Ontology highlight
ABSTRACT:
PROVIDER: PRJNA786382 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR17138606_1.fastq.gz | Fastqsanger.gz | |||
| SRR17138609_1.fastq.gz | Fastqsanger.gz | |||
| SRR17138610_1.fastq.gz | Fastqsanger.gz | |||
| SRR17138611_1.fastq.gz | Fastqsanger.gz |
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Project description:Targeted DNA sequencing approaches will improve how the size of short tandem repeats is measured for diagnostic tests and pre-clinical studies. The expansion of these sequences causes dozens of disorders, with longer tracts generally leading to a more severe disease. In addition, interruptions are sometimes present within repeats and can alter disease manifestation. Despite advances in methodologies, determining repeat size and identifying interruptions in targeted sequencing datasets remains a major challenge. This is because standard alignment tools are ill-suited for the repetitive nature of these sequences. To address this, we have developed Repeat Detector (RD), a deterministic profile weighting algorithm for counting repeats in targeted sequencing data. We tested RD using blood-derived DNA samples from Huntington’s disease (HD) and Fuchs endothelial corneal dystrophy patients sequenced using either Illumina MiSeq or Pacific Biosciences single-molecule, real-time sequencing platforms. RD was highly accurate in determining repeat sizes of 609 HD blood-derived samples and did not require prior knowledge of the flanking sequences or their polymorphisms within the patient population. We demonstrate that RD can be used to identify individuals with repeat interruptions and may provide a measure of repeat instability within an individual. RD is therefore highly versatile and may find applications in the diagnosis of expanded repeat disorders and the development of novel therapies.
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Project description:Short tandem repeat (STR) instability causes transcriptional silencing in several repeat expansion disorders. In fragile X syndrome (FXS), mutation-length expansion of a CGG STR represses FMR1 via local DNA methylation. Here, we find Megabase-scale H3K9me3 domains on autosomes and encompassing FMR1 on the X-chromosome in induced pluripotent stem cell (iPSC)-derived neural progenitors, B-cells, and fibroblasts with mutation-length CGG expansion. H3K9me3 domains connect via inter-chromosomal interactions and demarcate severe misfolding of TADs and loops. They harbor long synaptic genes replicating at the end of S phase, replication stress-induced double strand breaks, and STRs prone to stepwise somatic instability. CRISPR engineering of the full-mutation CGG to premutation-length reverses H3K9me3 domains on the X-chromosome and multiple autosomes, refolds TADs, and restores expression. H3K9me3 domains also arise in a subset of normal-length iPSCs with increased STR instability burden. Our results reveal Mb-scale heterochromatinization and trans interactions among chromosomes susceptible to repeat genetic instability.
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| EGAD00001005114 | EGA