emage edinburgh mouse atlas of gene expression

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emage edinburgh mouse atlas of gene expression
Jeff Christiansen PhD Project Leader EMAGE
Database
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emage edinburgh mouse atlas of gene expression
EMAGE - a novel bioinformatics resource
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emage edinburgh mouse atlas of gene expression
APOPTOSIS
METABOLIC ACTIVITY
TRANSGENICS
Acridine Orange J. Burns University of Bristol
Positron Emission Tomography R. Coghill Wake
Forest University
cre induced- LacZ expression W. Hsu, University
of Rochester
CELL DIVISION
CELL LINEAGE
GENE EXPRESSION
anti-BrdU staining J. McDearmid McGill
University
Sigolène Meilhac Institut Pasteur
Carol Wicking, IMB
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emage edinburgh mouse atlas of gene expression
EMAGE Aim to describe the expression patterns of
genes in the mouse during embryonic development
as detected by in situ methods
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emage edinburgh mouse atlas of gene expression
EMAGE Aim to describe the expression patterns of
genes in the mouse during embryonic development
as detected by in situ methods - in situ
hybridisation (detecting mRNA distribution) immu
nohistochemistry (detecting protein distribution)
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emage edinburgh mouse atlas of gene expression
EMAGE Aim to describe the expression patterns of
genes in the mouse during embryonic development
as detected by in situ methods - in situ
hybridisation (detecting mRNA distribution) immu
nohistochemistry (detecting protein
distribution) Develop tools for analysis of
this data
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emage edinburgh mouse atlas of gene expression
Wholemount samples
fixed whole embryo
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emage edinburgh mouse atlas of gene expression
Wholemount samples
OR
fixed whole embryo
Bind and then detect gene specific reagent
in situ
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emage edinburgh mouse atlas of gene expression
Wholemount samples
OR
Hybridise probe
fixed whole embryo
Bind and then detect gene specific reagent
in situ
stained whole embryo
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emage edinburgh mouse atlas of gene expression
Sectioned samples
section
whole embryo
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emage edinburgh mouse atlas of gene expression
Sectioned samples
section
whole embryo
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emage edinburgh mouse atlas of gene expression
Sectioned samples
OR
section
Bind and then detect gene specific reagent to the
section
whole embryo
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emage edinburgh mouse atlas of gene expression
Sectioned samples
OR
section
Bind and then detect gene specific reagent to the
section
whole embryo
stained section
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emage edinburgh mouse atlas of gene expression
Text based approach
Fgf8 Patrick Tam
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emage edinburgh mouse atlas of gene expression
Text based approach
Person 1 isthmus branchial arch distal
telencephalon
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emage edinburgh mouse atlas of gene expression
Text based approach
Person 1 Person 2 isthmus midbrain-hindbrain
organiser branchial arch anterior 1st branchial
arch distal telencephalon anterior
forebrain posterior 2nd branchial arch
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emage edinburgh mouse atlas of gene expression
Text based approach
Person 1 Person 2 isthmus midbrain-hindbrain
organiser branchial arch anterior 1st branchial
arch distal telencephalon anterior
forebrain posterior 2nd branchial arch
Problems with using text
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emage edinburgh mouse atlas of gene expression
Text based approach
Person 1 Person 2 isthmus midbrain-hindbrain
organiser branchial arch anterior 1st branchial
arch distal telencephalon anterior
forebrain posterior 2nd branchial arch
Problems with using text Different people use
different words (therefore controlled
vocabularies must be used)
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emage edinburgh mouse atlas of gene expression
Text based approach
Person 1 Person 2 isthmus midbrain-hindbrain
organiser branchial arch anterior 1st branchial
arch distal telencephalon anterior
forebrain posterior 2nd branchial arch
Problems with using text Different people use
different words (therefore controlled
vocabularies must be used) Anatomical structures
may not be named (or the biologist doesnt know
it)
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emage edinburgh mouse atlas of gene expression
Text based approach
Person 1 Person 2 isthmus midbrain-hindbrain
organiser branchial arch anterior 1st branchial
arch distal telencephalon anterior
forebrain posterior 2nd branchial arch
Problems with using text Different people use
different words (therefore controlled
vocabularies must be used) Anatomical structures
may not be named (or the biologist doesnt know
it) People have selective vision
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emage edinburgh mouse atlas of gene expression
To make things worse... Embryos are 3D
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emage edinburgh mouse atlas of gene expression
To make things worse... Embryos are 3D Many
modifiers are required to describe the subtleties
of an expression pattern (eg. proximal, distal,
lateral, measurements etc)
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emage edinburgh mouse atlas of gene expression
To make things worse... Embryos are 3D Many
modifiers are required to describe the subtleties
of an expression pattern (eg. proximal, distal,
lateral, measurements etc) Embryos change their
morphology over time (and size)
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emage edinburgh mouse atlas of gene expression
To make things worse... Embryos are 3D Many
modifiers are required to describe the subtleties
of an expression pattern (eg. proximal, distal,
lateral, measurements etc) Embryos change their
morphology over time (and size)
Zebrafish development 0-24hrs Donald Kane Rolf
Karlstrom Max-Planck Institut für
Entwicklungsbiologie Tübingen
1mm
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emage edinburgh mouse atlas of gene expression
To make things worse... Embryos are 3D Many
modifiers are required to describe the subtleties
of an expression pattern (eg. proximal, distal,
lateral, measurements etc) Embryos change their
morphology over time (and
size) Comprehensively describing the expression
pattern of a gene throughout embryo development
using words is extremely difficult (or
impossible?!)
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emage edinburgh mouse atlas of gene expression
EMAGE Use words (where possible) to describe
gene expression
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emage edinburgh mouse atlas of gene expression
EMAGE Use words (where possible) to describe
gene expression via an ontology (a
controlled descriptive vocabulary)
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emage edinburgh mouse atlas of gene expression
EMAGE Use words (where possible) to describe
gene expression via an ontology (a
controlled descriptive vocabulary) But more
uniquely... also use spatially standardised
images to show gene expression A picture
says 1,000 words
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emage edinburgh mouse atlas of gene expression
EMAGE database architecture
BIOLOGIST
Java Swing Application
Client machine (PC, MacOSX, Linux, UNIX)
CORBA
Server machines (SUN Solaris)
C Application Server
ObjectStore Server
Text data
Image files
The database software has clientserver
architecture. The application-domain information
is stored in an ObjectStore database. The
database includes C server and Java Swing
client software. The C server accesses the
database and runs on a Sun Solaris server. The
Java client software is delivered by Java Web
Start or directly through a web browser and
communicates with the C server via Corba. Java
Interface can be downloaded from the EMAGE
homepage and will run on any platform with Java
v1.4.2 installed. Following installation, the
Java interface can be launched from the EMAGE
homepage.
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emage edinburgh mouse atlas of gene expression
EMAGE database architecture
BIOLOGIST
Java Swing Application
Client machine (PC, MacOSX, Linux, UNIX)
CORBA
Server machines (SUN Solaris)
C Application Server
Web DAS Distributed annotation server
ObjectStore Server
Text data
Image files
The database software has clientserver
architecture. The application-domain information
is stored in an ObjectStore database. The
database includes C server and Java Swing
client software. The C server accesses the
database and runs on a Sun Solaris server. The
Java client software is delivered by Java Web
Start or directly through a web browser and
communicates with the C server via Corba. Java
Interface can be downloaded from the EMAGE
homepage and will run on any platform with Java
v1.4.2 installed. Following installation, the
Java interface can be launched from the EMAGE
homepage.
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emage edinburgh mouse atlas of gene expression
EMAGE database architecture
BIOLOGIST
PROGRAMMER
Java Swing Application
Client machine (PC, MacOSX, Linux, UNIX)
CORBA
Webservices
Server machines (SUN Solaris)
C Application Server
Web DAS Distributed annotation server
ObjectStore Server
Text data
Image files
The database software has clientserver
architecture. The application-domain information
is stored in an ObjectStore database. The
database includes C server and Java Swing
client software. The C server accesses the
database and runs on a Sun Solaris server. The
Java client software is delivered by Java Web
Start or directly through a web browser and
communicates with the C server via Corba. Java
Interface can be downloaded from the EMAGE
homepage and will run on any platform with Java
v1.4.2 installed. Following installation, the
Java interface can be launched from the EMAGE
homepage.
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emage edinburgh mouse atlas of gene expression
EMAGE database spatial framework - the EMAP
Digital Atlas
Based on Theiler (1989) and Kaufman (1992)
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emage edinburgh mouse atlas of gene expression
Current EMAP models
F1 (C57BL/6 x CBA)
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emage edinburgh mouse atlas of gene expression
Data integration In EMAGE
eg. TS17
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emage edinburgh mouse atlas of gene expression
Data integration In EMAGE
eg. TS17
Wholemount
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emage edinburgh mouse atlas of gene expression
Data integration In EMAGE
eg. TS17
Wholemount
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emage edinburgh mouse atlas of gene expression
Data integration In EMAGE
eg. TS17
Section
Wholemount
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emage edinburgh mouse atlas of gene expression
Data integration In EMAGE
eg. TS17
Section
Wholemount
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emage edinburgh mouse atlas of gene expression
Data integration In EMAGE
eg. TS17
Wholemount
Section/OPT
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emage edinburgh mouse atlas of gene expression
Data can be interrogated spatially
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emage edinburgh mouse atlas of gene expression
Data can be interrogated spatially - 2D
(wholemount data)
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emage edinburgh mouse atlas of gene expression
Data can be interrogated spatially
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emage edinburgh mouse atlas of gene expression
Data can be interrogated spatially - 3D (section
data)
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emage edinburgh mouse atlas of gene expression
Data mapping in EMAGE
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emage edinburgh mouse atlas of gene expression
2D wholemount data
Pax3
Ruth Arkell
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emage edinburgh mouse atlas of gene expression
2D wholemount data is mapped to a surface view
of the stage-matched embryo model
Pax3
Appropriate view selected
Ruth Arkell
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emage edinburgh mouse atlas of gene expression
2D wholemount data is mapped to a surface view
of the stage-matched embryo model
Pax3
Expression levels transferred to model
Ruth Arkell
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emage edinburgh mouse atlas of gene expression
MAPaint Warping Interface
Overlay of source and target image
Target Standard EMAP embryo model
Source in situ hybridisation image
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emage edinburgh mouse atlas of gene expression
MAPaint Warping Interface
Deformation Progress in warping visualised with a
triangular mesh
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emage edinburgh mouse atlas of gene expression
MAPaint Thresholding Interface
Signal Extraction Gene expression pattern
extracted from source image by thresholding
greyscale values
Mapping Gene expression pattern mapped onto
standard EMAP embryo model
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emage edinburgh mouse atlas of gene expression
Section or OPT data is mapped into the 3D space
of the stage matched model Section Data
OPT data
Bmpr1a
Sox9
Brigid Hogan
James Sharpe
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emage edinburgh mouse atlas of gene expression
Single section data
Bmpr1a
Brigid Hogan Yas Furuta
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emage edinburgh mouse atlas of gene expression
Single section data
Bmpr1a
Equivalent section chosen from virtual 3D
model
Brigid Hogan Yas Furuta
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emage edinburgh mouse atlas of gene expression
Single section data
Bmpr1a
Data transfer by warping and subsequent
thresholding
Brigid Hogan Yas Furuta
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emage edinburgh mouse atlas of gene expression
Single section data
Bmpr1a
Brigid Hogan Yas Furuta
Data is held in 3D space
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emage edinburgh mouse atlas of gene expression
Serial section data
Bmp4lacZneo Brigid Hogan
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emage edinburgh mouse atlas of gene expression
Serial section data
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emage edinburgh mouse atlas of gene expression
Serial section data
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emage edinburgh mouse atlas of gene expression
OPT data - 3D warping interface
Fgf8
Diego Aza-Echevarria Salvador Martinez
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emage edinburgh mouse atlas of gene expression
Spatially mapped data is then entered into the
EMAGE interface
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emage edinburgh mouse atlas of gene expression
Spatially mapped data is then entered into the
EMAGE interface
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emage edinburgh mouse atlas of gene expression
Other data entered in EMAGE
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emage edinburgh mouse atlas of gene expression
Other data entered in EMAGE Gene name/symbol
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emage edinburgh mouse atlas of gene expression
The combination of spatial and text based data
types enable searching by both space and text...
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emage edinburgh mouse atlas of gene expression
The combination of spatial and text based data
types enable searching by both space and text...
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emage edinburgh mouse atlas of gene expression
The combination of spatial and text based data
types enable searching by both space and text...
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emage edinburgh mouse atlas of gene expression
The combination of spatial and text based data
types enable searching by both space and text...
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emage edinburgh mouse atlas of gene expression
The combination of spatial and text based data
types enable searching by both space and text...
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emage edinburgh mouse atlas of gene expression
Synexpression
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emage edinburgh mouse atlas of gene expression
Synexpression Gawantka et al, (1998) Mech Dev
7795 - 141 Niehrs Pollet (1999) Nature 402483
- 487
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emage edinburgh mouse atlas of gene expression
Synexpression Gawantka et al, (1998) Mech Dev
7795 - 141 Niehrs Pollet (1999) Nature 402483
- 487 Synexpression Groups Sets of genes
that share a complex spatial expression pattern
(in multiple tissues) and that function in the
same process
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emage edinburgh mouse atlas of gene expression
Synexpression Gawantka et al, (1998) Mech Dev
7795 - 141 Niehrs Pollet (1999) Nature 402483
- 487 Synexpression Groups Sets of genes
that share a complex spatial expression pattern
(in multiple tissues) and that function in the
same process Bmp4 synexpression group
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emage edinburgh mouse atlas of gene expression
Synexpression Gawantka et al, (1998) Mech Dev
7795 - 141 Niehrs Pollet (1999) Nature 402483
- 487 Synexpression Groups Sets of genes
that share a complex spatial expression pattern
(in multiple tissues) and that function in the
same process Bmp4 synexpression group
Onichtchouk et al, Nature (1999) 410480-5
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emage edinburgh mouse atlas of gene expression
Synexpression Fgf8 synexpression group
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emage edinburgh mouse atlas of gene expression
mFgf8 mSpry mSef
zFgf8 zSpry zSef
Synexpression Fgf8 synexpression group
Fürthauer et al (2002) Nat Cell Biol 4 170-174
xFgf8 xFGFRL1
xFgf8 xIsthmin
Hayashi et al (2004) Dev Dyn 230 700-707
Pera et al (2002) Mech Dev 116 169-172
Lin et al (2002) Mech Dev 113 163-168
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emage edinburgh mouse atlas of gene expression
Synexpression Fgf8 synexpression group
Sef
Fgf8
Spry (1-4)
Isthmin?
Fgfrl1
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Searching for simple spatial overlaps
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emage edinburgh mouse atlas of gene expression
Searching for simple spatial overlaps
Database entries
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emage edinburgh mouse atlas of gene expression
Searching for simple spatial overlaps
Query
Database entries
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emage edinburgh mouse atlas of gene expression
Searching for simple spatial overlaps
7
3
7
3
3
3
3
3
Query
Search results for overlap
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emage edinburgh mouse atlas of gene expression
Test Data Set
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emage edinburgh mouse atlas of gene expression
Query Pattern
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emage edinburgh mouse atlas of gene expression
Patterns in the set which overlap with

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emage edinburgh mouse atlas of gene expression
Searching EMAGE for similar spatial patterns
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emage edinburgh mouse atlas of gene expression
Searching EMAGE for similar spatial patterns
A
D
B
C
E
H
F
G
Database entries
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emage edinburgh mouse atlas of gene expression
Searching EMAGE for similar spatial patterns
A
D
B
C
E
H
F
G
Query
Database entries
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emage edinburgh mouse atlas of gene expression
Searching EMAGE for similar spatial patterns
A
C
G
H
most similar
E
B
F
D
Query
no overlap
least similar
Results (ranked by decreasing similarity)
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emage edinburgh mouse atlas of gene expression
Test Data Set
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emage edinburgh mouse atlas of gene expression
Query Pattern
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emage edinburgh mouse atlas of gene expression
Patterns in the set which are similar with

Results (in decreasing spatial similarity)
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emage edinburgh mouse atlas of gene expression
Patterns in the set which are similar with

Query
Emx2 Wnt8b
Wnt7b Pax6
1 (1.0) 2 ( 0.
337) 3 ( 0.287) 4
( 0.248)
Foxg1 Pax1
Bmp7 Otx2
5 (0.239) 6 (
0.218) 7 ( 0.152) 8
( 0.120)
Results (in decreasing spatial similarity)
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emage edinburgh mouse atlas of gene expression
Patterns in the set which are similar with

Query
1 (1.0) 2 ( 0.
337) 3 ( 0.287) 4
( 0.248)
5 (0.239) 6 (
0.218) 7 ( 0.152) 8
( 0.120)
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emage edinburgh mouse atlas of gene expression
Patterns in the set which are similar with

(area intersection / area of union - strong
regions only)
Query
1 (1.0) 2 ( 0.
337) 3 ( 0.287) 4
( 0.248)
query Region (d1)
target Region (d2)
5 (0.239) 6 (
0.218) 7 ( 0.152) 8
( 0.120)
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emage edinburgh mouse atlas of gene expression
Mouse Brain Organization Revealed through Direct
Genome Scale Transcription Factor Expression
Analysis Paul A. Gray1, 3,9, Hui Fu2,3,
Ping Luo1,3, Qing Zhao4, Jing Yu5, Annette
Ferrari3, Toyoaki Tenzen5, Dong-in Yuk4, Eric F.
Tsung6,10, Zhaohui Cai6, John A.
Alberta3, Le-ping Cheng1, 3, Yang Liu1, 3, Jan M.
Stenman5, M. Todd Valerius5, Nathan Billings4,
Haesun A. Kim2,3,11, Michael E. Greenberg8,
Andrew P. McMahon5, David H. Rowitch4,7, Charles
D. Stiles2, 3?, and Qiufu Ma1,3? 1Department
of Neurobiology and 2 Department of Microbiology
and Molecular Genetics, Harvard Medical School,
Boston, MA 02115, USA 3Department of Cancer
Biology and 4Department of Pediatric Oncology,
Dana-Farber cancer Institute, 1 Jimmy Fund way,
Boston, MA 02115, USA 5Department of Molecular
and Cellular Biology, Harvard University, 16
Divinity Avenue, Cambridge, MA 02138,
USA 6Informatics program, 7Division of Newborn
Medicine, and 8Division of Neuroscience,
Childrens Hospital, Boston, MA 02115,
USA 9Present address, Molecular Neurobiology
Laboratory, The Salk Institute, 10010 North
Torrey Pines Rd, La Jolla, CA 92037, USA
10Present address Department of Biology, Boston
College, 140 Commonwealth Avenue, Chestnut Hill,
MA 02467, USA 11Present address, Department of
Biological Sciences, Rutgers University, 101
Warren Street, Newark NJ 07102 These authors
contribute equally to this work. Science,
3062255-7
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emage edinburgh mouse atlas of gene expression
Wholemounts
Jing Yu,
Andy McMahon
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emage edinburgh mouse atlas of gene expression
Wholemounts
Jing Yu,
Andy McMahon
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emage edinburgh mouse atlas of gene expression
McMahon Data
map 1800 patterns perform spatial
comparisons between each pattern then do
hierarchical clustering
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emage edinburgh mouse atlas of gene expression
McMahon Data
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emage edinburgh mouse atlas of gene expression
McMahon Data
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emage edinburgh mouse atlas of gene expression
McMahon Data
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HoxC5
McMahon Data
HoxC5
HoxD3
HoxB7
HoxB7
HoxC8
HoxC8
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emage edinburgh mouse atlas of gene expression
McMahon Data
Oracle1/Ldb3/Cypher
Meox1
myogenin
(myogenic regulatory factors) eg.
myogenin
maintenance of Z-band cypher
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Similarity searching in section data
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emage edinburgh mouse atlas of gene expression
Alx3 Alx4 Bmp4 Bmpr1a Bmpr1b Crabp1 Egr2 Emx1 Emx2
En2 Eya2 Fgf4 Fgf8 Foxc2 Hand1 Hoxa1 Hoxa2 Hoxa3
Hoxb1 Lhx2 Lhx3 Mef2c Msx1 Msx2 Myl2 Ncam1 Nkx2-5
Nmyc1 Nppa Nppb Pax6 Sema3a Shh Six3 Slc2a3 Snai1
Sox2 Sox3 Tcfap2 Titf1 Vax1 Wnt1 Wnt7a
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emage edinburgh mouse atlas of gene expression
Alx3 Alx4 Bmp4 Bmpr1a Bmpr1b Crabp1 Egr2 Emx1 Emx2
En2 Eya2 Fgf4 Fgf8 Foxc2 Hand1 Hoxa1 Hoxa2 Hoxa3
Hoxb1 Lhx2 Lhx3 Mef2c Msx1 Msx2 Myl2 Ncam1 Nkx2-5
Nmyc1 Nppa Nppb Pax6 Sema3a Shh Six3 Slc2a3 Snai1
Sox2 Sox3 Tcfap2 Titf1 Vax1 Wnt1 Wnt7a
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emage edinburgh mouse atlas of gene expression
3D - Searching for simple spatial
overlaps (Pairwise comparison of significant
spatial overlaps based on voxel numbers)
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emage edinburgh mouse atlas of gene expression
3D - Searching for similar spatial patterns
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emage edinburgh mouse atlas of gene expression
3D - Searching for similar spatial
patterns (Pairwise correlations converted to
global Euclidian distances a GLOBAL comparison
of all the data in the set)
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emage edinburgh mouse atlas of gene expression
Clustering using spatial mapping
A
B
pairwise
global
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emage edinburgh mouse atlas of gene expression
Clustering using spatial mapping
A
B
a b g
X Y Z
pairwise
global
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emage edinburgh mouse atlas of gene expression
Clustering using spatial mapping
A
B
a b g
X Y Z
pairwise
global
112
emage edinburgh mouse atlas of gene expression
Clustering using spatial mapping
A
B
a b g
X Y Z
pairwise
global
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emage edinburgh mouse atlas of gene expression
3D - Searching for similar spatial patterns
Global pattern comparison
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emage edinburgh mouse atlas of gene expression
3D - Searching for similar spatial patterns
Global pattern comparison
Crabp1
Egr2
Hoxa3
Hoxa2
Hindbrain Cluster
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emage edinburgh mouse atlas of gene expression
3D - Searching for similar spatial patterns
Global pattern comparison
Vax1
Bmpr1b
Bmpr1a
Titf1
Bmp4
Bmp4
Foxc2
Pax6
Pax6
Eye Cluster
Eya2
Sox2
Six3
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emage edinburgh mouse atlas of gene expression
3D - Searching for similar spatial patterns
Global pattern comparison
Myl2
Nkx2-5
Mef2C
Mef2C
Nppb
Nppa
Heart Cluster
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Curran Data
1 embryo, 2 sections each for 42 genes
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Curran Data
1 embryo, 2 sections each for 42 genes 4800
sections (2400 genes) - currently unannotated
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MRC Human Genetics Unit, Edinburgh EMAGE Yiya
Yang Nick Burton Shanmugasundaram
Venkataraman Lorna Richardson Peter
Stevenson Jeff Christiansen EMAP Margaret
Stark Guangjie Feng Bill Hill Nestor
Milyaev Jianguo Rao Derek Houghton Albert
Burger Ying Cheng Julie Moss Dave Clements Liz
Graham Chris Tindal Allyson Ross Mehran
Sharghi Keo Chanavinout Xinguin Pi Richard
Baldock Duncan Davidson HGU Bioinformatics Phil
lippe Gautier Colin Semple
Division of Biomedical Sciences, University of
Edinburgh Jonathan Bard Matt Kaufman
Mouse Genome Informatics, Jackson
Laboratory Martin Ringwald and the GXD team
genex.hgu.mrc.ac.uk