Structural variant discovery in MENA individuals using Oxford Nanopore technology reveals clinically relevant variation | LC26

Abstract
Structural variants (SVs) are a major source of genomic diversity and influence disease susceptibility in humans; however, populations from the Middle East and North Africa (MENA) region remain critically underrepresented in global reference databases. This study provides the first detailed catalogue of structural variations in 61 individuals from diverse MENA countries, using ultra-long Oxford Nanopore sequencing. A scalable and dual-reference alignment-based method was employed to comprehensively detect and characterise SVs in these samples, a method suitable for large-scale population long-read sequencing. A robust multi-caller approach employing CuteSV, Sniffles, SVIM, and Delly was applied to both GRCh38 and T2T-CHM13 reference genomes, requiring consensus from at least three callers to classify SVs as high-confidence true positives. This approach identified 97,765 SVs using GRCh38 and 176,494 SVs using T2T-CHM13, the latter providing improved alignment and variant detection. Significantly, up to 20% of the SVs identified in the MENA population were previously unreported, highlighting the region's uncharted genomic diversity. We identified population-specific variants within genes linked to diseases, pharmacogenetics, and immune responses, including SVs approaching near-fixation within MENA individuals overlapping with Online Mendelian Inheritance in Man (OMIM) exons. This discrepancy poses a substantial risk of systematic clinical misclassification. Additionally, by integrating data from the 1K ONT SV catalogue, alongside chimpanzee and archaic hominin genomes, shared ancient variants were identified, and MENA-specific SVs were highlighted. These findings establish a foundational reference for structural variants relevant to MENA populations, demonstrating that reliance on incomplete or biased genomic databases can hinder accurate variant interpretation and clinical decision-making. The results emphasise the scientific and ethical necessity of enhancing genomic diversity within precision medicine to promote equitable health outcomes worldwide.

Biography
Dr Talal Al-Yazeedi is a PhD-trained geneticist with expertise in genomics, bioinformatics, and long-read sequencing technologies. His research focuses on genome assembly, structural variation, and infectious disease genomics, with applications in both basic research and translational science. He has published multiple peer-reviewed papers and has experience working with human, vector, and pathogen genomes, including mosquitoes, parasites, and wildlife species. Talal is particularly interested in developing cost-effective genomic approaches suitable for large-scale and diagnostic settings, and in applying genomics to disease surveillance, population genetics, and conservation.