The long term goal of Project II is to identify genes on mouse Chromosome 16 (Chr16) and human chromosome 21 (HC21) and to determine their contributions to maldevelopment when present at dosage imbalance. Functional analysis of large segments of these chromosomes will be effected by creating defined dosage imbalance in mice, using techniques developed through this program to isolate and modify yeast artificial chromosomes (YACs) and transfer them into murine embryonic stem (ES) cells. Modified ES cells will be analysed for integrity of the YAC- cloned segments. Appropriate lines will be used to make chimeras and thereby transmit YACs into the germ lines of mice, creating """"""""YAC transgenic"""""""" animals with defined segmental aneuploidy. This approach will be used to refine mouse models to trisomy by creating dosage imbalance for genes on distal HC21 that are not represented in Chr16. The effects on development of genes in these segments will be assessed directly and after introduction into partial trisomy 16 mice (Project III). YAC transgenic mice will also be used to evaluate the effects of dosage imbalance for the conserved region of Chr16 and HC21 around the D21S55 locus. This region is associated with many characteristic of DS in """"""""translocation DS"""""""" individuals who exhibit triplication of a subset of HC21 genes. This region is also likely to contain the homolog of the cerebellum observed in DS. Further YAC vector development will be pursued to establish a highly efficient method for identifying genes and mapping exons based on homologous recombination with specially constructed PCR-amplified cDNA libraries; to examine the application of YACs in homologous recombination-based approaches to gene deletion and the use of this approach to creation of segmental monosomy; and to characterize YAC integration sites in mammalian cells.
| Singh, Nandini; Dutka, Tara; Devenney, Benjamin M et al. (2015) Acute upregulation of hedgehog signaling in mice causes differential effects on cranial morphology. Dis Model Mech 8:271-9 |
| Bean, Lora J H; Allen, Emily G; Tinker, Stuart W et al. (2011) Lack of maternal folic acid supplementation is associated with heart defects in Down syndrome: a report from the National Down Syndrome Project. Birth Defects Res A Clin Mol Teratol 91:885-93 |
| Locke, Adam E; Dooley, Kenneth J; Tinker, Stuart W et al. (2010) Variation in folate pathway genes contributes to risk of congenital heart defects among individuals with Down syndrome. Genet Epidemiol 34:613-23 |
| Freeman, S B; Torfs, C P; Romitti, P A et al. (2009) Congenital gastrointestinal defects in Down syndrome: a report from the Atlanta and National Down Syndrome Projects. Clin Genet 75:180-4 |
| Lin, Yan; Tseng, George C; Cheong, Soo Yeon et al. (2008) Smarter clustering methods for SNP genotype calling. Bioinformatics 24:2665-71 |
| Freeman, Sallie B; Bean, Lora H; Allen, Emily G et al. (2008) Ethnicity, sex, and the incidence of congenital heart defects: a report from the National Down Syndrome Project. Genet Med 10:173-80 |
| Parsons, Trish; Ryan, Timothy M; Reeves, Roger H et al. (2007) Microstructure of trabecular bone in a mouse model for Down syndrome. Anat Rec (Hoboken) 290:414-21 |
| Roper, Randall J; St John, Heidi K; Philip, Jessica et al. (2006) Perinatal loss of Ts65Dn Down syndrome mice. Genetics 172:437-43 |
| Maslen, Cheryl L; Babcock, Darcie; Robinson, Susan W et al. (2006) CRELD1 mutations contribute to the occurrence of cardiac atrioventricular septal defects in Down syndrome. Am J Med Genet A 140:2501-5 |
| Richtsmeier, Joan T; Aldridge, Kristina; DeLeon, Valerie B et al. (2006) Phenotypic integration of neurocranium and brain. J Exp Zool B Mol Dev Evol 306:360-78 |
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