Profiling human pathogenic repeat expansion regions by synergistic and multi-level impacts on molecular connections

Abstract

Abstract Background and Motivation: Whilst DNA repeat expansions cause numerous heritable human disorders, their origins and underlying pathological mechanisms are often unclear.Method: We collated a dataset comprising 224 human repeat expansions encompassing 203 different genes, and performed a systematic analysis with respect to key 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 model to discriminate repeat regions harboring pathogenic repeat expansions (DPREx).Results: 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 not significantly different in introns, 3’UTRs and 3’genes than controls. At the RNA-level, pathogenic repeat expansions showed 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 preferred to form coil than other types of secondary structures, and tended to encode surface-located protein domains. Additionally, pathogenic repeat expansions were also enriched in non-B DNA structures. Guided by these features, DPREx (http://biomed.nscc-gz.cn/zhaolab/geneprediction/#/) achieved an Area Under the Curve (AUC) value of 0.88 in an independent dataset test. Conclusion: Pathogenic repeat expansions are located so as to exert a synergistic, multi-level influence on stress responses and inter-molecular connections involving DNA, RNA and proteins, thereby impacting the relationship between genotype and clinical phenotype.