prr.hec.gov.pkprr.hec.gov.pk/jspui/bitstream/123456789/6225/1/4025h.pdf · acknowledgements...

MOLECULAR BASISOF DIFFERENT LEVELS OFAUDITORY DYSFUNCTION

ATEEQ-UL-JALEEL

Cf,NTRE OF EXCELLENCE IN MOLECULAR BIOLOGYUNIVERSITY OF THE PUNJAB

LAHORE, PAKISTAN(2009)

MOLECULAR BASISOF DIFFERENT LEVELS OFAUDITORY DYSFUNCTION

A THESIS SUBMITIED TO

UNIVERSITY OF TIIf, PUNJAB

IN IUIFILLMENT OF TUE REQUIREMENTS

FOR TI{E DECREE OF

DOCTOR OF PHIII)SOPHY

MOLECULAR BIOLOGY

ATf,f,GUI,JALf,f,L

SUPERVISIOR

DR SIIAIIEEN N. KHAN

NATNNAL CXI\ITRE Of fXCELLENCE IN MOI-ECULAT BIOIOGYUNIVERSTTY OF TIIE PUNJAB

LAFORq PAXISTAN(2txDl

IIIE NAME OF

THE GRACIOUS

TIIE MERCIFT'L

DEDICATED IIO

MYGREATFATHER

wHo coutD Nor uvE roNG ENouclllo sEE Hts WtsHES COmE nUE

IHTOUGH IH|S WOiK

TOMYMOTHER

WHO IIAS I.EFI NO SIOI{EUNIURNED

TO SEE IIE GTEAI AND PNOSPEROUS

ACKNOWLEDGEMENTS

Tb&ks 10 Almighty Alhh htb bldsed m€ witn a[ ihe wisdom, @nviclioi.

.c5,, pordrirl ud d.tuiie dnldiE lo or oc $b l€diG i3* dsigrEd ro rc

t .n higt'ly if,d.bled ro Prof. Dr. Pj@lddin Sheiktr Di.€clor, CEMB. Uniw6ity

of $e Pujlb, fd hi tind Eanrrr .'d h.tlitt

I dprc$ ny d@pes th&t! to my srthy suF*isr ProfeMr Dr Sl[nq N.

Kraa for hd .egula. *noLrly. ilhEiri@e &lvic., k6 iir6E! @pd.tid &d

domging attitud. which h.! bm a @l $ure of icpir.tio. for tu dding this

I m spqtally indebt.d to ny Mtor Sbnid Yd Kh!. for hs @6hir8 &d

dpgDrioi I m ds rh6r$l to dl ny rcspeied hior for th€ir 8!id&E ald

I .l$ wish rc dpB my th&tu to dl ny @ll..s!s od friods for tno. 8..'d

@npdry, tire devotio[ syerSi.tic bdt, @{pdatim !d eppon duing ny l!3wcn

FiMly I &lms,l.ds. rhe $ppon, @{pdition ..d .l1@6gEnd'l de.d.d ro

m by ny wife by shaing with ne dry ap61 of ny m* and givils valurble

ATEEq'UL''A|-EEL

CERTIFICATE

X is cdi6.d tl!! th. t@rch Mrk deiM in rhir tr6is b rh. odgirEl M.t of dE

.utlq At €C-Ul-Jdel .!d ha bd @i€d our !.d6 6y di61 $pdvirion. I hlve

pceElly s@. t!.ood a[ dte drt r€9dl.d in th. mesjpt ed 6fry lhor

@Eldrsvdridnidty lt is furlrq qtified th|r lb. nltsid incrud.d in 6b tnatu ha

rcr b€ u!€d in pan or tuI in a dmsipt dddy sbniftd o. i. lhe prl)c* of

$boiriid in p.nirt@spiac tutflD@t of t .Ed of .ry oils d"g* fr* !ryothq irltituton. It is dso enificd thl Ue rhdi! ha bd prcp!red lndq my sp€flkion

t@rdi.s b tb p@ib.d fdnx .!d t qdoF b cv.lutds fd 0E dttd of Ph.D.

d€E throush th€ o6.i.l prd€duG ofth€ Univesg.

In a@d.re with dE tul* of the Canre dli| b@k! * 5?8 dd ?36 e decl&.d

oMp6d.bL doorn d fid {ill b. t pt in dF tlritty oftlE Cdm! fd t niiinunitu6 rq3 ftom rh. dal. of tn. dBis defee ddin liotr

SigEn]c oftu Supdisor:

N!ne: Dr. Shnhcc!

( Ia \u- ,.t ttta-N. Khd

TAELE OF CONTf,NTS

LislofFi8ue. ... .. ........... I

LirofTo!€.... .... ........... . .... 1

Abtrevi.rid rd Sy!$o!........................ ....--...................... ..... .lvSuon rur... .. .- -. ...VI

rrrEddir...... .. ........................ .... .la\4r!rr:Rqi*oirheLi1ari6............................... ..,.... ...............5

sa.tdJ: Th.Er Andony ardPhysioloe/......... . ... ......... ........ 6

l.l. Arlrorltofl|l€HmE . .......-........ . .--... 7

Lr.L Orq Er............. ................. ... ............ 7

Ll.l.lPiM ........ ........... ......... ..... , .. ..7

Ll.f2EJdsElArdiloryMd6.............-- .-- 7

Ll l.3Tyr'pad. Mdhe............ ..... .... .7

Ll2MiddLE!........ ... ............. ................ ..... 8

l.l.2,l Audbryod:16...... . . .. ... 3

l.l.3.fffiE$..... ........... .... 9

l.l.3.t Osas lltldhlh. .............. . ... . ..9t. |.r.2 M.6ltDB rlbarlh

1.14 Orsuofconi .. ......... ..... ..... .... .12

Ll.4ll{ircdlt. .. .. . 13

Ll,t2 SlD.ili.lirb,.. ... .. . . 13

1.2 nrlsioloe/oftheH|||nEr' I5

l.2.l. SoEd@rnr.rb.pdi*6v.. .. ---....-- .15

I2.2 Mdt{Mlod dLlBdulbn ..... . .... 16

l.2l F!qE!qd!dbdi6.loo8S.tdilr@'!L@ " 16

lir.r,a-, ardiro.y drlndrin c|lsiEelih sn mb.ult bdG .... l3

I3 Clssitcdidofeldjioly 44n41ion .... ... ,...... .... 19

1.4 Clsoalnidy dFtdi[ . ... .... .. " 20

1.4.1 ENirc.lEtti @8, 20

L4.2 Ga6c@........,,,. .. .... . .......... .. 2)

1 .5 lrv.b of&ditory dysfurcrion. ....... ....... . . 20

r.6 srldtorsolaic h6i oa&niroryq^ntciq............... ... 2lI 7 Inhedia@ old*68 lnn..... .......... .. .......21

l7l NdsylrdMi Alo$nit R6iv. DatBs ............... 22

s?.rm-3 Mrpping dilde sa6 b Link!€! tu.b.is .. ..... 25

1.3 Lint!a.AElrsis....... _......... X,l3l. RMnbin tion6&lio. .... ..... 27

I 3 2 The LOD S6a md.d ... .... . 27

133 Munipoint M?9phg .... ..... ..,., .. ..... 2s

13.4 DNA PolymlllBm s ! iool for linlage !E&t . ..........23

Crrp.r 2 t teirls trd Mdlbds .. .. ... ..... 29

2.1 Fiddwo*..... . r02 Ll rddtifdionof h.ling a|Ie1d f.niti6 ...... ...... ..........302r 2. Enh[tHt ofid-tif€d tsiti6 !d ol€dion otb]ood

supt6.... ..... .... ......... ...302 t clinicd oduai@. ........

221. AudiolorirtTeshs ...... . .... ....... .. ...... 3l2.21 I Audiontry.. .. ..... .'2.21 2.Tytrp@nsry ..............- .............. ............ ...r1

222. Ve$ihdardng ..... ......... .... 34

2 2.2 l. &or$qB 16l ....

2.2.22 Ted@C!nl61. ...... ....... ...342 2r. Ctnirt trKd o dinni! ugGl@ . ... . ... 14

2 2 3 r. FunMpy or opl hdtueoDy .. ...

22.3 2 Etc.ftrsiDs'uT.s (EiC)... ...... ...... 3523lilodoryWo& .. ....

23 L DNAEI|r.di@dohttL.dsrqt6-. ............ .. ..... 15

232 QMlift.lion otDNA23 2l. onid d6iq n6rl!||!s (sp.elptdon qy)... 36

2.3.2.2 As{oscet denotb,en 6ddio....... .... ... 16

23 23. Wortir€ DNA dn,rj(s ........ ....... ..... 3?

2 3 3. Prlpd.lion ofGhr dd cplis DNA phr6.. ..... 17

2.3 a L!'||ec arbsi! ro. r4bned bFrndrdic tcsircd*h* t@i.. ........ . - ,... . ....... ...... ... ... 37

z3.4.l. Anplificado ormi@sddtit nEi€Eb pCR.. 37

23.4 a PCR cycL.... .........332.3 5. CoDGWide So ..42

2 3 5.L stlrdddidi,n of^Br pRtS#Li &. Mlppos Sa

MDl0 44

2.3.5.2 Mrlriptq PCR pol@t....... .... . .... ........... 48

23.5.3 Po€trdlirlqpcRcyck 48

2.36Pcpdllirnof$rDk ro.CaaicAdyF ..................

23 7 AuiozErel l|rclMr B-orypDS.- - ........ ...... ........4s2.3.3. tkplorye Ardysij ................. 5l2.39 Dalaoigetiio. dd db\36 6i.s Mlds ... ... .. .5t

al.9 L Ddlsi.d ...... ...51

2.3 9.2, Rdga SEa ...... ............. .... .................... ...5l2.3.9.3 M&o ot6.rbnd @'lfu&.... ...... ... ....... jl2.3 9.4 t\{odulG.

2.r t0 LODs6cC.lcut.rin .. ........... ................... ....5123.t0 | LODS@rhlroulpur. .... ........ .... .. ..54

2.3 r l DNA S6qmg for m,tdion l arulyli! ...... ..... .... . 54

2.l.llIEMuptif.ajd............. ...........,........... ...5423.ll2.EXGSApTran@r.... .... ......

2.l.ll3 S€qEiog Pjjn .. .... .. ..... ......... ....552 r l I .1. Prepei4 a pod'd ror !.ql&nte o cnEtjc ArE a....5523. r 1.5 AolsirofDN^S.qm ....56

C/,rp.e.,3 Rculrs rnd Ds4si@,gddJ: tiilrge An tan f6 Rltoned Aui@rrt Ra6irc

D€olbe$ (rFnE) bci ....

PDlo€E.... ...

Linlage lo Dr' B;Li ,4.roDFNa4p6 ..... .....Ln*\z. ro DFNAT/l L.....

Litr'ae$ DWD294:LDN l1 .

5r4'm-2: Mappiis of rhe N4 adoso4! R4sive Non-srn&omcDa66 LatrnDrt A/.rClrmrl9Pt33 ..... 70

Bckroud ......... ..... ..... 7,

Lr R@nin8ofDFJvtT2: Afoeln ht DFNS3|........................ . 72

PKDF335,..... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . :. . . . . . . . . 72

Cfiri6l ddtdin. _.. .,...................72

tudbntricF!6h.....................,........ ____...................... T)

HadoqF rr$sir ofPKDFJ!5 nd Urt,g.6 MNan,,....._........12

&6Emntof PKDF:|35 lint.gcboDdri6!odonFDr)v,dr.... .?3

Akr. ftqEq' 6fof:lio6......... . ........................,,,,..... .........j3

TFpoirtL,OOlscdordiN..............___................................73

32 r@?ig ofia&'f!': lEa DFNBaI __.........__.-......--.... jaPKDFl04t........................................................,,.... ..............?3

c1ini61d.1udion................ .. .... ......... ....,.... .... ..?3Aldiondric a.lurrim ........... ............................... ..............n

Li*.a. tCtli! ofPKDrloaa -d 4dls ofB bo! DFtvrBl 7i3.3 R.i.6E!r ofDrt872 houdtia..... ........................ .. .83

PKDFll04............... .....,................33

Cjiric.IHttory. ......... ....... ...................,,,,,...,.... ..........33

Lirrrg. .rutrii ofPKDFt 104 .. . ............. ............................. ajR!6rGdDtM22 borLn ....................._____.................... ..........86

3ac'qriBofcdihes!E.,........................._........,.,,,,..............3a

&ctd-3: Dision ............. ......... .93

Clipql R.fqa.e.......... ___.......... ............ ............. ...........td1Elcdror'ic innd! irforMioo... .......................I3Pabndifu -................. ........... ............ .......................................... l 14

LIST OF FIGURES

llRdti8.......... ....... . - .--. ... 35

'nm.ycltrE prolil6 of PCR prla,m .. .. ...

chm@e@*i* *16!ric E rsu&o ofib. AEI PRISM!

Link8. mpping * MD|oulHD5........... .44'IrE Dcydie pbfi. for &di6olim ofPld dl6 in

frJtiDlsBcR. {A

2.7. A lTfof ElehprEoeM ..... . .. ... ......tn2 3 troedE b m rl, l1ts5 @.x6t goq?. dd! ..... .. ........... .52

29 nldmqclina podl€ fors.qlen8eio... .......... .... .56

3l Pedgednwr€ of&nily PKDFI46... ...... ........ .... or

3 2 Audroerm oaPKDFl46 ...62

3.3.11C26,t, clmmr.gr4 .......62

3.4 /'edt odolosB ... ....... ..... ...... .....62

35.PdigerLr*in8of6nilyPKDF333.... ......... .................... d3 6 Aniogm of PKDF333... .... ... .. ... ........................653.7. Pedige dawing ofhnit PKDFT 107. . .... ............ ......... . 63.4 Ardiog|m ofPKDFl lo7

3.9.redt@&tuinsofftribPKDF488............................ o3 I0 Au{tiqmofPKDF4a . ... ..... ...... .............. 6a

3rr a7,D.t'r./,drmn{og'a.. ......... ...

3.r2.Cladt*uqtt]l,g6.............................................................69

3. It P.diSEd.rinc of nlit PKD8|35........--............--.........-......... 75

3.14 AullrG ofP|(DFJ35....,.......---.........-----............-.....-.-...........?5

3.l5. P.digF &e!8 ofn itPXDr1048..............----...........--..........80

3,16 Aulog|e of}XDF|043.......................................................,..,,3I

3.1?.P.dlg6||IlritrgoftuilyPI(DF|1O1,,,,.....,,,,.......,,,,.....,.,,.....84

3.18 AudiogmolPKDFll04,,,,,.... ...,,,,,.................... ..........,,,,.....8t

3.|t. Sdo.li @4qds othrrg. '!8im

ofputlil'.d &d EEn d

Dmt72 dr}.w l@ DFNtai...,............ ..........................at

3.r. CoE.iqed in rt6DFrrBS, [ {.i -vn.........................,.093.2f. G-- .q!rd n dE 6dn d DEND2 irtCt i,'an.----..........9

LIST OF TAALf,S

Ntt,bn PdstL L l,ci fq N@{tndoni. Au@ml R4!iw D.!68.............. ..22

2. L Crlo&rls fc ilE @r6rir of C.Dtric DNA ...... .......... . ..36

2.2. Miros.rdliL @,ts 6cd for [nl4e.Db6ir ofr.pon.d ]oci,

wilh droostr lpditio(incM)............. ...,.... .,,,. .........39

2.1 Rdin dn@ for PCl'.... ........ ..332.4Sut.Lrdiz6dldrofrdiplqPCRol@hpdd.. .......45

2.5. &dih nirtwforqUf cii!orPCR F.t81s.....................54

2.6.Radbrai.\r@lorE)(GSAPTT.&Ert ...... .......... .....55

2 7. n!.ciD trixrw for 3eqqcidg l{iid............ . .................... ...55

3.1. T*poir LOD s6 b.ctt@ 19 hlcd dl* ir tuitPKDF335..... ....... ......... ......... 11

3.2. TeFFhr LOD s6 for .h|ffim 19 116 in fuilyPI(DFIO{a.,. ............. .. ........ ..... ..............................82

3.3. Ttu.Doin LOD s6 for cl@nN@ 19 nEl6 in &ritPKDFII04... ............... .... ................................. 36

3.4 kinh wd for !.qENii8 of ?!'PIS'9 d6............ . .... .91

35 kidts 6.d fd !.q€d.g of tiN M..................... ......_.q2

3.6 Nat d6ign .t Di.ro6.rdtib wt86tt€6,turof DFN,72..92

ABBREVIATIONS & SYMBOLS

A Art rb. nil MueAT?^de6i&T'Phos|ulcbp BcP.n m Mill'Mc CIGiB nM Milin le

cl cNddciocM Cdri-NiorCs NaCl sodiM Crnoi.tr

Ci ColfuitrNsr|L Nd.yn rerc gding la

d.r D.ldiu Nelcdid.DFN D6ft6 X-rddtDFNADsn6.An@ndb|lld OHC!olrdH,irc.tkDFND r* Ad@cr R6irc oMtM onli4 n ndclio tlhail.& in MrnDNA Dalrihofloloiceid p tdgmof Cnsnl,lGdNrP Dor}lEldd.Tn-Pn qiic pcn potrn6cbtundidEDra Eln9or.diuimrel]@b -FAMj{jho5Frc.

q Shdmorchl]l|@3 cndt m Rdi! nPisl@@HEX ,r.7,2 ,,r

"5 .7:lkx,.htoft{- RrE RdietpjsndE rri€ru

dno.yal@in Di REvddicFMj@HL Hainrrd sDS s.djm Do&al Sdrare

Hld l{ord (in Fm qd.) :ril- s}dMjc }r€rjns 16bf. HM r fty,idt

,T E. Tn+EDTA

14 ft.m.qllmrd T@h Dom

K.Pda-uioKb Kiloboe €,bo(}durcjnKCr Pfujnchldi& fir Tdinn@&g/4(dmiJKcl PoBimct rjih Tfr MetinAT.rnDedDeLOD Ltcrihood ofod& Trp Telpd@(inpcRqd.)M Mor. rxE T,b-N,ct€DTAr'rb Megab& rds FietDdrdynErhit miodhmMacrr rr4Gju chbfi& usH usr.rsrdm

USI|IE rrbqd@lD. rB

S t.dddF da

c Coqdelrittr.!.

- lla.oqtu r&i.a!

x a'!dd.d.!.iou!.cd &.ld & CUr co.&ctd)

' $nid-dbr4qtrrdaddlogu (Bo. edldd)

o ltllddsn dr!.to-d!Gt!d;d!d(rir

t6c Uiiidtdsii. socd.tLrs Ti.dDlob nrbdi

riCBI rSol C-abHacbLd

SUMMARY

Au&ory dlEnDdion ir oE of the @t on]lm @roeery defdr6 h hulleln the P.kisla.i popuklion $is trait is obsd.d at a td. of I 6 pd l0o0 individuals, and

h.tr of rh. clg &. hsir6bl. (ELti ,, or., 193) TlE P.lisr4i popularion is a good

eu@ ior gs.lic sudi€s of deiEs s ddoNtra€d by lhc fa.l thd it ha altady

@.r.ibur.d to th€ idsnificaiion of 25 hcrtdiury datEs loci, ed in ih. idorifiqtion of

16 oalh. ols.tircgprc! !r th€e lci. whn it ir ecidt€d dtr a.ol!l of-loo 8e6 rcrcquir.d fo. nomrt tuncliming of thc tmndm d Ori.dlm rd Ctiffrth, 2003),

oilt ll8 d.anB ldi h!rc be. laelt d io d!re, !d tt @sliirc g@ !r onlv 49 leihav€ bd idoti6.d so f& (Hcrcdi&y hesng Io$ hoo@.9€r

l pJ r.bhol u &.b./hin) Thrt FMrr ! ncd fo. mrc llgch in this freld ro unlet

th. s@.e$ ofn|nM aldiiory phFiology ed dofttds

D€ 6ior obj*tive or thi. sardy 6lo idaniry the nololJ ba! or edno'v

d'5irclion *p!6r€d |t diltddl imp&mdt lercls (nild mod€rate, s*r€ or

pofound) by u$ of lh. Ssclic dstst t-hniqE kioM 3 liiltge .Mlvsis (M.4li a'

dl, 2OO3: Peiii .r rr. 2OOl). 1o rhide rh! objedive fiv 6nili6 with @ng@it l

dc.fn€s sgre8.iing i. & tutosnd tuBsive node of inhcriioe w@ iddfinen, dd

hlood eDpl6 w@ @[.ded. DNA B qth(*cd frd blood sd6 od lir'log'

Mdye! w6 p€rfomed on 25 $leled fimili.s to sr.h fo. linlag. to th€ previolslv

r€rDn€d Jno$n l cenve deafB loo 0ldldiLry HdinA t]N Hon p.gel

htror/w.bho1.u!&bs/hhh). Fou famili€s snowed liills. to DFtBllPDs, D|NB7,I

&d DI.NB291('LDN!4. S.q!.re ltbsb of two linlcd fsils @hed in

iddonqdor otoe eDon.d ruilrion (c?l6DA p.V239D) it SaC26A4 (DFNDI) ad

oft nov.l mr.tio, (c 23 r c>Ti p.A94v t i CLDNI a <D|NB'9) seM.

A gtuDFwide tu ws ps,bt4d oi tm sdcd€d udiik.d &n i6lo s.ch

fot rcvel loci itvolwd in &ditory dFtundion The e6one !q ofrh. f@ilv PKDF335

h.lp€d in th€ disve.y of ! na l€6{ve d.!ft.s !ms, Dlxr2?, al chrcmoe@

l9Dl3.l-13 2 *ith a dili..l linl,s€ itl.nd of0 74 .M berlN@ ln. rukd Dl9S2l6

(20 or cM) od DI9SIOI4 (20 75 .M) (N^ et al , 2007) tild ot! rcfilmml of

,FIVA72 ws oni.d oul *ilh lhe lldp ol nqly defrn d Mtd .nd two ture fN,nili6

(PKDFI048 dd PKDFI104) liil.d to the chrc@o'Ml r€gioi dc6'€d by lhe p@ious

DFND?2 tanili.s. Tn€ Gf.d€rtt indic.rcd thll ohrcdo$mc l9ol33-132 was a

h€rdog€|d3 l@!, nrtoring tm ditrqq d..fB lo.i @ tlE Fon'sl 6d di*d

6ds of the raioust r€po.ted cdtlc€l linlcgc intdtl. Thb @lt.d in rcdnoer orrhe

Dalvnz2 l@s to th. trncdlt b.rwd rhe nart@ D19S1034 (20 75 cM) trd Dl9S39l

(2a.83 cM) lDmins 8.08 cM. Sirulr,t@dy. . mv.l l@s Dlrvral (a dei8t ed bv

th€ HuGo nondd.rurc @min*) @ tupp€d bei$@ Dl9s8?8 (6 57 cM) ed

Dl9S895 (l8.l5cM), d@n!6si.g t linkag. ittdtl of ll ?a cM (Fig l 19) TlE

flmili6 Efinirg th. DFt 72 lro 3hostd . profound ldcl of l6ins losi whil€ the

fanili4 th.t d.ff..d rh€ Dli'Bal bdt snowc<t nodmlc to se@ h.rina 163 Trc

candi&te AoG in thc Dt-lvral lik gc i!ri6v.L ?MP&!S9 .td r'Z{/, q@ !.qua..d.

blt no mui{ion wa found

An int€rclting fdtur€ ssdilI.d with rh* l@i, th. noltl ,1'lVAa1 dd th.

n vty ..6ncd DIrVdZ, is in dif.d@ in rlEn ud@.ric pre616 This dv hdP

denn. $ft bdis for gemttlcphaotype @r.eJrtioro in dehe$ The @pting of 3

n@ l@s Dl.fVrE, is dsi$.tn v h rh. i4 thlt addiiion l dd&.!s@nig l@i

rdin to b. 'u9d, and splotl tlE hlToth6i. th.l tt P jsld population b th' best

euc to srki in thc iddiid€lrion orth.€ rFrcs.

INTRODUCTION

Audirory dFfutrtjon is Mif6r.d ty pdrial or @npl.t iMbitiq ro h@ or

piopett di,f6s id. soDds, ad by r.du€d Dotalid aor sp..cb n lhe all*r.iinlividusls It is one of lh. mosl pcv.l.it so@ry-neu.al d€ficils in nuur4 !d dlT*ts0 l% of lh. popllrim @nd d. Abo[ h.r of dE ce e @ic.\ hdiLbt.lMonon rd N&€, 2O(X: D!u.d. ., a/ . 2009I

TrF 6B of hcEdi&ry lEing inpdrnEn nsy b. lt|@seic or mlheaic(Babuntu ?, al, l9q; Fnd|M dd Cnfi \ 2003) Aboul ?O% of rhe hd.dira_v

66 ee non-Eldrodic \ts4 l0% e E dronic. in liich d.afn6 co,oau6 \itiorh6 tflom (6orlin .r al, le5; Kdlsir md P€ril. 1998) Th. ede of inhsitued4v b€ elo$hd t6sirc (75,300,4 or cs), @r@trEl domi,Er ( I 2,2a% of cB) orx-Inr.d (!-r% oa cs) *nib Y-hr.d !d nirodo.dn.l d..fr6 e atso tod.d(cr)6 @d Vd Cano. 2004).

C[.ic.lb, d..ftB nEy b. clssifieit 6 contucliv., s.@tuurd or mix.d

ecord'na lo lh. siie of6. def4t (M&uilo d al, 1993) The sq.rity oth€dins lo$ is

|@rd by tudiom.lry ed 6 cl6ili.d inlo vdio6 tacts bs.d on lh€ atitiry of a

!.Mn lo hd eunds of difad nidily a v.ryi.s ftquodB (BEn6, 2m6) Thel6€ls of $vdity e dlfdincd i' o nitd, trDdrar5 we sd Dofo@d (Mlmti,,ar, 2003). In Co@tic danBs" rhe aubsom.l lsive fom of heins t6s @ rlE mosl

evft Thq @ ty?ic.lly @nssit l, bilarsd ed ftly porcldt smrireural in

@n@ ed e. olmosr qduiwt due b 6.h!@ def* (cidio erat., t99s) rn @nl*(dE anoso'd doftin in fom of {te|'B & samrly Dosdinsud, prosair !d eo8a undr.l or mild bilddil, rld c.e borh @dudiv. qt $gdrud !dno,6.fi&<rim (F66., aa. 1976: peri( l9 )

c€nsic ed nol4ur{ apptwlB ha@ prova to b. pow.rtul methods forud6lodDA lhe plDtsiolory of tsirg rn p&liqrle, th. idotific€rion ot 8o6sDKssl in th. imd @ ard dE sn|dt, of $c chdlisr_v ed plDsiolos/ ofde prorciB

nbded b ln6. gc ns b€r very fruidul (FriedM ed o'iffo\ 2oo3: w@& ,, at .

2006). Idivdud! *ilh i.bdn d udnory dtdndon provid. t uie6 $os s@ asd md.Nl&i rh€ir 6ndim dd @de oa *p6i@ (R.jrno.,1992). rbwvd $is t&sk is ompticaLn due b dE exteoe saetic bet@go.ilv &dlinired g@9TdDhtuqpe @rrelrlion ol hsEdiEy d6fn6 in hl|m (pdil e/ al,

2001). ll ha b6.di!!t d |htr.r 16r l% (-!OO) ofhufu prcLilodi.s sgE espailidlt hrclv.d i! th. ndiB proc6, .d tns rDrrlioB tr r!'y difi.d scc@ 8clcn !n didol harog4ily (Frinm id criffiti, 2003; NrE , 2m3).

Cliii6l h.rslg4iry i3 .vidal $tF n'r.lio6 in 0r 5@ Ba ri.v c.e DFtrrd@ic lllourd 6tv., @$ni dorind d qrnrcdc d.!K fdl'mpf., ditr En an i ,llda ot WOTA r@ jt@@t tgiv. DFTVTZ

dr@n l doninar ux,r // rn trdremic L6lr/a (Li! ., ,l, | 9?4 Liu r, al, l997br

Ltu a ol., l99rq Li! a at., t993 ri wd.,ar, 199?) MooE, rh. e6iry oflEi'A 16 .lo iFs lsaeS.ldry. Fd eDpk, rurr.lH€ of Gra2 (D!Urr)hEbofot ro de hdirB 16 EginS fion dtd lo p@forld. .6 in dE {t6i.d

'Jmbds of fh s@ tDit (Ddbldfo .t al_, 199: tnvpi| a at., t999:5.b. d at..

2000 !d Snch d ,1, 2005). Rsi* ll,rr dld6 ol $m odE 8G h.E .boba r.toiLd io ..@ pbfourd 6 *dt 6 iod.lr. io s@ .lditory drltEuion ar.,Sl,C26r1 lDtNR./ )t\ (tn.@-Eie6 a ul, t999j Nqtar.t d al,2AO4), CItr2J(DFrVrr4 (C:hib.,41, r!r96b: w€.frn.t a|,2@7J,fEU (DF|D2| t O1z d al..

2@t , otoA <DFNB22) (7*ry.d.t at.,2@2' d rcDEt5lDtNB23) (rt r.d.t

To dlt 138 utaom.l lbrrdMi. tEir iq,nrrsr lod hn b6r dttE!?on d or |g*d. At49ofdE lci, ttr tutd slE h.€ b€rdqiddql F n.

ea ol lF locl (22 iddi6cd g6) e ssi!.d *ith !r@!d doMltrcnisio *tiL 3I lqi (2t i.bd6.d r.g) dFr -l@od tqirc in|,ireSn x-L*.d lGi (w jdlrrilid ga) tn $r rncrbdri.l saE he. d$ ban.?on d (Hrqlidy [-ias 18 horEFsc h@r/*talot.r-b.4$lt). Th. .v.it.bt.8a!dc htormria iidicdq 6r ddjd@t datB g.E G F ro b. '{!.d *nitr..quia lunhd iiestir,li@

I-i.r!e. dlFb of 14. qs4utF6 feiti6 lnn irrEibd daliB hspd.d ro b.$.nahod ofdDk for tr'{tirB B lci ieleld in lEinS np.rtfu({d .Lo fd t!tuiu rtB. li'*!g. i'n w.r5 ro id. i& $c mdr|d s@ (p.rit dr,l.2ml; F ntm rd GidirL 2m3} Tn p.ril|.ii poputd@ olf,a , q.otioEtpopuldd ro aty o trr.8. !dr!b ba4 d. ropddon i! diia inro dif@lIrib.+ chic gD!p6 rn G|6, rt'id h.v. t ray hgh lcxtsr, of hbi!.diis.d elildy to b. daiv€t gcsicl|t homA.e6 Aryding b r @d cardr d drP.ld.r.ri Fpd.tio! 6Ot6 of dr |ui.86 @ dloSui@ur ot rti.n fiE 0- m%F b6*e fial @Gi'! (HNnr !n Bint.4 199€). R6ivdy irlEn d dis46 e

mE psd.r in @EegliFs populdoc (hb6 '/ a/, l99t) Tht B 6id4l noh

de pFril€@ of dsdild j*sire d.dHr cg ir d. Pstisfin poDulato4 whjcn

e 6drnd.d ro b. I 6 td lmo, td ?ota of|i6. @ di$ in oBnarnnaa fmiliB(Elohi d, at. 1993) This ha allowd naDDins of 25 allosonal .€6ivo de5fE3 loc'

nd dF id.dincdio of 16 ssE b Plkaldi populr jm (Hdedtttty haninS lNnomplsd htrD://*bh0l.ee.bo'hhh) ed hB add€d cmidslbb lo d'e gqFtic

infomri@eE.swd..f6TIE nrajor obj.diw ofrhi! study wG lo idd'li& lhc ml@ul4 bsis ot ednort

d6frD<dd &o!!d sith ditrsd dnionaric DrofL* c/hidr dld h. hdtaul in

dllblishog e@t}lFphml,Te orelali@ in $n disrde ro ehi.ve lhi! objoclte,

50 f&dl!. s€gr!8ltns rrGord 'csirc hsEdiLty hdi4 lN re @[ed DNA

ws dt@l€i fbm bt@d spl6 tDd t &!ge E FD for |ne l oM dio$t'.I,tsiv. datB lai s pdforn€d d 25 sd..r.d ftnilis Fou fanil6 sho*€d

lin&Ieo ro th@ publth.d loci tL DtNBa, DtllDT/l I al Dtlll29 Sequre .nd).8

oa tro lirl.d fanili6 G lbo D.fonr.d enirr @i!d in lh. iddi6.ni6 of@r.oon d nurario (p.v239D) in $e SLC26A1 gN

^ n\. DTNIN l@c ud one mvel

dllrid (p Ag,tv) in crrr' s4 a lr DlnB2g lN.In o etfoft ro sch for @v€l loci idolvln in &dltorv dllfildto4 .3@F

*ide s using r33 nic@rdlll. mtt6 6 pqfodt*d d l*o fmni6 da sho$ed

rc linlagc !o lsDM datB locl Tte lsDtr M Bults in &tulv PKDI335 h€lperl

in |ne dbevd of ! @ l6.iv. daii6 l@rx DrM72, o d@I||o.@ 19?13 3-

13 2, wilh a criri..l li rSp oienal ofo.?4 cM bGnv€ th€ ndt@ Dl9s2l6 (d 20 0l

cM) ed Dr9sro34 lt! 2o-1s .trD {^n et al. 2007) h addilioNl dpdiDats.

rcfuEnF|| orDl)vr72 rc wri.d od *in d! h.lP ol tst ddetEd odts !n No

*s teili6 (PKDFloa3 {xt PKDFTIO4) [tr.d io llt DF]VBZ clmtusomal Eeion

Th. Efirkred irdioLd rhlI Dt?t47,2 M a ha@8qeu lo.ut hsbounng l*o

ditrsqn l@i d. €di @ dE Dqintl &d dind dis of uE r.tott d linLgt i4tavd

This EuI.d in dE ro4pins of . @ l@B DF r3l (d6isnar.d bt th€ hlM 3d@ors@izdid GruOo) @mim) d l9p 13.3 6.tu Di 9S373 (d 6 57 cM) 3,i D | gst I

(.r 13.35 cM) agot65DS. dreme@l id6/d of II ?3.M Thisds@lt d in

rhe efiftnqn of de lirl,se boudsi6 tot DINB72. rcN b.twd dE ma*6

Dl9slo34 (st 20.?5.M) dd Dl9S39l (.1 23 33 cM) spei.s o hisv.l of 3 03 cM

nE.Il6Ld indrvidn ls in dE fmili6 d.liniri.s DFnrNr 3rbw ! md..ac b sd@

&dlonunc potuc *lil. .IId.d nlividuls of ldilig tuepcd b tctdrd DINa12

itllsyd h!rc prcfoud dat6 The min@ IOD sE for tlE tlhily PKDFj043,

d€dni.8 rFnB3l, wa lodd !o be 3 59 (! I = 0) wirl rhc dtd Dl9559 | { al 9 34 cM)

*nib hnily PKOf335. eni:h sb..cuqrt $pDod.d Dfivaltr, $osrd ! @imMLOD sE of 4. l0 wii lne dtta D 19S424 (d l0 97 cM) md D l9sr4 (at 20 0l .M)Th. LOD src of loily PKD' I lo4, r'iidr iefn d lL DrxtT2 inhd 6 c€lcrtar.d

robe3 Il fdrh.8uidDl9s934(d28.6?cM'Ila tefabn DFNa72 atn DFNBSI diti.d i.tdlals {e locatod io a etu ricn

rgio on chmMr 19 (UCSC CrFft BioinlonEIi6, hlp://Edtu.lE..du4Son. of dE EcB Dc@r sirhin rhs loo @ 3po<t c&di&I6 aor ding $e ddtn6s

phao9le Two inpone[ s*, I]lf,Rlrtc ed ,zRl, s@ s.qucE€d, bul m nuLto!

lh. nappin! ofdr nd l@6 ,r,,va3/ in th. P!ki.l4i populadon sub6lamidc

rh. lD1olh@r ll r svq"l smh lai e nill io be idanine4 dil {!1 rhi5 lopuhtion wiU

tguin hdotul in |he ido!ficdron of lddirio., G of d..fK This 'datific{'on

wil sitl i4 dF unddredi.g of lhe n4hantu ot hdin8, qtich in th will b.

bd-fti.I io rh. i.|p&nd huju b.i.F Tte t*! dstEdr.d toa. DINB72 dDFlVatr. @ ssid.d silh difrds ludionertrc Dbfl€s, &d lnc idaninc5don of !rGiv. l@s f6r nbdr.t !o ffi uditory dFtudid qill @ftibut lo 61t!lish

|n. nu.! d.sird gooqrephaoq!. @f,dlrioE in h.redibty d.inK.

CHAPTER-1

REVIEW

OF THE

LITERATURE

sEcnoN-,

THEEAR

ANATOMY AI\D PHYSIOLOGY

l.l lll^tlouY oITtfE HUMIJI EAX

Tr! rl|ta &dilory stltatr ir ergri.d oa. nF.l @rpli.a.4 rt Srr.d dlng y sidv. .ttrduE, @lLdirdy drFd ro B ttF r, *nicb D.f@ t dudfrlldiN of hdiig rn bdr€. Trr hrIn d 6 D@it. ad disiniDr! sqb !rt qEi6 Er8ii8 tioD 20 io,,00o l&.t (D.llo., |996; crrd rn JohEoa l99B).

Tb d L dtpo!.d of thc rioniql oopara|!: rb. odEDl a, dtdt.@ $d

'|E d. Tl| boujry b.r61 |h. araDl * rd 6c niddL * i tt

IrnFi E hE *li|. d. boud.ry ba*6 d, Ei.LIo d lid |tr inFa & rh.

Tt oI- & cGitE of d. uid. (pi4), th. andrd lni&ry rEns (doql) dd dE 9Errric r6$tu(d{@ d Dtnpjd) (Fis. Ll).

A piE ir.!.crd d ho$ |!.rt sid. ofdF,tu! b tirlFrr od nud6Tl. PiD @6i* ott dri||gi.oB 6@*qt of dsrt dEiF dc 6vq!d *ir[*in (FiB. Ll). I s6 ro dpl@ dr sd|d strs fon rl, anrdnE d diFc!.

r.r.rl EtLd.l A.at tM.d!Th. .ddl .rirory .n6ra or d dd i! . tunrd-E l!b. ttu 6!Edr dE

p'm |,o d'. gDpoic nd@ (Fig t.r) ! ir &ut 26 tu i. tasrn dt r m indi@i6 .n i! [rd ridt 3qEb6 tcrbird !?itbdi'm, idr od.i! r.!@6glrds .rl h.i6 M irs a|!ie &.?.. ddin tu Eds G ti. tui!.q sttldt{a !.q!. dI@ (r l[) !n d r!a. d. tng.M $R ed *!rD@t !dF.vEnt f(ig| obr.6 nlD Fdi.s rt od|ur.r.rJry.td. M.!b!D

T'| rynp-ic 6$d!,.ho IroM ! dE oi^4 i! t din 'nb.c Bni:hs!d!. e algrd d t 6 tlE diddt - (Fb t. t) tr lca !. bjia ro DFrerrgt'id pnho86. vibdi@ of $. rynodc nFEh@ trGnir ord tom lh. dr lotF did- of EiUL -. RltnE d prfodid .f d'. rdm 6 t-d b didi*

r"lirii:)*'--**--

l-"- t***t,*.-dnor}4.b!d[

The middl. d is a naftk !i, tithn qvity lmrr€d bqw*n tho ours and nncrer. li ts epa.arcd tun rfic .xGnal 4dirory tMB by .he rrmpoic mmbdre edlibm the inner oo by a bony pannion, which conoibs No qindow\ d olat windowlfetusn venibutit ud a rcud vnc[* Cfere!tu .uhted. Tne niddre q h ,t$conn*red ro lnc r6.ph!.ru by o smal lub€. rhe Eusehie tubc (Fis. t.t). Thisconetion sts io equtia an lGsN on bod sides of rhe 9rpmic nhbdc od at$allort frcsh at cnter lhc diddtc d ovity. t.telions of dc Esrachie rub€ €!$aeumulrtion ol fluid in $e middte q sp@, Esxing in o coturirion *noM is orirismedi *hich nly lstl in haing tN. Tie mosr impotui studtE or rxe oiddtc 6r!rc |xe ln@ audirory o$ictes: incus,n.lt.6lnd $p€s.

Thc $e auditory o$ictes ,:s.. molt.6 (h!mmer) incus (!nvil) d slep.sGritup) @ pled in a sid in lhe niddle @ c.vity. At one e.d, rhe mllteB h lkhcdby ligmdts to the tlmplnic n.mb@e. whjlc .t lhc olhcr fld fie n p.s is conned rorhc oval windor of@ht.a (FiB. | .2). The sbp€s h the sm.ltd bone in rtE hun& tuy.Nghly oa lhc sin of ! gBiD of rie. ItE tundion ol.lhc o$iclcs is 10 mDtili Md

ft.smir e!.d rav6 !c6s the tympdic qvity i@m fie gnpsic m.mbtre lo the

Th. gometric.l orgoiarion ol th. o$iclcs .nd thc su.f@ !g difeEnce

b€rwE. lh. tympdrio n.mb@. ud thc o{l window 8iv. a N.nty fold mdifE tion of

F9 u ft & * .dd.: rr4 r.r -d rF r..d !d & 9ir.*cdry,n.bFi!*JLdF.dd ift r|. o-Fr|. .rbnx (^d*d rrr E .!dordi' t ibria

Thc ims @ is . mtld $ere drr is bori.d d6p wi$in lnc Enpo.al bdlr

of the doll ind is @rdt d *ith dul tuncriod oflFlirs a wll a Nin|linins b6heol lhe body. h onsiss ol No pm.: thc bony o osss l$tainlh ud th. mnbmoslabyri h (Hudsr.b 1989),

l.rar Oslr trbyrintTl. toy Fn ol lhc imr d is kmM s $. osss bbyrinlh- !t is fillcd

wnh a nrid kt|M a p.rilyntl. ftc ch.miol @p6ition of thc Filynph @bl€s$n or$c ecbcpiMl flli! in which l||cr b l@ K' {-5 6M)..d high Na'1-145

mM) orcnrdid (Gnhm zr al, 2000). h dsi.t of rh@ m.jor uromiol sccrions:

L tL fioniil ssry porlio is dE Cerra - ! bony spiml orgu with 2rl:

ums, about 35 mn lo8 and lmks likc a e.il shell ilhus nucd "c@hl.o"

mdins $.ili in mio. cE.{-). Th. @hkr is its.lf divided lenerhwis

trlnsmn eund rdv6 8crcs tne qdnp.nic sviry am th. iymp ic nnb@e b {r

The el.odnd d8@idim ol ft€ Nicl6 !trd $. s!rf@ '€ difcneb.t@ the llmp{nic nmb.de dd th. ov.l windN give . t*frty fold dplifEotion ol

F€uftrsrd+.r'||qL.qId{F|dfue'4ddry..t.bF{brr..e.fu tna ||. irrFn rdb'u (^d{r.d rr- Exr.hF.L sdo,rw.turh(dl

'Ille inncr ar is ! @mplex shciuE rhlt is hnied dep qilhir lne Ehpodt bo.c

or rhe sloll rnd b ..|:m.d wirh d@l funcliod of t {ins 6 stl $ tujftainins t6bEof the body, Il o.si$ of No Ftts: d. bony n (rsx l.b"inrh sd rlE ncmb6m6kbrinlh (H!dsp.h, 1989).

l.l.3.l Oso!!LrbyrldthThe bony p.n of lne imcr * h IroM s ih€ oss4s lobsi.rh. Il is fiU.d

w n ! fluid looM a p.rillDph. Tte ch.oiql @nFsnion of ih. Fitynph Mbtcsthol ofdE aEbF-+id nuid. in ehich $.8 ir l@ K' (-5 nM) &xt hish N!' (-145

nM) conqftrion (Guhd ., d, 2000). h coNkts or the mjd e.loni@l s..lioNrl. fi. frc d $mry p.iid ir de Ce?r&a - o bon, spirat orgd win 214

turnst .boul 35 nm log dd l@*s lil@ a smil sl'.ll (lhus nmed.€ehtea,m$ing \Mil" in ei{fi c@t,), The ohta is ierr divid€d t.nsthwie

hb rh@ chrdie: tlE r@/. Erer!.i riicn h6 $. o$l windo$ ar ns bettatula |m7ntj *indaisittcmEn vindow: &r., rh.r@btrr'ra

"nich.oloB lh. tue lFriie s@ry suud@ I e, d. o4s of Corti (Fic, I 3)

2. Thc @ p&r .Giln of rhF si<iftulr @ds (eaqi,i ldcd odpotu'or) whid e oriern d { rttd aigl6 !o d.h oth€r axt G liruFnposI4dry (ddslt) to lh. Etihie (Fis. I 3)

3. Inlaom*ri'e dF Gl'16 r,i lte smi.iEuld cnhB is lF v6libul., st'idris d'e cd rd pd ordF booy lobrurh @llinins rlE uricl. od @u1q lh6

reor8e GpoBiblefor bdtEl.lj,2 MdbnDc r.Dyrl b

M@D!u6 l.bFi,$ Ii6 widtn rb. boo/ hbrridL Tlt chtnds of dE

tunbr@N labldDd e 6[.d Birh I tuid qlr.d o|dobrpL *iid ta E6udompc'ri6 ta, high K- (-r 50 nM) nd lo* Nr' (-t.3 nM) ctr|r6irciotr A5 r r6utor rb. dirs@ ir idic @rp6idm bdra dE re @nDsnndE, ln.de.tochdical pohnirl dif.l!@ bdw odobrph rd pqibnph ir abour +ro nvThn n dE leged podin* polarid .litr@ foEd in rb. body. SiE lh. hr&.ltutaGrins pordi.l of h& 6I @@to6 t eud ?0 mv, d'. Dot€dri.t ditr€tog

':lNdE b.n cdl rtq i! EnEt bh ie, 150 hV. Thir lISe pola|ti.t diodae sgG s a

lEDadN idic fo@ ro d.ire dE n!.lEDd..liol r.Bduclio pro6 of dE h.nelk (Eis d R'14o, 200?).

A. intorLr f6n& .f dE oiolynptdi. !!c is ld ir ; @hDtd4lv bofrLdby dsB, di 0w @ rc du.rs or opo omeliN b€tw) pdibnph ddadolFqh The bord- bd*€ e $o tuib li6 n rh. t rd or dj. juEtiB b..l@di epitlFli.l elk thd 3utrlund in ddotn|rilric sDc. Tisrn judi@ ir 0EplE€llulo spe ot epitt lhl c.!s dinlrir dB gldidtj of Na'ed K' io6 alMgd. ouid onp.nr6|s of nE i'e s.

n&|.}rftfulidr:o..[|d'rrn6!.rbn|uh.''b6tu Larr$ e s..,rr. r 6E Erd.EL!

-5 & d d

eddct.|..r.crcdlr...d|aful'!.'*t.''j.&

rft .E t.!d (Mdd tul

ThE 1lF3 of .tideli! sm!'d tF 'm&uru hb,irnn .idolrnDl'dic

mFixd rt dE sst rtitldi4 dE ih ''qarFitHn

tn k speidiDd.riddil. s.brt .,i*ln (Grdorn.rd.a6)

Th€ ffiry .ritlEli. lim th. speific @ of rn. E$.diw tuEi ehich eeQonsible fd Me of pGition md snd. nE s$ry .pnn lal lini.g is p.*nr@od i,'e M&ul& of tnc ueicL ed sule! the rhe .rrda @r,,r!@ir in $e dpolbof *h sicirculf drc! !|lt !b. orge of tui *ini. ln. shl6 du

TIF min cmFEnts or $lsy cDidE|n e lEnDd.Bduq h.ir ellr Th.ssy €pinefiu k @v.Fd by lll. rdori.l n.hbMq Tn. site or h.jr c.n !&sdu.tioni3 o my or sicc@ilia tnal pojc. iion hair ells, @g.d lik !sloilw in mls orircEaing h€istu cdl.d 6. hnir budl. (Shotrcll e, al., | 98 | ),

IL loTn-Don EDrndr.

A ved&.pidElid lrld, dr. rrtr k@lei lim3 dF r.urr rrha oa@hl@

6d $e dod{ ccll Egio.s of the yenibule sy$.m. Thce rre rhe ion tansFning epithelid.

which aru invohed i. acriye tlrq'on ol ions ococsry lo maidoin rhc unusual

cndolymph cohposirion.'l1]e ',iz

ut da! is @mposcd ofdiR rn€s ofeus rhc

margjMl cll: the intemcdiorc els .nd rhe bael Elkiii Ld Spci.liz€d f,plil.lir

'1tu le$ spei.liad .pithelio includc the Reiss.er's mcnb€nc in cmhlea ed rhc

cpithelio lining rhe tuf of the sculc. rhe uLicle ald the mpulhc oade emicircllecoah. nr* cpitneli! fom Fdability b.rie6 ep..ati.s tte fluid $€6. RupoF or

ihc$ mcmbdes w.uld bc expeled b rcsult in fluid miing and physiological

The atility oa iumd dhld ro d.kr ed dislinguisi oon3 difeMr sund

fiequeDoics is pnnarily based on the snery epitElii oflh€ organ ofconi. situarcd in

ihe middle mp.nncnt e,t ru/a of the @hlca The o.gd of Corti is lhc

*n$ri.cuml cnd o.su specillize<l for hwiry vhich rmsdues ound sves idoelecticrl impuls ll is mmp.sd of polai?ed epirielial ccus Oan stk rnd supD.ni.g

@lh), I sp.ciolizd basild mehbBne, audibry neRe endin8s rnd thc ccrorial nmbrMc(Fis L4) (En8slrw e/ .r , I %7; Ha*kins ., d, 1965r Kitochi ./ ar., 1995: Smid. 1968r

SFrndli., l9ri WeNll.r/, 1965).

o@rorcod;sh'|4hr6ba|l'hedo'.nb hurn r rqr/ tt'jd.r.b'r}

TM t}T6 oalrt cdb @ pr6dr o dE o4a ofco.!i, inc h|ii Elb {[JC) edout6 htr ells (OHC), shi.l| e quiL dilt@t h t ir f@ctionrl rdony. At bin[ inthe hl|@ @cNeE thd. e lbout 15,00(!25,000 OHC5 &d 3,500 lHCs. Hrir €lls do

d Ia ! lif.d@ ed do DoI Esar.rr. s,no bsl (Slom,,,1, 1993) De4e lo dehlir cdh 6olE in dd@.d tsing $itivily, ia, mriEurl hdi.g l@. TIE

iMe. har @lls m dF tru6 so'r cdl!, sdnB inpukF ia rhe .uditory ndq l{)ile

llE ol'a hir cdk e Ecd ro d'h@ d'c psfo,tll'e of dE @dJa by i@irgsde.rivily (qudilai€ ai'@ ) !d iE6i'g sirieirt (qrdirniwnhoc.Mt. Thry e ffied lait @lh" b€a@ of th. protuding tufi of slersili!6on lb€ Aic.l dou; ofary cdl (R pnrd &d Alts.hlls. 2003)

'Ih6e m cliindn.el cdh 20 rM to 70 rrM lo.g ttu bave - l Oo slgacili! .r dE

.pa of.idr c€l, &d a nuds .r t|| botron. 15,000-25.000 OHCS de qul&trmepd iI nod @lid ^o-l Fj wnnir &E or $diG lq bs fodi'g !ch@rdirric lv strop. (R ph&l e, dr, l99l j Rlphel &|d Altsduja, 2003) (Fic I5.)Tb€ ouro hajr c€lls hlve bolh s€Mryd noror dnds &d coinribul€ io hsngsidiiry I t qEEy rd..dity by !rpt'&i.g $Ed

'loction G.rliFra rd

hE hrn cds nddi6 a g$ry cl@€d $tid @Er sod-bducld Dri@or tL. bail& nmb,e inro dE .l.dtrlEicil lom or i@ iftputsg. T|E_v Gdftrged i4 t stlish liE or Nid. Lr snq. lrl aom r @druous eay of

4p@xirurely 1.500 ctlls .lo\g lh. iffi ponion of dE orgd ol Coni (Fis I 5b). E&hitu hdn cdl is par sh.pcd lh a @rd!r loaLd .u.t4 &d aloul 2G50 sic@ i!rud. of -rih filelrd d |h. lgi€l surac (B.des, 20OOi Psnly dr al, 200tj Sl.tcryst at. l93si H&hrey d/ al, 2000). Tlp 8piod ponion ofhrn eI5 *ittr llF 3l€|wili.cd6 in E rela r&16 (qnobnp[) stm 6c betale.Nt ponim r bd.d in

Filr9t (R.9rrd dt AhelnJ6, 2003).

Th. sl.@cdia d. drus€d i. th@ ri6 *nn im@ing lFidn o. .!.r' sucivel6'd (IiB I 5c) (Pi!'l6d ltd Al6ddo, 2oo3) E dr li6 is dr'.o.d ro dE Er brvsoa 1}t6 of lin*s enicll oirai. fib6 rEde of Espn 6d fi,rrrr, DbLire (Bdle e,

dr, 20m; F.uiprle !d H!.h.J/. 2006). Ths. link irclud. th€ followirg !ps:

Tlp li.k!' lnd mMr the dp of dE sh..r.r tuilia ,o th. side or Ihe adj@rlllLr $etwili., This almgdor is b.liaed lo bc Espotrsiblc for op€.in8 .rd.losing of the chm.l g.1c by e.$ring onilom cxcibiion of ih!nEheotasdud chreL (MET ch@ls) (Pi.kEs ur d., 1984; Flms ddHrckrcy, 1935; Goodrd s, al, 2005; Fl@k .r al, l9??).

TnnreE or lonnl |ir]r !it!.h st 'wilir in lh. m€ w dd ftom bw !o

D{ (Ased .r rr, l99l i Sheph.rd dd CGy l9}4i Pic*ld r, aL, 1984i Fun6s

3d H**ney, 1985i .tlcobs .d H!.l'p 6. 1990).

an&le li c which cmct sr.€Gilia ar th.i. pbximl .nds. Th* linls eab*nt 6w rne h.n elb ofinl orSd ofconi, blt e pltgr in rhe hln bundl6

or rhe v.sibolr oBds (Cslrc s, ar-, 1987; Richlds ., d., 1990: h.obs rnd

Sh.ft .otrn.croB I pF$nr alonS ihe niddlc region df rhe $ere@iliary shaR

ToC<!!.etoE linl tuili. lae..lly jN b.low rhe Lhl of d. tip lintr

ne. E G, oHG blrdtr. rdD I turrpFnEdtnn$.hdrvh,u ihrF (.) arn4Earorhirdr.|tjdrl

1I PFYSIOI,oCY OF IEE TfUI'AN EAR

Inc llE Frrs of 6 e dengn d io c.dEl s!'d u6 ddeh lhdFimiFny dif.@t m.dn ia, tir, bo* ! ltuid- TIE cqdsr.d s.6 c mEr.dinb .L.iric.l lagmk tl'mgh ! si6 ofmDl* n p6.

1.2.1 Sourd @ducdo! p.tlnyn€ tud *.€ c collctcd ht d. o(hd o $,li.h phF lhc Dlc ol o

radic etcm: rh. pim (bgcrt6 *id rlE had) dift&rs .nd fa|s srd mc*liib 6c mh. .rd dd$l trdibry ftsB .d s |t$lo6, ft. 9Dp.ric mdbr.Edthe@tdtuvib ..inEsp6n$rosddpEs@rt*s.ndEehitsmEm.rs/rotodl€us of $e ntdle a which i. @in.d.d ro d€ inc6, Th. incN fttrnd ioim th.

staF .rd pur! ir in b*k dd fdtl nodon pustins lne ovd window in 4d Nr ThG

mvl'tEt of ih. onl rirxb* $ts up 16 i. tt FilFDh oldE sdowntuti s.@1. rh. b.tilr t|ht e is ,o5r!od ine.td. .rd hrle6 inb tlF salz Drtpora,

i|mi4rn pEffi orlh€.trdolynph ici& d'e €d'l6 d@r (Fis lO.

rJn'dc'iffim46

l*.- l*-."I-"*it 16 hrur or nr. dq.{-

'h e n.br qrt dd nr tu n. orFr. E||- tddr.rq|Gaad.r.krir

dedird.l.dFt.Enl|'*FI'il.do..jtd.}i.-a h rrra- .a r* rrc (..+. h rxrd.r.a. b.r-rr.rn.,/ r'.!.|bj.')

l.2J Mcbdod.rrieltuldu.{o.nE up and rioM vibErioa oa baile r@b8F 0..d. a st@i,s loE bdwM

tlts b6ile nmble ad |n. ie.lorid nmbr@, rhu cuilg lhe sllrwni. of thc ouldhrir cells of dE ors4 ol Coni 1o bard This dwins &lion cu6 defl€rion ofntu i! b@dlq *ldd' oFa rFddjcJly sr!.d id clEwls loer.d m rhc ,op ofa.h sLlaili. Q{udspd l esq shoi}dl ., ar. l est )

Due ro rh. bieb .oEfinio of K in didtf,ph ad slorg Ecdirc pola i.t oa

t|. hrir €llE K- ioE rush i.io d. |l.ir cdG. nit 6ds b Mhtia eE of d.n erdve d4e ad dAol{i4 th. IEb@ ol h.ir cdls. Exdr.d (deolaiud) OfiCs

r*l B c.ntdrq (a phtunldn reM B d..nomdliry) llrcucn o dirc a6ponndhdim rh!1 iNofve dD pror.in wstn tt"ih4]@ et. at,2$D, DE b ln. lishr

auplin3 or oEcs wih rh. bsild ndbro. ed raicule lmino, 6i3 &riv. nt .hsisnr*ds oer&/ b&k to de ors& oa Coni dd th. Itics re trit d due lo rclondmcnbre i.ti*lion of st 6cili! (Hud.p.lh 1939: Slrlldl .r ar, t93l ).

voltag. minve c.lcim dmds c ..dd.d i.IHCS, dd c€lcium sigS.ts ih.rdee of tmtNiih (@inly sl mtr.) !1 3yrrr66 lilh atreE* udiior! .@adiur ! rb. bel dn ofih. cdr. Th. idpds @ ps.d tia tu c!.||@ bEdr otriE Bt urc4tr@ Od) 6w ro ln. n d'nh F@ d. @<tulh inNts r.v.t to

tlp nidbEia lto to tb. thr|lhus, ri fnnlly ro rh. ediro'r @ ofdE rflooel lob. ot0E ccEbr.l d* Sou'ds oa dilI.rat ft.q6i6 {ire ditrsd '6 of dr pri@ry

udilory olDiex ordE bEin (Cill6pi. !d Con'y. 1997r Pict!€ .r aa, rq4; SLd rdrs,2ml; Stel,2002; Slr.s@i.r od CiIBpiq 2002j MrolNti e, a?, 2006:

Pet€M erd will.m,2006)

1:.3 FcqM.y diltdb(ton rlolt th. butt.r @nbd.Sinild lo nNic.l iNru@ls dE odto is . iodoropiodb lu.d oryu (Fi8.

1.7) TID b6* of th€ od a i5 tut Gpo6irc io hgh 6-.qFcr $utni rn.@ lh.q QttLotut ffi low 6!qu-ct $uldr rh. i@ F lg a vsict ofrEl'ois to a.hid. ltis booloph sititt, jetuding dE nri4 of dE bsilsl@be !r plniculr DGin6 dd'a ig logth ln addilion, ! Ejor r!.n!isinvolG dE mw b@d of |i.qu4i6 lo rfiid hlir cdls (Elca !i oHCs) @ nldr petculd posirion on dE bsils !Mb@. TIE exd prfen of bsild mmb@d.lomdio. is in'0orta4 b@e lhi3 Imb@ on&tG d* siliv. 'r.qo. cdh(h.ir cdb) *{dd rlcfom $ud Mv6 inro F. lnpotse Ar rh.6td of th. cNN..,closet lo dE niddle 6 @vily, lhe bails l1Mbte is r.hdv.ly slilt &d @or

(rlpoxioalcly 0-l nn wrlc).'I1lc ndbd. b6om6 moE etdi. hd vider 6 n

drends thdsh rh. cahld towairs dE rFr (rgooiiddy 0.5 nm *ide). The siffponior ofthc membtue clFn !o lnc Fiddlc d qvity (b{e) vibE6 inmedi.tely in

Frpolre ro FsuE chm36 tusnitd b thc o*l sindow. The tibnlim tsn rhe

b& lhm ravel alona rh€ baila nmbMc loMrd its apcx (lhe ride end). Horev€r. the

Egion of ddimal displrcmor of dic b€!il& n@b@ne vanes vith Md 6rqFcy.The p@peni6 of$c n€mb6e ndrcst thc ovol window (be) aE such rhar it Esnales

oPrinllly lunder ecs lne |rrg6t deim io) wilh hieh i€qudcy toes wniG tne moE

ditul regions oflh€ membrane (ncr $c !pq) vihmle maximally in esponse to to*

'itq$ncy eunds. Ttus lhc rEqu.icios ol inc@ing eund woves m $n€d our slons lhc

baild n€mbme ond erch f&q(ncy stimulotes hair clls in ns chmcteristio plee (Fig.

1.7). ve.y lw rftguenci.s (< 200 Hz) d conprcsd on ro a Flariv€ly linit d siion dthe apial e.d of de mmbEnc (MMousski

", d, 2006),

orlrft.t|o..ldtr.q!ff.ynnbnicorlunrtr.fthritrdrprd

SECTION-?

AT]DITORY DYST'IJNCTION

CLASSIX'ICATION

MOLECI,'LARBASIS

Df,FINIT'ION

Auditory dtsftftrld ii @if$rcd by pard or onplel. IEir€ disbilnr lnd 6

geddly @qiz.d 6 danB.PNf,VAI,ENCE

tlerins lo$, wn.{hd Eedic or dtDmcnlal, is oft of lbe Dorl pEvdalg$ry de6or5 ir hd|a (McKEici! 1992). Ir is .nimn d fta I iI 1,0()0 Hri6@if6l @sdil,l h4ri.e lN (Mon n, I eel ), oa tr'Ii.h .boul s0% e. due 1o sstt'cletoR lMl@itt et al., t991; Mond !d Na,.e, 2m6) h tdditid! p6dt$u.l d€rraalso qhibili th. s@ .dio itr its @6 (rorlrh ., al., 200) ) AsFElar.d plogBsive

lF&irg los (r'Errltu!) !|so nld I 0% oa thc popul.Iio 3t li! agc or 60 .,i up lo

50v, of indr'duds al Ihc .€e of30 (&vis, 1939)

13 CI]\SSTFICATION OF AUDITOIY DYSFUNCTION

Auditory dysimcton @ b€ cldilied m thc bdis of vaious c etu oclud'ns

rlE tT!. €. of oBd, ft.qu@y Enge ad 6@.rod

O' $o bsis of itTe audilory dFfuclid @y hs drdcrw ifrhs hdine 16ds froD drbtrr.lili6 ohh€ dlan l I or niddl. a, ot s€A..irc!'zl if |he lsring

16 6ulls ftln nElir*lion ori@ @ stuctuG (r:4. c..ltd) h4olsobertr''flh. hdnng b$ t a @mbindion or @ndu.liv. !d lqsriFral nrt6rD.rio6 cdralau.liory .lyfunction vnnch eolts fron de,se or dtsitrlion !l lhe level of lh€ vlll"c@i.l @e edilory boin sl€ta or ereb,t 6nd

Tlt o6a of audnory drlautrdon oay be pdang!.1 , t . MoF dE d*roD@l

of spGll or D6l lr4!.1, {)@ding.n r dE dev.lopmd of ernd sp*ch

o'r lh. bsn of i.quaEy. h@ing 16 is datned inlo:

. t^ nt{u.r t dtns lN i s, i..bilitv lo hd $'i& d frequ@i6 b'loN

. MiddL arq*cy t€tbr lK le. inliliry to lt{ soDds in dE fi-equary

6cl of 501- 2000 H7

. Hist a'qu$r h.i!8 lo$ i., iMbilny $ n@ eun& .t n quacie .bow

audnory <bs6sdim nuy be llt. !ol. svsploh in 4 rfdled indtridud. in *Iich

@ n is clsilied 6 mFsltddnic daf|6 N@tiitomic den6 is tlt N@

lBddr tu<t of h.ling los a@ulitrg aor ?o'4 of aI dF 8€nelicdlv d6i4iined csof d6frB !d is ottut ddGivdv g$ridd (Mon t! l99l: Rddd! 1992i

Mwih e! al.. 1993). In 100/6 of dE cs. datrs i3 fomd smd.d q h 0$6

'Edi€l nobtm &d is clsi6.d s sEdronlc d€:lK. Mor. d'& '10ro d€.''6_

El.r.d gdEn EDdbc h!v. ba Epon d in s{id hdiB 16 @y b€ @ducliv..

s6e.i@ol or mix.d (C.din er ar. 1995)

I.. CIUSES OF UDINOTY DYSfUNCTION

trelfB t . mltif.dond dientd 6d 6 t ..L5.d bt ddE 8aai. ddvnomnl.l f&1ou. or b.v onbinadon or borh

l.!.1 Ed@tl.tlgTte @jor ovnmmrd c.@ itctud. b&Gdd ai lid infdlio6 l're

qlhoid, rd46, naitgnn, bxodedx t|616, n!mF. rubdr., hca6 tirus dd

dlome*rloviru. Conplic.tjoN duills pt sD&.y or rur ans bdh aa @r@d

djaba6, t4?poxn q hyDodydra of fi. fdus, postuld bDt4 Fndll€\'rhroblsro$ !d fdalis nw .ltel lh. sodB or d !,i oe hsn8 h9lJlr@r

i' neDt6 (sb@oL 2006) o|hd I&lod lil. iodi* d€fciqcv oloroxc drucs ed

hsn fds ds qr$@ b lrds 6Frmn (Cha le33' Expo@ b loud me 6

de . @jor dwonmdd c€e of dealnds (Kowalsk! e, ar , 2008)

s[3D g* ml'lnos d€ th. mlt o|r@n s@ltc @ of h6edi@v h.@g

16 (Balciui@ d at, l!'gsi Monll er dl,, 199?), {nne dE drgoc ed @npld 'Dd6ol irhqit&E $ti.h @ re &|d drlfid]l to de@d! hw. tbo b€r rcPoned

fieynnlccl dd Yglt 2oo4; B.am arn xrE4b 2002)

r5 LE!€I,S OF AUDITOf,Y DYSFI]NCTION

tLrd.e il i6u@d in d{ibels (dS). Tht lhr6hold of 0 dB for a'r' fttquacl

r.fd ro lt ldd tr *nici midt r6us iulrs poEiv. t t@ busr 50"6 of dre tim

Hoe.s n co6ider€d nodul ia m individuol s $6nolds @ wiGin l s_2t dB of mmal

d"FtDId S.git oaheda los 6 8r.d€d 6:. Mnd h.{ht ls (2tu0 dB)

. Mod...L h.ri.t ld (41-70 dB)

. s.EE b€.r.c ro.. (? l-eo dB)

. Polomd hdrirg lo$ (a!ow 90 da)

I.6 STUDY OF CENETIC AASIS OF UDITORY DYSFUNCTIOIi

rrddbrdirg the tlDsiolog/ often'B hc bd a olDllaEr dle to @nplflqol il@ @. $,t!i.h s mogrisd ol vrio6 IrT6 of cdb, 4.n rdlritdy in stdl trmbd,

dus pce.lins lindr@ h bio.hdicd .nd pltsiolo8cai nudi6 (Frol{}ov dr a/

2$4, Adso a al , 2OO5t For Mptc th. cocl amb6onr, |u'huellselnch

ee diltrcult io i..ldc n i'B n dimcul o '.ldit ltr irioa ,blqE hw!.d i! rb.ir

frnction (ForsF orn wncn! 2002) O@ the p4l d4.dc, soetic &d no|4dd mdhods.

idolring d'. idd'dfi€lon of eqE drnsed in i|rF d a studid ot tlt pot i^o@d.d by rh* $16, hc b-o@ tlP prelenble strd.g,' for udd:ltnding c.dnd

nddr6 { lh. mlal{.d celd! ldd (Fri.dM on Grimo! 2001; w@ds e, a/.

2tu6, Indjldud! rrn ddnory dJffion rcpdar e oppon@9 b N 0be

d€f61iv. ss6 sd uIdaE d rltit tutnon ad nDd€ ol dptdi@ (Rsdcl, 1992)

Th. godic dpprosh b.*ad. is a dimcull l8l due lo lbo dlrffi Sdeuc

hdaoe@ily in lsr.dfity daf'.s3, sn ,D finir.d g@9?dpnmtTe @n@oN

kDs lor d..tB (Pdn e, al., 2ml) lr hG ba BlintLd |na d lan r% (_300) or

hung pDldnnding eFnd e invoh€d in hdinS ptu6s ard rubloc 'n

marry or

d6. Bc @ eG ld€l of tsits itrr9.i,lml ciba !n or $irhoul olE

5rprom (Foedry md Crifilh 2oo3: Ne€,2oo3) Bv uiie mldule ssEli'

kdmlosr th. chremsnd Io.4M of c ew e6c uddhn\g ttm svr ftmic

ann rdtr|dronic n€&rS los {t6.rdeu hav. b@ pEi€lv lod'd

Thi Epid ad!.@ in utdernading dE cq*lic c.6 or nutu hs€di$4

<t.fr6 h6 bs ad.<t bt d. aithbililv of 6h i6 s4t Crlj4 h@n3 16@npr*ilie. clinjcd ddA hldlv polForpbic cael|c mk'ri ceaic md Fdrs'c'r

drot|@dEl mp., gmtuc DNA s4q@ fo hlffi itn nic' tunpbcd.l!bs, ud by NNe dd zebo 6sh modek of h.c<!trv hdoB los

I.7 INIIETIIANC OF Df,A'NF,sS TRAIT

Her.dndv danK b clnsi6.d bv is mod. ol iiqillE in fdiliE a:

. Aurosotul rtBive d.dnN (Drxa)

. Auiosul dodimr d..nK (rFx.r)

. xlinted d..ft6s (DF7v)

. MnodbrnriddafrsTn msi @n@n Daftan of inndtle oamEvnenic do66 n &bson'd

ffiive (?Q's0o/6) *t!n on@nel dominn (l?_24%) x [tr'd (l_3vo) ed

nnocnondri.l inldrde ale q's| (Mono4 199!j R.!dd\ lrr2r Msuil! e, al.

tn3).1.t,1 Aoloord |t@lw mEyrdmd. d..|!d

To dd. (irdudis ttE pl!$l nudr). 3l M-rndodic lE6irc da66 singl@i hsebd m,pped, of$hich 6l hrvc b@publish€d 20 orthdc har. bm Bos€d

rirh uiq* los mDbo!. Al 27 of lh6.l6i, !t..!d!rc ssE r'!s bd Eporl4d

(It '!dila4

Hedig Los Hotkplee; HUCO @mitle) (TaU€ I I ) Th. mappei loci ior

mcslld@ic eloemil lEsiE de65 e d6igded 6Dtvrr. D|-NA2 tu.s@ oidr in *tidr drey *@ epon€d or r@.4 ed !.lisled inTabl. I I

T.bk l.t Ial fo. noFqdtunn. Dlo6.d.l |!GdE ddf@

sgcnoN-?

MAPPINGDISEASIE GENES

BYLINKAGE ANALYSIS

I' LINX GE ANALYSIS

U.rrs. ,sbai! ir ! ledDjque us.d ro d.Lmjno uE saotic lo.€liot or. dir@cme sd in die .bs€ ol dry otbd irfo ni@ (..&, @ ctrqasic .bdorndtt

@-inh.riud disord.n, god csiidlr. 8c6 or hbd p@tor podud) The 8o.l or

lir*lsp M.l'.ir is lo irldrit a pdicuLr t.3E6r of DNA wli pr&j..lv lroM lstohth.r is i'tEit d by.[ d!a-!f.d.d nabdt of dF tulv but Dl bv ev ortr!tr 6dl6d ddb6. This egndt of DNA is sad lo h. '@-!fiariled" or lo "@_

s.rr!err.'*ih Ihe dis.@ pnaot?. ono ibi $cnol is lod.d il is NM.d rhlt tls

dse grr. ns li. wilti! or h dd p@nnit lo |bd lo.diotr hmbig lE

locato ofd!. dis6o s@e (i e lh. dis@ s* loN) h th€ n6r seD toN{d denli64ns

Th. sqE6 or DNA wilh hDm |o.r'i6lh &€ N.d in U!r.8t $tF! ecrlled pohmrphic ietes or'pobmQhi$d Th. pobftorpnic rwts u$d in

Iinlos. nudi6 e lttic.lt cdidd€n |o be baist difidl6 in DNA $tr vlD

dlmnlv bd{6 mr@l hditiduds sd Fl di.& tutlri@ dmld6 Ths

Doltmllhims Ee tbu{tltl t. hutu €r.ome dd 6 be food htu€ ad cl@ to all

s6 By idslitbs t @inhsn d pobMDhitt! l6tros tddironl pot@rphEtu o

rlF vicinily. dxl 619 tlldniol trosrs 10 scF re LOD eB, 0E dise g4 db. Dld wilhin . dilr€l Eeion' 0& !d bv r.v polvmohic dr6 T1* SqEtc

dilrad of didctl r.grd is ,€sE!d in cM (6riMor9E)

Lorar! dd$is n@us s rel.toNbp ban@ ldi Tso lod on |no 3.m

ckomdft c eid b h. fitred if d* PlFomd o' c6i'a ov6 d@ng m6E

dc nol ep&.re |h.n 6 oi4 $ eourd b. 6pdt'd bv @don s'sF8'id If l*o l@

s6 DhFielt cl@ 1o a.b ods 6 dE se dhn@r|e !E d$v sill otnv mt b'

!.pmt d b ! rd'nbi&ti@ wan ar dioaa dd $6 lht tso l@ 'ill ldrd io t'hh@t d losedld. ft6 @.ns.dl or.ltsl6 of {tiredt dks ot aog @ iho l@o

drtlJ|j@ru 3.sn*d is ldn d !h!pkivD., dd Jl.l6 on dt !.r hqiolvp' e Pa"on ar?a* in pcdig6 ml* epr'I.d tv a c|lgvs

'vdt(Ou, l99l)

Ths Danicule dlel* eidleibd nlh th. dis ondt ditr!' bdwa fdnli6'

rdl€cliIa alclrc hd@ed ty or tEtrt Sadic @nbiEnd 6ds TlE |ats of 'ti'r,*p &Ebns re cton d 6 LOD sG reprenog d! rddiv' lil'[nood dnl 3

dis.s l@B dd a sftlic Detd e gasicdlv linlcd (si$ a @rbintdon fetiot

!ld! g). dha tbo sdaelt 'tlin&.d (O!' l99l ).

lAl narbin tiotr fntidAllel6 of dill@r saE on d! s@ dD'ffimt @.et!ede in propone 10 ttE

dd'liel disas bar6 dan Tltu ra& B .chd ilE lt@$nriin tutd (0). rh.hr.Dcan de pobltilily of a @nbindio .61 Mmi4 bdn6 dE hro loci T$o l@'

@ sid L bc !@i.d! lird.d rtE '@hhcEd@

6tcli@ 6 ld lt& 0.t. This ntdod oa

oul-sis is @tuj *t'a m of dB I6i n . diw kd *hile dE olh. i5 ! DNA tM*ab6.d 6 o @tjltM tobmalin b rh. topdni@ (std6 tn Rd. le96) TIE oli6r

of lnrlge d]ts is 1o eijtEle d€ @t$in id ftut@ an b &3 iro bd86 lso l@

is ts lnm 0 J ,:e . $/hdt!r - otsred ddieo fiun 50',6 @mbit'lIiq 6 nd'licdlv

sisnifidn d D! Tn Muldjo. tunt dErs &@ 0 = 0 ld loo abE\ do* lo

6.rr ods dmueh 0 = 05 tor loci tu lpst (or or dillsdn dmn@6)' !'d b ! iB@of dE sordic ditu q n4 dd'E bdw s4 h.i Thie @ 6t *dl fdsndl

dsl,l6 Ts h.l $oBnr8 lv' 'snbinllr@

c o6ido€d h be I qriMolgm (cM)

@rt @ d. ret t. ur4. &!d a lg|arc dir&e oa I cM Ep'ga o 9 Mb m dF $!vs4.d pbnol dp (Fodi, l99t) Hoas, bd@ tdtDb ctN6 truv @ b@rnbindion fialion mq @l be llla 6 o lddiive disl{E n6D od n6l lh'EtoF

b.lrcfdnEd by!np frdioo inro d4diraE (on' l9llrJ.2 Tb LOD md o.|n.d

M6u'E@t of li.bge 'qdc ouli.g ol @nbind s i' tn' p'd'er6'

homvs il b ofta eI to$ibl. !o @!r, do dt dlt For |xa r..q '1Muolik€lihood dethods tse bo .pplied ro tllow olculdid of dE lil€liM l|lll a g'vd

p.dig suppois dE obsaton ol liit gp uld6 ditfsqn sumpt@ lbou| |n€

@odbin lion filcrion (slt!d@ ed R.rd, 1996). In d6e cd.ulsdoa, @ombin'liot

ad M-@nbilErid tor adr posibL gdtlF e dtolli'd Conpulss @ ulilzdl

for dis- d rlE cd@ltl|os @ quile smDL{ A logdilhm ralio t c€lculated demt€d q

z. Th. @tculaEd sG prcvid. rhe stasth of ddae in f.vot of finrtge

Ir a LOD s€r. cdcultlio4 null hvpolbcit is udi7.d i ' , $e problbiltry otdllo tn

ttE fmily ,'e di* &d n!*d c linLd.d thd.aoF et 3'Cteg,trng ind'p"d-dJ

is 1akn 6 lh. nuffiolot dl lhe pobabihy if dD disw ed $' met€' @ u'li'ked tddEefor€ s€saCanB ina€dod,v n dio in Oe daohin ro' Il d! 8Er'r od rE

dis. sd e utlinl.d, tlF nDmrlIor *ill mt be ste{l{ th& th€ d@mj"lot t'd uE

logqitlh ollhe obbi'ed dio *itl be l* nld or.qud lo 0 Hor€d, slto de Mta&d tlE dis@ EFs &. linled, rh. ruEnr.. *ill be stEL' lhn thc d@nMtot ad E

logsirhm of th. nlio *ill be !ra$r thm 0 A positiw LOD st is e mdiQtDn of

linlr€e. A LOD sp of I or sr&b i.s Edialdlr' @6idd!i p'@f of lintaa. for

Manel'i lraiq $tih ! i.gdlvc se.urporls th. 3b6sE oflinbst, Hlh ! sE or -2

or l6s beins aNids€d proofolno-lin}j€e. (ot( l99l , T@iu3er tld olL l eea)

lJ.t M!ftlpoirt dptlngLirr,g! ady3is o b. mrc poRqtul if ln. d'l| for moE tbd M loo @

m.lyz.d sinolhously Mul|lpoitt trtppin8 is pim.ulet sin rot findi'g tE

.hromsorEl ords of ! s of li.l.d rutlR Tn 6utl sbnihg poitr u trrpptB a

dis6d l@u n b fnd . twopoi.r src ich 3uppons ltLcF b.'w a sp-'lic

mortd rd a dis. locus Usins infomdio frn lddlto"l DNA @k'6 in $e

.eio! s nulapoht eE is .roLr.d b bdd 6lin le th. lo@li@ of di98 c@'

rt,a DNA DotrrDttr - ! i-l r.1 ttL.a. ddtd.For [nrlgE ar,\sis, n is nd6s8v lo e pobmQhic turle6 rnil @ &

smirod fd idsirs ,nn d. di4 l(fu. Tt* e@t. tElt6 rcptsn obsdle

potmrphis *i6h rb poFdrim Ttt &sisnng of potflupnic nE*Gs lE if,gtoved

$irh iE6lE h0lM g.1@ dlrab@ Piio. to 1930 x a lirtEl e@ otSddc nE'rds

trs ddl,rbla Ile irludod blood eruP jtss. dd oib' po&in pdtrtulphis

(coilslly dd B.iru, lgSo) h lgso\ €r'dro 6!gnc ld40r pob@Dhs (Rrl'k)

l@ irmducdt 6 ! w chs ol gotdi tk6. {iid' 6'd wi'tid in dE DNA

sff itelt G Mqdeli{ '!,t6 (B.isor d ar ' 1960) subs'qMlb llllRt (vairb!

nn6s otEdd r.!.s) !.d STRS (srorl lldd r""ts) r@ iddjned Fot mrv rsSTtu pbved lo b. rlE msl ustul cls ot potmtphism

'or sdnic s.@ihs etd fm

Sqdc nEppi4r Th. din adv&46 ol SIRS @ tlE ubiquilo6 pls@ &6 tl€

eqbm, !6 bich d.sE 6r lobtudi$ it dt Fpoliio4 'n |h' srdl 'mun or

DNA dutr d c of,rpdld b RFLPS or vNTRs IrF lhon Edsn Epd d!' kDM 6

si@sddfei soludodad rh. m.ld of saotpnB in lbe r9q' s STR'3 e t'$s

@i.ble rrxld sqEE rEp.ds ntich cdE5l ofdi lll. o' la! Dckc{i'h ftt'ds TrE

dsr qiddy 6.il sflk d.dop€d lor ctFr}lirts re rnc onple CA ad GT lt'ats Tbc CA

@.* e edtab.Iv abdrt! lld a be aodi @ 'tagt @ tldt 3ero kb n h'm

smm tsurrq t! Rad lo96r TF sld rdFuLotd' r46ts e l6s |:ll|)@A bul

have tE .dMlrse oapodlcitrs g@q!6 lhtl d 6id 1o soE

CHAPTER-2

MATERIALS

METIIODS

To Ffm Bauic [nr.se ad pGirion l clomg ofg@ inrolrcd in ardnoN

4sfutrdioa dE worl pld nDy Bqlidly be divid.d inlo ,r@ phM.

' Clinical Evdudion

. L$odof M*2.I FTELDWOR(

The field wolt involvs:

. tdarilic.rlon oahdilg d€d.d f&riti6

. ErollrEn orid€,rin d fmilid d @lldion of blmd spt62.r.r |ddffeno. oftanlt.fidd f.nii€

FmilE *ilh ira or moro !f*td idividurls wqe jdarifi.d thmDgh iotd LiDj

dd i6lilul6 of sp-i.l eduq!6 &on dif.rs citi6 in pdtisld rldividurts n@6k d lo conplae a bnef hjsbry fom in UrdD lo &quiE prctimi,ary intomalion abour

dE lrmb6 ol terl8 .fal..t indiJdurtj i! lh. dadcd fdily, barinS ts/d5pffi or oorer disas, posrd addr4, lrd conrld relephore.@bg

1lJ E m|||Et oa lddri|t.d tuitid Dd @tb.tio! of bt..d udrt6r'eld Irip6 wd $€d ro mll |h. idalitj.d fuitiB. Munid. amity .@b6

ed .ldds ** ifldi.$d ro 6I*l dcGted infonution !bo,r dis@ hnory i, $.fanily A onprdftrv€ qBiomiE w6 6ttd oni by fhily ndbos ro N {Fnature ol oditory d,sfin rid s ovilol1lmrdt or Sqsdc &d ,'rn@nic or mn

tldtmic Ths h.lp.d b obrdr tonosirg infolMrid:. Ase or ons.i of h@ing impdimt (@gdibl, pretnSult, posttingual)

r &.oa*dtiiler stin o. hoir pisncnldo. Poblm d'r.d b br|!f,E visid! 6roid, tdd,:.rs, hdl &n Dd.l

Iljmonnc.t Any cidoE of inldlioc dis.c tik ngingiG, Ml6, n@p6.

rubdh or q?hoid.

. Hsior' of mtr dr,tr orB rdrl u!Ey.

mlibioridoroloxic dtug usas. (Nanyda cdrd}(in, Sreplo,rro.)A onpdE&rc pedigF *a d6M io Gdllin dE o@guiry rd |n.

.pp&an bod. of inn dt&e of dedEs ir th. a6iv Blood sepl6 wc doM fromthe lfcten a wdl6nomDl i litdu.b ofdE aM y !t r.bted i.diuduats, bs.d on

!hq. w iqgB &d lvailabtlily. Casdl_! l0 r ol voous htood Ns @uered deprm cM or v.ry tlul8 or eldqly subje!3 TrF sanptc w@ laboled ed t pl r 50 nlSlcntin'fd@ tut€ .l@dy mlbinS tm d of 0.5 M EDIA. An anforr.d o@4{ind @|drEd delaLd infomdjon aloul dr prcj..r *s siped by dd lolols

22 CI,IMCALEV I,UATION

Clinj€l l6rng indud.d:

. Audiotopd r€tirB

. Vslrbutd |Bnns

. W'@lo8i.it qei'lrio. aor rtriiris prg@r@2.2.I AUDIOII)GICALTFITING

For Minrlio. ol h@ins lbiliry. Audiom€r.y dld Tlspmomerry rerc

To n@ue hqing. audioheEy w perfoo.{ uing s udDnerq whjd! N6c.libr&ed ro idorry Md manor rhe q?. &d t.rd of udiiory dlstuEion (psin8 udNc*,r.q 1995). Dding dE t6! edds of vjio6 tr.quaj6 (trElrld in tE&) errecd to d i lividual a1 djftut itnGida (@6u.d in daibdsl dd 0E tor61mio!'ry thGhold al {hicb . pffi. pqeivB soud is dotqmined. ThcholdgEbriti€ of nShr rd ldt G rw tr6d.d iddcFnady n Gllrj G @dedm . clun cded e adiog.!\ in siict $€ fi.qleie h Hz @ prolt d on horoorlll&s aid Int@ily in dB on vonicrl si' TlE .udiosrm o,orjd6 a n14 of clasit nCodrrory dF[nuior t@rdile b rlF d.gE oa !4iry inro nitd, edsdq s@ orpr.rouxl (Fg 2.l) (BGds, 2006)

During lhc p6.nl sludy, e AMBCO Aodioheld nodel 65oAE md a Sim@sD 70 re u..d lor &diotoaiol Gring

All.ded idivid!.ts indudcd in it. pcar srldy hd <li|I.nd tads ofaldilorvdysfhcriotl .arSins b.l@ mdsdq evde sd pbfoud lev.ts d loud f,equ6ci6250. 5m, 1000, 2o0o, 3000. 6000 &d S0OO ltz. Tn udfd.d individurls hld lr.nngb€lw c2JdB d lh€. nqudi.., v,nicn i. cGid.Ed mfl!.j hdins l6rt

T@ t}?6 ofaldiomdry @@ gaeott perfofr€d:

. PoE to!€ rir colducnotr rdlom.rry GTA)ln Fft b. .n @ndEtjo .udiorn.ty, drpho6 m !s.d lo Drsl s.d

lhough rh. deml d. Th. rtu*Iolds dcpcnd @ rh. 6did@ of d. cxr.ful @ @d,niddl. .u, dd inF d (K.t, 2002),

1l& syrnboh usd for rish ud l.n 6 PrA meauMenls on audiogm m "o'md'X Esp4aiwly. TIE ilEF of $c cw. is. lrr..s of dE 6qlErct sitivity ofhod rhc niddle d dd d. illF d ( BFndd. 2006) (Fi& 2l I. aom mdmtton .dior.rry (BC)

aone sducion audimelry is p.rlomed to dhtineuish snFn.eu6l rm6

codaliv. n@irg lN. sdri i. Fenr.d di61ry ro ft w s thmd r vib'ator

*trich is ph.€d on rhc ak!U, usn lly lll. m61oid bon 6 fNha4 $c byp.rsins $€

ex&mll dd middl€ d. lf bore onducrion tlwsholds of h6ine e b.tr.r $m PIA,

tnis sueg.sk a onducrivc haine loss (Knrz, 2002) (Fig. 2.2).

!-i:':

Ft, rr (a'n r.rErdtldd dh'ry Drfrtu

3i ?t.5s:!

SdF.lneurrl lqrh: hs Ml!.d ho.irc t6Fi!- r,2 srrDr. ridi'rro (kn od idr4 tF d^dh4 Dlrudbr

To€v6lut fu*li@ing of.h. niddte d, lh. njfii*s ofth. 6rdM is n*urnby tympeonctry. This 16r Dbtides q@rir.live inaomrtion Nbout th. DEsnce ot nuid

in the niddle qr (oiith n.dh), n.gotivc middte €.r p6srq ed tual votumc,

di$uprion or rh€ osiclcl' $np.nic ndbmn FrfoErio., od oro$tmsis (Noble,

20or).

ln this 16! . en prb. is liddt placed h the exLmt 6 cadl, A@usiic .ne.6ris lEMilrol inr6 lhe Mlt by ! snd stinuts 8.n@rq. pcitive m{r neslrivcpE$ds c als i.r.doced inb rh€ .a c.nrl by a vrouum pump. Thc movcme ofrrnpdnic memb@. in Gspons lo pq@ cfidg.s k m6lred by rh! rlnFnome.rnd @td.d s a r)npdosm (Noble 2001).

lf fluid is F!$l i th. niddlc @, lh€ Dmp.nic ndbdE *i d vihdL

properly ari a nar lm will app.d oo $e qmpeog'.n Ia lhde is beho or loser

prdur of ai. h rh. niddl. @, dF lFp-o3m wil show . shiR in lim polirion

(Ciffi ed Sade" 2003)

2J2 v6rihr..t. rtu!TIE rglibulr stsrdl! .Nislir8 ol ilF llricle sule rd 6E s@<jrcula

4!L, ollroL dioriir of rh. body. v.6dbda lAtrB c psfonr!.d ro damiE 0E

frlxddiig ad ideeily of dE v.sjbllr epun6 Tm teds ollmdy pdfo !d lo

.vd@ rbe vaibdr fidid e t||o R.nbq8 161 rd d. Tad@ €Bt |6r

ln dris 16l ltre psrjd n dd. ro iad nill *ith 66 closd md bolh acr

rouchi,g togdns. |f th3 poiol! h.v. vdribulr d'€6erio4 rhet @ rcr @j.t!inbdae dd dEy bein 10 swly or fall Tl'is hqtd b@e lor.l sLbili0 is

dinldn€d by irpus lrom lh@ selory systnsr vdlihul&, vision md prcDrio€ption lf0r@ r ! nild lsiM in lh€ vBribuld or propnoeplion slslm, tlc psdrl ce@nFblL ty visud Dpul. wid' cl6.d .y6, hosM, 6u.l inpur is r@ov.d ediElbiliry b@n6 apparqtl (SlunFfdd, 2m r ).

TIE Eian s.n 16l ir a 16r in *ni.n d'. p!i.l i, 6t d io rdr i. ! shich lnE

,nh hn hntds.fl..b€d wilb dE body irI rc ofdE b$I tod buding dE lel oad.t@t f@t d ch na If rh.E E ,y peblo fidr rh. v6libule sr5id! rlE F@ m.!

tul sdk prcpsty (Rubin dr al, 1996)

12J Oitri.d .lsmt or R.tlnltl Pl8nrn|orRdidirts pi€l@lN (RP) i. I prog6liv. d.S$Erion of r.ti@ Ttre Dr.limrry

slmprom includ€ 16 of Dqipls.l risio and nigh blindB. h Lds sl!S6 il m' t<!d

lo lold blindrs (Hanong .r ar., 2m6) G*dlt lM 16ls @ p€rromEd ro diosnos. Rp,

2.23.r Fod|@ly or ODN|irrt.ottAr oDhrbrl@!. G 6.d !o ceia |hc tury ponio. ordE q. ($e flrtq)

stid imludg 6€ djrr optc drsc d@i4 d brood y6dr Eio.lo MiElioa rh.pup is dil €d 6ing t fd droF ol Tblioid. 0 5% - I % G,ly'lrieo ror ohtibi'rslh. b61vi4 iBi{t rb. .y! (Nov.r, l 93 l ).

Opldhainmpy of ltE raio in idiv uds wilh RP Bab l[. pr6oe ofd@F of bl&l de|Ml or Grir{ .idn.d EliDl vNL! lN ol d&t pig@lopilh.lim (RlE) ad Dano. ofrhe opdc nd. (fis. 2.3)

rEu Lrd.irrrlr*-

2l3l Eb.rDF|hoam T.t (iRC)ft! eRC pDrid6 d o6j6tiE ma@ ofod.!d oF nlrdd @ tn.

rclira. Dudng th. t*t lnc r.lin.l 6Fff. to a srinulG of lidl ir n*Bd silg.cdBl .Lct!d. &d NUFd d*rod4 tbcd d dre *ir 'tud ln..r!. A 06s[ of tidnis shou io rhc ldidr dd rh. .locr!d6 edd 6. rdiEt poi@ti.l5, snict &wlop a rEfloG. b tn 0.{L Ttir &ssdc Flc.dc n En|| fd et.'41b..wt.rtidy of dind diF ih $d B c@ 6 Dd dtlrDtby .!d R.dniri! ftgIFnE23 LtXOn ',TORYWOtrX

23J DNI artudon filo hlood F!pL.T!. coll*r.d blood s&pl6 r@ bPt n@n .ihe at -70oC fd 2G3o oin d !r -

2eC a6ldg-ran srongc unil d. @t:lrFElar orDNA cdr-rid. cddic DNA

lg .!6!dcd t6 di b&'od opL. folloln! t m{.guic o.t d b 6tr'ditrs ..p.

. Blo.d mple lw 6$qt ro lr$ dF tld blood etL.

. Bl@d spl6 w.E w.sh.d wiln oi 35 nl ofTE b{fi.r (10 nM Tris Hct, 2 nMEDT

' pH 8.0). Supk3 l@ 6tdn4e.l d 3()OO rro fd 20 Din dd rtF

sllqulinr sa.ti{,,!.d io rah dr th. Its.d RBCi W8nna wB r.Dat d

ri.€ !o fdrriG dn ri tEC Flla bm. trEof hdrogbtnr. DiSrda of F!ei6 ir 6G FU.rs of WBC ru did od !t .ddhg OJ rlg of

pFi.ile K .1og win 200 ld of l0% SDS b ln. DE$@ of 6 nt TNE tof.r(l0 hM Tri HCI, 2 nrM EDTA. 40 nM N{l).

. Thl supl6 eep bn ovmghl in s mub3Iilg sh.l.r d a l€np6al@ of l?'C

,i r sp€.d of25o ryn. Por.i^ @c pEipild€d by !r'di4 I r of $Frsdlrncd Ndl, follostd try

visorcN shltine.d ch inS d i@ for 15 ninut6 b6foE @nritusalron ar 3000

rpn for 20 minul6

. Th. rupM E dirftcd ro mlk SEiliilF lllon tub. lrd DN s6aold€d n@ |h. supmd&t by rdding a e{ud volure of isoDropsol

. TrE DNA p€nd 6 MlEd win 7()% €nEd !d lloNd ro dry. Th6 dded DNA

pdl€. E disr$d n t@ TE bufa (10 nM Tft HcL o l ord Ema pH 3 0) ddltd.d d ?ot in . sds bd fo @ hod io indilll. rt tlmi.ile nud6

tt, QrDrifiorio oaDNA

Tqo rFlho& *.6 u.d for quotific.rion ofDNA

23.2,1 Otliel d6ity MrlllEb (S0croDhotomt..y)

DNA cll|@rlri6 r@ ..I@Lr!d cing . dilutjd of t/100 h . qllft @!tneql t|Ering dE otrir.l dcity (OD) d My€lagdE of 260 m dd 230 m ir .sp€cr@photoneler Th. ..rio orlh€ t*o Rrlines v6 c.ldl.led b 6rm[l. lhe puriry olDNA. OD260:OD230 = 2 0, indiclld I p@ DNA splq rtile ! ndo 16 !@ 2 O

indiclle prd€ir 6|1hjrdj@ b DNA snpre (ct&I. t9951 T1E mdion ofDNA 6 olcd,Nred froh 0E OD y.le ains rh. aomd. shom in t bl€ 2. L

TrbLl.t C.lorrrid. tor.h. dd.ndd ot caork DNA

23Jl Aa.l* !d .LtErhoc{t dd-rtiorh lhis D€Ibo4 DNA M strirDd wih rb. torer inidot liIs dy! .llidiuh

bbnjd. dye ad d4fopho€€d @ r 0.3% aA@F ad .toe widr o hDM eun of !DNA sund&d Tne !!l ws Min d D ler w lishl. dd lh. nor.q@ of lhe t6lDNA rr risur'Iy @rlprbd b hoM st trdid DNA Tt Mounr ofn@tgq@ is

ptoponidd ro lh. mat of .@lcic ed This mdn d aros qudilcirc 6 "dl a a

qu.,xir.ljv. didid or DNA a rh DNA ntdin d .tE CFI L . 60di@ of is@lolt Ei8l4 &d rhis |!. d.sE ro *ni:h n |@iEd irrlcl dui'lg sloEa. rd

2Jg Wo.tltra DNA dhddDNA diluri@ w. rEn. h bw TE Bullq (10 nM lrb HCI pH 8.0, 0.1 mM

EDTA) Worlllg o'gnldoN w€e t pt r 25 ne4! ed 75 ne/$l lor siirl. mlq rdnullipla PCR !,plrddioq r6Daniv.ly (l!bk 2. I ).

2.'.' Prtt nito. ot|&.d r!tr.. DNA drraTo .!ry ou lidrge rdFis i! tdili6 .fi.ded eiri ardilory dy.rurdio[ o e6'

*!ll Ela pld6 nq B d6igFd, aigir8 i'dividu.l DNA 3 to . spei6c rdtSubr.quqIty, s rtr6L pbL andnina . DNA diluti@ of dn irnividld d .@eamdon of 25841 (for singl6 nEkd dpMdion) or 50ry/,! (aot nuhjpld PCR

dplifi.nio.) *a mrlq R.pli@ ol thi! Bio plar. r@ md€ by ! dlp.Nitrs 2pt

dilution i. .rd! *€ll oalaid wid l0 d of mineGl oil

2Jra UrL.F ..rrynr fo. Elortqt !*ltrdtudi. |@liE dalhd. to.iTh. s.r..sl @lkd tuil-! re eEt d io d.& fd li*e. |o paiocb

qofrdl d.dB kd IIE ri*r8r tdyis 6 @id oln by 8tu91i4 d td dcuidGr.Uit STR EIG fd adr loolr [,t&tss oeBis tigb tae4laiq (o74 3)

i. Fpulaid !n pmduig PCR lrodst *i6 *ide @ge or niot oir Nighs l@seL.t d lon dE Ma hndd nEp3 rr! foMd odt:E w hbd.d M$ oe of tFnD|Bdt drls IAnt NED or VIC Iie priD6 l@ obhiied on]lMi.tty eifd nohApplid Bio$dqB (ABI) o. ltd.gEbd DNA T.clDloe'B (II'I). nE rwt6 ur€d for

edr oftp €DqGd lo.j e lis.d h T.btc 2.2

23.a.r lltl|lclid oaril{rdr. dtbE Dr lCRTIE Ba@i DNA b tt 4tlio dd6 e6 @t6.d ti.oBh pobffi din

rwrid (PCR) u,i'B dE STR ru 6. Ttlic.t r.lcdon ninN tor DriG eptifrnjon

Rudo. dl trrc for lcr

I (rH 3.1), in d rcl 15,sd25dr.qcLoi rkfibERa'be!raDiqtc&cNlodi..rrtu rn 4irqrim d'E mr-l

Ci.EAnp' PCR t rtn ABI 2700 or 97OO tlEnsgrt* (Attli.rt Bi6ytu)r@ used for mplilicarion of mk6B Difre6l 0r@oqtclo progm wr€ uled to

dpli& 0'6a drt4 ft. !N on@ly !5.d PCx, pr.sm }s rouchdod

Drog@ oa oidFr 67t-57!C 6 6,1.C-54.C, or sinpL is!*tinA prog@ rbsnsb.n6r 52-60oC (Fia 2 .r).

snp|,E AnNlrtlxc FcR rlocnll|t |^T 5fcrrrffiFhs Fib or pcR Frritu Gthl.ird {4jrB

Ia g I

I E g I I I

6 !a a I

; 3 E e a c 3 T c E i i € : i fFi E

3 t:s E

g s IgA E

F s 9 E

a 2 E E Ig € ! 3 ! f e

IF v ;I

rgt3 e

E I 9i3

a a 8 I I

i i 6 E 6 t t- I E E F i I i If T

a5: E d i E

Fn E E E I

Fa e a 8

c E e F a 6E E

g { 3 i I ; E e a E Ej :

a f E 5; g a

IE E E

sa g 5

a a I I 9

e t 6 ! tE a a

2 i E i a Ej

I a a ! gE I

s E s Ie 3 g

3 4 F i t E a F TI x 6

I I3 q I t ! I

* i € E

F ! a !IE

E eI I

E i .3 l A l iI 3 E

s se e a

a E I I .i

iI f I

lJ3 GoorF ld.loA s@wiL sEh fo. h*.a. wa @i€d o!1@ te !d@t!d aeili6 ddr

djrpl.'r.t F linl,e. r. hou DDA hd. Tn ABI Pn$M' t.!'bS. MqpitrC S..,

vdbr 2.5 MDlo ( tplid Biar!|6E) @l.nidg !?0 ll@6cri d'+bbeled

,id$..[ia. Dlta., dg.iad ido 2t tn Lr 6 6.d fd lantS dr.ltomTIE .!td b 6i! 3.r M ba rdebd t@ dE 1996 Cad@ Huo Edic abc.d @ c|to't@nd lo{tid &d h.Go4g$ny. Mlna l*rd4loily $lB adalel.34 mi! P@ b.s.d d CEPtl ScDttq darlbs Mrt@ fion { sltdr.trc$! {F Uihg. MrppiDc S.lrlDs r@ u!.d &. r!6r@t of &. @p!d ho@agGity

i+= i-=i*=";ti-T- "-=

i+= i+E-:*= ;tEi*= :*=:+= .1-t- r-:F= "1-.t:--F-;-=x-n I:+G,I+a l+-

" l -!+Ei+'; t"-:f "-!-4

=:-Sl!+E

;+= l+="i+i :-=I+= r+= itE i#=r+F i+= i+9 i+=.rfE r*= 1+g i-=i#i+=i+E i+=;+= i+= i+ni a+=

I+3.;+=" !-= "i+=

"f+E i+=:-= n*'

r=51+i i+=;+="r+F '!F's=i i+Ei*E ;*= !.* j+Fi+: I+="l+* i+=i+= l+= i== j+=l+= !+= i+; t+=

n+= i+E I#:+= i+; i-gi+= i+= i+=:+E i+=.-+E:*= itF l*;

i-H"i-Ei#* i*='L- :--F-x Fri i+i5ti-= l+E:+= i+;Es+r' l! -r- F" L- ;T=t -L-"i+'st+E-r-;r=

.-T-*;--f -

;-'F":-=

r-++:: -t_

r|eIabd- .r ft ^al

t$srf u.r.r.!.Dpbl d mro l.r.cd r0 .M) .r. nD. iFd 5 dr M.aa r boufurR|r.lffbml.lddd.hJ'Tr.t*ft.f'.d..t.lEn.aA.&ldd.'..|4|h|.16lr,rl'l'r{..|-&..r...b.rdEb

23.t1 Sa!'Lrdhdi{ orABI PRISM! Llntls. it poirs s.r MDroTh. s.qe|a fd.ll tt Fin6 lirlh |[6. dEls h.w bco qrimir.d id *h

! uy lhlt lh. m. rcR @ndni@ c 'lquird

fd rhe adE !.1, Fd rhh l!a$, .nultipl.x PCR Drtgm B usn ro dplif, tl'e n&LB of r whoL pel d . eb-sr of. F&l sinult twsly- S.c .nd fuEs.t! oa FFb *4 {ruSo4 bri.S inb @rrt€ir dy.lru6.!rd th€ si6 of ihe mtli!.d F.d!cc, dxl slrddrlizd for oplinm

-t i+E;l-

;lf-Fi+=";+'3af=J-t--;=F-

udiidim Pud trE i.r s.rl ad $c q@!!v ol a.h nErd 6!d @ list d in T.bl.

T.bL 2.a St nd.riL.d !.l! ofmohiDL! F,cR ofadr prr.l urhquddty of th. pnd in . 5 id Eclion nirruq

D rw (o rJdr DrsF {o rtr! DrN2e(

m|9'DIu:'Ds:x'D*:IaD[!''D|9J

D:s:s8l6'E|dlDell

t$t:t;i;liijjs6"Dlrr57tDeo5 Dsr534D3s'6 bsaldse I@I

ffiffi

rA-luwor.r*ng,rorsaro:sc

D6sr (o r,ir hsrr. ft sw' D5v6

l)6w, 6S2?6 D{roC hr{& r8}

-Ds\h%:.

Dlsa Dib ram.b*r. Ds'

DM{(0[dr rt$r? (0 ts|u Dss

ttatiTiditt-^i-i6it'r Nz, Dt

a D?9.M!l'D'9i6m'a's''N'

DB']'Drs$o,D^!1'Dsb-

6iBcr?, Dr I sr. mr6t DrrrqD

ti;i-.Mnr.D'61,1Dg' sa;

ErKfl,s6,. D"eF, orc'? Dr'er

n'sre D'e'.D'sn. D'a'@ D

n'ar. Dtrs! Drae. D'e'.D'rt ''

DN.mltr'D8U1D|s,20.6

2352 MdriDk! PCR *toto.ol

150 .s ol s@ni. DNA w6 u.d ro dpli& PCR fn8Fda i, ! 5d .sron@.l!birs 0.04-0.06 !M (0.14.15 d) of ai prim, 200 tM of dATl dTTP, dcIT

ed dcl?, 0.3 uniE of Taq polt@e, o.5Fl ol lox PCR r@lio. bufet (750 nnt KCl,

loo mM Tds llcl pHr3.l, 2s mM Mscl, dd t 0 ln ovstty ol nieEl oil

23.6J r.d rDrdt|.! rCR .t $For snpbndr@ of pdnb h ! multipls fonE! PCR condrn@ hlving d

mF.lins tdnp.ralu. of 54"C !d d alsion lor 2 min !1 65'C w* N.d (Fi8. 26)

fk 26rltrqdbepn 'b

ror sDrlfdli d Fl.l '*' i! !ftprd Pcr

uJ Pat nlion of s9l6 aor lh. cd. adlldl-2 pl of dE all of th€ PCR produ.ls bsina ditl@t sid dd lalcled Mtx

dilldet dy6 Mo poole<l toe.dF in a 9i3 edl poolnB pkr' strg 12 clpillar,

rtuiilron! Sltep For 0F lclotuwd. sda 24 d rcR poducl of eldr p@l (b'Y

@n$iri'{ an sas of pdd) w@looLd lt sd ord'io zed Hi-ttTM foMide(ABI)

dtd o 2 pl of @ oflh. idd$l si4 dtntd. Rot' (c950o ABI) Lz'q TAI|RA'

(Peiin Elm) wd tdd.<t to ilE p@led ni\tuA Th' slpl6 mrc ddtsoEd d e5'c

tor 5 tuu16 tono*6d by quicl chllling on & for 5 nifli6 b'fdt lmns d dE ABr

Piisn 3l0o or 3?30 C6.1ic aMb62J.? utod.a.a ftrtgor !@irttrn!

Tlt @oLd 9cR lDDlioE ld .ubj.ded to elodLd so$lt?iog n dla tl6-!.oiltdy aBl PNsMo 3l0o or r 43 opilLrv 3?3o Gai'ic AIdvd lnrondlon

aboll 6..h sdq i.cludi.g 6le nme, smple @. d'€ tnd inMtl siz' sLodard w6

d.r.d in dE Gc)6@ eftwe !o idatry dF l@ Mbd &d @laL or dh

AulotDr.d [uo@t g@otvD'is aollos lhc pridipl' ol sd el*ltoplr6! I e

*na dE d.re ltbel.n DNA frcrFls del'<'!bo@ tmush rb€ polv@ (POP'4n')

dq m 6.pard.d Mrdins ro &oir siz At lowd od ofrb' capillds ds dy€ l'b'l€d

ficrMb ps rhrouS. rcam whe€ . 16g b@n contnuouly scs the cap,IeH

TIF le a.jr6 dr tl@r6c@t d)6 rr|rd.d lo dE DNA tteM6 ltd dE dn lrSbr

al a !pai6. mrcloE$ for adr d'€. A st6to8rah o[.d! !d 3+rd6 lh. l'8hts

e&rdi.e to Mrdogh dus .l fou lr!6 of ll@6cqn disim d he dde16d s'lh

Np6ofdE16 wih lh. h.lp of.ld. @ll.ci@ sn*.tc dF I'Cht intaEin6 e6ll€.red dd !to'€d a .ldri@l 3i9'ds (l* 4,r | 997I

Auiomrd dlde dia'lFr E Ffod'.d by Ca6d an ld. en*@ Eite

rlE &foruLd lm6@ d€tedion drrlilly of the AaI solaic dt ltd to si& ad

q@di.re DNA nlgrEa. Th. c'Jis of dlt 6p@rEr e dnpbd a ! reclrlcL{t

sd idge tlE d*fopkoem. CnDlyF tl.? !d CffEppd' v40 sn*e(Applied Bidrsieiro) weF u$d to aotlya de C.n66 dtlt Tt€e dElrsis pogsireoil GsFa fi16 dd @rqr ddt itlo I |0tliqti6 @rE C@q?i* dune

imlude lbe @lor, larrL fnetBrs st idedi&r'g labds, qurdnadve d!4 spleinfoiDlim &n @mrHE (Fig 2.?) TIE st lytb8 €d's @ tGfef,ld ro d!!3p@d!h€.€ lo. ilploryp. .rd sl.tis.{ lnts

FLlt a nr6! tk!t!..'F, dold ll[ cdtF/ YI' ftrR" -D;;-Etrei..ri- '.u.Lr b v rb.'*do'..*)Fd

6e:d*,d-nbd'rdEkqF-(oq.tng r. r * l *to. t an .nwr.r 'n bqtu br .ru -J"lL.k*d|.i..-!y'tr*

2J, tlrplotlF u.ly,ti!Th. s€ts or s@q/p€d !!€16 M6.rD,lsed @ddDg ro lh. ptrFicd na d a

.hre't@@ ro e€L h.plol'?6. ll.plo$T. rdj4nr 6 itrdic& rlE idEilepm.fr of s.cr.ening alld6. f ol Lst dre pobrDobic @t6 dtI s€ lulhido@live o the amiv ed lo.!t6d in dF lirk!€€ irr@al sltow hono2.ygosiq in dF

afi4rod irdividu.ls of ! aedt rtp f4it s cdidad ro be lint.d !o rhd DFtrt

239 D.o o.rrbrdd .rd.r.trt ubr M.6A lll@ n a dini-prcsm

'nich asul6 r rdi6 of 6mads in ompuicr

lesule. (wodn .pdebn..du/pqvw.bu). TIE Mim$R Ex..t bs.d M $.8{atuXy dcrdor.d by da Bioi.fotruj6 rr! a,r dp CEMB ro td, E orgDin'E r*t&ulpfg rli. eao9rirB .t!! of lEdil'y dig€e. ro e tt€ nle pbste,{tiff€Ent .sl si€ll qo made as., D!1! Sh€t Reg6 Sh@1, B6ic Infomdion Sh€!ed Cod. Sher Dif.6n ltfu @Dd5 e tu on d.i! sbel for d{f@r Dodutg(Mtsq olding codnB flbgdc)

Th. dala sb€€t is th€ prinD.y d€ld into dtd rhe OrDqlrrg dsri of i'djviduob

Msr@!d@udt, inrsBof sizoldLl6.Tt .dditi@didon'rid.ddcdlorhi3srE iEldcd: Pld lD. nr.rr6 Mc rup posirio4 h .lrt, tabdnB Oq alde sn&s. (ASR) irdiudud tt@ &d ils lD froo lhe p.djsr.q di!@ sl.'rul, lnd relri@.Met u wm U5&{ 6lumwi!., *tril. individu.ls *.8 @g.d hol'lnlolt Tso@lum wG signd Dc i'dividurt foi th6 rlo .[d6 oa6.b @t6 (Fis 2 3]

To M a nodule o c panicde ddq ! spsinc mnb6 of6ll@ dd os wasreed i. lhe ruEs sh6r

23$ M-D .Fnti...l oE!.atTh. D.a slEa !n 6. R&86 $-r I 6 . b&Ue !o M dilfcti{ snNe

modul6. Th. cscado ol e.do6 b M de nllms i.ctldesr clict "Tools , o. rhe Mftubs, &lcl Mcq and rho Mtru (AleF3). a *indow wirh rE lid of m.dur6IoFd, th Eleedt rFdul. E !d..t d !d RD @dMrl rE siE. TrE doi.pr6.du@ is degicleit b.lor h FS 2.t,

Oi,FFETEIL-!

b, F-_---------]

162.rrd|EbIn.Ia.rd!i.''.i.

Th. d.sisnd ExEl ntu Fovi& nrc dyMnic noduhs for noiDot.tim ofd.6. A dc$ndion of*h noduL t d folloB:. P.Frr.s.: This mdul. is B.d fq ofimarid of inhdit re p.ndn by compeins

thc !lLl6 of siblinss *itn FEn6. Thc M of thc .lkte or.U individuts rhd hardc Me p.@ll slbuld nol bG mE rhe 4, lf dy d.ri.tid Eeedins inh.rn !ep.nd isfond inrn &r!,Eld! ell is tighlish.n in Ed.

. Colorttr8: This noduk hilhliehs rhe imozygoB .tt.tcs by chsein8 rh€ir

b6ckgNnd 6ld. Fd ! sird. n.rtd, th. s @te is signcd lo s. $r ofElu6.IfoNtidon s.r of homozy8o6 .tlctes vs pEsnr in r d!t'*! ditr@to16 e signcd io rhsn.

. codlng: This nodul. @bzs nl $. lttcl* of ! mtk r dd signs th.n !nundic c.<t . lt thar ga.6rB ! sp.e ".o&" shct hrving rI rhis infom.lioninhct rs in qEir.l ddr sh..! .@p1$n @h dt.k is Epr@d by i13 nul8ic

. Filing: This mdule omdld !E allelic dar! for r Civd sl ofM!6 in de fom of

.o@@!ed .lld6 IrE ourput of dE '!dub is d ep&dro drr. $c{ te.d B6i.lnto'",licn porulald ! 6llm lrlded _drd6" Oda @ll|m ofdis $ci enled in hdudly @rdiry ro the inlomlio. conained m tbe p.diere Tne E6ic

nao sld is firoE !s.d to rul pr. tl. for LOD sor. dlcuistoa. c6t Po. Tlis tuduL picls rhe dlrr fi@ "Bai rrfo" !b..r d<l otuE6 it in s

spsific paneh romjMded by LNT.AGE $nw., &d eve in ! rdlfo'lddfile Nili ! !E d16io rhis pre f e is s.i a sEins Doht ror cslculrrins l-oD

23.10 r,oD S&n .dolid.ELOD scor6 Eplgd rh. dsl emcidn $dislicil mdd lor evdolns

t€digl* f6' linllae io Md'ddid frib (Monoti. 1996) LOD soE ws. coLulored

Ning FASTLINK (v4.rp), r DOs bG€d $ft*e prla!. (Scn f6. 19 is.i!11*€rdl. 1994). Two poir rd n bpoint IOD @6 8@ cdcohl€d slh MLINK d:d

ll}I(MAI p.og'e 6pdrv.ly (Twillgs ud O( !99a) For cdculario. purDos,

dsn6 "a $l- c e uroAomal lEsiv. lroil wilh @frplel. poa@4, dd@nbi..lion 0quai6 in nd6 !d f.rD.l6 rw sun d .qual Cdi. diltclg6 ldd€d lrom lh€ M.Bhn h nulM sadc mtp (*w.mdhm.d or3/e-di6) Dd!

$a ldded to rh€ cdoiat4 soN{e by follo$ing fr16:

. PnD flLE: h it ! sinplc el.?.d frlc $tidr duiE Dfotnttio. Ee?tdna lmibsirwor.. sfr*ri.. n$4 lrd s of i.dividuls, dorB wrh rhar eqo5Tic dd!

. PED IILE: In rhs 6le inlonndioD lbour lhe looDs ud @'MBri@6 ,rMrlce

n dE hn y is 6Ga{. TIE l@ps & bD\E ein 0E hdt of. pio8m .med

MAKEPED lo radd th. linlrg. dcurdim ls n o!rc. TIE plogm htts 3

double mtry ol ln* individuds ton Bh@ $€ lmps wq€ brota &d Bule h a

. D TIILE: This il. is flEd. rilhdElElp oIPREPLINK pog.dr! Dd @ntai.s rhe

all.le lrequdq, of erch @rt€. ortz.d TIE ftequ@a oa STR MLs ,lld6link€d b DFN loi wq. 61itr'!I€d b,v gft9ti4 lh. eaonic DNA tror 100

@.ld€d Pltisr.ni subjdls. For lhe nErd *t* ctual Fequnci6 Nerc .ol

dirlded, th. .ndc n quas6 *@ @Fidad equrl @rdirB b d. d.I! of

fdDl_v, o. lo .nel6 *tth €qurl frequdf,f of o.l wc amed lo trdG lolll sd

2J.l0.l LIOD Scoa ddt @tp{tThe Link4e Cotol Progre (LCP) &16 .ped ad dd fi16 a in ul fi16 sd

emsa16 o _p.din bar.h frle" whidr o aeulion sasar6 ! nb sith 0E detelt n@'rinal out- A FAM2PD PROORAM T6!ds lllo FiMl out 61. ed livs aat fleoaIOD $06 in noraai 61. aomat

8.lr DNA q6dnl for m|lttion.l D.lttitDNA s€quadng \6 6.d to a.dyrc lhe nuclarid. bs6 (A T. C, d'd C) in a

DNA nieMt {ad) lo i& 4' ndrid i ll, ssE tuire ddnory d}rf@cri@

Tl! trlsl n€? in thjs pro6 w io mplit d! t 'sn

*m tuouci PcR singsp€ilidlly d6'si€d pri.6 (Prii..3 $.bsite Na.s..mb.aorc/csi-butpnm3 w..Bi) fi. PCR producr !@ Irbclcd trith nu@rf dt6 ad*ibed a!ove?. You .!m1 rEl_\.r r.diolaHLd podsll on m ABI PRISM

irolru@! ,iich dsds nmr@t l.b.ls Morc lio orc pims D8n *s B.d to

mplity mlliple dl}li@N lo sllow s.quociiS of longd 4mAn dlomlr€d ABI PBISMe 3l0o Ca€tic Ardya *6 B.d ro lb\lr llE

labeled bes in aor did.Mt colo6 for .{ T, c dd C using B'g Ove Tmdalor

Chonis.,- 0lcjn6 a al, I {r3) Th. ABI PruSMo 3 I oo Cdelic And)zer luclioN de

s@ "!y

ror bo$ seqwins ed C@@ oaltsis .e, elaropnoretc sePadion ed

soed..l d.l4lion of dy. lald€d DNA fE3mnb

2J.ll.r E!o. iddinedo.PCR ra.liN r@ Ddfom.d rn 50 .s of l@91& DNA in 2s d r*don

mi{ur. The PcR @liotr rinN 6 lrla i. T.bl€ 2 5 To @nnm l'l. mptficdon

&rd puiry. 5 d oflh. PCR produd ws ddPa{ m t I 5% .esoe s.l

T!bl. !! Ro.don oit.urc aor dpllftcldo. of PCR Fdgflnb

JlsL4rlJrp.dn. eP)

'rox Pl:]lMqam lni t'it L eH 3 a. tu 'N(cL r!, d r,3clr.d r%rtib)

23.11: f,XOSAPTdtodtTlE eplifi.d p.oduct @ 0p t 3I€d widr . njxt@ of @Dud6dl ed

slrinp .ll,line pn6pbot& (SAP) b Move uiMrFnred nud@rid6 &doliaM&l6rid6 G.bl€ 2 6). Th. ninuE E itruhsrqt d 37'c ror oE hou. |||o at

80"C &r I5 mi. lo i@rva,!e he er4des lnd l6lly lr 25oC tor 30 di..

23.tl3 S.qnddn! n*dotrTo rh. EXO-SAI lrd.d 15 jj ldim hixr[., .quat votlm of dHrO *r

add.d ro dilure 6. $lr @l68!rior in dc sqt6. Clrl. s.qrry:ns witn torq!.d &|d

revw pdns ws Derfomed s@d?t ly 6113 lh. fouowinS rs.lion nirarre (Trble

2.?). Th. PCR prc8m for r.qE ng r...ri@ is giva in ri& 2.9.

T.bl 2n Ra.rir drtuF for Ex(lsAP ru@nt

T.bL 2.7 Ra.riotr dttuE for rqb.i4 qdio.

. 5r dirdio hdtr (Tro4t 4n Dll pH 3 r. MscI to nMr

ry.ae r4h.rl* tu:F-.t |gfusitrrad bFdu ryv{ytutu rtuR

23.ll.a h0.riag. pmrlo.l for oqldlr! o. Ga.ltc Atrdr*.S€qE,g .!.cic c@ sd up in % $dl MFTADp PrCR pld6 (-43I) &d

pFjDn r.d Ni.3 .d@1. r 9 0 !r of 95% dol dn 1.0 d of drl o E .dd.d io rhe

l0 pl *q@ds rc!.don b rEle th. nnd mslrnion of erheol up lo 60i J%. The

tla16 w@ sal€d wilh 3M S@lcleduiDd foil l!p€, vone{ nixed. &d l.n .r .oon

tdnF.nft fd 20 niol6 fq pEiDirdio. of lh..d6d.d poduds An wds rLphc ra @dnrgid .t !250 rDn for 306i. !r 4"C &n so!@r'll a di.dtu ur\

inv.ni'A the pL& @ ! p!p6 lord Th. D.ll.ls *@ w&nd wilh 150 d of 70% edaml

ad da d dded Th. &i.d p€nds @E dislved b 12 d ol deidirld Hj-Dift

Ftuil6 (aBl). Smd6 w ddurd I 95'c for t rin folloN€d b! qu* .nixing

b pltin8 @ i@ b.f@ lo.diis o rh. Aal PFJSr"f 3loo G.6ic Astz.23.rrl A.dylir of DNA S.qudd

Nt6 6!d rua rh. CsElic &!tzq B€d rhe AaI PFISM slqMcng &Ebsis

$n*c v6im 37 ro sba |n. s9l6 ad E!6 d6! o Bd*|. fom. TIE

s€qEs w rha @d MDdV 6 Clmru sowe vl.45 Th€s.qudE wiho@np.r.d to Dom.l $qu.re br 6iru .id{ Nuclolidduclodde BLAST (blatr) or

BLAST 2 Sequ@ (2.2, | 0) @ dE NCBI w€b.

SLAST (Baic Locd ligmaa S.eI Tool) i! t lmib of sd' pro3t@

siih ft d6igd.d io aplo6 3n lt. djLbL d.rlbe {Jd . qsy prDrd o. DNA

sqoeE (AlEdul e, al , l99o). BLAST 2 S.qua6, '3

. Dw BLAST-bBd t@l Qhich

is le tin+cmdin!. Ir is us€d for rlisd.r ont t"! homolo8oN s.q66 or p.ol.itu

or Ml&lid6 (Tloevt !n Mrdd4 199) B<{h d* pbgtM w us.d tom d.NCBI wb3i!. (hq7/*w.ncbidfrrihSovbld,,b'2s.q/*tlac.gr). I!. culli'rsalignma e p.6ald in bolll grehicll Md a1fom. Any por6ni.l nufiio. in lhe

DNA s.quoce M @Iinn d bys€qu*ing bolh sre lDd Dtw sIreds.

CHAPTER-3

RESULTS

DISCUSSION

SECfION-I

LII\KAGE ANALYSIS

FORREPORTED

AUTOSOMAL RECESSIVE DEATNESS

(DFNB)LOCL

PROIIrcUE

lin*!3c @lFi! h^ pr@.d ro b3 u .ft6iiw ndod to idarit w lmi in ld8.osE€u6u fmili6. Ii ha als h.lpld prcvide *do@ lor Inr.g. to the Eported

intsvals h smdr foln1 *tnch wuld od4ie t too !tuI !o suppon sis!i[6tlinbg€ on th€ir oM Th6. $nr[ lin*6d tmiliA h.ve ba dd|€mly helpful ro rfiftdc idErvals of r€pon d l@i *{ich s r@ h!. rd ponliool cldig (Ol! t99D.Uirlse ltlrlis I'a b€ thc pnnEry srfiing poid for idanifodon dd potrion lcloniry oa mosr ot lh. 27 lrDM @siv. d*6i6s sqE. Sixts of lh6e ctd.d Ba6hlw b€' ida.in d d!reWh bir,ee &b!is h P.lid&i foili6, dn includ.: G/4,IDFNAT||MIE lDr.JtB6\ ItK:] ()ma7/1t, TMPRSS3 (pr43et0t CDH23

lDhNR12r, UShtC \DFT$ t), poEts (DrNB2t\ CLDNtt (DFNB29\ DSRPJ

@Fta3t, t;scN lDrla3q urx lDrNB3 N)x (DtNt24 TNoAp (DFNA2uiAR 'EL2D (DFNB49\I.RTOMT \DnB63) si IMH9 (D|ND66/6, Nvet al.,2@21

Kwitudal, mo2,Borket al,2tfrlr Atured erd,2002iAhned e, al 2003btWil@x.? dr. 2mf ; coffh e, af 2mE Ne et al, 2004; Alrcd a al.,2(n1\xts.t ar.. 2(a14Rihddin dr ,r, 2c\06q Riaddi et 4t , 2ou6b, tnn n et al ,2003: shnbbn ,r ,1.

-rln! l'ge otibulion of rb. P.l6tdi populdid io ou ud*lttrdiis orhd.drtary d.,Ins giv6 slroe dido@ for de high deg@ ofgdedc nelebsad! ordae's latsq'€s ri Et6 i r idal popuLdd to sid h rh€ iddiEcnid of dEldse Nnbr ofnllm deanB sos vhi.h r@in ro be nlpped &d ids i6.d

Tr|. pl6at dudy b.gh *idr drbs6 t6iiry for lu*rse lo cpon d dadr6lei, an h fuili6 lnr€d b krm lei M hdptut in !€ducirs dE raoned lintls.d.flols &d lha .uli4 n @e ro frrd dD ulhsm sG I w6 ale aihed .ttlnms mw .frl dld6 oa Eponcd gn6 *tich nBy h.tp ro 6rruisr CtuqTeph-ot!. oftlalio.r dd rhu b€lp dddLed nnElion l mdhri.m 6f disee

Fi.dns noE f@ili6 lirled to . Epon.d lru is d$ n tptut i. poputdioD

l*li. sMi6 ro 6dne th6 Elatjve prcvdm of drdat l@i nil my evatu.ltylElp in dE Db8osi5 .d DEEnih of r$Disio of 6. jdqti6€d @.

(h. or rhe most inporld purpos or rdlins for tin*rge lo epon d too 6 ro

f,, tlE u, irl€d p.dis6. rvlid @ b€ lna b. lubjcLd !o i lFro@wid. li,Ls6s ir odc b 6nd mvd l@i This will 6fits ab,@ o( hD*t.dsr of saEri6 ofd.!6r* ed pmde ben€r iEish inb rh. pl!^iolos/ of hesng pro€s

Dui.s rt p|Ed srdy, 6oy a.mdi6 wirh rhd d mE .fded i.dividurtM. mlled 6:on ditr€t e6 ot P*isftL Liirrge aubsis fo. E ortd l6i ws

6icd out on rMry five fanili6 wnn dsdild audnory dsr@cl'on. Four fml'6@€ linLd ro Fpo@d lei iftludin9pY\DF3a3 dd p,/'DF b6 b DtilEl. PKDF I toi ta

,/)F/vr7l/l &d PKDF.|33 io DF A29. Mndionrl o.Dsis of SL2d,4J g* s6pe.fonnd for PKDFI46 ud a p@ios! rooned nulllon (c 716T>4) ss lodd The( ,artlJ aft B s€q@ed in fM y PKDF,133 nd . nov€l mut tio (c.331GT) B

TM otlE fMili6, PKDFI043 ud PKDFllo4, .tso gaw lu os€ b Mt4ndlinB rh. DlivrT2 loc6. PKDFI I 04 h€Ip6d ro Etim uE tint'3€ iwad ot DrNa72.ttlTL PKDF 1043 ra hdpin in a$pinS of . @vel l@, ms d6isnden DiMarlTINXAGf, TO DNVA'

PKDFI46, a R.Jpul tuit hwrB aou alldld ildi,iduds in lh@@Bosui@B sibships, w6 sto .d fbn R.$dDindi (Fis 3.1) The &do@rrtpbfil. ot.f6ld individurts V:9 ed V:t I shoqed bjtdLEl &dilory drsrun ljo ofvlryin€ sdily in bolt s (Frc a.2). pbBicd .@jElio or dri*l€d ndivid!,t@al.d rc aoiter or dr.* olhds}npl(j6

'sidld wirh &diloav dljtuctjon shdeindividu.ls v:r .'d v:2 l@,Ettt.d&ted bul hld @ adirory d€ficn.tlotu4t6iry .r@pirg db*td ld.Sp .o ni@s.tdtire nEn€s D7S2420. D7S2tt56dd D7S2459 al d!.oll@m ?q3l (Fie. 3 t) Th6. @r* 4omps a.egion ll)erc.'r€ ldi fo. Pqdr€d stidoe ar|d m-sytdrchio Drrv84 oEnrp. A, L\.8 w6 .otnnory of soiter in |n. d.3f individuab of 6€ rdity, gis sug86t! nurarj@ sr rh.DFxr,, loos ca4 only noFs_,lmni da6ls i! rhis reila a nsDh tsepoolLOD @E (ze) oa r.49 B obbin€d ror lhe ror.r D7s2420 O re.sl cM) .l@nb|di@ tr.aior 0= o

S.q@ .rlbsis or p€,r'.r, coding qo6 ot sa(:26a, 8dq heboEd in rtF,txr4 inEral, Dv6ted. Dpon d hoDozlgo6 subsrjtulio, (c.7r6T>A) in qon 6 ofrlF .ffed€d individllh (F,s. 3.3) This ojssee @brion €u& n ..pt@man or

iT* "*" (v) or Berh 6idu. ot peturk voki. *irtr sD.nic &id (D)(p V239D) in dE rtrird ardattull don la ot p.,1drtn (Fie j.4)

?:'iiiFi;€i3Seqti&1

:t5iE"

:;F:+trEF:&<t::iiisqr6!rFla3sic

EE!.ii-

!Itr1l

oaa"i?i4uat

nar.rP.Eld.|r6*dhr.!e!uo.b..l'..tdhd|ddtdrxDrl.6ari|bd bdh'rutv:t (r.!ar.r).'t mb Fr..d ddr r ftd.r*-.Ft...r.b'|{|.L(rc! 1.'.')ffa lreb F||ri dd-b h *L pd..rd rdb!b b dr l||h -r, .o" d .x.

''Db d'qd b n tI-dn4.Hrd.|'. |it drdd-E ori.rdtu-bn .hlnn|.|d_

tt, rso6t .ri-lro.dd.n a scir., dr&rE .. r.tddhftlfu|o.Pnn.6l'h.d.ftd.cn.D^E.|d.s||p'ra9Ddn|.

IGYA'D)

oaaa?trrrta

Fr....r,.i.t tE-'r.rcnd-,Lr!t,r.r*.

LINX GE II' DT,V'IPINPKDF:'I3

rxD683, .lar. MdiM tdit s mu.d toD Surlr Siidh TlE ADitn d Oirld.ff.s.d iditidu.b in te Scl.(rio4 t.rSh irdividut.nibu. ar

d,. ri@ oI colLdi@ Oig 3.5) Phricd 4eiraid of ln. .ldr .f.d.d i.dividud5

doa€d Dtq@ of Soiia {idivno,|| DlO, V:5, V:8 d V:10) slin. soi!. $ Dtdid.ar in 0E youl8 .tr r.d irdiidud! of 8-r.rbn vr (.96 5-12 t€s} T!.&ditfii. pb6b of.&d.d idivtu.L V:10d Vl:5 slrrid !'drrd redr|r &ed d.&s h bo|b s 1Fi9 1.6). Hllorrp. ldydr $owtd lid.g! !o

DFNi4PN hil.q.Dr3z.2o,W S,J6 rd D?S2459 .r dFtr@D 7q3 | (Faq. 3.l)A di'lM rbtd.r LOD !oor! (Zn) of 5,28 E obtdd 6. th. 6la DlS2459

(l 19.81 cM) ! t8ltin lid Adio. 0 = o

EiEiEE

et€:!.I!=5+.:-9

ilqE&l

;!i-lET

!.o9!lo

.r.r"c.rp.tccc p"cdd*tdfdd.dI

rt,i6 I\E h ir dd-.d.cflr Atr&r r.ddM v:ro (.c.31rxr) I

^trnd bdv|'lu|| r'l:l (8 lr

'x- rFb dEr-. n rL rtr..a !n s, nt .rr'.t

Lr{taaca To DFNtTn 1

H(DF 0'Feily PKDFtlo?, a sndl c@t'sui@a ADit wa col*r.d nos Mnli,

Pujib r|d bdo'E d lo Enr GL T|l f.dv i4lu.t6 tdr df4r.d individu.ls in |so

looDs .dd rLE ofrhcn bdo.siig to on loop w olc(i.d (ti& 3 7) all da d*i!dindiidulk (V:2, v:3 od V:4) d!o*d pDlouDd IE iig lN n! bolh d (udiqm ot

idividun V:3 srbm in Fis- 3-8) b mil6Ld 6 odludiLrv stnplom. Duiie

li.lde€ dly:i H.plot?. ,or d''e hi.G.&l!1. ffiire 'udo r!9S1337,

Dqsll24 rd D9Stl76 ErsLd |t!r dl D. .f.d.d @n!6 E@ honD4lod fqd6€ @dcrs *lil. tlE 6md i.diriluds l@ lEl4o44o6. ,45 dF d*6oonps the @iv. dstB l@ DFNaT/I I a &bM.9qI3'21, Ih. fimlv

N miidtd [r(t io b. IhLd iol8b lid4. dt& E .tt $atsE TIE

nwimd L,oD sF (zE) of 2.l7 ws oblarEd tor de @16 Dqsl 124 (67.39 cM)

rd D9S 1376 (6?.39 cM) ar @nbincion fr.tdon 0 = 0

PloFltgt

HtH gi IF93.7 POFrlo'r Pdtn lfu b Drnrzlrr otr. brhoF rE h|r,r|hd,

Ifr .yrM nF*n dlid-r rb .!&r tfrxnc ud.. rtL.ndddr r..d odtu b.M rntt- de|.n oredv'.

i||il||ti

trt.i"

rrr"ddf*f,ct {rddle.d.cdfdddB

tl3r ^, ^.dq

ot.dk'qbdnndr|rryi(+.oy-')a hdd sdlcnn ndng.r d.rftdd r nddor v:3 .t .KDfuo (4. r!Fr) rrdh. rr!ftoda'..|od i. 6. dar. n. m i, EFndy. I dF Ldr* r+r.9odradElot..|8.||dd

LfilKAEE'fO DFN'29/CLDN I 1

PxDF,ltS

Fhily PKDF|88 6 as@in d fron Goj6r hnj.b ud b.loqs b Mlghrr

caE. Tnis 6nily hld fu alf@r€d individ@ls in two N8dnms lo.pc (rE. 3.9),

all .fci.d sbjFti disllay.d bileol prdiryull hding 16 rirh m 3i8rs of ntnr

blindn $, eoiEr, b.lre prc,btm q oda cli.iol $nmlili6 @ssFllting *ith

rDdnory dystunction. $e oudimeLic .v.lunion of th. afTect d indiridulls Iv:4 tdIv:6 indi6&d s6 ro FDfsid dcsE orlri.3 la (FE" 3,l0). an r gcndypin8 30

sIR mdteE ar 29 dciftEs lci (Tablc 2.2), ft. dafiEs pi'eiottpe sgrttri.g in rll.rd.d irdividuh snw.d cvi{kE of li.},*! b Dtvr2, m.tt6 D2ls20?8 .nd

D2lsl252 (Fie. 3.9). A mdimm M poinr LOD s.c o12.07 q6 obloin€d for

micFstellire m*er Itl Sl252 (35.45 cM) rt Mbin rid li.clion 0 = 0.

D66s !r the DF,vr29 le6 h.s bco shoM 10 be assi.r.d eirh muldions in

rhc CLDNI 4 eefr (wi 6r .t d!., 2001). DNA tcqEE lElysis of tE Cu)Nl1 g6c

EvaLd ! honozrSous sobstitltion c.23lc>T in lhc ain8L coding.xon I (Fig 3.ll)

Thi rdioBly unnF.r.d nissae nohrior tgh. in d mim eA $bdidio or

%lii. (V) for hidrly @een ahino (a) (pA9av) Oig. I 12) in 0'e s€@d

rds.mbte dotuin ofrh. c/6dtFl, Dotein.

PloF48a

ll llFt, !, t'rsttrat anr.G br..rr- rd brmtri:ID{,1 Dr... rr0rvF e d

|l'}.||'.|M:Fh.lFI*e|din|r.irrbFfu(Lbd.Mmcfu.ll[.bndldiga

j:E ll

, a e +, d.f f,ttdt

FEtl0 ^.a.

PD b d! cfr.nr rdlq'td or.rtu hdtu N:. (|3. eF ) d lvs (r n rlB) , l|otli r.ni rilful nr br,*-d d..tu c tdrrr r. --l r-.i rtr r *, (... tFtl _a

-d rx'Dr.r drF. - t rl| -d s-, ird'{. +||.r lrdd

-tFrsd-brr.!n-rrrr.d

.rrtr{'dddddtf

d4f.l{cCl/dd

rEl!|f cr.r-9l -'il b ctNrlo|r.-.Er.nirrrl.E{d^olvr.i'or.i.t[-.'.ftd..ffirdict ar rrqtc.ltreTsldfi.. 'rdn,t,trodd d{.F^'i|V. C, CrEftsEn or. i.r|l4d -'r.r hdrnrd.

r|3ar o!d.r. cm.!E rro'rr ffido.oft. r.a ft luE

SECTION-2

MAPPING OF THE NEW

AUTOSOMAL RECESSIVE NON.SYNDROMIC

DEAFNESS LOCUS I'FNBTI

AT CHROMOSOME 19p133

A lag. D@b. of dd6!d lsi &.1 g@ 6 $iI op.or.d to b. m!rp.d. Ou

hb de dso eptdrs |hi! @dioq !c.e tuE rh 50% of rh. d..f ftni[.t

'nh 'dlinted to lh. Eporr.d lei ud, tc!for., r'ry nenor mvd lod &d 9e.5,

h'cro uE€9orr.d i' 6. irdory ofle .L6* eG Tlo P.&d-i p.rdridt ta $oh 0o be *.@nFry

'!.ftr| fo. otliq DfNB bd

b . .en to ihi& @El crd of t|-c'.\ w udaro.t socrid.li&9. s d tm b'il-r |id ditl4nd D Ii.r.C. b rb ldo* .L6... lod. On

of |no (P(Dfi35) iildt n4.d to h.dir. . dd itav.r @ .hotted l9pl3.3(DFlVt7, id .nd ddiiod sr(|y .d nltd E6jEH! H!€d lo idrdry . mFlr@r!, D*rl€iCn r.dDF t 3,l.

3.1 REPORTING OF Dfl|rTri A FORECAST FOR ,r|/r8]?KDf,'iI6

TIE fmily PKDF335 wa d@ll.d 106 Sidrol Oujab). IXis a@ib belo.ss lo

lh€ Cqle cde ed th. Puj.bi elhni. group. A p.disrs M dr.M rne. m@4ngnultple r@iv ddbd. Th. p.drg@ @Bisls or tou g.Elaios, includins sm

'.<livduds (lv:2-lv:3, in lwo l@pd (Fi8. 3.13) dhibidng hil.lrat cons@id audilory

d,snDcdon. Tne p.ililrc rd.ded erosotrd @6sirc nod. or ohoiil{e silh rwo

mmau|l|Fus nfrrg6

Cloiol hinoris ol p.nicipdin8 foily ndb.6 w6rc obtdr€d ro .rl€ our

edqd 6vilr)ll@td .!e of lsirs 1o.., Dd Dbdc.l aduditu w uridrtdlo vqi4/ lhll dad6 wa M{yrxthmic TrF Romb.B sld Tedm sair r6rs w@uled to t6t v6ribula fuFlion ed ol. oul !!y bde€ probl@. The atrELdidividu.b w.a &o r.d.d lor |,t pl6.@ ot soilq, orlfidr@loic dilordeG skirp's@ldi6 $mmulitiA lrd di!b46. btt me of da. alr&ud'rory phdb$!6

Pw roG ludionady for lir drl boc @iduclion M Ddfof,!€d rd dE lfdt d

idivd!.k (IV:a &n W:6) d filqu*i6 .trgita lrcn 250 b 3.000 }lz TtE individud

rv:4 slb*rd *vw ro Fofould ldd ol aditory dJ6iiruio in $. nsh * ehne.nodd. ro 9@ l.d E obsdd in dE Ln d Gis 3. tit^I lidividu,l rv6 h.dtbrlcde lo pbtodd h.&|g ka o dE nght 4, d'il. h dE LE d dje kv.t oalEing16 M s@ (Fig t r4B). a* cdnudid &dionay idri.n d dbl dE enrc ofurtitory dr.nlxris E soricsd. Th. 6dc1.d indisdud t(a shs.d r mm,ledilory phftt?. (ai& 3 l4c)r|.tbrrF rDB o, I(DEli|s .$ thttl1. 6 rrFNRT2

'nE [.r!gc db6is oa fMily PKDF 3J 6ins STR n *6 for rne h'otuDFlva lfti olble 2.2) sho$d tn!1 rho di5!e phmqle w not li.ked lo e of dEprcvioGly rcDoncd l@i. So ! g@r. wid. s *s p*fonEd wid th€ HDIO prElM*6 Initat didde of liok gr lo tk dise pnqbit!. in tdiy pr!DF3t5 16p@vidod by two bfomari@ tulou (D19S209 !d Dl9S2l6) rnich wft homo4losi. ad6l.d indiidu.is rrd h6i.bzysoB in @mal intividuats. Two addilioul nEt*(DI95836 ad Dl9S394) fron d. HDs Pel, s wctt s ctosety sDald @te6 setded

br *lloing 8@@ drrba3cs ld etuD!€d in l6e irLJwl h odq ro @,im dE

lirt g. !n aic' pdiel ad digrl !ou{ri.s flE Sed.d idiridurls (lV:4, tV:J,

lV:6 $d IV:7) init'dry pbvnLd l!. Dronnd boud{ry d BIs Dr9$36 (0 cM. 0 95

Mb) od disr"l bralpoirr d Dr9Sr034 (20 7J cM, 6.06 Mb). HlptotrT. &.b68 (F,s

3 13) B.ded ! €Bie oI homo4lolity of rpp inEtdy 20 75 cM, Iknred by tle

Mle6 Dl9S336 dd Dl9sl03a, lpmin8 r phtic€l di.tde of aboul J. | | Mb on

huB drrcnmm l9pl3 3 (Fig 3. l9) Trlis lirlge ftgion slieh!\ overl.rD.n *nh lha1

d.lird h tuths fDty ir thc bb (P(DFr9l ) sidulIDub ui..3oinS 8@Fwidc$&r *tid st s€d li.r4e ro clF||t3od 190t3.3,13.2 (Air 4./, 2m7). ArDttEfdily, PKDF793, ale poidd didds lor br,ge ir a @gio dal ovdllpp.d dE

@hbi..d ..Ci@ ofPKDF33s od PKDF29I (Ai 4 at.,2oO1). C.mltnjr8 rh. &A offi6. 0r* reili6, n @ pnF..d O.l . $dl @gi@ ofovql4 (1.16 Mb, 0.74 cM)

d.,ic . @ deanrd Iru DF ts7 2 (A^ et al.,2oo1) $iE 3 rgtn ntrqEtoaPlol33s tirtog. bdnd.rtr to d€6Nrf,4r'rrt

AiE th. Dublicdia of tlE DFIVAT.? l@!x .frorE se d.d. lo tudnd r.fiE lhi.linLg. mewl. Nw md6 q@ sde.ted or d6tDed (T!bh 3 6) in th. r.sotutrljr\g lh. ,Fl\47? bMdrjd T1e naf6 ndp€d io mw doM de finfrs.trrldll lo 13.,14 cM (3 13 Mb) rddls dE pdidl bordry r Dl9S8'?3 (6.57 cMl

2.31 Mb) lrl disr.l dd at Dl95549 (20.0 | cM; s.aa Mb) (Fis. 3. | 3) TIE d.r. '!dr!ed

Up ovai.Fpirs r.gi@ b.ls@ dE two fhiI6 (PKDF29| ed PKDFI3J) Epor&d i,,rlvAz b a bt l r.gi@ rp{dla 0 5a Mb.

AltlFugn $e dist l dd prcxim.l bomduis of PKDF335 ai PKDF29I srilt

ovdl.p, lhis sug8eled runb6 dEl$tu ws weeledAlld. fcq*r.y .d.drdd

ln ordd io dlculal€ tOD srcx .llch fi,6oMci6 for .dr ni@er.llit Mts*itlin dF ljr*.g. ituwl w 6rind.d by gtutpi.s 96 @do4t i.l&i!d tuddudividuilt itr lhe Prristai populrrioo. Thir poeiLd t ||6@ of dE .[GtG t qKi6.ludlt pBdrs in the popdnion. Fo. s infodi@ nic,c.!.Iir. rut r, n@ eD. rM, $c or mry dld6 ir I populdid eith v.ryirg li.qEry A5 ! !sr.l tuio,

lh. dtre dld. iiequ.Ey in dE populadd i! lw. IFv€g ndy, n @y b. n@ ln&

TcDoLl LOD *oF dlcdrdo[T@poin LOD sB for |l!e fmily P(DF335 *w c.lcd.rld 6ing MUNK or

th. FASTLINK 6n d{ pur,€! (ScrllId, 1996) Dedr6 G ra.d s o

ibdt!..d|!t-.It dlr. rr..dd. flbDdd, d b di* &r.nqry 9! r r o@1. ndodc n odi'ir. tup.d. rft.d|d b tqdtuedb. IPn|!5 prbd. @ rot bt llD Dn(za) of a.lo ar-rr.eto tdo(Q = o) ri6rld Dl98a2,l Oo97.x) !dDlS,|@.0l.lO(T&tl)

PtoF*45

8€.413 crnrc reDr$ r.ddyF b rorr pxDerB 'hbiDFN,72 kr' ... n rl' b DFtlt t br* h.prdrr6 .E tr&rd FutFt.lr.p'gA.rll.d..hdn|d[|t'ft.srR[rr.EmdMrn|t|ly.sdt.do

Frbrr h aldM.rtu (.M) r$d. d e rdta r6bb.&r hr.dr! dnr.. r!.s.M (-3,!3 Mb) br.

b{H b 6. hdkrdrrlt tv4 rv:i tvr6 Dd tv:?,

rcaaee84e4r,

, tP<rtddtd.fd

d.f 4" {'. dr/dd

i.:ito3!

FE!r. r ?rn h n r. r... r-r{- r.di|I, rftd. .dndd ry:. r'xotts

r+ ra 'ED)

id.a m r F*i &i- b.t fir -r A.dq|I d.ltad brridrr:. t$ rr r.'r |r'q d4 b dr.d td4 b tr .r. d.ni d

c^ld|.'[d.Dldr.dr]bd^rncd[t'. t.t. n ]!!) ,o" rd {x" .yrnor El'td .1, .od*{d nd6m.F.dre,i.r..d6.l'q..ddy'sF!.|.9d

'lF..ben.hIdri*j

rrir. '.r.

ricrori r,oD *6 l0r dMn re br.d dtr.E h ||lrv rnBs

3.2 MAPPTNG OF NEW DEAFNf,SS LOCUS 'FIVB'I

PKDF'O'8

Fdily PKDFI043. a lmly oa M.lit lirage 6 idedind !i!m Jalnia.PEjab, id h.rt e6 d*le.l $!j.ds @l of *nicn firc s.E imlud.d in dF srd): Tbe

p.dge (Fig 3.l5) shos [d6 cld d!&rrlhiy hn .l ol dE 'rEir3!.

*@ *irbir

Th..ldcG !@ qu6ddEd ddir w deimin€d td rn lllitory dy:tuErion in

lhe add€d individu.ls m org6lrl TiE af6red nenb6 w.B ptDEicdty qmined

to q.lud. dy aviME d,l c.e of darB Tald crir .rd Rombqg l6rs [@Frfqn d lo idqdi6/ w r6ribu|J d:/dul|im nE.f€d.d ildiridu.h N:3 &d Iv;9v@ 3l$ i.nd rr th. pl€@ of Rainiis pisEiN or orh€r q! daerd6. The

sfdLtd individuds re slso .lEt d for otho @mDn smolom as!@irred Nirh

sy.d6mc ce of ddilory dl4tulrlio. A3 rc afoadirory d.ld! B* foud. drhM4 lo$ in th. lmny I @6iderd lo be non-Erdromi. The pdisre srructure

3'lo ifllic{tld ,€i* rFde ofidqile ol dafB in dE fMilv

Audiom.tri. i6ting ol !dd.d nxlitdub lV{, rv:g rlt tV: lO 6 pqfonned

ro t|sss 0E l.r€l ofrudi(ny djdnlEdon. Atl th. irdjyiduds C&*!d nnil& &dioldicpolilr, wilh hild to se@ hsi4 los al @md-h@iig frequdi. rn s€@ loprofoud.l hiSh fr.q@ci6 (6000"8000 Hz) (Fig. 3.16) Tne ddioSrms ww clejrly

d*dnguiihlrl. lrcm thoe ,.viild wlh prcfo@d h@dg Io$.ril.t r.l:tr1ol PXDFroa{ rd rtttra of 6 h.D Djc]vrt

Th. lin*€. !Dt^G in rdily PKDFlo43 B pafomed ritn ihe nhrr6d@Epaia dE egio of frrrgc on clotu$E l9pt3 3 drlr B d.tired ir fdilPKDFJ35. Tnir et only $ow€d Ulrte to dE reeioA br.t o trlp.d lo ne* dodtlp DFNB?2 r.gjoq sd e r€d in rh. napDins of a E dodB t*6, dsienaftdDFNDAI nfi Aor.l DtNBal l@w is bouded by @k€6 Dr 9S8Ztt (5.57 .M. 2.J I Mb)ad Dl9Sr, (l8.ll cn14 69 Mb) ddimidrB { ll.?3 cM (2.33 Mb) lin*!s. Eeron on

dmmo$ru l rp | 3.3 This regtor acld6 mt only dD reDon d Dr. rz, intqwi blld$ dcludd d. r'lblc l,inlrS. i,rdrl ot t tsmly PKIn29t qoflr! h DFNB72 (Ajne, aa, 20(r). Thi! qclGion lbdlf@ ali|! |||. rlgio of .l|trl|l@@ | 9 sid.d sirtr

er.3omrl MsJ, mnic da&6! into iwo difr@l l@i, e{d hdbonB ! g@ ilvoh.njn uDrory dlafidtd (ria 3.I9)

Tt -rlFis or Irr!8. dL of bnit PXDFIoa8 CN ! p|wrl c|!eE .IDr9S$3 i. daf ildividud lV:2, *iich d.6c lh. pmxiDt bdDdsy for DFMAI .

$nic d. dinrl bo'rdrr/ a .Ld4d by . 6rdl idirind IL7 c,no dDq .|@dtdnr i 6. neta Drgs,l rti.t, h.e.q qEd rt dird tdd.. ofDfrvrsl (F'g 3.15) taD i@F qlod{i8 riditr rh.lilbge dsnl ir PXDFloa8

podtFd. dim lFrrt'r lrD s! (Zoa) of 3.5e i .@ditriid fidio (0

= 0) *itb 6t- Dr9659l (9.34 .M) ( T.6L 3,2)

PtoFloat

.r r.r3 elbt rr brroF . hrt rKoft... .,r. r*r.. .d r.*rrr. dd re,errr. DNd. !F.rF x r|rrgt!Hy.Fd.r'ldlh....b.'[

1.M) .r.r dr |-. r& (Mb) u L..d . D rd! & d ir r..trn rr..M (-2r Mb) Hrai Ll.mt ft' Dm.,

d.'|'d|ndP,!d.rd|d|lidnl'EFd'd''

.tt"eelleaS

otaatllltlt

ooa4iPrlrrCC

4tc"eeilt88

lr9"T"r'

n]rr r" ht rc.ar c.|r|- Ldiid rv:..Pmn.. {.. r. r-., .rra { r d..- b,t r- h rr. |tr *rrd..n..jrd.gr|r.|ry,(r. 12 r.n).rr|. ie.r { - r-d r,t b 5 h 5 c^i..r , .idd ddd lvn C.r 16 r.rr) i,! -d .,rff -d ..&r . r*-a r-4 r- b i.r ..d |.n 4'tr.d'nt D

^.ciD r rfrd D:? (r, 16 Fd 5E -Edr..t,.or -..x' rrr-rir-d bt rr.r rd |.. -, ir..rHr.

Tlb& 3-a l\l!-lelrt I-oD hG fol.hMod. 19 mrla6 ib fmtly PKDlloaS

3.3 REFINEMENT OF 'f,V'72

BOUNDARIES

Fuilt PKDF I 104 a @ll6Ld fron Lodltrrq Punjd ed b.lonsed to Qu6li-Hrdni 6r. I'e p.digE sh.B $o co@usiB6 nq\s6 lalrine in rhc@ngdrrl daf.hildro nr two l@ps (Fig L l?).

TIE .loi6l birory of tt'. f.rib w @89r.\ ud r @lg& ol s'mp{oE in

diferd! d6f&'d mndly hqi.g nirvilud! nE clinN-.lLsls r@ p.rfod€d for {rindividudr snovirB rulilory lbrcnbdili6 Tne individuals v:4, Vs dd v:7 {.F6t8ar.l dr4 silf,. pblound ld.l ol&dib'y d)€fDEf@ (F,r; 3.13). lrdtvidu.lt

Vr3 &d V:6 rbo $drtd I dcd pl@ttp. $i.n, e.d6g lo infdrrid porid.d by

dder! G not @gdid. Th. individud V:3 had &quitud de tuil anB $ifsins fom

|€led ad w& also .qdt @dod wilh sleler.l shnondirie. Boih th€ pdiat3 w@

cliti.dry Mi'.d dd flun E foun iD 6.n ci iidicli4 wa odi bedit *ni:his ! g*ral as or .oc&rditiry d668. So dr6. individuds w csideGd

eodictlly er.d Ldividu.l V:7 m dwrf .nd congot l Fofoddly d@f Individud

Iv:3 sa dtul dd sirhour ey ba 8 tobLd. aldDlgh sbe brd etrlQsy. Anough

rporndic dis@ gniploB w@ plEar h difisd fdily n@ba3. n@ of d6e $6@{€r€gtlirs wid de!t'6. B€@$ of dis, lhe s€gt srtns d€trK tnt

'r dE &hit

a @aidd.d marrdomiqridt,l. .dti' ot P(DIr roa

Lu*4. @ltsis in fDtly P(DFI loa wih n[II6 0elilg $. rrr-r\472 leBshowed lirk g. b€rvd dE nE*6 Dt9Sl034 (20.75 crv! 6.06 Mb) dd Dl9S39l(23.33 .r,1, 3.s2 Mb) ognpsins ! ioLl F8,@ ol3 03 cM e.a6 Mb) 6 l9p 13 31 3 2

TrE djn l bdndry E ddani.it ht ddl inditdurl V:7 *io disptt€d . p.laEl@iotic @nbiMdor d Dl9S39t Th. poxint boEdary 6 dedi.d wnh rhe ndp ofhalot?. ..dF! of rcmd individual lv:3, {tD @id r t@nbindio dol nd&ng. ldA r€gjd of toDAAGiq d 'ioG.t llir. dwlr D | 9$3a (FiC 3.I 7) A didMtwpo LOD sE (ZN) ol3.l I Ba obninl fdlll.trwtaDl9S934 (23.6? cM) r,r

lMnbin lion frulion 0 = 0 G.bl€ l.l)

llt|;!H$$ !iltlltltilltIti$l$iill&. lllllllii€ftr,r$*!$!!ts:- ff!$ltatlglr

giEIg;rrE:

igiligiiEi

ii;5:i!ii:iti 3;icFti

E{iE{;1ii1

iiFIiE|1;ti!;:ri Eii:s:iii

ea.4Jal4,tt tra.t,?ir*tu

o, c r t?l8rt, nat"4ellall

4,1r. ^. rL! - dr a&-..4rr- rd dnd v:.... *!

(t 6 a Fr .|.) a tbtr|.a .4.'l rL.l r.fia a.d- c^.air - -rl r.t rff v:r {r. ra r-.rl D

^rtr,r.t- rv:! (tt x Frl.-i -d bra r - - 'a -.'r.r.r- qt!-r b.. rtl... - -, i.r.dii. 15L.t-{q-rEJ-r.|.atr-a,.da

TrbL 33. TbT-p.int I-(tD (oE for.ho@rom 19 mrk B ir fullt PKDrrloa

t fr.d D[Va7? bo..d.rl€TIF lin*rge de f6n fnily PKDF| lo.{ h.lD. .o r6E DIXB7, boirdqi..,

{tich rcw occu bel@ Dl9S 1034 el 20 75 cM ad D I tS39l at 28 83 cM. The lDl€ge

r€ron d.fh€d in PKDFI104 ov€rl.ps dF hr.g€ ini!fl.I of Fpotld D|NB72 fai\PKDF29I (ba€DI9S2I6 d 2O.Ot cM !d Dt9S916lr31.29 cM) bul mlud6 dcr€pod.d oricil lnrrg. inEtul dctuiq DF]vt7? oeN€ Dl9s2r6 ed Dl9slo34)(Ain c, .1 , 2007). This dala sus€lt a rcfid.rnc of lintrse iilerul ol Dr 87, on

dsm@e l?13 3-13.2, disLl ro iE Eoon€d cdric,l in@d, &d sh.dd nos b!e.gniz.d b.r*6 d! trlllm Dl9Sl034 ed Dl9S39l. dDnpars a 3 03 cM

(2.46 Mb) rc8ion (Fic L 19)

t-_tTBt Iot I*l *

6 tu*-*re

II IENIEI*l,e I

Fr&..re sd|dd. oFio d F,rdt F*r.. rd !fu h*. q|I r.r

i.*otEEI|EndbyI|hdch|6rrdGg.l*pddmlr.M.idMb.h ||ro d*] c|s @bolt rpJud [.ht tolrtura drd iy frbd.lel|r.6q|jd.j||dtrddhh'!l.Tt.D.ddc.rfulrrGdarrrddri*DB',,U.rn'l.tn.l.E.k.ndrfud.c}6...d.(DnrxaaDnBlood'!c..4-& b {t ran r-(!hIt)te&ErtntaDfrtzr- ar.d.rcff F..-at d-rr-r- ttu-ut

l,.l S.q@.irg of odidrl€ todTh. Fai@ of dr ,Frvrrl rd r.th.d DENA)2 lei @.in rati a& ld I

ir qrer€d dd tut td r d lcr oe sde al ai of lh* l@i it iNolv€d i. ludibry

dsincion ln m efion 10 ids it dE pdicul& dd66s<@.9 affi d rh6.l@i, .@'did& scs rppoa.,Il *6 adoDbd Tlis b€cFn rilh ! s@ch of tll lnE widtn tlF

diti.d rl€dd bo'rdei6 ustra [F s@rc dt&!s lon UCSC Ct E bosd,Eemble !d NCAI (hr9://gtum |e €du; rw.grsbl.olg: odM rcbi nln.nih8ov) (Fi& 3 20 ed Fia 3 2l ) Th€ lhe fuolids of dr.I 8g1q d.tsD6io in ilE 6, rhc plvg of rF.rou daf mE ddds, !d homlog/ ro

rootud delns 3o6 @! studicd i. delnil Tvo !o141ial @didate s@ sec Ihus

slDn lined in F DINAAI iil@4 IMP?"SSY dtd ,ZRI, 9@ t 4uorc..L Th.

equ*irg prib6 ror de g@ w€ ddsrFd aiig PriE3 eb silc

(M c embmtoE/ca-bi/prind3 m.€) Cloble 3.a dd 3 5)

botmnbture Ptot@e, Senre, (nfi$s9) qa a Bood crni{l8I g@ in fi6

DatBal inLFd Ir ffiirts ol 17 qffi droding. singlcps tlF I 'lmbteOnta\ polyenre Fotu:e-l (P.lWt@J) n^nE rO59 njno eids in ihr6 donoiN:

s.l6e1. S.|@2 &d Sdae3. This pror.in 6 frdvcd h cdlrzins dE tj/drolrsis of

duin p€pud6 (c.l ., al. 2003) &d ts qprded in hmy lissu6 includhg hd...v.

li'q. Iues, hsn od brdn (o*unw et al . 2tto6: cd et al , 2007) 71tzr,5x9 @ ttuns @diddc bele ol lasi iNdv@r or ods rGmrlre pols nudnory dlsfuNnon: TllP!.tsi is iNolv.d n rMei d dddopnd ed muotons r.dis e* l8v. bs repon.d io .e da66s d Dl aSilo (!qt d o1..2$ll,n1l,RJ'Ji h6 b6 repotud ro cle dails i. h!lr@ (Guipp@i er al 200?b)i Mu1ml

tllPRssl ha bF repon d b eNe prcaourd hdi.g l6s in nie (CuiDDoni ., ar.

200?a) Mo6v€r, dE lln €ff of rtlPAtl9 llFs ! hotulog/ *ilh Diroclendn.l

i@r .mb@e 13 a* gA4l13) *hidr b involw{ in lrunw denB dFoni.srdrm (Ro€dr d. 41, 2002)

Frzzyrclard Fot in hMoloAw (FZXI) *a ertE crdt.td. C@ in lhe

DFlr'aal im@al 11 16 I 5 do6 dd -.ods rhe /.irl Dro!.ii! stid ha 4,x omo

-ids. lr as 6xrra.d in vdio6 tsu6 iEluding frc iftr @, ed n involv€d in polan

nodinarid .Dd ubiquia!'rioD 11 rle pl.rs idportdr ble in .dl dlin@ (zhou ,, ,1.

2!oat.

Ahhoulh LltPxSt9 !i ,"2x, e@ dNibL qndlhle g@s, lh€ 3equdcin8 of

dl $. codb! qm ofrlF in fmily PKD'335 sho*.d m nur.rio.

UcsC G.roo. Brm..r or E.D|r M.r. 2006 ArsnbbocEEIEEEa-'tu@i;a-.d@mGi.ibfiatlffi.at,i-b EfE iE 2j.3,o!o h'' C€

'ma Dt 'm!|1| D't tul mi @l elNslr 18.14 dEsr fr'l m

ofll n. Et D'l L?.1

.hl mf al !{rst .6t . .t r !" -l ml nftl !.1 r.l

r!.3, c.f,.errd b r. Dfer r a.n&,vdr|ad!.dbrn u€rcFdlffiixd-^dr)

UCSC Geuome Bro*rer o! E[miD M.r. 2006 Alt€obly

"*EEffi I* o@E@@mot @tr@ponriods.t -rsd&qs laf-1G2.{60.6a3 h. [.fu l

Fealt C*sDdba.ntudrr/9 7zbr4rrrlldbffi byslJea*

T.DL J/r Prlmn !*d aor *{|mht oa l-fP SJ, dolr

l5 566

l.bLl! Prlm6 ur.d forcqdina of Fzxl6d3

t] l7l299

Trbl.l.6 \aly ddlgnd ni(tu*ldliL qrlaB |.r ntbdor of Dflva t?

SECTTON..I

DISCUSSION

TIE slr&1wl @hplqiry of iE d iurAe*s thlr . lrg. rubs ol gG &iNllrcd h pDviding i|l Eioa 6dio6 Abod 30O hl|@ Doi.in 6di4 gG (t%

or rh. tot l 30,000) @ ! icipd.d b bc rhlved in i|! mcdEis (Fri.dM &dCrimd\ 2003). Urril mw. 133 4toson8l loi hnv. b6! rDpped to r&io6.hotusrd positioE (.nnd publi.hd or Med) rnd 49 g* tarc b6 idd itr.{t

sid dEn csa,iiw muirrioE. Of rhd., 3 | lai e ir$dir.d ir lgiv€ nodc dilc 5?

in domid p.nd! (H6ediry lEin8 hs noD.prsr: htlr ,*ml h& boltS)Rc6ry€ hits @ mE N'@n in inbr€d popddioE lile Prlind *tr@@shsMily poponion is "60% (Hu8in ed Bitd6, 1998) hd lhe r@si! d.do6s

nlt is pr.valal ( |.6 Dd l0o0) (Ehli d, dl , 1993) Bae of $is populidor 3lrElurc)

0r Pltisrri popuhim pl€aa d a..gdoEl s*tic @lE for llE |ilr!e! nuij6of |gAnv+idEiLd di!€ pdierdy da66

rrE lirte. s|u(li6 of fdili6 vith uditory 6|3furtm narc ! rumb6 or

b.rcn|s. TIE pnmc on6 e io hdD in loc.lizins ilE s6d i.volvcd in h@ins dkord.6sd 0E poslio.l cldin3 oaltF loc.liz.d $SFE !o iddiiry th. ddabrC gn6. n is

d$ hdptul in idcnifrc{iq oflhe hbm godic c.|g ir | lDpuliri4 qrdd dy be

tEbtul ro @n@l rl.r tmisid ro Gl gffiai@ br eatdic 6'Elirs ol 0r.fi6r.d f@ni6. Th. linl4e darl n dso h.lpfrd in 6hblishirE smE?cDhoory?.

Tte pl66l nudy E ainEd a ninins dE gqarc bsis ol srdiiory dFluFlio.of diftren i q6ili6 h |h. Palisii popubrim This auld be hdptul @t o'Jy tor

llori&ibg @@ @dive da66 gcr6/ld, hr ako h 6t blislins lhe m!.h eudr-Jt.r stuq}6pnaoty!. orrddioc. To ldi.rc dE obj-tiB or rhe Dc6t study,

Ii0y oE r8Dir@us tuiliB, segr.s.ri.g d€!t6s ri.jl ed ahibni'lg rild. nodd e,

evaq or prcroud dafE w @lbd non ditrqdlr .6 of Pltislar Twory firc

oadE feilid !4 s.ldt d &d subi.d.d ro [nr,s! rdrsis. Fou of dE tdili6*w [nred lo hom danK lci DFNS4/PDS, DFNB?/] I rd DFNB29rcLDNI4

Tm fdilid PKDFl,l6 d PKDF333 slDved li.fae b dD r.gion

@mDAsin3 rh. ovdhppiB loci for ,FXtr, PDS ed ,/,,1, otl ce!€d drc io all.licaidfi of SLC2&11 A@ DtNBa is deEized by mn{ydrcnic tsiv. d.rtie(Li d ar, 1993) *nn ir PDS, daiB i! era.d *ith goils crti.e in rqxtrld

sJn&ome (Erq.tl ., d/, 197) dd t/,{ is a Eidrohe signiryine 6lu8cd velibure

lquoduc *id data ,ltut?e (usi r/ al, reeg) Th. dif@ b.iw6 DtNDl

rd PDs ir mt 6dly ridan h tous .f.d.d indiedurL b.o* goita !r@9De tiMnd.ldy padrml a smElt d.vclops aftd tlE rye ol l0 )6 (Radon d ol,2ooo) Ow dl rle sLC26,u turdim .@ul for lpponmdy r0% of hr.djlary

d€an6 in Aen Grt r, aa, 2trB) dd b.i. b@ foEd to b. d. ml 6m ..e oldadr6 in P.Li6i poDlldiol! rEpr*lriu 7 2% of rh. cs (Anrr ., al , 2009]

Th. cli.icd exmirdid of rh€ old6r dd€d iriiidurl in fmih PKDrl,6(aged 23 y6) @e.lcd m $gN or goilq !d lh@roe M.'ndromic d6nr* alinlld to DFxat iD lhh fhny Fmrt PKDF333 is c sydmmic t&nib, wnn evidat

epild ir.lds.trd.d irnitduds !n j! [,led ro Pdnr.d s]ndrcft loc, PDS.

MuLtioEl lrb6b oa PKDF|46 rnal.d ! pHioLdy r.pon€d @|rllM mdrtjon

c.7l6T>A in qd 6 of lLc26,4,t snq R|ncn reuts in & mi.o &id subtlitulio. ol6pelic r, (D) for ! @tEd€d v.b. (v) (p.v39D) (Anw d zl, 2009). TrE djornle of tli pddrh prohnr i, ro trulon iodiE ro dlow FoF ptoddio of lb'mid

homN (Ollm rt al, 2004). ln additor\ this prol€i. is thousnt b sna.l.y rcle itd€ functi@;s of rhe ba.l dd inlmdhlo o.[s oflh€ rr.ia wr@r'rr 1o minrdn rr€

odod.hla poralid (wogajm.r al, 20or) Tbe replstEr or. e.polr oni@

rid si$ r dsr3ed mirc rid is lrdy !o 6@ confonDnon l cbd!96 in dE prorei4

atudns ils turdior e'd ruir€ &dilory d'srhcijd (Pst ,, al, 2003) TlE.udibry

dlsidcrio in ttF !tr*Ld idividurls of PKDFl.t6 i. of e@ 10 Foloud lq€l B|liein P(DF333, h@i.g los is nodcll. to e@. TIE haring lo$ ifl4ilv in

DFNaI|PDS rB b@ t.ponA b vdy ir ints- 6 rdl a irt: f&DiliJ cg Qip€z-BEs 4 at, 1999; Mmudi .r ul, 2000t Mpiol|teh 4 dl.i 2004).

Tl. harloqTs ol one lmly slFraB Drofound hsins lo$, PKFDllo7,

dm6Ir.bd li,l4. b DwrTl// !r c&otrs6ore 9ql3.q2l origiidb rwo l6i,DFNAT d DFNA I | . w6. iddffid s.ffddy (r.h e, al, 1995 -d Son ., ar, 1996

Bp€liv.l') in dE s@ cl[o@eml rcgion. l,ld ths. wqe sboM ro b. lhe lmr(ru sd wse @mbirod d DFNBl/rr l''/s cnq .t al, leeTl DFNBT/II deovsr.p3 tilh DFx,€4 rn bo|h e 6s.d by r!!ni6 ii dE gd g!r, 7rtl. TIE

?l,cl e6. oNisls oa 24 aN cEoda.g th. Itrl pDr.ia stich ba! 6 restrhb@dmt! ttd is dtrs.d in cocll|w hrir ells ad v6libule qd orss (rurim er a|.2002). Kiltjin d, al. 2007 hlv€ r€Dort d d[| ! R34X ruridon in Tm] o@url3 lor I 3%

ofdafnd G in |he Pditei popularon

Tirhr Jumr@ e spQlrlt€d IMb@ prol€iN aoud d d. non tpical rc*ion

of poknd €pnneld ed -dolh.lid elk, rtidr m.i rit ellult poleity b}

etuo ing rh. dimBid of !|mb|e liprds dd Drellic (Frer,dl, 1993) One mlror

E o@ ot liSht jLdt@ pDra6 n dE.rr!d,n fdily fTsnib !d Futu!., 1999) rnid@6isrs oa l? h0lM ac dpr6.d i, diltqd rns6 (Modb ?r 44, 1999) d,,r'/,-l4 h . g* on crro@s@ 21 d.r *a idatned $reuh ! CDNA dd.be s{d! Il@tujtr dE @6 lhd dEode ! Drol{ of 239 ditu 4ids du1 B dvolved in DIta29

d.afB (wil6 "r

z/., 2@t). u lB 2545 % sinnrirf ti'D ottu dadi, tnjtnmb.m, p.nicul{t ck!di,-;, dd @nllire four lremnb@ domna fisuliii sdfuruq lr99). I n loud a1 c.ll jwlioc Dd is m i egrl, nulli-Das lMbme proton

qprs.d in lis, hdr€y &d im I ll'{ontt d at , 1999) l|J @ror rcj. .r rb€ rjst

junim i3 ro pbride elciu indep4krr cdl-t dl !dn6io. M'ttrio6 itrD.n 0F

0bilily oa./ardrr-1, !o lom dghr jun lio6 Nln.h e @dal b tha h.@g pm6s

aw.tratofd 4 ar. 2m5). T1r* nu6ds in clrr.l., (393d€lT, v35D ed Glola)h!rc b6 pEyioGly qon d nd @ pofo@d dabd Tn tEr t*o orrh6. widanifred lom |ne Patisbd populdio. (wilox er dl., 2001. warl6nof6 ei ar, 2005)

'tue phootr€ of Clrrltu' mi@ he ba found io be sinil& ro th€ hl!@pl@rtT., bmg pbfoud hdine 16 *ilh brDI v.dibulr nrdi6 (Ba Youd e,

rh. sequ@ dlFn of de C.r,r,V./4 sft ir fmily P(DF433 r.w.l€d a @v.l

shindon dullliur c 23lc>T. BulritB in e oi6 aid cto€e or ddi* to valhE .lrh. e{q 6idu. (D.AqaVl l6ird h 2r rctre$@ do@in Tne deift d rllsposln@ b hiEl'Iy clr|r@.d re niE ortnolo3!6 (F9.3.12) ad jB sub6tirrion br

vrline ha Eull€d h prcfoun udiory drsfhctio in lh. |!nny PKDF483. Ou sw€y

of t00 6mal P.Lin&i dbmerc ilFrtd m @ulrqB or ed€mErtrin3 |nd |nn L ml . cll|l'lM mrml lobmrDhin *ilhh dE Pllidripopdnion S.rh dniN hd idie N mFpol& dd ntubl m Ei&, h.6ov.line s @E rcn-pohl ud hos ldC.. htdiophoh. sido du The nuLlod prord roybe f.ili'E lo 6ntul rh. l|Id.l didaio ol lipids nd lroliB nor o.ll nmble &dihur r'!y h., involrcd in inpFF ion bd'6 *iid! crlt in fliluE oldvBior of

so@d wav6 nno @e inruls.TIE lise Mbd ol da66s foin6 rlint d io rcpon d loci susFl dp

sjigE ol. R looa4o.i csirl8 danE ir lhd lmni6. ln dds 10 sadr for

d6e two ol ln6e udinled fmilie wd. sd{r.d for . sd@*id. lnrae€ s@

rmily PKDF335, wilh mddlre ro $vac harna imptirnF& shor€d a novd linli!€e

reei@ or 20 75 cM or drerde@ I9plt.3, dqDrt d by DimsddliL dttdDr9S336 (0 cM) !d Dr96l0t4 (20 ?5 cM) Th. dirbl li*4e tordd slb*d r shon

r€sio of orcdar $d $e p@nnd bord.r d.fuEd by mth6 fmny in tnis siud

PKDF291, whjci dirplq€d pofohd lEir! lo$ rd wa sidulrfl@ust 'ddsE

g@@sde se PKDF29l db*d lDkg! lo ch|(',rlMre l9pl3.3-13.2 b€rwa t!€

ml6 Dlgs2l6 (20 0l cM)ed Dl9S9l6 (31.29 cM) CombiningdFdalaofth6stso

f,,Dili6, n *r prop.€€d lhd lh. ov.nappins F8ron d.6G lho criliod Uloal of a ftwdei6r* lotu DF?r'r72 nis w tudha.urmlod hy 0E [nr!8. dl1a from @|hE

fdnJy, PKDF793, wilh mod.rde lo sd.re hoiiS inp.itrMt As ! Esull lh€ ditic.r

r€on ol I 16 Mb (0.74.M) bcl^@ dF ru16 0195216 and DI9DSI034 s5Eponed 6 DFrvaz Gis 3.l9)(Ainaa1.,7001).

TrE h.lebEcEiq of g@lt?ic dd pnoot]tic dnl oa dE reili6 r€poned bDwr72 nied a posibilily of loN hddos*iry (An .i ar, 2007i dd C6Iillo ,r ,4,

2oo2. clEt ei al.,2(n5: t1ili et .l , 2005; Shlbbir .r d/ , 2m6). so, .na dE publicdon

orDFrr'a72, morc amiliG ** @llcLd en $EFd for dE DFlvaT2 md iE tla*ing

r.sid\ 'd

B mrl6 w (k'srd 10 ttGF of dE ln'l,e. itLddi Tm fmili€rPKDFT 0r$ ad PKDF I 10.1, slD$ld lirl!8r !o d. clronbdnrl 5.8D.G mEpa.dhy |l'. E otud DtlvrT? foili6, bur.l5o Cro*ld 3 d@ difrcFni.tion in lhen [d!geidd.b rd plmr'?6 PKDf 1043, wnn rdd ro e@ ldihy dlsnadoE dDFdlnr,sF bdw ih. Ntas Dl9S373 (6.57 cM) !!d Dl9SJ I O 3 35 cM). Tbis nor only

dcluded dE "601.

.dticd ht*r.l of Dr,xa72, tut d$ indi.{.d dd de lirtae. rceion

of PKDFIO43 rc quiio disliEl fron d. l!*t€p imdv.l of PKDf29l. IlF 11.73 cM

linlz€F unddr of PKDFI043 ea d6ifn t d a . |B loru for ruroEonal '€dircde.tus, DFlVrsl. br 0E HUCO rcMclaurc omilt€. Tne [n}!e€ .e€ion ofPXDrloa3 ovdllpped with lhc Gaion ir leily PKDf335, rlici Na rlso it6n d wirh

the bdp or.d @lG6 ddfing ..w bodde6 Hrm Dl9s3?3 dd Dl9S54e (2o0r

cM) T1E similai9 of sooqlic d!r. ed Dhdolypic similaty or their audiogmsuggd. lhd bo.h dl60 fdilid @ IinLd 1o th. w loos D'' rr./, dd PKDF335

shourd @l be @6dq!d io suppon Dl,vr7.?

ThE lin*lsc dd! from lmit PKDFIIo4, riich qnibils profou.d danles.

telped b .eim Ih. DF rA7z l@B bo@d&6. The PKDFI104 ljnt4e Fct@ li6b€{ua Dl9s | 034 (20 75 cM) lrd D | 95391 (23.33 cM} This 3.03 cni irr@l orEtr{E

{ih dE linlas. Eeion of dE publBhod tunily PKDF29I. An auirss of dE g@o!?ic

ad phaDtlT@ d.ra or dE iwo foili6 3u88r$s rh,r bolh of th@ Ep.gt rh. 5@bc'a wnidr li6 dtrd b rh. ilpon d rXtrT? qiridl idrvC. itF Ef,Fd did@l

irtd.l ofD,lvr72 mw li6 bara d. nr.l4 Dl9sr03a dn Ol9sl9l, 3Ddrnirg.

tord 3.011cM rtunrl o demoem I9pl3 t.lr.2 (lig .l lor

Th. fmry PKDF793, 'tuludd

ir DFND72 p,0q lAk et al . 2ot 7r. ws dtor.Doned b qhibn modsde r,o sqd. dedrs. Although iE disld linhg6 bords

ovotlaps aith the efrn.d DF7iA72 int6val, on th. bais of phtutpe w. 3pe{ht6 lh.t

m oetv. gm 6 D$lv€d a jrrli. DFNAS I fanjll6.

Allhwh v.ryirg deg6 of lEiig lN hs. ba Eport€d to b. crn d by

drlfN r nery g8 ea, (rB2 \Dt,NBtt, sLc26A1 (DmA4t X), TE|A(DltB2D in oTlo (DFNR22) tll ot te e fuypidt hddo8d:@6 re..?@!l eg or@dslIe ro ffi a sdl a e* 10 pbro',n d66B (DqD*nd ol, lgtt, Nqiolrek et al. 2004; Ne.r al, 2003i z@&Doe et a l, 20oz t. fhedrtu.rd of trc lci on chremson. l9 by (E splir orrhe rcponod DrlvrT2 d rh.

bai. ol Be@lt?ic dara or fmilid havi4 *idddy difrs{t udionaric Droild sillndD io 6lrbli$ de s@gt6phdDrlF @trd.nd |o a gans dtdr This sill also

ll.lp in urdfiLrding lte @lols bais of E |.li:lly ilasiLd hdina l@ ofdirf.d

Anc d. t fiGEn of dE tFivtT2 inrdrd en dp |milizdid ol )va8/. rh€

dn gorl uG ro idd'ry dE Ddstin3 cds.rive CF5 in lb6e loo. TIE UCSC gaede

bole s 6.d to iddii all dE eG in lh6. tusnh. Th* @ g* nch '6,

*iO ?6 idafie! ga6 Dl6ml in th. D/,lra/ imonl, stlile 16 o@r i. $c Elired

DFNR72 intwd {FiE 320 dlA 3 2l). A ldgE Mbs of d6e e lpod ddjddBbs@ of drn expr*im in $. il@ a or hmlos/ silh ods dafls .uin€ss. Teo pordti.l @ddde gl* IMI'ktSg tA lzRI i DINtsl i ad *6..sleLd rn s.qEEd. T'Mb@ polas., TXARSS9 E Middld r sr'drg

dldid|. t-.e of qci6 ol o0E lruErbre tor6 7l3 ssr, n Pnttjdrt ?VP&'SJ in th. im s dn O.ir @1. h cuing d.aft6 in @ d mie(Cflippdi a al , 2ooiq s6t.t al., 2o0 r; Cciltori , dr, 2o07b) Th. dp@i,o. of dF

,t7 p@ro. by rh. IZRI gtu * Epon d in rh. ij@ @, dd ib irydvc@i in

pro$in mdi[dtio. dd ubiquiltrulion !!s!sted i @uld he lh. cs4rlive l@ in de

DI:l'tB't i^ad IAN 4 al.,2@3) soq!tuins ofdl lh. dm of lLiPRssg tl ERIin fdit

'KDFJ35 did ml id6dt &y mu|!rid. n'is h6 luh€d ou ddnio b o$a

nronS c&drd'le CE6 in dF r.sio Th6. itulud. dE solule wia (SL(3eA3), H\eE

dobiliy Crcup (// 4t204. n&l jundion prcisnJ (?PJ), UBx don@. ptolan

(DNq etz E trspt -d B'IB dnn irQAfBT'{) TtE tE tggdidlle Er# h the

rdntd D B72 hri.l iEhrde |i. $l!r. @ir (src2rr, d 4Lc25123\

Ctubs3 (CXr3), 8a! tubrti.-a (?urr4. MuolipidiFl (KO!^rr) nb@od poldn

S23 (rRPr28) -d nad.el!'ilfu dbontaaqol4iaM (It RNPA.

TIE idatii.llim ol a uiqw lod! Dfltaal uppon d h! fibiliB sG8t gdirg

md.r.1e ,o sw.6 h.eng impalMl b ! o.tribudon lowed. BLblisllnS lh.

s@tt?cphaoryF @rdiiN ir d66*!s, !d @ dE u,'drbins 3* toGhDwr tlis ei[ b. hdptul d E&!t xli4 rlE D.&is ol !96i@ of difaqnlacl5 of bddir.ly &dil('r dr.6.tliod

CIIAPTEN4

REFRENCES

RETRENCES

,ddq A. Micb.l v.. (i}}r@ Y, n4ircE, J. Atlsmn, K. N, rv.il. D, o..r.q H, worana U,ElAl|llmi A . Pcrir c. (2005) I'll.di@ ir rh. n6or* ot uls sr{tqE bT. I pmtia

Alm4 J.. Kl@ S N.. Kh.A S. Y . Rr'l|e x.. Pirzrddi4 s . Atr.4 Z. M., Wik & E. R, FtidlM.T. 8.. Rira&i^ S. (2005) Dtta$, . r dt!&mic rc€sE &tE lq r4d bohtllllxxm I sqzr{21 l. Hln GCnd t 16r1o7-all,

Abt*d. Z M . r.rs@!di, S , Kdsy, E . acl,fua I A., l{oda!. M a , Con . R v . R@uddin. S .

Hlui-^ifr,M..V@rd,H,K.w,MN.,ni[A,m&'Zw€"B.,Ln aS.Y,A!_.di.L..Rnalddi4 sa, irddr, RJ., critlt\ aJ, cE qf4 t, c'yrr4 R., oodir! ,., rrh€r'd- a .

Gho.b.l f,, iilddin, s . rri.doa T.8., Arrdi &. xl@, H. (2003) M@je ofl.|.n,rtf.itu idsoc *irh.h.miE ddlng 6:,q €u* no.sndrqnh dafitdin

anr.4 z. M.. Md€I. R J., rjraddr S.. G'q@q a. Sh.!rr. S.. Anr.4 M M , M.hiddi4 S A .F!@n L..C.tqR C.. HEA T.. r.b|r S N., Ri.arldiq S, Gimh. A J., FridaT B, v,'rlcoa E R. (2o0r:) M@i6 ot MYO6 m Mi.r.d eith 'ciE d.oft6DF!,ra3Z Ar , Hrn cd 72: lr l5-l:r2l

aln .l z. M . Ri@ddi4 s., alDa4, , 3.dd4 s L., cu. Y., s.h.r, M. F , siding, P., ,l,rainin. s..Cimd\ ,r, J.. fricda T B, Bcb'deq L A. wiloa E. R emsb) .t D/t/J 66p(...din rh. @ry.tihelim of ri..}€ td d it md.||cl6 e 'rs.njbk

ror borD

'sll rF 1d DqNB23 rtunMot cd r2 t2t5-3221

Ann d. z. M., snid! T N, ri:uuddii, s., Mdilhid. T., GbGb. M, ao*h!i, s. Ml4 P s N,D.dnutb. D., Gnfiid\ A , , rjMddt! s , F*tnD4 T B , u/iko{ E. R (t002) Nosqlronj.

'eew ikanB Dal!?r3.id usl.r sr'dDm Inc lc e dlolic rMio6 of Lsnrc Hu

ai! Q. Nrr'. s., Ridrldia s. &,L.L a u , Riaidi4 s. ,1.,z'sr. A. u.. r.h.a s. N. H'Eui! T.Onni|l! A J., Ahti4 z M. Ftid@ T B. Ritsrxia S l2m7) Thc.d6n'i lsmnsy

'Jmic d.afK Lstd on chFie@ I9Dll:l Hutu cFm'

^ri c. s.nq R L, $n^ P, wtulo, M !t, Ld K.. ]|nD4 rv , Lal. s. (1006) rb mr!n8 of

DFNB62. a @ l@ br i@d ,eg€ m{rdMk bsn4 toFr|M! 1o

chol|dm l2Dr r t-pt t.23 clh ciff 69(5) 4?9-3r

ai&hul. s. F . Glsi. w , Milld, w., MlrG E. w., LipNn D. J. (1990) Bsio loel al'8lllMr $eh br

,^lM. a". aoi4ni4 M., Ant 4 !r. s.lE4 rr! F.i?-d+Lq i'1. liqE s, an!.d. w. lal s M,(20ora) a Mrcl AdMl R6i€ Non-s)rdmic Dah6 IlE[ (DJ']\'ri$) I'r.p6 b14q24 l-14{21 3 i. t'se CoNnguintu KiidEd filn h}$bn. EN., Hum Gd I I 77_30

Ans.4.,R@llt.Ph.aT.L,Y4K.,Jansl,SM,HnES Ahn 4 W.,l-i. S r{ em3b)tdlianio oa A l{o'd Ad@l R6'vc NGsitdtdi lrain! hFi,'d L@(D!n 14 b 6qr6{27 in a Co6!!uir.6 |(irdnd fim Pd.i:tu Hm lr.:.il tr:? L?r

A@. M . Chrnmr M. H., Amitr ud Din. M., &sid, M , Hrqq s, Pn€a T L, Y4 X, Ahr.d, W.rar. s. M (2ulr) Dr?[r,/r. , |ml d@ml '6iE M+yDdDnic h.dng ampoj,]Mtrac n 16 b cht.M 7pt1.l{l1.22. rtE Hdnl t7re5n99

Ans- S., Ri.zidjt S. Aift4zM. T8...d. S., rdcd, AU, r.tE S.Y, Grttrith A J. Fri{lM'r.B, Ri,zrddi( s. (2009) s?,c.?6,{., 4@lion sDebn dq{.d *irh Dllvr. detus inPond'an s)Trdr. in Pltituji J Hm tu lEpl6 dad ofptl.tl

asr4M.,wajr4M,cbab|W,M H.,ANr,M,H4c.S.Phr4T L.SrdqRP,Ym,K,Ahnudw . ta! S. t4 (2005) a NNI an16.ai Raan* Ndt$dMt H6ri4 lrIoil]d LItr(rnrrr4 M.F ro ch|!@ ]q rt.1r{t?,r. An r M.d Gdd ll1: l&12

As4 J. ,\., Sb.rlErq G M. .i Corq. D P 0991) Tipli int.3riiy od Ghdi€l t aidioD indd*blnelk Ncum ?. c8J -991

Badaft, I L and XMia N. (200?) Boyond M.{lcl d mld'8 vid or hllllm 3.dk dj*tui$im. Ntr R@ C.n i 3,779-739.

Evid.c for drs{ic iniEdbne ol btrlyidmic lE ldib'y h.$ing lG in. S*.disn &ni\An J H@ C..d 61,736-791

B,idsir c r, v.iq s, F'fu. L A, D. sbfts. A 1., Ar,rir, n, FE tlv., B, Kid4 K K.Kon{islEv*y, M. Bo@TMi'. B (199J) Linl4p ot@uentrii, e$iF dc.f6 (D]-'lr't)b cbntlM 7q3l ad fldc@ ror scndlc hc@eSoBity in tn. Middle E3sd DnEo.Fllarior HM Mor Gcd .: t637.16rr.

BarO6 r. R (?00) P,'rrrcr din brdL6 ard dEir d jpl. din6indin! r'deG cm oti c.t, Biol

B.tr-vdI T. BdF@A I 4., Srdba T. L., lluale E. D., xrwdq x. ve |oniq c MBqd. L. a, g,le, K, Ctn!6. D J., Wi&o! E R. Rml,*tr J . arb$A I rd, DoI4 Dr.. Fdse a, n4ti{, Y., c&F, s. a., Friq[@ T. B. cmt cbdind.l fo lulNmi l6N &.fE DFNBI9. e ddf da ro 6}l..r lsir ell d.:@dtmHurMolC'd l2:204q2061

Ehn'dd. u. {2fl1) Nafu8ody lnfu! clirt l cs Y.k u'tnsnly stul.alr.iho4 }i.s

sEnder. E. (2006) adiiEr,r I Ad ir.il Ae l9r(,1) .160.

BotFT@i., B, D.Sr.6& ,{ L, Briss C E. Adri R. F@rbt B Y.j* S Kdisb6,rlqi M,Frvd@ M.. B.ldsia cr.Fffi, L A. (1916) u'4. of duFitd 'GiE6re(srOF rIOrodrll|E@2t.22I Ar J HM Gd tt:125+1259

Bc'!, |{, PdG L. M, Ri:E*lia S., Bd@iG S L. Ann d. Z M- Nq S L Folon@ L.R:Gl'. 4., s. 4 M , snedp.rtv. c. &, $&vG s . Bdl'e t. Ddnullt D - anDed zKb! s N..xirddia v. M, u. x c, ri6i.,\.. ii.zrlda s.. e@4idi€,M.N.Gw E- Li( x 2.. wi!d, G, $'ih R I lt,Gitr'th A J,Sril4E R, Fti,D. TBtvtddt, R J (20or) ulls 3}!tdE lD !n mnsv mi. rdBral diE dar6DrivrlJ m a8.d by .lLli. t'Mios ot $. 6d sdb.iin_lilc ge crlt-'J An J Hu

Bd*h D.. whiiq R L. Stuhid< M and D.*, R W lltrro)Co|fui.. orr srdic liirlcF ra tn

@@uKridior€sr{l.ngrhDdyftrpnkru AnJHun6cE rllla_3rr

C.! S,qxdav,Or4bala,C, tiltolit!C.Pdyml.rhutMDolr?@* b$.ab:l,rtbgem& f.bFrrla! sir Dtd@ tunod frcm . tDtL Fntlaion p'srd @0or) Ptu NdAdd s.i u.s A. lm:glsl'9 lq)

L.ps.l'n C (?&tI E:Dondrtrs tl* onpkrD of rtu hll@ dtgndoftmh ffi dnd ftdr urnem *nn. o@( thu'n( ronr BrM ll 46al _e

&nljberr. D A.illHdqD P.B'!4l\ ^.,

tr/tolnrho, L M.Hou|uM.Xr|h. G FJr, C' irnm^ H Ndd.V.rl4ul'.L.Muthrm,A F,r.mh N I Mu.lle R P il@Are"i tm t

' m*roaroal, autoo.d dirc, &nenmd lErins lo* @rx,lo mps ro

hllt@ dmtlM r5qzl{22 J M.d C.d 31:1015'1017

ft.ib.n. fld, C., Srra4 N. Ch!ib6\ S., Vitdr, C. Wosbr.h. J, EEn E., Loi*L! J hitc. (lee&) A ss sFsbh ror ! &tr*tBnl mst'nmc @siE &anE n'F ro

chD'@m2'22.B.HMMolci*15]15'.153

Cbaib, lt, Pla C.. S.leo. N., Dodc, C.. Chrirda S., V.ist d 1., ElTii E.- Ldeki. ,. Pdir C.(1996b) M{rtu8 or DF rr2, ! 3c ra . @ s''d|lml tnd..ci IEiE brB bcinl@ l0q2l-22. Hm Mol G6d 5: tml-m64

Ch.( A., walD, S , Bdl, A, r@b, 4.. Srisilerhx C. R., Soc D A , Sl&fi.I4 v. c., vm l&urc,P,6!r. n I, Ashiey, J.,Id.( I\4. Vr Crmp, c, sn x, R I H. (199n |&r gN foraln@dsl 'siE mhlndrq.n bering bs naFloe le.ch$nom 3qd l9D .An J i{.d

CIE n (19$) Idrddir io H@ erics In: M.di:l CdislLln d G@ V. H.

Chq w, xdnir. X., rre}ti N C, RiMrbc€ini, Y., vm c,dp, G, Nqj@b{di, H., Snit\ R J {2mt)MDllrid otcorrr-4? @!u(Md llais mi$dtoiic h.iriry 16dd. D,.rrJJ ho!J. M.d. C*6 42(61)

.hi4n M.S.l!. K.. McDo4l4 M L. Hrs4 M.r., Alw, Nl, AIn'd w. ra! sM (zd9) frortlad6!i 'gi€ tu!.trnmtc tafg ioFi'ld hoE (DFx374 G!6 b ch|clM3p2l.ll.:r J Hm cd tal3): la l-4.

Ci@ U Nnd S* J.120o3)TynFmrn ty@ditlcldddlc*p|t&frl'Ellfuinadi6ddnodcr i. TlrpamnEry .n lccl@ tund lo '@ niddlc dr p't$rcl oroLgtv .ndNdoroe/ ,4 35F3t.

cou! e w. r. x.lit E T'rq lil Pdq .r. m&r. z*&3,3, v.rr.Li, }lod'il I Lq K A]d.4Z. lv( Cato. R. 14Y' Sp'E hn& n r. Ey4.ehr q l|.i@,

^ ni.adi4 s, B{h! E

Anra s wolbi! B.B'ljNi H c! c't|4 c. w R J, rsd€Bl, a Ahr.4 q c'tl6 rP M, Vi.n4 G, Fri.d@ T G, Rieu.tdic S, raL S t'r, Xffi, ll (2@' M@ri6 of,5en dddins drcd-aLdr n qd bc. .!e @dl ffiiE FosrdMic h.rirsiryimdDF rI. AnI tumCid32(l) 125-33

con@Iy, P M !d Rn6 Oe30) ur&p aElsn in mn (Na Yodq Plcnuh).

c'!E I(.rd vo c.4, c (nrN) Daf6 3.G rd rnd' dirsdic apllidic A'tial N4dd9

csr4 s R, Ro..@i.. T. H., M'rlq, M. J. (1937) Cddi@ t lwa tu n in rudik'ry hrnalk ofrr'..lus.br Edrd H4 R6 r0r,r7-55

cuhll J.D. .!d loh@ Lw (1993) PhFi6 ,|rh .d WiLt, Nq Yo*. pp ,166

orn6 P. I lt92) Tlr dtc @hla , tlo'6o t2: .5?5 .{545

Dd4 A c.0ta9) Tbe 164lce of tsi.g aq.itld!'d 'Eoried

hari.ldis$ilty.@3ldis r6di Bnlin Iff, Frdoiol r!:er Lert.

&l cadillo,I., Vill.@.l!t, nlllsPdrEnd A., dd Cdilto, F. J., Alo4?,4..-r€Je4 D,l"{obd%I , Mom, F. (2002) A dddid involvin8 rhc mxin 30 3.nc in m.sndnnic h@nsir{oimiL l.rd Enc J Nlid 3a6:243-14e.

D.rDsbdi. S. Asnriq A. Co4.in-brEine s. Aliq A, Idnr*.4.. zairli, S. rrb!.a M,wdl D. Fdi. c Omr) DFNB,lo.. dsiE r@ or gdiorJ tatrc tc '!t bct@tw22qll.2l-12 LEdrHmC4! ll 3lGal8

DolruslBni, S. &l cldillq F. J.. Mich.l, v, r.ibovioi, M..4bai., a., Rotr, U, vu l*r, L, Bct_Tai.N., V.n C&p, G , weil, D.. kn!r. F., lrht A M., A@ P

'nd Pdi! C (2006) Metids in

E ss .oddioe p.ivrri!. . Bly ilalilid polon or rb. &d &didy F$w'. @DFNB59 flnio,l F!.Ddny. Na Cad *:7r0 773

DdFrc t, M.rt@ s . wsl D, Mdri, L , cboM4 P., G.r*ddio4 E N rd Pdir. c. 0999) clinialfd@ oadE @]d ft.r orcbildhood r|.lB D,F il, dr e ! @itr_25 3@ rLfrd:ifrdidim rd cFdc ou*lli.c l,d ]5r,l2e&303.

Dun.Br. ao.. DurnE&. A.D , Tow, OA , Tl@i, A R, Kdelall T M (2009) a $n*re nturor di,s@b dnd d$inedon ofd.dE3 Eu I So ns 25(4): J97{05

Ei4 ltt D. ..d Rrusq D K (?0o7) Hdios mlEi6: tultlio.5 tm 8{dic dlrlB C€I MolLilc s.i DOI l0 lm7ffl&(xt{,117-r2o07.

ElrN. r,1. ElrDi. F., ELN, ^

, Ebn! S B. O99t) h.diitic lsins ks h ord hritu I orol2tlaco|

ErgdDq n (196?)TIl'nMofrh.wyelhoaln dt'14 J Lftngol obl3la37 715

E\da L. A.. GLs. B.- Bod! I c . lrld. J. IL. bd& 4.. lro@ lt. AtbeiBer.a A. D., Stdcl4 v C. C@ E D (19t7) PEt||ld 3yalr@ isdtscd B tuimin a FffiwdplEEbrr.'rq r@ (PAs) }Jn Gd l7:4rl-{22.

?diDlq r drd tL.kEy, C n( 6)06) Tb. $@ry dn tu d6 ot rdibt

Fl6t. A - Fladq 8., Mdq. E. Oe??) $ni6 d th. *rry h,iB ol t ..rrd al,s in rhc iGr @ Adoi.lr4ruol33: a5 9l

Fo[a A rd wdgtr, T. (2002)Tbo.l@r.rdiildsddFiEd.FN!4 r. OeeT) ,luundior ro sencn ftrue an Ddr c.lF Inwd l5 5,13_551

Fonl@ Il M.. SMRr6d4 A Q. r,'ssrBt! D H.. Dlvir, a C, Bufo'4 J. M (!001) Pkdm oflElr'l,d dil.thod bariu ih!d@ in lnc U.iLqd Kb€diF od jrpldid rd ui€E ldn&r hantu @inr: qdimiE b.id &idd dny. B.n rhdl ltl: l{.

Fer, c R (rt6)Thc@dFor@ndd.aftdinchildlFod Tt rdc l{.*ia U.isi$ Pq

tri.dM T B . Cdfii$. A. I (2001) 8ulm n nrrdDdi. sdimd it .f's An4 Rd cElMHm CioC rJrl-,{)2.

ftidr.AT B. Ln.g Y., w.b.., r. L.. Hinsr'!, T, arb.i T. D, wiole S, A&a l N.^lhr'i H

,r (1995) A !.r 6.@s.or.l, t.sE&{h6rFxrJeFbtncFitu c 'tE

rorchtt)llgd 17. N!tu916-9r

F dsnrN. G. l , B.l'€cm, L A, Frisla T. B. rid Cri6rl\ A J. (2(n4) Cdic iri$t ido rb.mahoccmirof iErdho'alb Nd Rr c*id 5i43c-{93.

Fuloili@ ra. R lclr A, S.si|slnr- C L S,Ni,l-.. WDG S,(t{dll rrf,E.vdc.4 G. CodqP..,.4P, wiloqE R, Snit\ S D.. Kdyc J. E. zb.r, t I S. SonLf,, H O99$) Ana@l lrdE.o.rdtdi:rmordiMl lEnnsko 4.b3vDntaa. ere

Futubi@ K, nr.slr A, srieib!.lxy, c. R, Ni. !, ch.4 a, o Neill. M, vd ci''p, G.. cqlrq P,sN|\s D.Kcl@J 8., J.i4 P.. WjLo* E R, Zor, R L S., SDi4 &

'. H O99sa)

c@r,irE.!dsr firili.6.a b ih!i'.6 ho! rd @t* @.1!.hoi. baninc16@ l,la Hu rrol cd.r ri 16{r-16,13.

tllj16 D. N ,nd Karney, C. M. (1935) C,wlitLlbclare@ili.hrlEsuiEDiSd!!t tkdtE

Fu6c, M., Fu,i', K., Hriqi,r.,hiiritr, K, .!fiq s oes) oadt' l sd , otnr4rBnhcmb6.FEi6 rcrli'og{'iibii@.!nsvid@*qEo.. mitdrybddudin r '}n

e' kr r53q1s(;rh. M p, sdluF,

^ R- rd, ll J, n!bi.c!,r.. sEpt4 c w rrd x.?p, P cr$t FqF';o|t

cln sFtn: E iid. 6l nbJli'iFli'ld aicrt Io&!.mu I BioL ch.o 2D0t:13@1rr0

Oilhlr., P C. s{d Co€y, D P. (1997) My@n and tdlpbdon by b,n ent Nelm 19:955'953

GLrl. J. a ( 1995) v||idiry or\\ddc Atjl| Psjri.Mdibld by ir6dAzl0 /|lstt E Rii!. Bid*h

Cio.dla. R J.. lr!6ni. V.. KE C. J. .d Pj.hnihd\ G P. (X005) D.ElorrM .id '|lFnis

or.!tuiltuy liiL l}16 jn bir clk orln. N drtla , C@ NoDl .15: 75 $.

tuitr R J . Td*Iq H v.. Coh.q I\{ I{ O99t lld.dilry }L.rirB 16 .rl lu StlrlrcE ffinlUniEiS P|s Ne YoT

cdinur4 J H ir, wr'ft, s., ch.{ A. H., s4r. D A,af.Rr,rr!n"M.L,PE!d,s,R 16\ A.,CoEk , P , sneihrsrhy, C R, te( M.. van C!'nr. O., smid! R J. H ( 1993) Ldridid ofa no!€l g@ re motndsibt berjne rG (r/,xtl4 ro ch@ F8i

cnxitrA. (2000)Ircvd.?c rk r,barfddiier6. s.i29o:rq)|-5

Gdnb.lg i. N.rdiL s., B.lhldq L, lvLl(6 R, Tud( a, Fi"d'-8. A. (1939) A sjrde rid.ficid bcdCe prlad@ 6. d. ildtid of l.mn DNA trtrr U..d. l\\ELa Acib Ra

Gui)ford. P . Ai!b. s B , BkEh.d S . I'ilnq J , wcienbadr J , Be*ini.. A., Psir, C O994r) A

'usN d..n6 nsp6 to rh. !.riccnhMic ftgior ot.hDffi l3q Nd cid6i!4-23.

Guirdn P . Ar:di n, B&Eb'( S. Ch,jb, &, L Prslnr. D , w.tus.d..l\ J., Dd4 r{, Pdit C.(leao

^ h|@ 3c r..0o.sitL ror @cne.y, m{rndmic c^€ datrls is .

onditt hoologE ofth. lrc.Lr t@ lnn Mol C€E r:94q99:r.

GuilFd, t!t. Ta J., C.|l@ zF.P.. DdLy, L, CMIE, P.- Clrrlq M, wq O, sltlrd. RK.,se( Hs (?007.) Mi!. Ddcid fq tr TyD. I Ttusdb.$ ssiE Pr.i*,rMP,esslnEpsin, Exhibir P'lronnd Hains rrs An J Fttx.l. l7l(!): 603-516

GuiD!.ni, M., To\ M Y, Trn, J., tr"< D, s.l@ K, Bdha E, Kmns. D. Crnoi, z.F.P, wqO,Gca A, Delmi. M , SF4 T P, sni|\ I H.L. Drll, H.H., Pd4( M., Tos&r., RD,Erivi4 L, Prnq C/.r.. S..4 nS emtb) An idr.*rd.d tdic .d tudidEl rEty$ d rh.DrcofrrF tr h5Etr$lr *rir pIIN@crrPnsst inh6bclc. Hlr Md 2e(Dr tro

lr!.}ry. c ir, rdrr|d..' /| rd Fdre.a D. N. (!00o, Did'ihiid d t!r..i'6! in sliH Diccchlear rrjr €l|! r. Pnyli,r (jd) 527: 92

tl@n. M. J. Sd6, R L,. R.nq, M A, Chlhdr, M. n, Pxm, T L. WqJid, M, tlij.b, N,wunbonso, M , 14, K.,

^tM. M . Ya K., Ahm4 w, tar, s. M (2006)

^ n@cl al@@l

tsiE m{rdrwk hdi.g iqailrd ltu (DFt 14 lsr 6 oh|!M 2p25l-praj Hin C*d I 13 (t,:6o510

tLnd!. DJ.- 8.lq E L, Dryll T P (2fib) rdirili3pi3tu Lad 168 (9r{e): r?e5 l309

&*ri4i E (1965) Cn@driEurl b.is of rb. dikr tnrilE, Co|{t.spnu ]rl,tr s]4. Ald

H.i06,C.R,hrLqind,X L,Cn4S M,Cls, l,CtqE.Y.O9q)S.q|ffin3nurdn'.$hac.rerl& DNA Biln Bi8Dt4 @imd chairry. c.'Mc Res 3 tt7-r6l

ibniB.r! v. !d Y.ytu, P.L (2004) MebrNesof M{rddetidinlsi|.@ io $dhds HmMol Cd lll2l): 22r.231.

HdecL Al (r$, HN rh. dt ul.sHsir t .nd Biul6 A }|. ( l99a) Tbc FarL@ .nl d@3F!6ic clrdddiG of @gri6

lMi.s6 inF.Litu., oi@&i l0:26L2?5.

IEhld. s., s'ft, R L., Munanu4 D., rE, K.. McAnhd, N., niq4 S , An rd, W, La! S M (n[5)L@ridion of a IMr rtunrl l6i€ Mtnlrlmic bsii4 inroitrM lru Dr',\tst r0cbnBx[c..q|2"elr'2c|in6El6s:262n67'

J!b6.1., HrlFq C I, SLl!| M. (1993)llEin!-lotmrsunnrmrtdviib.CdM cid ll2r?.

rtcobc R A. .td Hrdrpdll A J 09!O) UlNellrl sELr6of 'd@Ldriol r6cddio. i. hrirrdls of rh. hllfi.at hrrn l @ qld Biol ,J:51? 61

Jri! P K. Fur6ni4 K.. D6lmr}. D., R G|.| A.Tbo@ E., r.l|oi A L,K'|.g, s., PLPir 8..Sr.i.a H., Sdsilryny, c R (1995) A htrdi @iE Ere@y mos'nd|mic h-nngirr.i@nr ls is rddrirl bomlo€u or nlntu d\.rnB (dn) h.u Inm Mol cid I tr9l -

Jao. P. K., LrlM ,A K,u,x c,srslebrT L , smith, T N., chd, a, D€hnur\ D, voru,l. c.,Sni.h. R. J 11., Wilco4 E. r 0993) A c@ ror 'dalE dtr)ndM c *@iGlrl &atM(DFN,/8) mpi to rhc chono$mi E ion I lplarl5.l onbinine r|- Usbd srndEc rypc lCcFG ciMj6 50:29$29?.

x3r&i! v. ..d PcjL c (193) It fudEm n di6l in!d. of @i phcE tn |e!cn obddi[ry iadia 16 rl|mrlrol Gd 7: Itt] 159?.

rii,y. E. c.vr. R. Ki.odr A. r- YM, r, collia R. u/.. H.itu r G., oodri4 J, ctG c v.BM. H. C.. K.igu.l

^, X@, H 12007) A 6d hd6 re .!@'!i tGiE

ontnr'ronic ibrin! i@.im.d, Dnr'r6j, us bcn|!!fu | \13.!{t3... J l'rol rr.rl ^!]

XrLy. E., !i. Y., U@ a, UyslE, o.. conia R. w.. Carlm, R, UlDbil-Eminslu, M. K.d4 F F.ltiliz-C,hn wilt. E. kysili H, Pdtu4 E., Wr3estdl6, J,Hcblrr(L H..9@T.M..N0rtq& C, Bffi, N., Ddr tlolLnt .. A. L, C'!l4 F. P., Cm6, C. w., B@li.r, C.,Euna, H. O , Nordeu; P, r@C@| 4., Eus, S . KtrbtEb. C., Kll@. H . Wolldt, B(1006) Mui.riN in dE lipotu HMCIC fiEior DanGnik s (i,cFPat g.E c@ d@l'8sivc

mDrndDdic hEnng la. Hm Md 2?(7)16319

rila , G002) Cli'iol H'neo.& ofaniobar. 5tb .d Utp"rood w'llim & witri4 Pbib.Lllhi!.

Kba4 S. Y . An!.4 Z M., Stff4 rt L rlnrji4 S.. viis! S. T@ s, Sh.t{, S. Ar!..L ,sdqir!.rhy s.. Khn s. N,s-n\f, JH,Ri'di^ s., F.kd'& r B, Ri.zlldia s.1200?Mur4io6d0.n xg@€@ M'd!W hdnns h6sd th. rJF?trrr4lff Hm Mnbt 23

Kh.(s.Y.Ri!z.Ui4s,Triq.14,aM,s,shlbbiiM l..Rnud.liqs A,(n,qs N,HMi4T.An!'cd. z. M. Frid@T. B. Ri:tnltii. S Omn AuiMdl EcesE@lndMicrt.lB

Kit{hi. t., KihuE. R s.Prn!D L,AdrnrJ c 0995) Csp jdi@ in rhe er whL€immumhirehmi€l ..d Dthddnol &rrly.it Ad Fn'lrl'l (Bdl ) l9l r0l I l3

Kihjin. s r., McN@ R., Mar.Ghi4 r. H@i4 T., z.tr. a.u . xi&a rf. AhddL zrrr. Fri.deT.8.. Ribddi( s . Gritrn\ A, (2007) kt iie ftlq|ei6 and mec of I,|( 7 MtiosaEns DrMTAl / d€f6 itr hritu clii 3@ 7l(6): J.l6.so

KM|ltr M.S., T.c[ * N, kwle}! M., Kdrti, T.J Cq}3)siqLn (bllldl@Dtitri"rh.dhdi. 23 (ctlt?, Fo. in lblidr *t!s .,9o.ql b ituil tui- a- , rhr Bidl 20(a):

LE. L c. sgl soo, S L, a.is, c L. Bden, S C. R@$l@ B. B, r.tendq S M., OnhlnRJ., Conn ditlq A, UFdlga K G , Ci..l. J M ( 1t97) Nd @dE/ hl{.. d'6 rd DNA!.q@'dng NrLic acids 16 2r:4Gr322.

Li. x. c . ErcEr. l. A.. klmi. a K.. D6@rb D, Fricdna4 T 3., GeqE D.. wilco\E R(r9r{i)Al|fuiminPI}S6Em{y Mi Gi€ da,6 Nd G.d 13:215-21?

LsdlMl. M. c., C4 J.. Hq D z 2.. wq ra, Ji. S .nd Zq , e(l(l2) Prdii i. @il.d rdcldnndlirv oldE d6 h.ir err ud for fi.6br.{r 5@ritur. !&tu 419: roG]lx

L:q x z. Horqc,wrk|\J.-N@(V, Ke, r M.. Lisg, C V.,X\ L R, z.i.u, J. M,TlmD,D.Srel, L P,Bud.t, S lldBbeA s D 0913) Mffim in dE nren \4rA sc @.*rd. pndr)Dic ad4 i.dqti6 rt'par u.hs

''dt@ b J Hun coc 6r:9@r!.

Liu x. z,Ndd!v. E., src!K. P. niB@s D, o997c)ld.miftdiodaB,|@idof&.qy6in \4I hcrd 4ion in U3htr syndn@ 9pc l Hm Murat l0 163-70

LiL x. z, warsb.1., Mba P, KdnridJoEn 1.. coF, M.l T. v, srel, K. p, Bb@ s D. M.0997' rrd.ir ir dE Drldr vlr ec @ @ $r&od,rc |GiE d.f,E Na cd

Liq x. z. warsb. J, Tam!@ Y, Kihun K.,Nkhiam,M,srel,K F.E4n.s D. o997b)Aulo@ai doniul rc'slndlodc d.aft6 o8cd by r f,lhion h rhe nyo.in \4lA sere Nur

I43z{ir4 N,R i'..! R. d. Ci.l, e, Gorq N, C-r.ritri, P., zdda L. r$da M.L. Eendl x(1999). Wie 5i! fr@im in rh. P.lse@ @t Err b dEf.niri.r !:n*fi$ tn &a66,nP. tJ.d.yidm HmMdn la(6) 52G26

MrmE!.li. D . Difliui.dir E K .n chtdBid( !rs. (2dx) cchla! cdd€d cietur md @ tdFEqEnq w.g PtFPs rlr 96, ol3ml

rrmj|a M L, ndshm4 L Nt, R.ilingn 8., P@in3bq E. A06 K S., N.@ w E 099r)C{dtc.pi&Diologjel nuli6of art(M &.tB itr U. S. sbel{a. pqrLtu An J Mcd

M$@di- S., Cnatf.diE. L, Hlmi M., Cdi M, Ghcnct A t{. Etg.it,Bo it , 4.. Drire M..tLd.litr J. P. .rn Ar?d! rI c00o) Fcnd'ld Sldt@:Ph.d${ wi$ilirv ii tu fanilkanryina !E c@ Pa\s nisr n@ic b J Md G@ 9oJt4

M.$o!dr. s., TriI, 4.. Mrirq I\{, Choh.r, a M.. ch€d.m! s , t Mimlc ^..

zii| z. B , ndti.J., Msm *q M, Woir, D, krhr,D,l,L, Ah-Koltq L., Dri4 M, pdir, c., Ayadi, n cfiB)Mr{Di4 oI a n.! mni}idma l!.nn3 ros 166 (DFNBrl) rocbtlllM rp|].3-?rr Eu, Hu cd I I135-lr*.

Irrrzrli. M. va cml G, N*rq v. Gi:jitrj. N. Derr. F. (200r) Rtundd.ic for rhdederim or 3cdc lrd &diololi€l drb 6r hnilii. eirh md'Ttumic hqd.r.ry hdii'isimplim.nr turrror M€d l 143.50

Itb'n, P., Md4b4 M, V.El4 A, W.il. D.. El-Alll|&i,4", no{m, R H, rrrp. A- H!rdie}, L E.Blcn d s, C.in.i"a R S.. P.lhitri I, Pxriq N.Mnh A M, Gl.rilE r. i.ccM. t., Prisq r, ,. Mon, L., cl9, J.. R@l}!l, A. rj4 r z. Brl4c, sct K. P., P!i! c..Be4 S D (?0or) D.Xeis in *ninil r PDz d(ruin ml€otle iMtrd in @iti.clonsrlr4 @$ d.dK in rhc wlnder 4e lrd &[jrj6 o DFNB3I NorGcnd1442!

r?lcKdii. v A (l99t) Modi.. bndi|@inMd rotElrdid U'nlEi9 hq E rri@MrdLj-Hahi4 i,t, Muqlrq M, choar!, E, weir, D. Pirndld, r., er.q N.. Dd,34 v, r.i*ld.

J. rjrftrp, M., Perit c, Mcg'to& a. (2002) M.4yrdMic ,Esis d.rf6 in J.d..:dppjne oi r @ rM b ch6'M 9q3,r 3 and rBrro4 of ,/lvr? 'Mris. Ed J Hun

Mn, A, A@. I!t. Ch.ntu, M. H., Phitr T L. w!ji4 M . g.qE, S, Ye x, Ai!.4 W., rai. S M.(zcrot) n.!?iry .f r 'lml rddnrl tciw Disr!'dMi. d.dt6 h.d IDA?.r'O b

Am l Mcd Ced r]r:2r-b

l,|dia K., Fl|@ M., Fuiile. K, Trrri., s (199i) cLudrn rdr4@ fmilr cltodfa ldlffinlblam ddn in pei. €trsoMc of dsn| Ju.lion turd! P'c N8d A.rd sci u s A

MneL R J., Kn, H. '..

lio.4 l. J., Cffid\ L., Fritrii, K, Fids, R, Vr Aq. C., 3dri4 C r.,Odd.q C., Olrftr, tl.. Ka, B. Fri.dna T B. (l99l r ddiN in rh! c.nnM 16 c€m(c.Br) llnr ar*a&'i J€* riitr llx5r.dmic P\6d€ DatK N E,8l , M.d 3r9: l50G

Mdb4 C. C. atnN4 W. E (20o6)N.i6drHdi4 Sssirs A Sildndddim NEig Jir.d

Mdd. N. E. ( Ittl) Cidi. cpi&mioloer oa haline ilt .i@r Afl NY Aed S.i 630 16'r I

Monoa N E (1916) Lo!'rirhn ordt (lah) for [d{. ir co@q ittu. PrE Ndl ad 9i

Mor'iia L, rh.s!, rlt, Naea V, Mdra. R. L.r.\ N. 0999) DFxrla a 6d LoE ro'al@ml @dE. oi+}ldDnEl sedmrd liannl h5 446 b.t'@ Ilqzt<tEl@ J lird GM 7:243-r,16.

rftrsia A, ozd, E , PoI4 R, rl,rrdl!4 M, M|W4 C,lo@rI. E. A6l.nb, E. aridk F0999) ct?6 d6f'6 mudion arrl$! and clini.d En{b,li.y J Mcd C*d 36:3t9$2

Mui4na M, c1ml|6d! s, Nie, !|. S.Lo. N.. Wdrdd , , .l&, E.. t ieL( ,., Pd1 Cllgrda) A e@d@d pr.36iE .l|tM.t Ec.sE f@ or jeLr.d dah..s, Dnrrr3,Nr6 b cb'W 7q3{{16. Ea J Hq Gic 6:!,13-250.

Mod4hr.M, cl'My, E.. ch.'d.q S, Nlhdni, M. Pr@o!d,,., rmilqt , 4.. i,i.8'rt.n ,4..riisrc. J. wcir, D, L€rlr@. r'[, Pdjr. c (?0or) rF,vrJJ. r '6i* f@ of &eiMolharrru kq D|F b cb|m gqrz-rr EeJnmGd t0:rt0 t2.

MuerDha M, S.la N, Wcil, D, elzii E, Loi*ld, J, Pdir C (1993b) khdindion of r lms dchl!@ 7q31, Dlrr'al.r, Ea@rbl. for pElingul @d!.unl mn-gdr!@ &.frE

MMDh4 M, wd D., Ch.d.ntu! S, Eriq S. ELzn E.,B.or.@ J S.. r.idn,1.. p.rit C 0999)An id.r@nn C.d d.{.d g|s.4ity ihdi6.d.!bod l6i* tun orslMiFqlpariulrl M*rndmir dafiq Dri{r,, ltm Mol k 3:,to9-lr2

N,8. \r/.E. (?mr) Tlc edi6.f &.rB Md nad ftv Disbil R6 l|lv 9:109-l l9Nrridr.l. u., Sotd( c., Mdkr.Fddt rv., pfrr. N., Boftdq a, xcit@ A.. tbt @ I t20on

Ioba&dlill Vfti.hiliry or ln€ Dcaftdi rnd Cnik phomgl. in plndnd Sydm Causcd bv 3T.r6P Mdid in rb..vfrd,l, cft J ctitr Ei.bcrrn r\rcabol 39(ll) : ,1,t?-JJtr.

Nq s., Aldi, F.. M4joodi, 4., Rie,idia s., Struri M H., Fdcd@ T. B , cdfntn,4. r., wiko( E RRiad4 s 12003) Di.ridis r'|l.'"''i. !..6b did.d dn DFNa2l arhk o{IE(tr. Jrrdr cid ,10r@16l

Nq S . Gisee C M.. Kohtnb4 D. C , Mfth4 X L., Riuudlin. S., Ma!I, R J , nod! a ,sne Fnr, s, D..nenh, D, Rilzndi4 s, crif& a L Frii|M T B , sDir\ & J. H.,wil6x, E. R. (2002) MuLi@ in . @r [d, Tt{Iq e Ni.r.d d|n lEriig lGliit d bDFNB6lru A0

' Hm Ctu 7l:6r?436

Nq S., Gitirh, A. r., Riazdci\ S,lhrs.4 L. L, B.n r, J. r Jr, r!h!4 s N, Ri@|ddj^ S. Mhx.E. R., rridt4 T E (2dN) r'lnndjoE of EspN qr ol6n.t '€si* drdB ,nddrhdr d,lJdim ,

'r.d Gd at ]tl-595.

N0hlc. J. T.{bok ol PriiMry Ce M.djore (2001) 3d ed Sr tiuis, Mo: Md6by. pp 173l-1715

Now. ]t rt @rr turdE: di.rb oaqmidid.rt bDid nodiq. T6FC Blddi (r9rl),|tn edLs .rd FSi36. Phtu&rpnia

don6, Y, H$4 M, T*.i6hi. E., FuiEti, M.. Sbin*&!q A. Y4 M, Kido H (!x)6)sd&lB, . @ eli.. v.ri:d or FryGlm(P&ssc, eiEc r*inr6.!1. pLtDDeo*naor !n !i. pd6ldc didjd i! Eg'dnly ,word.d by slrMtnogy@ Bjersr r

oii. J. o99D Arly$ of h'lfu [dri$. Joh! H.trinl! uni6i9 P,q B.ti@ !n Lond.o

Orux V.xrx r. v@,E,DqL L,tDdB4..F&La.Bdr.4.T.NaEw E,LeX 7O00]) Mul.llc in $c rlMr.b $l$.d .rE or t6r/C @ mntlndtlln 'si{d..fis Hu crmr I I l,tG30

Prd( H J, Sh.!t1. s., L.iq x. z, H,nr s. rr, N4 s., cb6h. M. Ki^ n N., Meq s l(.Abc. s.Td..dq K.. Ri.addia s, xitc li!t, E dd!.€rLc, f,, n dn*zr. 1.. Kha s.. hn4aa- us', sL. NaB w E, wil6! E R, tu&rddia s. (nifiln A J (tm3) orisia idfrlq|mi6 or srcl61, (tDs) rulni@ in Frn 3id sdrh Ade: slot l implidid for rbe

a'dssoLg/ of{,erfN J Mql cad {r:242-rat

h'vi'rs 4., N.ilc v ors) crildic6.d6itid.f inhtcd hanrslB J aniol M.d 'l:2'5Pd,rq. F., PionL@a R, H'ldsFr! A.J. (rfl.|) iidnin i. t 6die.l or redili! i' b{ el|! Pm

Nad ,red Sci UsA l0lr 2frl -2606 (955 959)

Pqdr Ir[ B. .!d wil&rs P. J (2!06) Nd*tndom4 'ffirl'@iE d..f6 Cli. Ctd:

Pdn. C. O9%) Cis t pon.iblc rc Hl|fu H.Edidy Doft6: Svn dv or, rhoend Nn Ctd

Frjr. c', ldiniR J.. n n di4 J P l2IDl ) r.r.koJat !.rcir oaLrioa tos Aflu ia Cid 3t:539_

Pidrd.r o.,cmqs.D,G.r4M P (19€4)C'*lirsbdqE!&@ir,intlEcuepddFnof coni .dd iben Biblc r.ldud b @v tu!&did Hd n6 r10r-12

PllleE L J.,,.d@ A r. R.tdl' E., c.ridie A. Muraq$v. C Hd@a M AI_Crtli L I.rd N r M,nh.n f, F. MctL( R F 12000) A w l@ ar.ub@l6t{ @qardntl esiDod bs''nr hlFit|M @F,vrr4 @ ohl!|M h!3{rl Ed r Hu

nrl4 K. sh.irr R s. Ann4,, xi4 s. N., Riaddi4 s. anncd z M. Flirlru4T B. wircolE R. Rralddi4 s emt a w looE &r clttq c &.nE DFl,r, nq bclj!'|l.dft5ar2l<l.l I HmGdd r16:r?-ll

RrDhler, Y rnd Alr&hLr. R A. (2dJ3) Sln&18 ,nd in@tim ofth. ochr6 B6in n6 Bull 6oJ9-

R!h.d.Y. Losr Ir/1, \vr$lordqL,Put.R (1991)n *M!9(b.limrdiai'llEdjmi!rb.mle d dbla J cmp Na!o, 114 167 131.

iadoa w (19J2) Godo d.'frB J NLd tu 2e:t2l_56

R-r6r W - Ovrh.s. C. a, TEffit! R, 14 tr- Plrlrq P D (200o)FiL4.d dnd.r|{tdu:a Edioldiel;rra.f Pd'qt rlndluE rd oudim of ttc PDs sd qd r M'd er:e_

Rjozrdd4 S, Anne4 z M., F.dirs; a S, beal, A., Kibji4 S, RuEa ( Kh4 s N. Ch'@iP,r;.dEaP L. Aidae., J. M., Bd'ld.q t a Focs A xitzlddi^ s. Fri.dDn.T B(2ir06) Tliduri" i. r dshidi." !,*j" 6rv [o.lstilc |f i rno Gd ?e(6)] lo'c

n]!,u&4 s. c4Liq c. M.. AbE4 z. M., kl*mi A K. Mrsiui M A.NqS Soirh. T N

r-ihn{ N ^.

Fridtu T. D.. Cri6|\ A 1.. Rnzdliq s. w q E. R (?000) Ddndradifd,r.xM, nlIlrs |giE ik krfJ'. 2d N{ Gd 26(a):ar rar.

tuuunid. S.,tu n. S. N., AnrE4 Z M., GhGb. M.. clltro4 K., Narj, S, X$a M. arar- A U-cla K,l&a s. Anmll4 4., ka w r..G@ED.wikrlE R,Fd.d@P L.I\addf R l- Rn',iritr s.. Fri{na T. B. cm6o MMiE io lvorP, rni.n d@d6 rldriE cyb*.ldrl{3uitg 0o.dq 4 eod rin cttdmE '!.diE ek

tuchli,rn. c. P. BeLni. s , nreu. I J o99o) I&idndioD ota 275*D DIlGin Mitr.d *irh rhdiql srt$ of *ns h.ft els in rb. d@ iircr d i C.n aiol I l0r 1055-{6

R@h, x , c@ s P., TdEbia r . Kcn|s. c. M. (20{') rb|m &aftd dlelr. q!,iq4 i.a!&d hy a d€rd in a@bly of .n DOPI/TIMMS. TIMMTI @'l'ld Hm Ltol c.d

Rubitr R.H. vG C.M.. OatE D I, Qtrdd, Rw., Au C-Ly, M-D (1996) ridioE I Fmiv@! trtcb. EteiEH..Lb k tt 16r

s.d6 R L. s,s M J. Sik !&r, S,rE, X.. Ari.c. Mdi4 P E Jr. Wdb.!go. M. A, An@4w- tal. s M (?co6) DFdr64 a tNl tu@nd 'w& rcHf,nd'lnL hsring msd'lMlru 0r ct@dDl cgtoi ltr3.2 Hm csc lr0:3t er.

sch!ftr. a A o9%)f*rli .s. mrids 6|qud* 6. pclisG firh loa6 d uns.d 'tt ld

Hu H.ttd .|6:?2c,]5

sct tr{.a r,c|q4s. K.. Sin@ K, Cdilllr R W., Jr (ter)artidi4 t c.4ruid 'iri'*,e. rEryni t4 rbql rr:2?tr7sdr. D. A . C.ni R. Elt ddt K., Yc&.rs, S., Sh. E [1. SL.6d4 v, C (19%) & d@'ll

e$ivc mlrDdDmiehedn3]N k * n o{jfiql by DNA polju ain8 N inbEd BcdouinrindEdr An , H@ Crcn t t9J35-391

sh.nin- H. warst. T.. sd.. T, att! s5..4 J.. r\h! Raa a. LF.I. E D.14M K Avnn o K.Ariry M. c., r@ M G006) Ilnn ri6 in ! I*l isi'fom of TnloBP th, .n od.s !ar.Md6*ir u'diis D.*tn & rqoFblc fo.,tF{az r6it dtqld@a ianns16 An , Hd Cld 7l: l.r|.lt2.

sblitlrf, s.,n@K.Nr/-li.s.sdr,$,r'hlas.N..Ri.adrias,arhnt 4z M F.dt4T B.Rieuddi\ S (2005) ,^ Nd lM rd Nonsridimic Dah6 DFxrJl ['t F b chnn(M.|lor:r-DD amJli{.dc.d

sh.Di.'4 C M. G. .d c.r!y D P 0994) Tt cld or ld,Dirid in htlt!3 16|.' nai. e t ,N@i 1416217 29

shrdl, s. [, rrcotc IL rd ftbdn,,| J (rql) Djdidl EElirnvof i.divithol d&:E h.t6U3 b dtdLd d.ltdio.rl|t h.nhdk An NY Aad lki l7r: I -lo

sL..d.v. N. Dd chn$oldl s c {1945} Innumlaen niffioc .td immtr'r)lefl- lr.lidiotroto&.t.lcbl.!druslc-lilcsrdilcltlleiBini'Md*Mrytair€lls

smith. C.A. 0963) rnhlhrlttr ol lI€ orFn of Codi. Ad! So 24:4l94rr'

sno.*{ r. Huys4 P.L.M. C'tl4 CWf,). vu & tLv.itrs. P. 'd c.ht G €m5) o31m@iN?d d.rEof haiirslG ao ridr dulv ,^D J Hun C..c 716):9a5at7

S.h., T. vrcu€d., S.. Shalli!, fi., Beit4 M, Dayii N., rs@A M., YNq Y. OFU .gs. A.Fnd@M. St ld, M.. Av€Ln K. B. (2000) Tt p@l.G In oe(6id of j'hditd@Bir ?6 nuoriB ddM€d siin mqdtwi. bann3 lG itr dE iti-li poF)ldm. fiun

SFIi||^ rL (rs) So$dr annd orldidinortn dri\aI t ar{ol orol9:! 35r {77

SGI K P pm2)vaind{ddxi ! dd6l. whrftry fd hann3. PN Md r€d Scj USA99:116lr.

sr.d. K. ?. !d (& c. J. eml) A e.djc srEi e r*drdic t'niMv fdi6 Nd cd

Sl@.1 (2cro6)D.dE:laa@p'4diuud.mHtryColh4Oxtd{nUtisitsbs J s. od<le E. c , Rdd. E w. (tgaq nenr itr*ha i@ r4.l4i.n d !dib! $d

€ihndh&r<dk oEqtuleml I l:lt-24.

Srdch.n. x ,nd R.a4 A P (1996)DNAtudd!@at'lgid ,4n J H@ Goat tl:l_26.

Sr|!sia, lif, and CitLq*! P G. (2tD2) Tb. lar cdl! trsdEio cnod. Cd OPr. N.t hrd

Ta4. a, s! G, f L, xtu4 M N.. l4, x, lks@ M J., Ahnr4 w, lsi. s M (2006) Losliationof ! lod dl@lEl '*iw Fcnd@ic b.,ing i4.i|'d l&T Dnvr65 b .n@@toq rr 2{rr.r} J iro rlal 3.(6}$,L9o

T.n@ T .iir rrdcq T. (r ec9) BLAST I s.qxnc.s, . w hl ltr dtp4riqEtE. FEMS Microiiol rad l7,r: l,l7_2$.

T*i[s!i J. D..'n OU J (lt$) ]Ltu of h@ ldic [irt!. rohl HdCdE U.iEFrv PrR

Tlili,A.,Mruirld.M,Chtrfedi4l.LhDiI,B.MieZ,E.Am,M,Dts.N. AIr_KoL*o,lDria [r, Metun! S.. Ar{d! H. A. (zi)ot Nstl ordn l'giw bo.ry.duhdBrBhd4 DFrr'r6d, naF b chtu|ME 6!2t 2-l!.3 in. Lttc Tmii:s 6@.st@ frn'ilvHm H@d 6r{3),l2r-3.

n i A.l\reno{di. S, Db.trib. H. Bo@ia S.. R.h.tq I B, Chqrnq l. Tui!.i K B@ z.ch.rfdlts 1.. Dn4 M, Ardi Il. (20oD rsrtid ot. 6d .'|!Ml '@ @_$n@ic l-rins i4i|rd hos DFJ'rrrJ b .b@ I lql3.3{1r.4. ao +[D Gc's

T$rdh s. rld FllE, M. 0999) Oel'ldh .d .raudid i. ricbtj!tud d€r&r Ladi4 ot toontuDlrs? Tands c.I Biol 9:263-2D

Usi s., Abc s , w6b, M D., Shid.lq H., vd c$'' c, xi'!hctti!€, w. I (1999) Nol5'idDmichatils los s$idrdwithdbs.d ltdib'n r4rdIl i5.ru.dby /rs'lfuiG FlD Cd

vM c'm. O.. urilLc P I !n Srt|}. IL I H (199?) No.sTdFmk barttrg inpdiM roF€nnd'dli*FseEiry.

^n r Hm cd 6o,753-76a

v@.1". M,mdr s, zwE d I tr'hold M. Hddr T P D.l c.lil'a I lrEdL sBLrhrr,, S, r,4 s, P('o(, L,M1@F.Mdts tF Pd'(C (

B s@ .n@ding a p@! of .lE hu htrd|. .rE mi.)donio d.66K d rlE DEral'tlocd. Nd cd 29:145-3,19.

v.cq a. o.hl@ f,, Y@ F.. Inob^.tdi4 r, M' a.tvl$5r. 8., rr.i.n s a c.l l\ oe96)At@ml G..sE D6tntmic de66 looE (Dllv&t ttr46 d cntt)lliBm t\'2 h 3

larsc @engniF6 tindrd film Ptlitu. Hm Mol c.na 5 165"16[

\r.@ M. x|bn R. S{al4 H, Ftrhdq H td@ Y Utu S ()dttr Dloihiion aDd

fH|ftE or cDtur tmum r hDtK Fr.M with mtr{}trdJtd- bc4r€ lN cln

va' r M. Atta A A. AE M., Pt 4T L, Ye K., rb{G s. An!.d s/ rsr s M c0olrunl hdiDs i@md moa ro Lht.ltffi ?qll D'

o2r. 12 Er r t{m Gd I r:31?{ 15.

wrhL T. D . Shd4 H .Ir/tr@, J., K!s^ Iv[ C.. Lncn E, Avn!.b. K, (.fl rt (!O00) Dr]vi,3, a

'Wl Im3 f., tElirsoai mqn&m ,u@@l '6iE hatins hs dF b 22qll itr 'h!! 6@.!!i'fu eddiniu lidql /$$e o{cqlibrv h6tiD€ 16 horD.Fge)

w'k|! T.. W.kb. v, VESd., S., rldu.io, R, $6ni4 tt, Htr4 S.1..,lttx rJ|@M.KinC.Mc.. AvoI4 K t. (2002) Ftm [i6 .yc b d 4: l|dnq in , hm clr$ lll DvM€6 !r!r!sE lsyld6orc haiu kE rF,vrlo P'G N.rt a€it so u s rt 9e:?tlt_'t513

wuA.Lr@Y R.Tdrnl@' W.lrilmc c MoEn- R J. Noho.Tm n. K., canF4 s a Fnd]@T B rlq'AMof ulrodmrsii MYOI5 lfrisnith h@

'E}TdMiod.aftd rFt J Sci 23o:tra?-l'l5t

wm6ruP rhLM.AlhEnrB,Wq t,r*,sv.M4eRl reJH Eld LA lrl.ll- sM ibtu le. G'@ LD., Mei Dc (luoa, Le ol K(NJ|0 pMi 6p'r*ni.lkhb.rd@ikar lburl !.d 6c &ofi6 ii Podtd svrton noE ood.l BMC

\J\dbnor.'. M Ro@4 A, F,ro.l4 v, cba'.11,\ A c. qD B.rl c L'|c R.Elieix xtncr .6. \'t d4 P ArbDdiL SE Am'' D'lId n..D/v/; !.*i6 160 rominsridtrj@io6 ineh r|ln M@ ?5(6): tr_e

weil. Ir , Kn4*l- P, BlrelEr4 s , r-y, G., L.v!ac.td4 F Dri^ M At di *. P!4 C (l9l rb'-''' ";*;l;.* k"ih"dd;h."", DFria2rd rb. Usba lB svrt@ e ttldic d'ftcteor0€qsn-\4lA 3.G Nd Gdd 16: l9l_l9r'

\Idett.l, FIGL a, rrdqd P O '1ft5r

ShFml bo$ fot d@ml mhn io ar't@ ud' *'ur. * 'i"orq caa_soans Hiio $Ip Od Blot I I t luwildE n.hn@O L,N.as ft.,i.trs soirLT !l Pl.'pt(B B'nd* r" B*Yo6dT-*

"{i;.'r'.t JG J.K;; s wLDK cifillla i R''ida s hddnn rB

;;r , Mtu ( ln. ctr En@dnc f'sh rudd cr'diFr' c'r ^u@mi

nG$eDek DFNA2e. Cdl lo',rll6tlt2

Y,sBa S. CBtj, v. c.h.n_Sdd M f,l_A'lr|.d A Md'pb&M Sald N Azr'E rricld'"--T'pL-il,tde' r '* i. o,or...6a,nsd.&'nc I Fln-Lhr' pdt" qeDAs' r

r dmtr lbmordarE N.r cd )r.r/,j.169.

/h@.r.. cbns,v P. Ns. R.w v. rm D Y r?oo\ D'n*dd.l!F4l@rzu6 ud d;$rvor rw'-- i6;€\ d..d Eoro.BothuM ^Pc 'tsdt'r 'D'l'

kElE I r7' r+rt3

l@l! l. Mdaba M, LaDdd M \dpY E c'od4 to LirI Z NM cs Ne\{E'---ii;; ; i.ir',i. r e.ra,,arihi"r" r 'brhFe M Rthrdmc Psn c r20o)l

ir*'ili" - .- - r.*" -*.4 h 'n 'Gts bd*

'b 4€r drc d @];;fi;-,i";;r6';-nd. ;u B d.'.@* d u*-r '* daftE Dl^Brr** Nd Aon s.i U s A et:6!ao52a5

ELECTRONIC DATABASE INFORMATION

URL'S MOS-ILY USED

cdr.. rr l|.d.d Ga.d.1 r.ratrdl r.dor xad lffi.hdOrts.d.dhdditi..d/!di6/

CIPE turad World Wrd. W.D rffi

Cd..dD rd ad6 troq.!.

Th GDT trlN C,@ D"'bA

Eqdh..! f,4iia l4aEd ir fiE

tr.!rr.'' aai4I- f,qrhnDt/d.dd*.ri.&t'tnrl.utru

MaGdl*'dotrE//r'itrtoldaF !/

Nd.rd Cdlc lor Ei6trlos, If.drb (NCII)

Iqlrw Et1t|lDhrd

ndbur rd'bL. d tralrl (NtE)

O.lln MdddL! Lr.ri.!c. b llt (OMIM)

h!@://*grr.ri dE'nLsFronE/o{\{n,

tdrtlft qhci inlnr/cgt{tnrr{iG3/Fidr-rd.cC

h!!://rw.!(,i ' D nil.e@/cd€./q8v tst

Gd.tL. bno F.6.li,l$ r.t

Tr. ||.i! Gd. o.!.|ne @uGo)

blp /llw.s@ud rc uMn{tr'

rr. rrd@ rd S.rcts bdtt

PUBLICATIONS

aro. N&l'. S. tu ^ddq

S.Jrt el^' U., Rrdnrn S a zrl|r' A L Kirn s ! Humn Tc'6lll a J. 4nr.4 z 1,1. Fd.dtrA T B, Predd4 S (!00?, Tls !u@l ffi!''stldoot et6 b6 D/qxrl, i. Ldd o d@. reDr3r. tlD coa

Ami s- Ri&ldlic s. Anno4 zM, Tendl s., Jrls.l,l,u. Kh.n sY, cd6rl. ar. Fdrdm,TB.. mird{i s (2m9) srcrs,ra md!@ !p.d@ aci.Ld dtn DFt r d..fN udF.|*.lf. rrd@ h P*ituia J r|no Goc lEFa.had oaFdl

prr.hec.gov.pkprr.hec.gov.pk/jspui/bitstream/123456789/6225/1/4025h.pdf · acknowledgements...

Documents

studio 6225 poster

ukas management systems in accordance witn t ne …

interpretation of electrocardiographic, … · 6225 rev.mvz...

htb implementation on routeros qos -...

butts ot stamps witn tnese eoiinailoa...

htb series, high temperature circular connectors · htb...

help to buy (htb) · home. the provision in entitled help...

studio 6225: stage ii - poster

infs 6225 object-oriented systems analysis & design

record of meeting · lorraine heath (htb) lisa mannall...

ingÉnierie et rÉalisations Électroniques &...

record of meeting · 12 january 2017 . members of board,...

likeable layers - schoolbelles · 2014-12-02 · versatile...

record of meeting - assets.publishing.service.gov.uk ·...

blazer 2403 - htb fashion

dept. htb/gm s - screw jack gearbox

qos, htb, multicore - mikrotik

17730-261 rev b technical procedure - htb 210 rear air

what is the htb discipleship year? - org-htb … · •...

smart & friendly design! htb-100 brings you more...