ARTICLE Mouse models for the Wolf–Hirschhorn deletion syndrome
Gene action in a mouse model for Down syndrome
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Gene action in a mouse model for Down syndrome Joan T. Richtsmeier Department of Anthropology The Pennsylvania State University http://oshima.anthro.psu. edu
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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. Inconsistent. Consistent. Characteristic facies Alzheimer-like histopathology - PowerPoint PPT Presentation
Transcript of Gene action in a mouse model for Down syndrome
Gene action in a mouse model for Down
syndrome
Joan T. RichtsmeierDepartment of Anthropology
The Pennsylvania State University http://oshima.anthro.psu.edu
Down Syndrome
Down Syndrome Features
Consistent Inconsistent•Characteristic facies •Alzheimer-like histopathology•Brain morphology•Cognitive impairment
•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
• All DS features occur in the population at large
• DS phenotypes are highly variable
Ts1Cje mouse
HSA21
MMU16STCHNCAM2GABPA APPGRIK1SOD1TIAM1CBFA2GARTSONGAS4IFNGR2KCNE1CBR1CBR3C21ORF5KIAA0136CHAF1BCLDN14SIM2HLCSDCRCTTC3DCRADYRK1AKCNJ6KCNJ15ERGETS2DSCR2WDR9HMG14WRBSH3BGRB3GALT5PCP4DSCAMBACE2C21ORF11MX2MX1TMPRSS2
TFF1,2,3D21S56CBSCRYA1
PDXKCSTBNNP1TMEM1PWP2HC21ORF33DNM3TLAIRE1C21ORF2PFKLTRPC7KRTAP12-1SMT3H1ITGB2ADARB1COL18A1SLC19A1COL6A1COL6A2LSSS100PRMT2
MMU17
MMU10
Region of MMU16at 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
•Consistency (completely penetrant) •Correspondence (due to evolution)
Phenotypes:
Obtaining knowledge of gene action through the
localization of dysmorphology
Msx1 Goosecoid TGF-
• 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?
BUT…..
• 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
• 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
Why do we need bioinformatics for this task?
• 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.
