Chromosomal fragility, structural rearrangements and mobile element activity may reflect dynamic epigenetic mechanisms of importance in neurobehavioural genetics.
Advances in human genome analyses have not yet allowed identification of specific genetic mechanisms underlying the expression of human neurobehavioural disorders. There is an increasing awareness that several genes may contribute to behavioural phenotypes and these genes appear to interact in as yet undetermined ways. It has been suggested that the problem needs elucidation from an epigenetic, gene expression perspective. Cytogenetic instability manifesting as chromosomal fragile sites, translocations, duplications, deletions and inversions, when co-occurring with neurobehavioural disorders, may offer a doorway to the investigation of such chromatin level, regulatory region, epigenetic processes. Due to earlier indications of non-specificity of chromosomal aberrations, poor phenotype:genotype correlations and a shift to analysing candidate coding regions on high resolution map level, the only utility of chromosomal breakpoints came to be seen as harbouring possible candidate genes of interest when segregating together with particular neurobehavioural disorders. More recent findings of the expression of highly specific subsets of fragile sites in association with Tourette and Rett syndromes need to be extended to other neurobehavioural disorders to ascertain whether observed patterns can be considered representative of 'chromatin endophenotypes' correlating with discrete sets of neurobehavioural symptoms. Environmental/epigenetic factors could affect the chromatin characteristics of the genome arising through DNA strand breakage, mobile element activity and retroinsertion, establishing new architectural features of regulatory control networks very rapidly in comparison to coding region evolution rates. Microarray-based techniques for the genome-wide mapping of in vivo protein-DNA interactions offer increasingly comprehensive views of genetic and epigenetic regulatory networks. It may be informative to include functionally significant chromatin structural variation analyses when considering candidate genes for neurobehavioural disorders.
Gericke
G S
GS
Genetics Division, Ampath National Pathology Laboratories, P.O. Box 2040, Brooklyn Square, 0075 Pretoria, Gauteng, South Africa. gerickegs@webmail.co.za
D002453:Cell Cycle; D002843:Chromatin / Q000235:genetics; D043283:Chromosome Fragile Sites; D004249:DNA Damage; D005809:Genes, Regulator; D005824:Genetics, Behavioral; D006801:Humans; D014158:Transcription, Genetic
D002843:Chromatin