Envisioning a new era: Complete genetic information from routine, telomere-to-telomere genomes

Abstract

Advances in long-read sequencing and assembly now mean that individual labs can generate phased genomes that are more accurate and more contiguous than the original human reference genome. With declining costs and increasing democratization of technology, we suggest that complete genome assemblies, where both parental haplotypes are phased telomere to telomere, will become standard in human genetics. Soon, even in clinical settings where rigorous sample-handling standards must be met, affected individuals could have reference-grade genomes fully sequenced and assembled in just a few hours given advances in technology, computational processing, and annotation. Complete genetic variant discovery will transform how we map, catalog, and associate variation with human disease and fundamentally change our understanding of the genetic diversity of all humans.

Figure 1

Sequence resolution of complex, biomedically relevant human genetic variation (A) Sequence resolution of LPA, including the region encoding the Kringle IV domain. Gene structure for 20 human haplotypes and 4 chimpanzee haplotypes (PTR and PPA) are shown with haplotypes predicted to be at risk for cardiovascular disease (CVD) and stroke based on the reduced number of Kringle IV domains highlighted in red (adapted from Vollger et al.¹⁹). CN, copy number; NHP, nonhuman primate; pat, paternal; mat, maternal; pri, primary; alt, alternate. (B) Structural differences in the organization of the SMN1 and SMN2 loci revealed by long-read sequence and assembly of two human haplotypes (adapted from Vollger et al.³⁰), which includes an inversion (orange) and ordering of shared segments (blue) across regions enriched with segmental duplications (illustrated as colored arrows with orientation indicated).

Figure 2

A graph-based representation of structural variation of the CYP2D6/D7 locus (A) Genes CYP2D6 and CYP2D7 are annotated on a graph-based representation of the locus (indicated as blue, light blue, and green color blocks). Variable portions are indicated as bubbles. (B and C) Six different paths (starting from red and ending in blue) are depicted (B) based on linear representations (C) of this structurally polymorphic locus from 94 human genomes (adapted from Liao et al.³⁹). The count and frequency of each haplotype is shown in the table.