SOFTWARE Open Access
QTLmine : iden i ying genes egula ing
quan i a i e ai s
Rudi Albe s, Klaus Schugha
*
Abs ac
Backg ound: Quan i a i e ai locus (QTL) mapping iden i ies genomic egions ha likely con ain genes egula ing
a quan i a i e ai . Howe e , QTL egions may encompass ens o hund eds o genes. To ind he mos p omising
candida e genes ha egula e he ai , he biologis ypically collec s in o ma ion om mul iple esou ces abou
he genes in he QTL in e al. This p ocess is e y labo ious and ime consuming.
Resul s: QTLmine is a bioin o ma ics ool ha au oma ically pe o ms QTL egion analysis. I is a ailable in
GeneNe wo k and i in eg a es in o ma ion such as gene anno a ion, gene exp ession and sequence
polymo phisms o all he genes wi hin a gi en genomic in e al.
Conclusions: QTLmine subs an ially speeds up disco e y o he mos p omising candida e genes wi hin a QTL
egion.
Backg ound
Quan i a i e ai locus (QTL) mapping is a powe ul
me hod o iden i y genes egula ing complex ai s.
By combining molecula ma ke da a o gene ically ela ed
indi iduals wi h pheno ypic ai alues, genomic QTLs
a e iden i ied ha likely con ain gene ic egula o s o he
ai . This s a egy has bo h been applied o ‘classical’ ai s
like body weigh , blood p essu e o disease suscep ibili y,
as well as o ai s measu ed using high- h oughpu ech-
nologies: mRNA abundances measu ed by mic oa ays
[1,2], and p o ein o me aboli e abundances measu ed by
mass spec ome y [3,4]. QTLs gene ally span a genomic
egion con aining ens o hund eds o genes. Iden i ica ion
o he mos p omising egula ing genes wi hin QTL in e -
als, which can hen be unc ionally es ed, s ill emains a
majo challenge. QTLmine has been implemen ed in he
GeneNe wo k [5], a la ge esou ce wi h geno ypes, pheno-
ypes and gene exp ession p o iles o mul iple o ganisms
and gene ic e e ence popula ions. I au oma ically ana-
lyses a QTL egion and in eg a es in o ma ion abou he
candida e genes, so ha he bes candida e genes can be
quickly iden i ied.
Implemen a ion
QTLmine was implemen ed in Py hon as pa o he
GeneNe wo k [5].
Resul s and Discussion
QTLmine akes a QTL in e al as inpu , which is
de ined by he ch omosome and he s a and end posi-
ions in megabases. The p og am au oma ically gene -
a es a lis o genes wi hin he in e al and e ie es
addi ional in o ma ion o each gene. The i s pa
comp ises anno a ion da a such as gene name, desc ip-
ion, genomic posi ion, Gene On ology (GO) e ms and
KEGG pa hways in which he gene is implica ed. Nex ,
he amoun o non-synonymous single nucleo ide poly-
mo phisms (nsSNPs) wi hin he gene is displayed.
nsSNPs esul in amino acid changes in he co espond-
ing p o ein. These changes may modi y i s s uc u e and
may hus be causa i e o he pheno ypic di e ences
which we e mapped. Fu he mo e, he use can selec
h ee GeneNe wo k exp ession da a se s. Fo each o he
da a se s, gene exp ession and in o ma ion abou cis-
egula ion will be added. In his way, he use can see
whe he candida e genes a e exp essed in he issue
unde s udy. Genes ha a e only exp essed in he issue
o in e es and no in o he s migh e en be be e candi-
da es. The use should howe e be awa e ha high
exp ession is no always equi ed, i.e. lowly exp essed
* Co espondence: [email p o ec ed]
Depa men o In ec ion Gene ics, Helmhol z Cen e o In ec ion Resea ch
and Uni e si y o Ve e ina y Medicine Hanno e , Inho ens asse 7, 38104
B aunschweig, Ge many
Albe s and Schugha BMC Bioin o ma ics 2010, 11:516
h p://www.biomedcen al.com/1471-2105/11/516
© 2010 Albe s and Schugha ; licensee BioMed Cen al L d. This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e
Commons A ibu ion License (h p://c ea i ecommons.o g/licenses/by/2.0), which pe mi s un es ic ed use, dis ibu ion, and
ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed.
genes may also ha e a s ong in luence on ai s. In
addi ion, in o ma ion abou cis- egula ion is added. A
gene is cis- egula ed i i s exp ession maps close o i s
own genomic posi ion. Any cis- egula ed gene in he
QTL egion is a good candida e o egula e he ai ,
since cis- egula ion indica es a di e ence in gene exp es-
sion le els, which may egula e he ai . Albe s e al.
[6] ha e shown ha ‘ghos ’cis-eQTLs (exp ession
QTLs) can be de ec ed i he e a e SNPs o o he
sequence a ian s in he p obe egions ha cause a di -
e ence in hyb idiza ion signal. These cases migh also
be in e es ing since he sequence a ian s in he p obe
egions migh esul in changes in he p o ein s uc u e
which can egula e he ai .
To demons a e he u ili y o he p og am, we ook a
QTL ho spo on mouse dis al ch omosome 1 as exam-
ple. This egion, also called Q 1, con ains many QTLs
ha con ol neu al and beha io al pheno ypes, including
mo o beha io , escape la ency, emo ionali y, and sei-
zu e suscep ibili y (Szs1) [7]. Mozhui e al. ha e u he
in es iga ed his egion and e ealed a highly complex
gene exp ession egula o y in e al in Q 1, composed
o mul iple loci modula ing he exp ession o unc ion-
ally cogna e se s o genes. In he dis al pa o Q 1,
hey ha e iden i ied he gene Fmn2 as a s ong candi-
da e. To e-analyze his in e al using QTLmine , open
a web b owse and go o h p://genene wo k.helmhol z-
hzi.de and click ‘Sea ch’and ‘QTLmine ’.In he o m
ha appea s, choose Ch omosome 1, iew om 173 Mb
o 177 Mb. Selec wo mouse s ains o which nsSNPs
should be analyzed. Choose h ee GeneNe wo k da a
se s and click ‘Analyze QTL in e al’. Th ee hippocam-
pus da a se s in BXD, CXB and LXS mice a e chosen by
de aul .
Figu e 1A displays he esul s o QTLmine . I shows he
genes wi hin he Q 1 in e al, as well as hei desc ip ions
and posi ions. To ob ain mo e in o ma ion abou he unc-
ion o he genes, Gene On ology e ms and all KEGG
pa hways in which each gene occu s a e displayed
(excluded om he igu e). Nex , he amoun s o (s ain
speci ic) nsSNPs a e shown. Clicking his numbe links o
GeneNe wo k’s SNP b owse whe e de ailed in o ma ion
abou he SNPs can be sea ched. In he exp ession and cis
columns, one can di ec ly see which genes wi hin he QTL
in e al a e exp essed and cis- egula ed, and also compa e
exp ession and cis- egula ion o o he issues (da a se s).
The use should, howe e , be awa e ha o en gene
exp ession alues a e measu ed in whole o gans. These
alues migh no e lec he exp ession alues in a speci ic
cell ype o in e es , especially i he amoun o his cell
ype is only a small ac ion o he o al numbe o cells in
he o gan. In he Q 1 in e al, o e 100 genes we e
ound. Indeed he gene Fmn2 shows up as a e y good
candida e, because i exhibi s a high exp ession alue,
s ong cis- egula ion and con ains nsSNPs be ween he
pa en al s ains C57BL/6J and DBA/2J. To help he use
o in e p e he esul s, we added a sco e o each gene and
he possibili y o so he genes acco ding o ei he posi-
ion o sco e. The sco e anges be ween 0 and 4 and
inc eases by s eps o one uni i 1) he gene has an exp es-
sion alue g ea e han 8 in he i s da a se ; 2) he gene is
cis- egula ed in he i s da a se ; 3) he genes con ains
non-synonymous SNPs; 4) he gene con ains indels.
I should be no ed ha hese sco es a e jus helping he
biologis use o so he lis and o ge he mos in e es -
ing candida es a he op o he esul s able. The use
should s ill s udy gene desc ip ions, pa hways and o he
in o ma ion o all genes o ge he bes candida es. A gene
wi h a sco e o 1 which is known o be in ol ed in he
biological p ocess unde s udy migh be a much be e
candida e han a gene wi h unknown unc ion and a
highe sco e.
An addi ional ea u e o QTLmine is he isualiza ion
o he haplo ypes wi hin a QTL egion. In he haplo ype
plo (Figu e 1B), indi iduals a e so ed acco ding o
hei quan i a i e ai alue, and hei haplo ypes a e
indica ed by colo s. The gene Kcnj9 is one o he genes
wi h a s ong ans eQTL in he Q 1 in e al in hippo-
campus. To ob ain BXD haplo ypes o his gene, sea ch
he BXD hippocampus da a se in GeneNe wo k o
Kcnj9, click p obese 1450712 a , click he bu on ‘In e -
al Mapping’and ill in Ch omosome 1, 173 un il 177
Mb. Selec ‘Haplo ype Analys ’and click ‘Remap’.I is
immedia ely ob ious ha mice wi h a C57BL/6J ( ed)
allele a he QTL loca ion ha e a low ai alue,
whe eas mice wi h a DBA/2J (g een) allele ha e a high
ai alue. This isualiza ion may be used o ine map-
ping QTLs. Suppose ha a QTL sepa a es wo g oups
o indi iduals wi h low and high ai alue o mos
indi iduals, bu some indi iduals (which we e no ye
s udied) ha e a ecombina ion wi hin he in e al. Then
hese indi iduals may be used o u he geno yping
and in his way, a QTL egion can be u he na owed
down.
Conclusions
QTLmine au oma ically in eg a es gene anno a ion,
Gene On ology e ms, KEGG pa hway in o ma ion, gene
exp ession and cis- egula ion da a o all genes wi hin a
QTL in e al. Wi h only a ew mouse clicks on he Gen-
eNe wo k websi e, he mos p omising candida e genes
wi hin a gi en QTL egion a e quickly highligh ed.
A ailabili y and equi emen s
P ojec name: QTLmine
P ojec home page: h p://genene wo k.helmhol z-hzi.
de (click Sea ch - QTLmine )
Ope a ing sys em(s): Pla o m independen
Albe s and Schugha BMC Bioin o ma ics 2010, 11:516
h p://www.biomedcen al.com/1471-2105/11/516
Page 2 o 3
P og amming language: Py hon
O he equi emen s: none
License: none
Any es ic ions o use by non-academics: none
Acknowledgemen s
We hank Robe W. Williams o e y help ul commen s and sugges ions.
Funding: This wo k was suppo ed by he Helmhol z Cen e o In ec ion
Resea ch and by GeNeSys (Ge man Ne wo k o Sys ems Gene ics), a
Helmhol z Vi ual Ins i u e, inanced by he Helmhol z Associa ion.
Au ho s’con ibu ions
RA concei ed he s udy, w o e he manusc ip and implemen ed he
p og am. KS concei ed he s udy and w o e he manusc ip . All au ho s ead
and app o ed he inal manusc ip .
Recei ed: 7 May 2010 Accep ed: 15 Oc obe 2010
Published: 15 Oc obe 2010
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doi:10.1186/1471-2105-11-516
Ci e his a icle as: Albe s and Schugha : QTLmine : iden i ying genes
egula ing quan i a i e ai s. BMC Bioin o ma ics 2010 11:516.
Figu e 1 QTLmine esul s and haplo ype isualiza ion. A) Pa o he esul s e u ned by QTLmine . The genes in he QTL in e al and hei
desc ip ions and posi ions a e p esen ed. Nex , he amoun o non-synonymous SNPs wi hin all a ailable mouse s ains is gi en, and he
amoun o nsSNPs be ween wo chosen s ains, in his case C57BL/6J and DBA/2J. The exp ession columns display he mean exp ession alues
wi hin h ee GeneNe wo k da a se s. No e ha mul iple alues pe gene a e gi en when he gene is measu ed by mul iple p obes. The nex
columns show cis- egula ion. I a gene is cis- egula ed, he LRS alue (likely a io s a is ic) ha indica es he signi icance o he cis QTL is also
gi en. B) Haplo ype isualiza ion o BXD mice o he Q 1 egion. A ed (g een) line indica es ha he mouse ca ies he C57BL/6J (DBA/2J)
geno ype. The e ical lines a e exis ing geno ypic da a and colo ed lines in be ween a e in e ed geno ypes based on he mapping o
su ounding ma ke s. Blue lines indica e a egion con aining a ecombina ion b eak poin . S ains a e o de ed acco ding o ai alue. Genes in
he in e al a e displayed a he op (colo ed ba s).
Albe s and Schugha BMC Bioin o ma ics 2010, 11:516
h p://www.biomedcen al.com/1471-2105/11/516
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