Research co-led by King's College London and Sidra Medicine, Qatar, has produced the most detailed map to date of large-scale genetic differences in the Qatari population, providing a clearer picture of the genetic diversity of Arabs and the relationships between genetic variations and health and disease.
Over the past decade, scientists have built large global databases of human genomes. However, people of Arab ancestry remain significantly under-represented, meaning important genetic differences in these populations are not well understood. This creates gaps in global research and risks making future genetic-based healthcare less accurate for these communities.
Most earlier studies of Qatari genomes focused on small changes in the DNA sequence that involve one or a few "letters" of the genetic code. While these are important, they only reveal a small part of the picture. The new research, published in Nature Communications, represents the first thorough examination of structural variants, which are large-scale changes in DNA that affect long stretches of genetic material that can be missing, duplicated, or rearranged. Because of their size, these structural variants affect much more of the genome, making them highly relevant to human health.
To study these larger DNA changes, the researchers analysed more than 6,000 Qatari genomes. This allowed them to see where these variants occur, how common they are across the five main Qatari sub-population groups, and how they relate to health information from the Qatar Biobank, including blood and metabolic measures.
The analyses revealed over 150,000 structural variants within the study population, with over 12,000 of these affecting regions of DNA within genes that carry the instructions for making proteins. Notably, many of these genes are involved in biological processes related to cardiometabolic health and diabetes, aligning with the elevated prevalence of metabolic and cardiovascular diseases in the study population.
Structural variants have an important impact on human biology, but they've been largely understudied in global genomics because they're hard to detect. We've created the most detailed map of these variants in the Arab population. This gives us a much clearer view of genetic diversity in the region and paves the way for precision medicine.
Dr Mario Falchi, Reader in Computational Medicine at King's and co-senior author of the paper
'A unique global resource'
High levels of consanguinity - marriage between related individuals - offers a unique opportunity to examine the impact of inheriting deletions of pieces of DNA from both parents. The researchers uncovered more than 180 genes that had lost their function completely or been "knocked out" as a result of inheriting the same deletion from both parents. The team showed that when certain genes are completely switched off, the proteins they normally produce are missing from the bloodstream.
One notable example involved a gene called CD36, where individuals who inherited the same DNA deletion from both parents had little to no CD36 protein in their blood, alongside clear changes in blood-related health markers. This confirms that these deletions are functionally active, i.e. they directly impact protein production in individuals who carry the deletion.
However, there were certain regions of the genome where the loss of both copies of DNA was not seen, despite the frequency of people in the population who carried the same deletion. This suggests that maintaining at least one copy of these segments of DNA may be essential for human survival.
These findings highlight the value of studying consanguineous populations to better understand how genetics can influence human health, something that is much harder to do in populations where family relationships are more distant.
Mr Elbay Aliyev, first author of the study from Sidra Medicine said: "The study adds a previously missing layer of insight to global genetics research. By producing the most comprehensive map of structural variants in any Arab population, it supports global efforts to make precision medicine more inclusive and accurate. This provides the foundations for future research into rare diseases, inherited conditions and population-specific health risks that cannot be uncovered focusing only on small, single-letter changes in DNA."
Professor Khalid Fakhro, Chief Research Officer and Lead Principal Investigator of the research study at Sidra Medicine, said: "Not only have we unveiled the most comprehensive map to date of structural variants from an Arab population, but we have also leveraged extensive biobank traits to link these to health and diseases. This work is presented both as a unique global resource for anyone studying the genetics of Arab ancestries around the world, and as a demonstration of the importance of consanguineous populations in improving our understanding of the human genome. We look forward to expanding these studies to tens of thousands of Qatari genomes in the next phase, and to contribute to global efforts in genetic mapping and population-scale health discovery."
The Qatar Genome Programme has played a pioneering role in ensuring that Arab genomes are included in global genomic databases with detailed health information from more than 40,000 Qataris, collected through the Qatar Biobank, alongside large-scale genomic data from programme participants.
The research was funded by the Qatar Research, Development and Innovation Council.
