The impact of long-read sequencing on human population-scale genomics

Abstract

Long-read sequencing technologies, particularly those from Pacific Biosciences and Oxford Nanopore Technologies, are revolutionizing genome research by providing high-resolution insights into complex and repetitive regions of the human genome that were previously inaccessible. These advances have been particularly enabling for the comprehensive detection of genomic structural variants (SVs), which is critical for linking genotype to phenotype in population-scale and rare disease studies, as well as in cancer. Recent developments in sequencing throughput and computational methods, such as pangenome graphs and haplotype-resolved assemblies, are paving the way for the future inclusion of long-read sequencing in clinical cohort studies and disease diagnostics. DNA methylation signals directly obtained from long reads enhance the utility of single-molecule long-read sequencing technologies by enabling molecular phenotypes to be interpreted, and by allowing the identification of the parent of origin of de novo mutations. Despite this recent progress, challenges remain in scaling long-read technologies to large populations due to cost, computational complexity, and the lack of tools to facilitate the efficient interpretation of SVs in graphs. This perspective provides a succinct review on the current state of long-read sequencing in genomics by highlighting its transformative potential and key hurdles, and emphasizing future opportunities for advancing the understanding of human genetic diversity and diseases through population-scale long-read analysis.