EXAMINING THE RATE, DISTRIBUTION AND IMPACT OF DE NOVO MUTATIONS ON HEALTH AND DISEASE IN QATAR

Abstract

While de novo mutations (DNMs) are key to evolution, they are also responsible for a high number of rare disorders, and thus ascertainment and annotation of DNMs is important to both disease and population genetic studies. Here, we devised and optimized a combinatorial approach comprising three DNM calling tools to improve DNM detection accuracy. For a cohort of 353 unique trio combinations from the Middle East, we found a median of 76 DNMs per individual – 70 single-nucleotide variants and 6 insertions-deletions. We also found that Middle Eastern and Caucasian families have lower DNM rates than the African populations. We examined whether parental consanguinity impacts DNM count but found no significant differences after correcting for paternal age at conception and family size. We also observed that nearly 80% of phased variants are paternal in origin, and that DNMs increase with parental aging. Moreover, we found a significant enrichment of transitions over transversion DNMs, particularly at CpG sites. Examining this further by assessing the role of methylation in DNM development, we found that highly methylated CpG sites are twice more likely to have DNMs than low-methylation sites. By stratifying our cohort based on disease phenotypes, we did not find a significant difference in DNMs by clinical phenotypes versus healthy control siblings, likely owing to the small group sizes for individual clinical conditions. Finally, we identified in one trio a de novo start-loss mutation in the EFTUD2 gene, causing mandibulofacial dysostosis with microcephaly, and validated the effect on gene expression using RNA sequencing of the trio. Altogether, this study serves as a reference for DNM discovery and annotation in hundreds of trios from the globally under-represented populations of the Middle-East, and demonstrates the important role of accurate DNM detection and annotation in solving rare genetic disorders in humans.

Date of Award	2022
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences