Computational Tools for Population-Scale Assembly and Genotyping with Pangenomes

Capturing the full allelic diversity in highly variable regions of the human genome requires large- scale sequencing efforts, yet current approaches face significant cost and privacy-related chal- lenges. The Human Pangenome Reference Consortium (HPRC) aims to expand its pangenome reference to 350 individuals by 2025, but scaling further remains difficult due to the high cost of long-read sequencing and barriers to data sharing across institutions. To address these challenges, our proposal brings together experts in genome assembly, genotyping, and privacy technologies to develop scalable and privacy-preserving methods for pangenome construction and analysis. Our specific aims include: developing co-assembly pipelines that leverage shared genetic variation to enable cost-efficient pangenome assembly from low-coverage sequencing data (Aim 1), creating privacy-preserving tools for utilizing pangenomes together with private or controlled-access data (Aim 2), and building production-grade software and resources to facilitate adoption of our tools by the genomics community (Aim 3). By enabling efficient, secure, and scalable pangenome con- struction, our work aims to accelerate population-scale pangenomics research and improve analysis of complex, multiallelic regions of the human genome. Project Number: 1U01HG014892-01 | Fiscal Year: 2026 | NIH Institute/Center: National Human Genome Research Institute (NHGRI) | Principal Investigator: Hyunghoon Cho | Institution: YALE UNIVERSITY, NEW HAVEN, CT | Award Amount: $1,967,182 | Activity Code: U01 | Study Section: Special Emphasis Panel[ZRG1 MGG-W (50)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11294551