Strand-seq and the future of personalized genomics

Sequencing the human genome came with the promise of refined risk assessment for heritable diseases, drug responses and other applications of personalized genomics. Genome-wide association studies that linked thousands of genetic alterations to heritable disorders have partially delivered on this promise. However, many patients with rare diseases remain undiagnosed after genome sequencing, in part because conventional sequencing studies struggle to characterize and phase all genomic variation. Chromosome-length phasing, enabled by the single-cell Strand-seq technique in combination with long-read data, has done much to improve the situation. For example, new diploid assembly analyses for personal genomes allow nearly complete descriptions of genomic variation. Moreover, a new Strand-seq-based phasing method can leverage DNA methylation to assign genetic variants not just to haplotypes but to maternally or paternally inherited homologous chromosomes, representing a new frontier in personalized genomics. Here we review the principles and application of Strand-seq, a key enabler of these developments.