22q11.2 deletion syndrome (22q11DS) results from a hemizygous microdeletion on chromosome 22 and is characterized by extensive phenotypic variability. Penetrance of signs, including congenital heart, craniofacial, and neurobehavioral abnormalities, varies widely and is not well correlated with genotype. The three-dimensional structure of the genome may help explain some of this variability. The physical interaction profile of a given gene locus with other genetic elements, such as enhancers and co-regulated genes, contributes to its regulation. Thus, it is possible that regulatory interactions with elements outside the deletion region are disrupted in the disease state and modulate the resulting spectrum of symptoms. COMT, a gene within the commonly deleted ~3 Mb region has been implicated as a contributor to the neurological features frequently found in 22q11DS patients. We used this locus as bait in a 4C-seq experiment to investigate genome-wide interaction profiles in B lymphocyte and fibroblast cell lines derived from both 22q11DS and unaffected individuals. All normal B lymphocyte lines displayed local, conserved chromatin looping interactions with regions that are lost in atypical and distal deletions, which may mediate similarities between typical, atypical, and distal 22q11 deletion phenotypes. There are also distinct clusterings of cis interactions based on disease state. We identified regions of differential trans interactions present in normal, and lost in deletion-carrying, B lymphocyte cell lines. This data suggests that hemizygous chromosomal deletions such as 22q11DS can have widespread effects on chromatin organization, and may contribute to the inherent phenotypic variability.
Keywords: DiGeorge syndrome; chromosome conformation capture; genome organization; long-range interactions; schizophrenia.