Approaching an error-free diploid human genome using a support-based validation framework

Public summary

* A new way to verify human genomes: a support-based framework reveals and fixes hidden assembly errors.

* Toward an error-free human genome: T2T-YAO v.2.0 is among the most accurate diploid references to date.

* A more reliable resource for human genomics: a stronger basis for studying diversity and precision medicine.

Abstract

Complete human genomes now resolve regions long inaccessible to genetic analysis, but repetitive and structurally complex sequences remain prone to assembly errors because of limitations in current assembly algorithms. We introduce a support-based framework founded on the principle that each sequencing read provides independent evidence of the underlying genome sequence. Implemented through sufficient alignment support (SAS), the framework identifies regions lacking concordant read support, localizes residual errors, and guides correction. Applying SAS to T2T-YAO, a haplotype-resolved Han Chinese genome, produced a support-validated assembly in which nearly all sequences outside unresolved rDNA arrays and long homopolymer tracts are supported by independent sequencing evidence. This work establishes a systematic framework for genome validation and refinement and provides a support-validated East Asian diploid reference for investigating human genomic diversity.