Transcript Developmental instability in a mouse model for Down syndrome

Gene action in a
mouse model for Down
syndrome
Joan T. Richtsmeier
Department of Anthropology
The Pennsylvania State University
http://oshima.anthro.psu.edu
Down Syndrome
Down Syndrome Features
Consistent
•Characteristic facies
•Alzheimer-like histopathology
•Brain morphology
•Cognitive impairment
Inconsistent
•Heart defects
50%, clinical problem
AVSD, 20%
outflow tract
•Hirschprung’s disease (3-5%)
•Increased incidence of leukemia
(15-100x)
•Dermatoglyphic features
•Hypotonia
•Atlanto-axial instability
• DS phenotypes are highly variable
• All DS features occur in the population at large
MMU16
HSA21
MMU17 TFF1,2,3
MMU10
D21S56
CBS
CRYA1
PDXK
CSTB
NNP1
TMEM1
PWP2H
C21ORF33
DNM3TL
AIRE1
C21ORF2
PFKL
TRPC7
KRTAP12-1
SMT3H1
ITGB2
ADARB1
COL18A1
SLC19A1
COL6A1
COL6A2
LSS
S100b
PRMT2
STCH
NCAM2
GABPA
APP
GRIK1
SOD1
TIAM1
CBFA2
GART
SON
GAS4
IFNGR2
KCNE1
CBR1
CBR3
C21ORF5
KIAA0136
CHAF1B
CLDN14
SIM2
HLCS
DCRC
TTC3
DCRA
DYRK1A
KCNJ6
KCNJ15
ERG
ETS2
DSCR2
WDR9
HMG14
WRB
SH3BGR
B3GALT5
PCP4
DSCAM
BACE2
C21ORF11
MX2
MX1
TMPRSS2
Ts1Cje mouse
Region of MMU16
at dosage
imbalance in
Ts1Cje mice. This
segment spans
10.3 Mb and
contains 89 of the
225 genes in the
Chr21 gene
catalogue.
From Joseph and Dawbarn, Measurement of the Facies (1970)
Craniofacial phenotypes in
DS and in Ts1Cje mice
Phenotypes:
•Consistency (completely penetrant)
•Correspondence (due to evolution)
Obtaining knowledge of gene
action through the
localization of dysmorphology
Msx1
Goosecoid TGFb-2
BUT…..
• What if the genes known to affect particular
features of the skull and brain are NOT the
genes on the segment of dosage imbalance?
• What if the genes at dosage imbalance
APPEAR to have little to do with the head
at all?
• How else might we determine the role of
the genes at dosage imbalance in the
production of defined dysmorphology?
• How can bioinformatics be used to do this?
• Identify the genes at dosage imbalance (this
is done)
• Use data on gene ontology* and expression
for these genes and try to EXCLUDE those
that do not appear to have a role in brain or
skull development. This approach should
substantially reduce the number of genes on
the segment at dosage imbalance that
should be considered as contributors to
craniofacial variation in DS.
*ontology = molecular function and/or biological process of a gene
Why do we need bioinformatics for this task?
• Contribution to craniofacial variation does
not have to be a direct involvement but can
implicate genes that might be responsible
due to their interaction with triplicated
genes. This means that we will need to look
at gene networks.
• We need web-based knowledge of the genes
at dosage imbalance in the Ts1Cje model
• One idea is to use the Gene Ontology data
base of integrated information under a set of
structured vocabularies to closely examine
the function and interactions of the genes on
the Ts1Cje segment. There are 89 of
them…..the GO vocabularies focus on
molecular function, biological process and
cellular components.