Genetic and Epigenetic Studies in Imprinting Clusters

Jörn Walter
Genetik; Universität des Sarrlandes

To understand the genetic and epigenetic control of imprinted genes in the Beckwith-Wiedemann and Prader-Willi imprinting clusters we have performed comparative sequencing studies between mouse and human and examined methylation profiles within imprinting centers in gametes and during early embryogenesis. On the basis of the comparative sequencing in the BWS cluster we identified several new genes and determined their imprinting status. We observed that imprinting extends beyond the previously defined borders of this cluster. Furthermore the observed similarities and differences between mouse and human provides a basis to locate important genetic elements responsible for the control of local and regional epigenetic events. In our methylation studies were focussed on the three known imprinting centers (ICs) in both clusters. Here we made the surprising observation that important methylation imprints are apparently established around or even after fertilization. We could shown that the maternal to paternal imprint switch in the male germ line in the 15q imprinting centre (IC) must be established post fertilization: Sperm of IC deletion carriers in 15q exhibit a normal unmethylated pattern at several genes in the cluster, although offsprings from these fathers develop Prader-Willi syndrome and have an abnormal methylation on the paternal chromosome. This finding may have profound consequences for the general understanding of imprinting defects associated with change in the epigenotype.