The haploid genome can be envisioned like a string of pearls –– linear arrays on each chromosome (humans having 22 autosomes plus the X and Y sex chromosomes). Several decades back, it was found that a foreign segment of DNA –– placed randomly where it is not usually found –– will often have a “position effect”, or a “neighborhood effect,” i.e. there can be perturbation of a nearby normal gene’s promoter region, enhancer regions, function and/or inside the gene itself, resulting in up- vs down-regulation, due to unanticipated effects of the newly added foreign DNA segment.
Interpretation of variants of uncertain significance, especially chromosomal rearrangements in non-coding regions of the human genome, remains one of the biggest challenges in modern molecular diagnosis. To improve our understanding and interpretation of such variants, authors [see attached article] used high-resolution three-dimensional chromosomal structural data, plus transcriptional regulatory information, to predict position effects and their association with pathogenic phenotypes in 17 subjects who have apparently balanced chromosomal abnormalities.
Authors found the rearrangements predict disruption of long-range chromatin interactions between several enhancers and genes whose annotated clinical features are strongly associated with the subjects’ phenotypes. Authors confirmed gene-expression changes for a couple of candidate genes –– to exemplify the utility of their analysis of position effect. These findings highlight the important interplay between chromosomal structure and disease and demonstrate the need to use chromatin conformational data, when trying to predict position effects in the clinical interpretation of non-coding chromosomal rearrangements.
Am J Hum Genet Aug 2o17; 101: 206–217