What question did this study set out to answer?

To assess the recovery of African Pan-Genome sequences missing from GRCh38 and their functional relevance.

April 19, 2026Cancer Research0 citations

Abstract SY38-01: Gapless but Not Global: Ancestry-Enriched Functional Sequence Still Missing from Human Reference Genomes

Key Points

To assess the recovery of African Pan-Genome sequences missing from GRCh38 and their functional relevance.
Evaluated ∼296.5 Mb of African Pan-Genome contigs absent from GRCh38.
Aligned contigs to T2T-CHM13 and Human Pangenome Reference Consortium assemblies.
Analyzed mapping patterns and functional annotations related to immune loci and GWAS traits.
∼40% of contigs aligned to T2T-CHM13 and ∼83% to HPRC assemblies, confirming sequences as human origins.
742 contigs did not map to any reference but contained important coding and regulatory features.
Missing sequences disproportionately affect patients of African descent, impacting precision oncology efforts.

Abstract

Abstract Precision oncology depends on accurate read alignment, variant calling, and transcriptomic profiling - all of which inherit the biases of the reference genome used for analysis. Despite the availability of gapless Telomere-to-Telomere (T2T-CHM13) and Human Pangenome Reference Consortium (HPRC) assemblies, the field overwhelmingly relies on GRCh38, a reference that underrepresents global genomic diversity, particularly African diversity. We systematically evaluated ∼296. 5 Mb of African Pan-Genome (APG) contig sequences absent from GRCh38 to determine how much is recovered by modern references and whether the missing content is functionally relevant. While ∼40% of contigs aligned to T2T-CHM13 and ∼83% to at least one HPRC assembly, confirming them as authentic human sequence. Ancestry-associated mapping patterns, overlap with immune/HLA loci, OMIM genes and GWAS loci, demonstrate that missing reference sequence is not functionally trivial. Most notably, a subset of 742 contigs failed to map confidently to any current reference yet were not repeat-enriched and contained predicted coding and regulatory features with transcriptional evidence in two breast cancer cohorts. These findings demonstrate that reference bias is not merely a technical limitation but a mechanism by which clinically relevant genomic variation is systematically excluded from discovery, disproportionately affecting patients of African descent. Integrating ancestry-enriched sequence into population-aware reference frameworks is essential to improve variant detection, biomarker generalizability, and the equitable reach of precision oncology. Citation Format: Nyasha Chambwe. Gapless but Not Global: Ancestry-Enriched Functional Sequence Still Missing from Human Reference Genomes abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr SY38-01.

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