Towards population-scale long-read sequencing

• Published in: Nature reviews. Genetics Vol. 22; no. 9; pp. 572 - 587
• Main Authors: De Coster, Wouter, Weissensteiner, Matthias H., Sedlazeck, Fritz J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-09-2021; Nature Publishing Group
• Subjects: 631/114/2785; 631/208/457; 631/61/514; Agriculture; Animal Genetics and Genomics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Computational Biology - methods; Computer applications; DNA sequencing; Gene Function; Genome, Human; Genomics; Genomics - methods; Genotyping; High-Throughput Nucleotide Sequencing - methods; Human Genetics; Humans; Industrial Development - trends; Methods; Nucleotide sequencing; Population; Population genetics; Population studies; Review; Review Article; Reviews; Sequence Analysis, DNA - methods; Belgium
• ISSN: 1471-0056; 1471-0064
• DOI: 10.1038/s41576-021-00367-3

Long-read sequencing technologies have now reached a level of accuracy and yield that allows their application to variant detection at a scale of tens to thousands of samples. Concomitant with the development of new computational tools, the first population-scale studies involving long-read sequencing have emerged over the past 2 years and, given the continuous advancement of the field, many more are likely to follow. In this Review, we survey recent developments in population-scale long-read sequencing, highlight potential challenges of a scaled-up approach and provide guidance regarding experimental design. We provide an overview of current long-read sequencing platforms, variant calling methodologies and approaches for de novo assemblies and reference-based mapping approaches. Furthermore, we summarize strategies for variant validation, genotyping and predicting functional impact and emphasize challenges remaining in achieving long-read sequencing at a population scale.
Long-read sequencing at the population scale presents specific challenges but is becoming increasingly accessible. In this Review, Sedlazeck and colleagues discuss the major platforms and analytical tools, considerations in project design and challenges in scaling long-read sequencing to populations.