Down syndrome (DS) occurs as a result of Trisomy 21 and is among the most complicated genetic conditions compatible with human survival. The Reeves laboratory complements genetic analyses in human beings with the creation and characterization of mouse models to understand why and how gene dosage imbalance disrupts development in DS. The models then provide a basis to explore therapeutic approaches to amelioration of DS features. We use chromosome engineering in ES cells to create defined dosage imbalance in order to localize the genes contributing to these anomalies and to test directly hypotheses concerning Down syndrome "critical regions" on human chromosome 21. Quantitative phenotypic assays that we have developed give a precise and sensitive readout of the relative effects on phenotype when overlapping subsets of genes are at dosage imbalance. Developmental analyses of these traits are underway to identify the timing and location of divergence between trisomic and euploid fetuses. We have used mouse models to :

1. validate epidemiological findings suggesting a lower incidence of cancer in Down syndrome and to identify the candidate genes (Sussan et al., 2008);
2. identify direct parallels in the development of the craniofacial skeleton in Down syndrome and trisomic mice (see Hill et al., 2007);
3. establish a deficit in cranial neural crest as the (initial) basis for the hypomorphic craniofacial skeleton;
4. discover the basis for and potential “treatment” of a fundamental structural deficit in the trisomic brain (Roper et al., 2006; Reeves and Garner, 2007).

Definition of the timing and location of divergence between trisomic and euploid phenotypes and of the gene(s) primarily contributing to those differences provides the necessary basis for genetic, pharmacologic and stem cell therapies to ameliorate these anomalies (Roper and Reeves, 2006).

Genetic modifiers of Down syndrome features

Many features of Down syndrome have highly variable severity in different individuals with trisomy 21. In a multi-Institute collaboration we have combined genetic analysis of patient samples, candidate gene sequencing and mouse modeling to identify genetic modifiers producing congenital heart disease in human beings (DS Heart Project). The study is based on the 2000x elevation of complete AV canal or AVSD in Down syndrome. CHD is the most frequent birth defect in human beings regardless of ploidy. The increased “signal-to-noise” ratio for gene expression effects in Down syndrome will contribute to understanding and treatment of congenital hear disease in all people.

An analogous genetic approach is being used to study genetic modifiers that contribute to several common features of Down syndrome, including variable cognitive ability, sleep apnea and craniofacial dysmorphology.

Inflammatory response

In addition, we collaborate with Dr. Antonio DeMaio, UCSD (http://drdemaio.ucsd.edu/Home/tabid/36/Default.aspx), using genetic approaches in cell culture, mouse and human to understand the basis for the improperly regulated inflammatory response that causes multiple organ dysfunction syndrome (MODS), the leading cause of death in surgical intensive care units.