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<p>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 (<i>n</i> = 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.</p>

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Near-complete Middle Eastern genomes refine autozygosity and enhance disease-causing and population-specific variant discovery

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月5日

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  • Mohammadmersad Ghorbani,
  • Shabir Moosa,
  • Zenab Siddig,
  • Radi Farhad,
  • Haroon Naeem,
  • William T. Harvey,
  • Francesco Kumara Mastrorosa,
  • Katherine M. Munson,
  • Rozaimi Mohamad Razali,
  • Elbay Aliyev,
  • Ilhame Diboun,
  • Rawan Abouelhassan,
  • Melissa Tauro,
  • Sondoss Hassan,
  • Rebecca Mathew,
  • Muna Al Hashmi,
  • Lisa S. Mathew,
  • Kun Wang,
  • Abdul Rahman Salhab,
  • Fazulur Rehaman Vempalli,
  • Ahmed El Khouly,
  • Said I. Ismail,
  • Wadha Al-Muftah,
  • Radja Badji,
  • Hamdi Mbarek,
  • Dima Darwish,
  • Tasnim Fadl,
  • Heba Yasin,
  • Maryem Ennaifar,
  • Rania Abdellatif,
  • Fatima Alkuwari,
  • Muhammad Alvi,
  • Yasser Al-Sarraj,
  • Chadi Saad,
  • Asmaa Althani,
  • Eleni Fethnou,
  • Fatima Qafoud,
  • Eiman Alkhayat,
  • Nahla Afifi,
  • Wei Liu,
  • Stephan Lorenz,
  • Najeeb Syed,
  • Hakeem Almabrazi,
  • Ramzi Temanni,
  • Tariq Abu Saqri,
  • Mohammedhusen Khatib,
  • Mehshad Hamza,
  • Tariq Abu Zaid,
  • Tushar Pathare,
  • Shafeeq Poolat,
  • Rashid Al-Ali,
  • Omar Albagha,
  • Souhaila Al-Khodor,
  • Mashael Alshafai,
  • Ramin Badii,
  • Lotfi Chouchane,
  • Xavier Estivill,
  • Khalid Fakhro,
  • Jithesh V. Puthen,
  • Karsten Suhre,
  • Zohreh Tatari,
  • Iman Alazwani,
  • Sara Tomei,
  • Khalid A. Fakhro,
  • Alia Satti,
  • Ruba Benini,
  • Arang Rhie,
  • Evan E. Eichler,
  • Younes Mokrab

摘要

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.