DoOP: Da abases o O hologous P omo e s,
collec ions o clus e s o o hologous ups eam
sequences om cho da es and plan s
End e Ba a*, End e Sebes ye
´n, Tama
´sB.Pa
´l y, Ga
´bo To
´ h, Csaba P. O u ay and
La
´szlo
´Pa hy
1
Ag icul u al Bio echnology Cen e , Go
¨do
¨llo
}
, Szen -Gyo
¨ gyi Albe u. 4, H-2100, Hunga y and
1
Ins i u e o Enzymology,
Biological Resea ch Cen e o he Hunga ian Academy o Sciences, Budapes , Ka olina 
uu 29, H-1113, Hunga y
Recei ed Augus 15, 2004; Re ised Sep embe 29, 2004; Accep ed Oc obe 13, 2004
ABSTRACT
DoOP (h p://doop.abc.hu/) is a da abase o euka yo ic
p omo e sequences (ups eam egions) aiming o
acili a e he ecogni ion o egula o y si es con-
se ed be ween species. The anno a ed i s
exons o human and A abidopsis haliana genes
we e used as que ies in BLAST sea ches o collec
he mos closely ela ed o hologous i s exon
sequences om Cho da a and Vi idiplan ae species.
Up o 3000 bp DNA segmen s ups eam om hese
i s exons cons i u e he clus e s in he cho da e
and plan sec ions o he Da abase o O hologous
P omo e s. Release 1.0 o DoOP con ains 21 061
cho da e clus e s om 284 di e en species and
7548 plan clus e s om 269 di e en species. The
da abase can be used o ind and e ie e p omo e
sequences o a gi en gene om a ious species and
i is also sui able o see he mos i ial conse ed
sequence blocks in he o hologous ups eam
egions. Use s can sea ch DoOP wi h ei he seq-
uence o ex (anno a ion) o ind p omo e clus e s
o a ious genes. In addi ion o he sequence da a,
he posi ions o he conse ed sequence blocks
de i ed om mul iple alignmen s, he posi ions o
epe i i e elemen s and he posi ions o ansc ip ion
s a si es known om he Euka yo ic P omo e
Da abase (EPD) can be iewed g aphically.
INTRODUCTION
Regula ion o ansc ip ion ini ia ion was among he i s
success ul a ge s o bioin o ma ic analyses. I is unequi ocal
ha his egula ion always in ol es he binding o one o mo e
ansc ip ion ac o s o some pa s o he p omo e egion (he e
e e ed o as he egion ups eam om he ansc ip ion s a
si e o a gene), called ansc ip ion ac o binding si es
(TFBSs) (1). The sequence o he p omo e egion o genes
can be de e mined expe imen ally, as well as he less exac
posi ions and scope o hose egions whe e he di e en an-
sc ip ion ac o s bind o he DNA. Al hough he expe imen al
app oach is e y di icul and slow, and in mos cases gi es
a a he ambiguous esul , i soon had yielded enough da a o
s a collec ing hem in o da abases (2,3). F om he bioin o m-
a ic poin o iew, i was easy o suppose ha p edic ing
TFBSs would simply imply inding ma ches be ween expe i-
men ally known TFBSs and he p omo e sequence. I became
clea e y soon, howe e , ha i was mo e complica ed, and
e en using sophis ica ed me hods o de ining TFBSs such as
posi ion-speci ic weigh ma ices ga e unsa is ac o y esul s in
mos cases (4).
Besides he expe imen al app oaches o iden i y TFBSs in
he p omo e egions, se e al mos ly s ing-based s a is ical
me hods ha e been de eloped o allow hei ab ini io p edic-
ion. As inpu , hese me hods can use p omo e sequences o
a se o ei he co- egula ed o o hologous genes. The i s
app oach has been applied wi h some success o example
in yeas , whe e he in silico da a a e in good ag eemen
wi h ei he he expe imen al esul s (5) o a se o well-
cha ac e ized p omo e s (6,7). The second app oach whe e
a se o o hologous p omo e s a e used o ind conse ed
o o e - ep esen ed mo i s is called phylogene ic oo p in ing
(8). Se e al examples p o e ha his is a good s a ing poin o
disco e TFBSs (9–12).
The lack o a publicly accessible o hologous p omo e
da abase has hinde ed he widesp ead use o he phylogene ic
oo p in ing app oach. The bes known Euka yo ic P omo e
Da abase (EPD) (13) ocuses a he on he speci ic ea u es o
*To whom co espondence should be add essed. Tel: +36 28 526112; Fax: +36 28 526101; Email: [email p o ec ed]
P esen add ess:
Csaba P. O u ay, Ins i u e o Medical Technology, Uni e si y o Tampe e, F-33014 Tampe e, Finland
The online e sion o his a icle has been published unde an open access model. Use s a e en i led o use, ep oduce, dissemina e, o display he open access
e sion o his a icle o non-comme cial pu poses p o ided ha : he o iginal au ho ship is p ope ly and ully a ibu ed; he Jou nal and Ox o d Uni e si y P ess
a e a ibu ed as he o iginal place o publica ion wi h he co ec ci a ion de ails gi en; i an a icle is subsequen ly ep oduced o dissemina ed no in i s en i e y bu
only in pa o as a de i a i e wo k his mus be clea ly indica ed. Fo comme cial e-use pe missions, please con ac jou nals.[email p o ec ed].
ª2005, he au ho s
Nucleic Acids Resea ch, Vol. 33, Da abase issue ªOx o d Uni e si y P ess 2005; all igh s ese ed
D86–D90 Nucleic Acids Resea ch, 2005, Vol. 33, Da abase issue
doi:10.1093/na /gki097
he p omo e egions, such as ansc ip ion s a si es (TSSs),
TATA-boxes, e c. han on de ining o hologous se s o
p omo e s. The Hema opoiesis P omo e Da abase (HemoPDB)
(14) con ains linked o hologous p omo e s, bu only o hose
genes ha a e in ol ed in hema opoiesis. The e a e se e al
me hods o clus e o hologous genes such as he COG da a-
base a he Na ional Cen e o Bio echnology In o ma ion
(NCBI) (15), he INPARANOID p og am (16) o he
O hoMCL (17). They a e all based on an all-agains -all
BLAST sea ch o p o ein sequences, hus i is di icul o
use hei da a o e ie e p omo e sequences. The Ensembl
Genome B owse (18) p o ides links o o hologous genes,
bu hey a e limi ed o he species in ol ed in he Ensembl
sys em. The CORG da abase (19) also p o ides o hologous
p omo e sequences, bu ini ially only om he human and
mouse genomes and po en ially om he species in ol ed in
he Ensembl sys em.
We belie e ha all a emp s o iden i y unc ionally impo -
an mo i s in ups eam cis- egula o y egions o genes can
la gely bene i om a collec ion o o hologous p omo e
sequences. Once we ha e a se o o hologous ups eam
egions, we can loca e known TFBSs, o y o p edic
new ones applying ab ini io me hods, o simply sea ch o
conse ed egions. Se e al me hods and da abases a e a ailable
o ca y ou hese asks (20), bu hey always equi e a se o
o hologous genes.
We p esen he e he i s e sion o he Da abase o O ho-
logous P omo e s (DoOP), which p o ides clus e s o o ho-
logous pu a i e p omo e s wi hin he phylum Cho da a and
kingdom Vi idiplan ae. The cho da e and plan sec ions
o DoOP a e based on he NCBI gene anno a ion (21) o
he human and A abidopsis haliana genomes, espec i ely.
We use he i s o he i s wo exons o genes as a que y in a
BLAST (22) sea ch o ind o hologous i s exons. Sub-
sequen ly, we ex ac he 500, 1000 and 3000 bp ups eam
egions o hese o hologous i s exons o build he DoOP
clus e s. A low cha depic ing he gene a ion o he DoOP
da abases can be seen in Figu e 1. The aim o he DoOP is o
p o ide esea che s wi h se s o o hologous p omo e s
o acili a e he analysis o egula o y egions, including he
disco e y o conse ed non-coding mo i s.
CONSTRUCTION OF THE DoOP DATABASE
Sea ching o o hologs
We chose Homo sapiens (NCBI Human Build 34 a ailable
om p:// p.ncbi.nih.go /genomes/H_sapiens) and A. hali-
ana ( p:// p.ncbi.nih.go /genomes/A abidopsis_ haliana/) as
e e ence species o he cho da e and plan da abases, espec -
i ely. The i s c i ical s ep o he da abase c ea ion was o
choose he mos sui able que y sequences. We analyzed he
genome anno a ions p o ided by he NCBI, and decided o
di ide he que y ypes in o six main ca ego ies. These ypes o
que ies a e dis inguished acco ding o he s a ing posi ion o
he i s mRNA exon wi h espec o he p o ein-coding (CDS)
sequence and he leng h o he i s coding exon (Figu e 2).
In he BLAST sea ches we used coding sequences whene e i
was possible (Figu e 2, ypes 1–4), because he 50-un ansla ed
egion (50-UTR) sequences a e usually less conse ed han
he coding egions. Howe e , in ypes 5nand 6n, we had o
use he sequence o he anno a ed 50 ully UTR exons. To
imp o e sensi i i y, we used he sequences o he i s wo
exons ( ype 6n) o he i s wo coding exons ( ypes 2 and 4)
i he leng h o he i s exon was <50 bp (Figu e 2).
Fo building he local BLAST da abases, we used he gss,
h gs, n and wgs sec ions o he NCBI BLAST da abases
( p:// p.ncbi.nih.go /blas /db/) and he whole genome
sequences o mouse, a , ugu, zeb a ish om Ensembl
( p:// p.ensembl.o g/pub) ha we e a ailable a he end o
Ma ch 2004. We buil wo da abases by emo ing all mRNA
(cDNA) sequences om bo h, and he non-cho da e sequen-
ces om he cho da e da abase and he non-Vi idiplan ae
sequences om he plan da abase u ilizing he NCBI
axid–gi numbe , phylum–kingdom assignmen sys em ( p://
p.ncbi.nih.go /pub/ axonomy/). In he case o he e e ence
species, he 3000 bp ups eam egion wi h he i s o he i s
DIALIGN
Repea Maske
sequences
Figu e 1. The da a low o he gene a ion o he cho da e DoOP da abase.
The same me hod is used in he case o he plan DoOP da abase, excep he
sou ce BLAST da abase comes om all Vi idiplan ae sequences and he que y
sequences a e gene a ed based on he NCBI A. haliana anno a ion.
Figu e 2. Di e en ypes o genes acco ding o he posi ions o he i s mRNA
and coding (cds) exons. The ypes 5 and 6 all in o di e en subca ego ies based
on he numbe o he i s coding exon. I i is he second as in his igu e, we call
i ype 52 o 62, bu o he wise we a e e e ing o hem gene ally as 5no 6n. The
posi ions o he que y sequences ela i e o he i s exons a e ma ked wi h g een
boxes, while he 500, 1000 and 3000 bp ups eam egions ha ha e been pu in o
he da abase a e ma ked wi h ed boxes.
Nucleic Acids Resea ch, 2005, Vol. 33, Da abase issue D87
wo exons co esponding o he selec ed que y sequence was
used in he da abase. The de ails o he da abase c ea ion,
sea ching and p ocessing can be ound a he DoOP web
pages (h p://doop.abc.hu/de ails.h ml).
P ocessing he da abase
We analyzed he esul s o BLAST sea ches using Pe l sc ip s
u ilizing BioPe l modules (23). Fi s , we had made a esul s
able (Figu e 1) using a minimum h eshold alue o 50% o
iden i y and 75% o he combined hi leng h compa ed o he
que y leng h. In he nex s ep, we selec ed he bes sui able
o hologous hi s wi h he ollowing simple algo i hm. In each
species ha had mo e han one hi , he hi wi h he bes sco e
was chosen. I he e we e wo o mo e hi s wi h iden ical
sco es om a species, he sequence ha ex ended u hes
o he 50di ec ion ela i e o he hi was chosen (i.e. he
one ha had a longe ups eam egion). A e he mos o ho-
logous hi s we e de e mined, 500, 1000 and 3000 bp long
ups eam sequences we e ex ac ed om he o iginal da abase
sequences i a ailable.
In his pape we e e o he se o o hologous sequences as
a clus e . In o de o ind conse ed egions wi hin he clus e s,
we gene a ed mul iple alignmen s. Since local alignmen s a e
be e o his pu pose, we chose he DIALIGN2 p og am ha
implemen s a segmen -based alignmen algo i hm (24). The
conse ed mo i s we e ex ac ed om he consensus
sequences o he DIALIGN2 esul s using a Pe l sc ip . The
pu a i e in e spe sed epea s we e iden i ied in he clus e
sequences using he Repea Maske p og am (A. F. A. Smi
and P. G een, h p:// epea maske .genome.washing on.edu/)
wi h he app op ia e epea lib a ies ob ained om Repbase
Upda e (25). Posi ions o he TSSs as anno a ed in he EPD
da abase we e de e mined in he wo e e ence species using a
BLAST-based pai ing o EPD sequences wi h he co espond-
ing DoOP en y. A simila me hod was used o he cho da e
da abase o e ie e Ensembl links and de ini ions o genes.
The posi ions o he epea s and he conse ed mo i s along
wi h o he in o ma ion such as he posi ions o he anno a ed
50-UTRs o ypes 3 and 4 (Figu e 2), and he TSSs we e
compiled oge he in a g aphics ile using BioPe l. The da a
ob ained du ing da abase p ocessing we e ed in o a MySQL
da abase.
CONTENTS OF THE CURRENT RELEASE
Release 1.0 o DoOP da abank con ains p ac ically wo
dis inc da abases, he plan and he cho da e. They bo h e lec
he sequence and anno a ion da a ha we e a ailable a he end
o Ma ch 2004. The plan da abase con ains 7548 clus e s ha
ha e sequences om a leas wo species. This numbe e e s
o he clus e s con aining up o 500 bp p omo e egions. The
numbe is lowe in he case o he 1000 and 3000 bp clus e s
(1088 and 973, espec i ely), because many hi s, especially
hose om he Whole Genome Sho gun sequences sec ion,
con ain <500 bp o p omo e sequence depending on he posi-
ion o he hi wi hin he sequence en y. Mos o he plan
clus e s con ain sequences only om A. haliana and B assica
ole acea. The e a e only 1096 clus e s ha con ain p omo e
sequences o a leas one species ou side he B assicaceae
amily. The cho da e da abase con ains 21 061 500 bp,
20 009 1000 bp and 18 911 3000 bp p omo e egion clus e s.
The e a e 15 178 clus e s whe e a leas one en y exis s om
a amily o he han Hominidae. A de ailed da abase s a is ics
is a ailable in he DoOP web pages.
DATABASE ACCESS AND WEB CONTENT
The in o ma ion ha is s o ed in he DoOP da abases can be
accessed eely om he DoOP websi e a h p://doop.abc.hu/.
A e selec ing he cho da e o he plan da abase sec ion, use s
can sea ch o a speci ic clus e o o a g oup o clus e s. The e
a e ou ex sea ch ields, whe e use s can en e a speci ic
clus e ID, o a scien i ic axon name, o a species axonomy
ID ( axid) om he NCBI Taxonomy da abase, o a keywo d o
sea ch in he de ini ion lines o he clus e s. I is also possible o
selec a clus e (i.e. a gene) by a as BLAT (26) sea ch using
any cDNA sequence om he e e ence species (H.sapiens o
A. haliana) as a que y. In he nex s ep use s can selec any
clus e o u he iewing om he esul s lis . In he clus e
iew (Figu e 3), among o he da a he e is a g aphical ep e-
sen a ion o he clus e sequences showing he species names,
possible 50-UTR and TSS in he e e ence sequence, any epe-
i i e sequences and conse ed mo i s. By de aul he clus e
iew s a s wi h he clus e o 500 bp long p omo e egions
(Figu e 3), bu use s can selec he 1000 o 3000 bp p omo e
clus e s, oo. I is also possible o iew and sa e he mul iple
alignmen s and he FASTA o ma sequences o he clus e s
and he sequences o he conse ed mo i s.
CONCLUSIONS AND PERSPECTIVES
The p ima y aim o he DoOP is o p o ide an easy way o
ob ain clus e s o o hologous p omo e sequences. These clus-
e sequences can be a sou ce o a mo e de ailed analysis o
possible p omo e elemen s, including TFBSs. The da a
p o ided by he DoOP web se e is also sui able o a d a
iew o he conse ed mo i s in he p omo e egions o
di e en genes.
Ou me hod o ind o hologous ups eam egions elies on
wo impo an sou ces. The i s is he genome anno a ion o
he e e ence species (H.sapiens and A. haliana). Undoub -
edly, we need o ha e he exac posi ions o he i s exons,
including he 50-UTR egions. We know ha he anno a ion
we had used is a om being comple e. Fo example, he e a e
s ill a lo o anno a ed genes (4031 in he human genome
da abase) whe e he s a ing poin s o he i s coding and
mRNA exons a e he same ( ypes 1 and 2 in Figu e 2),
which is e y unlikely in i o. We expec ha he genome
anno a ion o hese wo e e ence species will be s eadily
be e ed, he eby imp o ing subsequen eleases o DoOP as
well. The second impo an ac o o ou wo k is he a ailable
genomic sequences, especially he numbe o comple e gen-
omes. I is p o en ha he mo e he sequences a e a ailable o
phylogene ic oo p in ing, he be e he esul ha can be
achie ed (27). The si ua ion o he cho da e da abase is
qui e p omising, since al eady se e al mammalian whole gen-
ome sequences ha e been de e mined, and he e a e qui e
a ew ongoing p ojec s, oo. Un o una ely, he e a e only
wo comple ed genomes om plan s, A. haliana and ice.
We hope howe e ha he sequence da a appea ing om he
D88 Nucleic Acids Resea ch, 2005, Vol. 33, Da abase issue
ongoing plan genome sequencing p ojec s such as Medicago
unca ula,Populus ichoca pa o oma o, will imp o e he
plan DoOP da abase signi ican ly.
This is he i s elease o he DoOP da abase. The nex
mino upda e will be a ailable by he end o 2004. We plan
o gene a e wo da abases pe yea in he u u e, which will
e lec he sequence and anno a ion da a a ailable a he end
o Ma ch and Sep embe . Ou plans o imp o e he DoOP
da abase include e ining he BLAST sea ches o be mo e
sensi i e, using o he me hods o mul iple alignmen s and
o de ec conse ed mo i s wi hin he clus e s, o elying
mo e on he da a o o he da abases such as Ensembl.
Figu e 3. Examples o he DoOP da a iews. In he pic u e o he clus e he boxes numbe ed om m1 o m13 show he conse ed mo i s, he black box shows
a p edic ed epe i i e elemen , while he blue box shows he 50-UTR.
Nucleic Acids Resea ch, 2005, Vol. 33, Da abase issue D89
The me hod we ha e de eloped he e could also be applicable
o he gene a ion o DoOP da abases based on o he e e ence
species, such as he yeas o he ui ly.
ACKNOWLEDGEMENTS
This wo k was suppo ed by Bio echnology 2001 g an
BIO-0117/01 om he Cen al Technical De elopmen
Ta ge Funds (Hunga y). The ecipien s o ‘Bolyai
Fellowship’ awa ded by he Hunga ian Academy o
Sciences we e E.B. and G.T.
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D90 Nucleic Acids Resea ch, 2005, Vol. 33, Da abase issue