Genome

Mapping the depths of the Genome

Posted on 2 December 2019

Scientists have recently developed a new technique which combines stem cell, CRISPR/Cas9 and Oxford Nanopore sequencing technology to examine previously inaccessible regions of the genome.

The approach was to find a way that enables determining the length of short tandem repeat (STR) regions, and their epigenetic signature, which had not been possible with conventional sequencing methods. STRs are the cause of many diseases such as Fragile X syndrome; when a repeat sequence expands in the FMR1 gene on the X chromosome, the cell recognises the repetitive region and methylates the gene thus, switches off gene expression. These expansions of DNA repeats are still very difficult to analyse as conventional sequencing methods are limited when it comes to highly repetitive DNA sequences.

In the study, researchers at the Max Planck Institute for Molecular Genetics in Berlin investigated the genome of patient derived stem cells, used the CRISPR/Cas9 system to cut DNA segments from the genome that contained the repeat region and sequenced the genome and epigenome of those segments using Oxford Nanopore, all designed as a single experiment.

Illustration of the CRISPR-Cas target enrichment procedure

‘Pre-sorting’ the molecules (cutting out the regions of interest with CRISPR and preprocessing them) facilitates data analysis, as the sequencing signals are not drowned in the noise of the rest of the genome. However, the researchers had to develop a new algorithm specifically for the interpretation of the electrical signals generated by the repeats.

Most algorithms fail because they do not expect the regular patterns of repetitive sequences.

The researchers envisage many applications for this technique in clinical diagnostics, due to its speed and low cost.


References

  1. New Device Permits a Closer Look at Previously Inaccessible Areas of the Genome: https://www.technologynetworks.com/genomics/news/new-device-permits-a-closer-look-at-previously-inaccessible-areas-of-the-genome-327566
  2. Giesselmann, P., Brändl, B., Raimondeau, E. et al. Analysis of short tandem repeat expansions and their methylation state with nanopore sequencing. Nat Biotechnol 37, 1478–1481 (2019) doi:10.1038/s41587-019-0293-x
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