Near-complete Middle Eastern genomes refine autozygosity and enhance disease-causing and population-specific variant discovery
Advances in long-read sequencing have enabled routine complete assembly of human genomes, but much remains to be done to represent broader populations and show impact on disease-gene discovery. Here, we report highly accurate, near-complete and phased genomes from six Middle Eastern (ME) family trios (n = 18) with neurodevelopmental conditions, representing ancestries from Sudan, Jordan, Syria, Qatar and Afghanistan. These genomes revealed 42.2 Mb of new sequence (13.8% impacting known genes), 75 new HLA/KIR alleles and strong signals of inbreeding, with ROH covering up to one-third of chromosomes 6 and 12 in one individual. Using assembly-based variant calling, we identified 23 de novo and recessive variants as strong candidates for causing previously unresolved symptoms in the probands. The ME genomes revealed unique variation relative to existing references, showing enhanced mappability and variant calling. These results underscore the value of de novo assembly for disease variant discovery and the need for sampled ME-specific references to better characterize population-relevant variation.
Authors
- Ahmed El Khouly
- Melanie Tauro
- Francesco Mastrorosa (ORCID: https://orcid.org/0000-0003-0579-1895)
- Fazulur Rehaman Vempalli (ORCID: https://orcid.org/0000-0001-7715-3185)
- Elbay Aliyev (ORCID: https://orcid.org/0000-0002-6469-1854)
- Shermarke Hassan (ORCID: https://orcid.org/0000-0002-5045-636X)
- Rebecca Mathew (ORCID: https://orcid.org/0000-0001-6501-0574)
- Rawan Abouelhassan (ORCID: https://orcid.org/0000-0003-1105-7371)
- Shabir Moosa (ORCID: https://orcid.org/0000-0003-2645-2497)
- William T. Harvey (ORCID: https://orcid.org/0000-0003-0646-7528)
- R. Farhad (ORCID: https://orcid.org/0000-0002-4669-3637)
- Haroon Naeem (ORCID: https://orcid.org/0000-0001-9019-8345)
- Lisa Sara Mathew (ORCID: https://orcid.org/0000-0003-3177-2233)
- Ilhame Diboun
- Kun Wang (ORCID: https://orcid.org/0000-0001-5910-1568)
- Muna Al Hashmi
- Rozaimi Razali (ORCID: https://orcid.org/0000-0002-8996-3975)
- Abdul Rahman Salhab
- Katherine M. Munson (ORCID: https://orcid.org/0000-0001-8413-6498)
- Mohammadmersad Ghorbani
- Zenab Siddig
Institutions
- Qatar Airways (Qatar) (QA)
- Howard Hughes Medical Institute (US)
- University of Washington (US)
- Cornell University (US)
- National Human Genome Research Institute (US)
- Sidra Medical and Research Center (QA)
- Hamad bin Khalifa University (QA)
- Weill Cornell Medical College in Qatar (QA)
- Hamad Medical Corporation (QA)
- Qatar University (QA)
- Qatar Foundation (QA)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-05-01
- DOI
- https://doi.org/10.1038/s41588-025-02173-7
- Citations
- 4
- Primary Topic
- Chromosomal and Genetic Variations
- Type
- article
- Field-Weighted Citation Impact
- 7.00
Funders
- Qatar Foundation
- University of Washington
- Sidra Medicine
- Fonds National de la Recherche Luxembourg
- National Institutes of Health
- Qatar National Research Fund
- National Human Genome Research Institute