Identification of genetic and epigenetic variations in a rat model for neurodevelopmental disorders.
A combination of genetic variations, epimutations and environmental factors may be involved in the etiology of complex neurodevelopmental disorders like schizophrenia. To study such disorders, we use apomorphine-unsusceptible (APO-UNSUS) Wistar rats and their phenotypic counterpart apomorphine-susceptible (APO-SUS) rats that display a complex phenotype remarkably similar to that of schizophrenic patients. As the molecular basis of the APO-SUS/UNSUS rat model, we recently identified a genomic rearrangement of the Aph-1b gene. Here, we discovered between the two rat lines differences other than the Aph-1b gene defect, including a remarkable cluster of genetic variations, two variants corresponding to topoisomerase II-based recombination hot spots and an epigenetic (DNA methylation) difference in cerebellum and (hypo)thalamic but not hippocampal genomic DNA. Furthermore, genetic variations were found to correlate with the degree of apomorphine susceptibility in unselected Wistar rats. Together, the results show that a number of genetic and epigenetic differences exist between the APO-SUS and -UNSUS rat genomes, raising the possibility that in addition to the Aph-1b gene defect the newly identified variations may also contribute to the complex APO-SUS phenotype.
van Loo
Karen M J
KM
Department of Molecular Animal Physiology, Nijmegen Center for Molecular Life Sciences (NCMLS) & Institute for Neuroscience, Faculty of Science, Radboud University Nijmegen, 282 RT, Geert Grooteplein Zuid 28, Nijmegen, 6525 GA, The Netherlands.
Martens
Gerard J M
GJ
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001483:Base Sequence; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9; D017931:DNA Primers; D004195:Disease Models, Animal; D015321:Gene Rearrangement; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D001523:Mental Disorders / Q000235:genetics*; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D017208:Rats, Wistar; D012559:Schizophrenia / Q000235:genetics
C508903:Aph-1 protein, rat; D017931:DNA Primers; D008565:Membrane Proteins; D001058:Apomorphine