Faculty, Staff and Student Publications
Publication Date
2-1-2023
Journal
Human Genetics
DOI
10.1007/s00439-022-02500-6
PMID
36344696
PMCID
PMC10290229
PubMedCentral® Posted Date
2-1-2024
PubMedCentral® Full Text Version
Author MSS
Abstract
Whilst DNA repeat expansions cause numerous heritable human disorders, their origins and underlying pathological mechanisms are often unclear. We collated a dataset comprising 224 human repeat expansions encompassing 203 different genes, and performed a systematic analysis with respect to key topological features at the DNA, RNA and protein levels. Comparison with controls without known pathogenicity and genomic regions lacking repeats, allowed the construction of the first tool to discriminate repeat regions harboring pathogenic repeat expansions (DPREx). At the DNA level, pathogenic repeat expansions exhibited stronger signals for DNA regulatory factors (e.g. H3K4me3, transcription factor-binding sites) in exons, promoters, 5'UTRs and 5'genes but were not significantly different from controls in introns, 3'UTRs and 3'genes. Additionally, pathogenic repeat expansions were also found to be enriched in non-B DNA structures. At the RNA level, pathogenic repeat expansions were characterized by lower free energy for forming RNA secondary structure and were closer to splice sites in introns, exons, promoters and 5'genes than controls. At the protein level, pathogenic repeat expansions exhibited a preference to form coil rather than other types of secondary structure, and tended to encode surface-located protein domains. Guided by these features, DPREx ( http://biomed.nscc-gz.cn/zhaolab/geneprediction/# ) achieved an Area Under the Curve (AUC) value of 0.88 in a test on an independent dataset. Pathogenic repeat expansions are thus located such that they exert a synergistic influence on the gene expression pathway involving inter-molecular connections at the DNA, RNA and protein levels.
Keywords
Humans, DNA Repeat Expansion, Introns, DNA, RNA, Trinucleotide Repeat Expansion, repeat expansions, DNA structure, inherited disorders, genome instability, DNA repair, genome evolution, RNA splicing, gene expression, intrinsically disordered regions
Published Open-Access
yes
Recommended Citation
Fan, Cong; Chen, Ken; Wang, Yukai; et al., "Profiling Human Pathogenic Repeat Expansion Regions by Synergistic and Multi-Level Impacts on Molecular Connections" (2023). Faculty, Staff and Student Publications. 2807.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/2807
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