Genetic and epigenetic landscape of self-identified Hispanics in All of Us | LC26

Abstract
Hispanic populations in the United States are highly admixed and genetically diverse yet remain underrepresented in genomic studies. To address this, we present the first large-scale nanopore sequencing analysis of 1,490 self-reported Hispanic individuals from the All of Us Research Program, capturing small variants, structural variants, tandem repeats (TRs), and CpG methylation. We characterize global and local ancestry across the cohort, enabling ancestry-aware analysis of genetic and epigenetic features. Over 10.3 million previously unknown autosomal variants are identified, including medically relevant alleles stratified by local ancestry and pathogenic risk revealing 402 carriers with potential risk for subsequent generations. We discover 135 individuals with TR alleles exceeding established pathogenic ranges and conduct the first genome-wide tandem repeat methylation quantitative trait loci (TR-mQTL) analysis, identifying 3,329 TR alleles associated with methylation. Allele-specific methylation (ASM) is resolved at >12,000 loci per genome and 24 novel recurrent ASM loci are identified. This includes ancestry specific regulatory activity such as activation of paralogous genes driven by ancestry-enriched variants and epigenetic markers. These findings establish a foundational resource for biomedical research and highlight the critical role of ancestry-aware analyses in understanding gene regulation, disease risk, and personalized medicine.

Biography
Dr Fritz Sedlazeck is an Associate Professor at Baylor College of Medicine and an adjunct Associate Professor at Rice University. He has led a research group at the Human Genome Sequencing Center at Baylor since 2018, where his work has become central to advancing bioinformatics approaches for the detection and analysis of genomic variation, particularly structural variants (SVs). These complex genomic events span multiple positions in the genome and are critical to understanding evolution, disease mechanisms, gene regulation, and phenotypic diversity. Fritz is widely recognized for developing cutting-edge computational tools, including the popular Sniffles SV caller, and for his leadership in benchmarking methods to ensure robust and reproducible variant detection. His group has been instrumental in uncovering the mechanisms of SV formation across species and in diverse human populations, participating in major international efforts such as Trans-Omics in Precision Medicine (TOPMed), Centers for Common Disease Genomics (CCDG), Center for Alzheimer's and Related Dementias (CARD), and All of Us. Through this work, he has helped set standards for the field while deepening our understanding of how complex alleles evolve and contribute to human biology.