Computational Prediction of Position Effects of Apparently Balanced Human Chromosomal Rearrangements

Abstract

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, we used high-resolution three-dimensional chromosomal structural data and transcriptional regulatory information to predict position effects and their association with pathogenic phenotypes in 17 subjects with apparently balanced chromosomal abnormalities. We found that 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. We confirm gene-expression changes for a couple of candidate genes to exemplify the utility of our analysis of position effect. These results highlight the important interplay between chromosomal structure and disease and demonstrate the need to utilize chromatin conformational data for the prediction of position effects in the clinical interpretation of non-coding chromosomal rearrangements.

Quantitative prediction of enhancer-promoter interactions

“…Currently, both experimental data describing 3D-genome alterations for known rearrangements and tools modeling spatial landscape of novel variants are limited. In the same time, others 20,21,29,30 and we 31 have recently reported novel variations with unexpected pathological phenotype, which might be explained, at least partially, by changes of chromatin organization 32,33 . Future development and validation of models predicting chromatin contacts in rearranged genome is essential for better understanding of biomedical consequences of these rearrangements.…”

Evolutionary stability of topologically associating domains is associated with conserved gene regulation

“…The disruption of these enclosed regulatory environments enables the recruitment of other cis-regulatory sequences and might prevent formerly established interactions [37]. The detrimental effects of such events have been shown in the study of diseases [32,38]. There are also incidences where pathogenic phenotypes could be specifically attributed to enhancers establishing contacts to promoters that were formerly out of reach because of intervening TAD boundaries [8,9,39].…”

The Iceberg under Water: Unexplored Complexity of Chromoanagenesis in Congenital Disorders

“…49,50 Importantly, TAD structures have been shown to be tightly linked to regulation of gene expression, 50,76-80 as they limit the contacts of enhancers to their specific genes within a defined 3D space. When disturbances of underlying TAD structures occur, long-range position effects of neighboring gene expression have been reported, 56,[81][82][83][84][85][86] mostly attributed to a re-wiring of local regulatory networks delimited by chromosome topology. Position effects in pathogenic genes such as FOXG1, SOX9, and SATB2 have already been observed in connection with congenital complex chromosome rearrangements, 56,84,85 and mis-expression of TWIST1, FOXP1, and DPYD due to lost enhancer interactions upon a chromothripsis event has also been reported in an individual with craniosynostosis, facial dysmorphisms, growth retardation, and intellectual disability.…”

“…When disturbances of underlying TAD structures occur, long-range position effects of neighboring gene expression have been reported, 56,[81][82][83][84][85][86] mostly attributed to a re-wiring of local regulatory networks delimited by chromosome topology. Position effects in pathogenic genes such as FOXG1, SOX9, and SATB2 have already been observed in connection with congenital complex chromosome rearrangements, 56,84,85 and mis-expression of TWIST1, FOXP1, and DPYD due to lost enhancer interactions upon a chromothripsis event has also been reported in an individual with craniosynostosis, facial dysmorphisms, growth retardation, and intellectual disability. 59 We thus hypothesize many chromoanagenesis SVs to have important contributions to clinical phenotypes through long-range position effects, and various tools have been developed to aid in such discoveries that incorporate regulatory and chromatin conformation data.…”