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Long-read sequencing provides insights into genetic influence

Nature Reviews Cardiology (2024)Cite this article

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The ideal reference genome for determining causal sources of variation in cardiovascular disease (CVD) is one that is without gaps in sequencing, error-free, and fully annotated with regulatory, coding and non-coding regions. The ability to reconstruct genomes and transcriptomes from short-read DNA or RNA sequences represents a great technological advance from the use of expressed sequence tags, protein sequences and in silico prediction for gene discovery. However, short-read technologies produce sequenced reads that are much shorter than even the median transcript length. As a result, alternative transcription start sites, exon splicing and regions containing tandem repeats remain difficult to characterize. In variant analyses, separating maternally and paternally inherited copies of chromosomes into haplotypes (so-called ‘phasing’) depends on the sequencing of mother–father–child trios.

PacBio HiFi technology assembles DNA or RNA into a circular form by ligation of two hairpin adaptors, upon which DNA polymerase and sequencing primers also attach. The circular library is applied to a single-molecule real-time cell containing tiny wells termed zero-mode waveguides. As DNA polymerase incorporates labelled nucleotides, analysis of emitted light signals produces sequence data. By contrast, ONT sequencing utilizes protein nanopores embedded into a synthetic membrane, through which ionic currents are passed. These currents become disrupted as DNA or RNA molecules are passed through the nanopores, and the disruption of the signal is analysed in real time to determine the sequence of the DNA or RNA passed through.

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Acknowledgements

The author thanks Anne Kwitek (Medical College of Wisconsin) and members of the Rat Genome Database for the opportunity for training, discussion and feedback. The author’s research is supported by a BHF centre of excellence grant (RE18/6/34217–FS/10/56/34893).

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  1. School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK

    Cara Trivett

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  1. Cara Trivett
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Correspondence to Cara Trivett.

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Trivett, C. Long-read sequencing provides insights into genetic influence. Nat Rev Cardiol (2024). https://doi.org/10.1038/s41569-024-01012-2

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  • DOI: https://doi.org/10.1038/s41569-024-01012-2

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