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We study unusual gene regulatory mechanisms involved in the specification of individual cell type in the nervous and immune systems. We are also beginning to explore the role of epigenetic heritability in complex human diseases.
A major focus is on a class of autosomal genes with properties similar to X-inactivation: random monoallelic expression and asynchronous replication. We have demonstrated that the replication timing of these genes is coordinated at a whole-chromosome level. Thus, there is a randomly determined non-equivalence between the maternal and paternal copy of each autosome. Using molecular biology, microarray technology and informatics we are dissecting underlying mechanisms of monoallelic expression and chromosome-pair non-equivalence.
Another focus is on alternative splicing. The Drosophila Dscam (Down syndrome cell adhesion molecule) gene is essential for axon guidance and has over 38,000 possible alternative splice forms. This extraordinary diversity (encoding immunoglobulin domains) can potentially be used to distinguish cells. Using a custom made microarray we found that each cell type expresses a broad, yet distinctive spectrum of Dscam isoforms. Single cell RT-PCR experiments then showed that individual cells express ~15-50 distinct mRNAs. Thus, each individual cell’s Dscam repertoire is different from those of its neighbors, providing a potential mechanism for the generation of unique cell identity in the nervous system and elsewhere. We are also investigating mammalian genes whose alterative splicing might be used to similarly generate diversity.
Recently, we have begun to exploit the power of the Affymetrix 500,00 SNP genotyping arrays, making modifications that allow us to explore epigenetic differences between alleles. This allows us to explore epigenetic polymorphism across the entire genome, and to investigate the role of epigenetics in complex genetic disease.
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