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Men Into Mice

Men Into Mice

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10/20/2010

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TransformingMenintoMic(polynomialalgorithmforgenomicdistanceproblem
SridharHannenhall
andPavelA.Pevzne
 
DepartmentofComputerScienceandEngineering InstituteofMolecularEvolutionaryGenetics 
 
ThePennsylvaniaStateUniversitUniversityPark,PA16802 
ThenPusssaid,\Iunderstandthatyouhavemagicalpowers,that youcanchangeyourselfintoanykindofanimal...But,itmustbe easytoturnyourselfintosomethinghuge.However,itmustbe impossibletoturnintosomethingvery,verysmall-likeamouse".BrothersGrimm,
PussNBoot
Abstrac
Manypeople(includingourselves)believethattransformationsofhumansintomicehappen onlyinfairytales.However,despitesomedierencesinappearanceandhabits,menandmicaregeneticallyverysimilar.Inthepioneeringpaper,NadeauandTaylor,1984estimatedthat surprisinglyfewgenomicrearrangements(178 
 
39)happenedsincethedivergenceofhumanand mouse80millionyearsago.However,theiranalysisisnon-constructiveandnorearrangement scenarioforhuman-mouseevolutionhasbeensuggestedyet.Theproblemiscomplicatedbythe factthatrearrangementsinmulti-chromosomalgenomesincludeinversions,translocations,fusionandssionsofchromosomes,arathercomplexsetofoperations.Asaresult,attherstglance,polynomialalgorithmforthegenomicdistanceproblemwithalltheseoperationslooksalmostas improbableasthetransformationofa(real)manintoa(real)mouse.Weproveadualitytheorewhichexpressesthegenomicdistanceintermsofeasilycomputableparametersreectingdierent combinatorialpropertiesofsetsofstrings.Thistheoremleadstoapolynomial-timealgorithm forcomputingmostparsimoniousrearrangementscenarios.Basedonthisresultandthelatescomparativephysicalmappingdatawehaveconstructedascenarioofhuman-mouseevolution with131reversals/translocations/fusions/ssions.Acombinationofthegenomerearrangement algorithmwiththerecentlyproposedexperimentaltechniquecalledZOO-FISHsuggestsaneconstructiveapproachtothe100-yearoldproblemofreconstructingmammalianevolution.
ThisworkissupportedbyNSFYoungInvestigatorawardCCR-9457784andNIHgrant1R01HG00987.AuthorsE-mailaddresses:
hannenha 
cse:psu:edupevzner 
cse:psu:ed
 
1Introduction 
WhentheBrothersGrimmdescribedatransformationofamanintoamousetheycouldhardlanticipatethattwocenturieslaterhumanandmousewillbethemostgeneticallystudiedmammalsMan-mousecomparativephysicalmappingstarted20yearsagoandcurrentlymorethan1300pairofhomologousgenesaremappedinthesespecies.Asaresult,biologistsfoundthattherelatedgenes inhumanandmousearenotchaoticallydistributedoverthegenomesbutinsteadform\conserveblocks"
syntenygroups 
)Currentcomparativemappingdataindicatethatbothhumanandmousegenomesarecombinedfrom approximately150blockswhichare\shued"inhumanascomparedtomouse(Copelandetal.,1993)Shuingofblockshappensquiterarely(roughlyonceinamillionyears)thusmakingitpossibletreconstructarearrangementscenarioofhuman-mouseevolution.Belowwepresentthecombinatorial formulationoftheproblemInthemodelweconsider,ever
gene 
isrepresentedbyan 
identicatio
number(positiveinteger)and anassociated 
sign 
(\+"or
")reectingthe 
directio
ofthegene.
chromosom
isdenedas
sequence 
ofgenes,while
genom
isdenedas
se
ofchromosomes.Giventwogenomesandwiththesamesetofgenes,weareinterestedinamostparsimoniousscenarioof 
evolutio
ofinto;, i.e.theshortestsequenceofrearrangements(denedbelow)totransforminto;.Fig.1illustrates 4rearrangementeventstransformingonegenomeintoanotherLet
 
(1
::: 
beagenomeconsistingof 
chromosomesandle
 
)=
 
::: 
)
beingthenumberofgenesinthe 
t
chromosome.Everychromosom
 
canbeviewedeitherfrom \lefttoright"(i.e.as 
 
=
 
::: 
))orfrom\righttoleft"(i.e.as 
 
=
 
:::
 
))leadingtotwequivalentrepresentationsofthesamechromosome.Fromthisperspectivea3-chromosomalgenom
 
(1
 
(2
 
(3
isequivalentt
 
(1
 
(2
 
(3
o
f
 
(1
 
(2
 
(3
,i.e.the 
direction
ofchromosomesareirrelevant.Thefourmostcommonelementaryrearrangementeventsinmultichromosomalgenomesar
reversal
translocation
 fusion
an
 ssion
asdenedbelowLe
 
=
 
::: 
 
::: 
 
+
::: 
)beachromosomeand
 
 
 
.
reversal 
 
ij 
)rearrangesthegenes 
insid
thechromosomeandtransform
 
intoachromosome
 
::: 
 
:::
 
 
+
::: 
)Le
 
=
 
::: 
 
::: 
)and 
 
=
 
::: 
 
::: 
)betwochromosomesand
 
 
+1,
 
 
+1.A 
translocatio
 
ij 
)exchangesgenes 
between 
twochromosome
 
an
 
andtransformsthemintochromosomes
 
::: 
 
::: 
)and
 
::: 
 
::: 
)with
1)+
+1and
1)+
+1)genesrespectively.Wedenote 
 
 
asthegenomeobtainedfromasaresulofarearrangement 
 
.Givengenomesand;,th
genomicsorting 
problemistondaseriesof rearrangements(reversalsandtranslocations
 
::: 
suchthat 
 
 
 
 
=;an
isminimumWecal
th
genomicdistanc
betweenand;anddenoteita
( 
;)Wedistinguishbetwee
internal 
reversalswhichdonotinvolveendsofthechromosomes(i.e.the reversal
 
ij 
)ofa 
-genechromosomewith
<
 
j<
)and 
prex 
reversalsinvolvingendsofthchromosomes(i.e.either 
=1o
).Alsonotethatatranslocation 
 

+
1)concatenatethechromosome
 
an
 
resultinginachromosom
 
::: 
 
::: 
anda
empt
chromosom
 
Thisspecialtranslocationleadingtoareductioninthenumberof(non-empty)chromosomesisknowinmolecularbiologyas
 fusio
.Thetranslocation 
 
 
i
1)for
<
 
\breaks"achromosom
 
intotwochromosomes
 
::: 
)and
 
::: 
).Thistranslocationleadingtoanincreaseithenumberof(non-empty)chromosomesisknownas
 ssion 
.Atranslocationi
internal 
ifitineitherafusion,norassion.Fusionsandssionsarerathercommoninmammalianevolution.For example,theonlydierenceintheoverallgenomeorganizationofhumanandchimpanzeeisthefusion ofchimpanzeechromosomes12and13intohumanchromosome2. GenomerearrangementsprovideamultitudeofchallengesforcomputerscientistsseePevznerandWa- terman,1995forareviewofcombinatorialproblemsmotivatedbygenomerearrangements.KececioglandSanko,1993suggestedtherstapproximationalgorithmtoanalyzegenomerearrangementsiuni-chromosomalgenomes(reversalsonly).TheproblemwasfurtherstudiedbyBafnaandPevzner1993,KececiogluandSanko,1994,KececiogluandGuseld,1994,BafnaandPevzner,1995aandHan- nenhalliandPevzner,1995.SeealsoSankoetal.,1992,BafnaandPevzner,1995bandHannenhalletal.,1995forbiologicalapplications,aswellasGatesandPapadimitriou,1979,EvenandGoldreich, 
 
1981,Jerrum,1985,AignerandWest,1987,CohenandBlum,1993,HeydariandSudborough,1993 forstudiesofrelatedcombinatorialproblemsKececiogluandRavi,1995madetherstattempttoanalyzerearrangementsofmulti-chromosomal genomesbydevisinganapproximationalgorithmforgenomesevolvingbyinternalreversalsandinternaltranslocations.RecentlyHannenhalli,1995devisedapolynomialalgorithmforthecasewhenonlinternaltranslocationsareallowed.Allthesealgorithmsaddressthecasewhenbothgenomescontaithesamenumberofchromosomes.Thisisaseriouslimitationsincedierentorganisms(inparticu- larhumanandmouse)havedierentnumbersofchromosomes.Fromthisperspective,everyrealistimodelofgenomerearrangementsshouldincludefusionsandssions.Moreover,despitesomeshortcomings(seethelastsectionforadiscussiononcentromeres)thereversals/translocations/fusions/ssionmodeladequatelyreectstheexistingbiologicalchallenges(JoeNadeau,personalcommunication)Itturnsoutthatfusionsandssionspresentamajordicultyinanalyzinggenomerearrangements:theproblemofdevisingan 
approximation 
algorithmforgenomerearrangementswithreversals/translocations/fusions/ssionswasraisedbyKececiogluandRavi,1995.Thispaperpresentsan 
exact 
polynomialalgorithmforthisproblemEveryanalysisofrearrangementsinvolvesrevealing\hiddenobstacles"whichpreventa\fast"transformationofonegenomeintoanother(likedualvariablesinlinearprogramming).Sixtyyearsago DobzhanskyandSturtevant,1938alreadyusedanotionofbreakpoint,whichisthemostobviousexampleofsuchanobstacle.Basedonthisnotion,KececiogluandSanko,1994,deviseda2-approximation algorithmforuni-chromosomalgenomes.However,anestimateofgenomicdistanceintermsofbreak- pointsisveryinaccurate.BafnaandPevzner,1993revealedanotherobstacle(cycledecomposition) whichsignicantlyimprovestheboundsforgenomicdistance.Finally,HannenhalliandPevzner,1995 foundadualitytheoremforuni-chromosomalgenomes(reversalsonly)whichexpressesthegenomidistanceintermsoffourparametersdescribingthecombinatorialstructureofpermutations.Inthe caseofmulti-chromosomalgenomescombinatoricsofrearrangementsbecomesrathercomplicated. Thispaperpresentsthedualitytheoremformulti-chromosomalgenomeswhichcomputesthegenomidistanceintermsofseven(!)parameterscapturingdierentcombinatorialpropertiesofsetsofstringsOuranalysisofmulti-chromosomalgenomesextensivelyusesthedualitytheoremforuni-chromosomal genomes(HannenhalliandPevzner,1995),whichisstatedinsection2.Insection3weintroducean ideacalled 
 ippin
ofchromosomestoanalyzearelativelysimplecaseofso-called 
co-tailed 
genome(approximationalgorithmforthiscasewasproposedbyKececiogluandRavi,1995).Insectionweintroduceanotherideacalle
cappin
ofchromosomes.Insection5,usingcappings,wetakethe rststeptowardsapolynomial-timealgorithmforgenomicdistancebyprovingaboundwhichisat mostonerearrangementawayfromthegenomicdistance.Thisboundprovidestheintuitionforrathercomplicatedpotentialfunctionthatleadstoapolynomial-timealgorithmanddualitytheoreforgenomicsorting(section6).Finally,insection7wepresentbiologicalapplications,formulateopen problems,anddiscussourresultinrelationtotherecentexperimentalbreakthroughinZOO-FISH chromosomepainting. 
2Cycles,hurdlesandfortresse
I
reversaldistance 
problem,theorderofgenesintwo(uni-chromosomal)genomesisrepresentedby (unsigned)permutations 
 
=
 
 
::: 
)and 
 
=
 
 
::: 
)andtheonlyconsideredrearrangementsarereversals(i.e.both 
 
an
 
consistofasinglechromosomeandthegenesdonothave associatedsigns).Given(unsigned)permutations 
 
an
 
,the 
reversaldistanceproblem 
istondseriesofreversal
 
 
::: 
suchthat 
 
 
 
 
 
 
 
 
an
isminimum(Fig.2a).Wecal
th
reversaldistance 
betwee
 
an
 
Sortin
 
byreversal
istheproblemofndingthereversal distance, 
 
),betwee
 
andthe 
identit
permutation(12 
:::n 
)Le
 
=
 
::: 
)beapermutationoftheelement
:::n 
.Denot
 
i
j
j
=1.Extendpermutation 
 
=
 
::: 
)byadding 
 
=0an
 
+
+1.Wecallapairofconsecutiveelement
 
an
 
+
,
 
 
,o
 
breakpoin
i
 
6 
 
+
.Th
breakpointgraph 
o
 
isanedge-coloregraph 
 
)wit
+2vertice
 
 
::: 
 
+
.Wejoinvertice
 
an
 
by
black 
edgei
 
andbyagrayedgei
 
 
 
.(SeeFig.2b).Laterwealsousethenotionofbreakpointgraph 

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