Grant: Project Grant

Twenty years ago, the sequence of the first human genome was completed and became the steppingstone for a revolution in various areas of human genetics and medicine. Over the years, this reference has been incrementally improved but it still contains errors, rare structural configurations that do not exist in most human genomes, and gaps in regions that have been difficult to assemble. There is also a growing appreciation of the importance of diversity and inclusion in human genomics, which has led to widespread calls to improve methods for detecting and characterizing global variation. In short, the human reference genome is overdue for an upgrade. We are part of the Human Pangenome Reference Consortium, which has just released the first human pangenome reference that combines multiple genetically diverse individuals in a graph data structure. We propose to build on these efforts and harness recent developments in long-read DNA sequencing technologies to improve the detection and analysis of variants in two well-characterized human cohorts. We believe that by using a more complete and diverse reference, we will improve genetic analyses and reveal signals of association with human diseases and traits that would have been missed otherwise. This will be especially true in difficult regions of the genome and for under-represented populations.