An Icelandic pangenome reference.
basic_science · Level V
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- Record sourced from PubMed, PMID 42618781.
- Also identified by DOI 10.1038/s41586-026-10924-7.
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Abstract
Reference bias is an issue that affects most genomic studies analysing short reads mapped to a reference genome<sup>1,2</sup>. It can be mitigated by mapping to multiple haplotypes represented in a pangenome<sup>3-5</sup>. Here we introduce two new methods to address reference bias: Emblask for pangenome construction and Weaver for mapping to pangenomes at scale. Emblask is a hybrid long- and short-read haplotype-resolved dual assembly pipeline for parent-offspring trio data. Using Emblask, we assembled 698 Icelandic haplotypes and added them to the Human Pangenome Reference Consortium (HPRC) pangenome<sup>4</sup> to construct an Icelandic pangenome reference (HPRC-ICE) including 51.41 million small variants. We mapped the short reads of 57,630 Icelanders to HPRC-ICE with Weaver and called 98.96 million variants, representing a 6.17% increase over mapping to a linear reference. We uncovered new variants in low-mappability regions, including a pathogenic single nucleotide polymorphism (SNP) in GBA1 that associates with early onset Parkinson's disease and a missense SNP in CBS that is pathogenic for homocystinuria. We replicated the GBA1 association in the UK Biobank<sup>6</sup> with a targeted remapping of 429,193 British and Irish participants.