Here, Aaron Wenger, Principal Scientist – Bioinformatics at PacBio (CA, USA), explores how advances in accuracy, throughput and cost are making long-read sequencing more accessible at scale. Advances in genomic sequencing have led to significant gains in our understanding of human, plant, animal and microbial biology. Repeatedly, every technological breakthrough that uncovers new layers of genomic complexity also reminds us how much more remains to be understood. For example, breakthroughs in cytogenetics during the 1950s enabled scientists to visualize whole chromosomes for the first time, but researchers quickly realized that the genomic resolution was low and most variants remained hidden. Over decades, subsequent innovations expanded the depth of biology researchers could study, but the final 8% of the human genome wasn’t resolved until 2022, thanks to advances in software algorithms and whole-genome sequencing (WGS) technologies such as HiFi long-read sequencing. Once reserved for specialist projects, this level of genomic resolution is now becoming accessible at scale as the throughput of long-read sequencing increases and costs decline. Short-read vs long-read sequencing: how do these WGS techniques compare? While both techniques aim to give scientists a view of whole genomes, short-read sequencing lacks the context and completeness of long reads. This is because short-read sequencing splits genomes into fragments of 100-300 base pairs, which provide limited information and require alignment to a reference genome for interpretation. Although effective for identifying single-nucleotide changes and small insertions or deletions, short reads struggle to characterize repetitive or highly variable regions of the genome because…
