1. Gene action in a mouse model for Down syndrome Joan T. Richtsmeier Department of Anthropology The Pennsylvania State University http://oshima.anthro.psu.edu

2. Down Syndrome

3. 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

5. Ts1Cje mouse HSA21 MMU16 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 TFF1,2,3 D21S56 CBS CRYA1 PDXK CSTB NNP1 TMEM1 PWP2H C21ORF33 DNM3TL AIRE1 C21ORF2 PFKL TRPC7 KRTAP12-1 SMT3H1 ITGB2 ADARB1 COL18A1 SLC19A1 COL6A1 COL6A2 LSS S100  PRMT2 MMU17 MMU10 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.

6. From Joseph and Dawbarn, Measurement of the Facies (1970)

8. Craniofacial phenotypes in DS and in Ts1Cje mice Consistency (completely penetrant) Correspondence ( due to evolution ) Phenotypes:

10. Obtaining knowledge of gene action through the localization of dysmorphology Msx1 Goosecoid TGF  - 

11. 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…..

12. 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

13. 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?

14. 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.