Integrative Computational Analyses Implicate Regulatory Genomic Elements Contributing to Spina Bifida

Authors

Paul Wolujewicz
Vanessa Aguiar-Pulido
Gaurav Thareja
Karsten Suhre
Olivier Elemento
Richard H Finnell
M Elizabeth Ross

Publication Date

1-1-2024

Journal

Genetics in Medicine Open

DOI

10.1016/j.gimo.2024.101894

PMID

39669613

PMCID

PMC11613821

PubMedCentral® Posted Date

9-14-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Deep learning, Intergenic variants, Neural tube defects, Topologically associating domains (TADs), Transcription factor binding sites (TFBS)

Abstract

PURPOSE: Spina bifida (SB) arises from complex genetic interactions that converge to interfere with neural tube closure. Understanding the precise patterns conferring SB risk requires a deep exploration of the genomic networks and molecular pathways that govern neurulation. This study aims to delineate genome-wide regulatory signatures underlying SB pathophysiology.

METHODS: An untargeted, genome-wide approach was used to interrogate regulatory regions for rare single-nucleotide and copy-number variants (rSNVs and rCNVs, respectively) predicted to affect gene expression, comparing results from SB patients with healthy controls. Qualifying variants were subjected to a deep learning prioritization framework to identify the most functionally relevant variants, as well as the likely target genes affected by these rare regulatory variants.

RESULTS: This ensemble of computational tools identified rSNVs in specific transcription factor binding sites (TFBSs) that distinguish SB cases from controls. rSNV enrichment was found in specific TFBSs, especially CCCTC-binding factor binding sites. These TFBSs were subjected to a deep learning prioritization framework to identify the most functionally relevant variants, as well as the likely target genes affected by these rSNVs. The functional pathways or modules implicated by these regulated genes serve protein transport, cilia assembly, and central nervous system development. Moreover, the detected rare copy-number variants in SB cases are positioned to disrupt gene regulatory networks and alter 3-dimensional genomic architectures, including brain-specific enhancers and topologically associated domain boundaries of relevant cell types.

CONCLUSION: Our study provides a resource for identifying and interpreting genomic regulatory DNA variant contributions to human SB genetic predisposition.

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