wdyp Ys On Hybd Zgb m D E F H I K L M

141 BBREVIIONS spgn Pon umn gnn Sn honn Vn ypophn N P Q R S V W ns h nomnu o pn gns oows h bdopss sndd: ENES: upp s s; mun gns: ow s s; PROEINS: upp s gu s S S RN MV MOUS L MOUSLIKE P PEL L ULIFLOWER IRDIN LOK REULED DF () YLIN DOF FOR () O ONSNS O O OL () ONSNSLk () OP ONSIUIVE PHOOMORPHOENESIS y ypohom y ypohom DNF DY NEURL FLOWERIN ELF ERLY FLOWERIN FBH () FLOWERIN bhlh () FD FD FKF FLVINBINDIN, KELH REPE, FBOX (DO) F FLOWERIN LOUS FUL FRUIFULL I INE US βluoronidse H HISONE HD HEDIN DE HY ELONED HYPOOYL LFY LEFY LHY LE ELONED HYPOOYL LKP LOV KELH REPE PROEIN (DO) LU LUIFERSE LUX LUX RRHYHMO NOS NOPLINE SYNHSE Phy Phyohom PhyB Phyohom B PP PROEIN PHOSPHSE PRR (,,9) PSEUDO RESPONSE REULOR (,,9) RFI RED ND FRRED INSENSIIVE SO SUPPRESSOR OF OVEREXPRESSION OF ONSNS SP () SUPPRESSOR OF PHY () SPL () SQUMOS PROMOER BINDIN PROEINLIKE () SU SUROSE RNSPORER P EOSINE BRNHED/YLOIDE/PF FL ERMINL FLOWER O IMIN OF B EXPRESSION

142 BBREVIIONS SF ZL WIN SISER OF F ZEILUPE (DO) (LKP) Sps pn bs pn bum honm bum y bdopss y hn bdopss hn umns gobum umns bs pn honm bum bdopss hn B npus Bss npus B ng Bss ng B o Bss o Bs Boh s ub ps ub hmydomons nhd E o Eshh o Hv Hodum vug Lj Lous jpons M Mdgo unu N on Nsuum on Os Oyz sv Pn Phbs n Ps Psum svum P Popuus hop R Rsd uo S o Ssymbum o S on Ssymbum on S Sonum ubosum hssn ny hssn (om hssn) pvu hung pvu (Eum pvuum) h ny hssn Vv Vs vn

143 KNOWLEDEMENS KNOWLEDEMENS I woud k o hnk Po og oupnd o mkng hs PhD wok possb hnks o ndng h bn bwn good gudn nd h dom o dvop my own ds Po U Hök o bng my sond supvso s w s h suppo dung my PhD wok nd n my gdu suds Po Mn Hüskmp o bng h hd o my xmnon omm D Fnzsk uk o uu dsussons ov h ys s w s bng h ouh mmb o h omm h mmb s o goup oupnd nd goup uk You w g hp! Evy Dy! spy muy d Mongu o ndb nu suppo n h poj Mkus Bns, Fbo Fon nd Mk Rüh o hp gng sd wh h poj Sn Wöz und hsn K ü vo phyognsh Unsüzung obs b nd R Mnz gos o hn suppo EvM Wng, Vm Rv, K Nodsöm nd o Vkkkm Jms o bonom suppo h gdns, spy Monk Büg nd Hk Eh o kn o hs pns Isb W nd h Innon du Shoo o Hh nd Dss s w s h Mx Pnk Soy o undng Mh, Bg und P ü n o Z Md, Lon, Lon, Ju, Lngyu nd ho o sn bu spy so o nonsn suppo Ih möh bsonds mnn En dnkn ü d Unsüzung n dn zn Jhn En bsond Dnk g uh dn bn Mnshn d mh üb d zn knpp v Jh unsüz hbn

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145 ERKLÄRUN ERKLÄRUN Ih vsh, dss h d von m vogg Dsson sbsändg ngg, d bnuzn Qun und Hsm vosändg nggbn und d Sn d b nshßh bn, Kn und bbdungn, d ndn Wkn m Wou od dm Snn nh nnommn snd, n jdm Enz s Enhnung knnh gmh hb; dss ds Dsson noh kn ndn Fkuä od Unvsä zu Püung voggn h; dss s bgshn von unn nggbnn pubkonn noh nh vönh wodn s sow, dss h n soh Vönhung vo bshuss ds Pomoonsvhns nh vonhmn wd D Bsmmungn ds Pomoonsodnung snd m bknn D von m vogg Dsson s von Po D og oupnd bu wodn pubkonn gn nh vo Kön, Novmb Smson Smon

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147 LEBENSLUF LEBENSLUF Psönh ngbn Nm Smson Smon busdum 9 buso Kön Nonä Dush Fmnsnd dg usbdung bu, ymnsum d Sd Kpn, Dushnd Zvdns, S Fnzskus Hosp, Kön, Dushnd 9 Sudum d Boog, Unvsä zu Kön, Dushnd Huph: nk Nbnäh: Bonk, Bohm 9 Dpom n Boog, smno: sh gu d Dpomb: nspon guon o h owngm gn ONSNS n bdopss hn Bgnn d Dokob, MxPnkInsu ü Pnznzühungsoshung, Kön bsgupp von Po D og oupnd