Chromosomal fragility may be indicative of altered higher-order DNA organization as the underlying genetic diathesis in complex neurobehavioural disorders.

Preliminary observations concerning increased chromosomal fragility in association with certain behavioural disorders in humans allow an opportunity to suggest a cohesive theory regarding the possible importance of higher-order DNA modification in the coordination of gene function in brain evolution and during development. Visible or submicroscopic acentric chromosomal fragments are formed as an accompaniment to chromosomal breakage and are associated with sequence amplification. During genomic reintegration of such extra chromosomally amplified repeat sequence elements, functional consequences could include unequal crossing over with gain-of-function, and/or deletion with loss-of-function. This process could result in regulatory changes in gene function in association with normal coding regions, since fragile sites appear to be located at or near upstream DNase-I hypersensitive areas. Earlier research on chromosomal breakage in relation to transposon behaviour in maize has set a precedent by which many elements in a network could be coordinately controlled, a principle which may allow transcriptional control over multiple areas in the genome simultaneously. The hypothesis proposed in this paper implies that a small number of fundamental higher order changes may be responsible for influencing a wide range of genetic alterations leading to complex phenotypes, sometimes segregating as distinct entities within pedigrees, or alternatively, and perhaps more commonly, presenting with several overlapping phenotypes in some other families. Current emphasis on the investigation of only pure multiplex families in psychiatric genetics may assist with identification of a number of discrete behaviour-modifying genes, but may not be sufficient for an understanding of the broad underlying genetic diathesis in these, and perhaps other 'multifactorial type' disorders. Validation of a role for altered fragile site expression and the molecular consequences thereof as proposed in this paper may offer additional avenues for gene therapy based either on preferential integration of exogenous DNA at fragile sites, or utilizing the acentric fragments formed during chromosome breakage to modify sequence amplification extrachromosomally.