Mapping the Arab genome

Large-scale genomics and precision medicine are not what most would associate with the Middle East, a region often linked in the media to conflict, oil and desert. However, in the past two decades in the small Arabian Gulf state of Qatar, a sizable investment has been directed toward creating a regional hub — an oasis — for science and innovation, attracting local, regional and international talent to realize this vision. In 2015, the first whole-genome sequencing operation in the region was launched in Qatar to study local and Arab genomes and contribute to the global efforts to unravel the secrets of human genomes at large scale.
“In 2015, the first whole-genome sequencing operation in the region was launched in Qatar to study local and Arab genomes”.

Home to more than 400 million people and situated at the crossroads of the three ‘old’ continents of Africa, Asia and Europe, the Middle East is one of the world’s oldest inhabited regions and one that has contributed immensely to human history. The area of the first human settlements and ancient civilizations was also a focal point for ancient human migrations out of Africa to different parts of our globe. Studying the genomics of inhabitants of this region will add central pieces and clues to the efforts to unravel the full map of the plurality of genomes that define the allelic spectrum of the human race.

Most research performed in the past decades is biased toward European ancestries and those from East Asia. Such ‘Northern’ bias is a result of the overall developmental gap and its economic consequences, leading to a lack of research funds and laboratory infrastructure in the Global South. However, there are a few exceptions whereby some countries within this South can bridge that gap. The Qatar Foundation has created centers of excellence where geneticists from the region who have studied or worked overseas can return and work on bridging the knowledge gaps, capitalizing on their training and exposure gained from time at leading international research institutions. Needless to say, reversing the directional flow of the brain drain is not an easy task. Creating a lush ‘Oasis of Science’ and removing obstacles that could curb the ambitions of returning scientists is proving to be key to the Qatar Foundation’s success story.

The Qatar Genome Program (QGP), a member organization of Qatar Foundation Research, Development and Innovation (RDI), is one of the largest efforts to date launched to fill such knowledge gaps on behalf not only of Qatar but of the whole genomically under-represented Middle East region. The QGP seeks to decipher the genetic makeup of these populations and build a solid foundations for the implementation of precision medicine1. Our database currently contains more than 30,000 whole genomes belonging to Qataris as well as to Arabs from all around the Middle East and North Africa. To produce the first wave of groundwork from these genomes, in 2016 we established the Qatar Genome Research Consortium (QGPRC), encompassing around 200 local scientists and their international collaborators2. The vision of this consortium is to enable researchers to mine the wealth of genomic as well as deep phenotypic data collected by the Qatar Biobank (QBB). We believe that the first step is to produce meaningful and robust research findings and that then we can develop, promote and internationally integrate the new knowledge from this large and ethnically rich region into the knowledge base of the global scientific community. We built the first phase of QGP research projects around ten fundamental research questions spanning the spectrum of rare and common genetic variation and designed around studies leading to translational research and serving the national precision medicine agenda. To promote collaborations and break down silos, we request that all projects have local multi-institutional collaborations, and we also encourage international research partnerships. For example, we signed a Memorandum of Understanding with Genomics England to share knowledge and experience, and many of our researchers joined the Genomics England Clinical Interpretation Partnership (GECIP) domains. We also have onboard in our consortium projects prominent reserachers from Weill Cornell Medicine in New York and the University of Liverpool, to cite just two. Logistically and operationally, we did not reinvent the wheel, having learned from the experience of our colleagues who had initiated their own large-scale national projects ahead of us, such as those in the UK (the UK10K), the Netherlands (the Genome of the Netherlands), Iceland (Genomes of Icelanders) and other countries. In parallel with the consortium, we have established, in collaboration with the Qatar National Research Fund (QNRF;, a genomic research funding scheme called the Path Towards Precision Medicine awards. Conscious that a large-scale genomic program should not focus only on research, we also have other initiatives, which include conducting benchmarking surveys of the general public and healthcare professionals to gauge public awareness and attitudes towards genomic medicine and to identify gaps in the healthcare system before comprehensive implementation3. We have also initiated local graduate programs in genetic counseling and genomic medicine, along with various other educational and awareness schemes1.

We recently published the first wave of founding genomic literature by this consortium, including articles describing the reference genome and population substructures4, the largest Middle Eastern genome-wide association study for 45 clinically relevant traits5, a catalog of medically actionable genomic variants6, the genomic landscape of familial cancers7 and a comprehensive overview of the pharmacogenomic variants in this population8. The growing body of scientific literature that QGPRC is producing will help build a solid understanding of the genomics of this part of the world. To cite a few of the important findings so far: we have characterized a broad spectrum of genetic variation in the Qatari population, with 24.6 million previously unknown variants not present in current databases2. We have identified five non-admixed subclusters in the QGP database4 and found most of the new variants to be cluster specific. In our GWAS study of 45 clinically-relevant quantitative traits, we have replicated many previously known loci and identified 17 novel and Qatari-specific signals across the studied traits5. We have also showed that European-derived polygenic scores have reduced predictive performance when applied to the Qatari population5,7. The availability of electronic health records allowed us to report some key findings related to the medically actionable genetic variants reported by the American College of Medical Genetics and Genomics (ACMG)9: a total of 60 pathogenic and likely pathogenic variants in 25 ACMG disease-associated genes in 141 individuals were identified7. In addition, we characterized a set of novel variants in genes associated with cardiovascular conditions and functionally validated their impact using zebrafish models10. We also provided intriguing insights into the germline predisposition to cancer in the Middle East, observing a high degree of heterogeneity for cancer predisposition genes and cancer-associated polygenic risk scores across ancestries. Next, we looked at pharmacogenomics, which is often considered the poster child for precision medicine given its direct clinical applications. Our findings indicate that 99.5% of the individuals studied have at least one clinically actionable genetic variant with a potential effect on the safety and efficacy of medications. Several of the medications involved are widely prescribed in Qatar and other parts of the world, and our results thus have potential implications for preemptive pharmacogenomic implementation in Qatar and neighboring countries.

In addition to producing large data and conducting comprehensive genomic research, QGP is spearheading the national efforts to pave the way toward making Qatar a regional hub for genomics and precision medicine. We have initiated educational programs to enhance the genomics content in the science curriculum from early to late school years. We arrange school tours to the local DNA museum, which is an interactive purpose-built Qatar Foundation facility providing rich and informative insight into the world of genetics and genomics. We even have a comics series whose main character is a geneticist in a lab coat. We also work with various national stakeholders to produce guiding documents to help prepare all the essential legal and ethical frameworks for the implementation of genomic and precision medicine.

Human civilization has had its fair share of challenges over recent years, but none greater than the COVID-19 pandemic. Because we were ready with genomic and phenotypic data for hundreds of previous participants in our program who caught COVID-19 during first months of the pandemic, we joined the international scientific community in the COVID-19 Host Genetics Initiative to tackle the genetics of COVID-19 and how it affects disease severity11,12. Rarely have thousands of researchers acted on an issue so swiftly and in such an open, collaborative manner. In another effort to increase diversity and the representation of Arab Middle Eastern genomes, we have also joined the Global Biobank Meta-analysis Initiative to empower genetic discoveries with specific phenotypes and across ancestries13. Locally and in the spirit of our overarching national role, the QBB stepped in to support our partners in the response against the pandemic. Together we managed to contribute not only locally but globally to improving understanding of the virus and the disease it causes. We supported the swift sequencing of thousands of viral genomes, as soon as the disease started spreading, for genomic surveillance purposes and made those available to healthcare authorities and the research community14. This resulted in a string of the world’s earliest reports on crucial issues such as reinfection and vaccine efficacy against emerging variants, as well as the waning of their effects over time and the need for boosters15,16,17,18,19.

We think the next few years will be an exciting era for genomics, precision medicine and precision health overall. Several countries have been making rapid progress in establishing national genome projects, and the pandemic served to accelerate this, as well international collaboration.

This genomic revolution presages a post-genomic era of brisk progress. However, we should not forget that the scientific community in this region, like many others in similar places, still faces many challenges. Examples include publication bias, difficulties with recruiting and maintaining talent and, as the case all over nowadays, budget constraints whereby researchers are asked to do more with less.

Even in countries with established research infrastructure, research is receiving less funding and less interest from governments. In countries with developing research infrastructure, with only few exceptions, the picture is, unfortunately, far more grim. It is widely agreed that genomics and precision medicine will revolutionize future healthcare. However, this is not a standard product that can be manufactured around specifics within a producer country and then sold as is to a consumer country: fundamental genomic research work must first be performed before precision medicine initiatives can move into implementation. Young scientists in developing countries are key to achieving this, and they should be supported and celebrated. Money is not the only thing they require, however: they also need connections with established research institutes, more chances for publication in top journals and, very importantly, a helping hand from influential established scientists.

Throughout our journeys abroad, we have indeed ourselves been very lucky to come across world-class scientists who guided and inspired us during our PhD or postdoctoral studies: Francois Cornelis, Yusuke Nakamura, Dorret Boomsma, Alan Kingsman and Edwin Southern, to name a few. These experiences gave us the confidence to move back to Qatar and dare to build things and venture into uncharted territories. The support received from Qatar Foundation leadership, QGP colleagues and the wider local research community was extraordinary. We are happy here and we are committed to our mission.

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