Construction and Integration of Three De Novo Japanese Human Genome Assemblies toward a Population-Specific Reference

ABSTRACT The complete sequence of the human genome is used as a reference for next-generation sequencing analyses. However, some ethnic ancestries are under-represented in the international human reference genome (e.g., GRCh37), especially Asian populations, due to a strong bias toward European and African ancestries in a single mosaic haploid genome consisting chiefly of a single donor. Here, we performed de novo assembly of the genomes from three Japanese male individuals using >100× PacBio long reads and Bionano optical maps per sample. We integrated the genomes using the major allele for consensus, and anchored the scaffolds using sequence-tagged site markers from conventional genetic and radiation hybrid maps to reconstruct each chromosome sequence. The resulting genome sequence, designated JG1, is highly contiguous, accurate, and carries the major allele in the majority of single nucleotide variant sites for a Japanese population. We adopted JG1 as the reference for confirmatory exome re-analyses of seven Japanese families with rare diseases and found that re-analysis using JG1 reduced false-positive variant calls versus GRCh37 while retaining disease-causing variants. These results suggest that integrating multiple genome assemblies from a single ethnic population can aid next-generation sequencing analyses of individuals originated from the population.