A T2T-CHM13 recombination map and globally diverse haplotype reference panel improves phasing and imputation

Area of Science:

• Genomics
• Human Genetics

Background:

• The T2T-CHM13 human reference genome offers improved sequence resolution over GRCh38.
• The utility of complete reference genomes in genetic analysis beyond mapping and variant calling remains to be fully explored.

Purpose of the Study:

• To develop and evaluate a T2T-CHM13-native recombination map and phased haplotype panel.
• To assess the accuracy improvements of this new panel compared to existing GRCh38-based resources.

Main Methods:

• Constructed a T2T-CHM13 phased haplotype panel using 3202 samples from the 1000 Genomes Project (1KGP).
• Compared the T2T-CHM13 1KGP panel against a GRCh38 1KGP phased callset using long-read assemblies as ground truth.
• Evaluated imputation accuracy for Simons Genome Diversity Project samples using both panels.

Main Results:

• Alignment to T2T-CHM13 reduced assembly-discordant genotypes by 38% and switch errors by 16% compared to GRCh38.
• Significant accuracy gains were observed on chromosome X and in regions near copy number variations (CNVs).
• Imputation of Simons Genome Diversity Project samples was more accurate with the T2T-CHM13 panel.

Conclusions:

• A T2T-CHM13-native phased haplotype panel substantially improves statistical phasing and imputation accuracy.
• This enhanced panel benefits the analysis of diverse human populations and complex genomic regions.
• The findings highlight the importance of complete reference genomes for downstream genetic analyses.