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Q&A: Kuwait University's Fahd Al-Mulla on Genome Arabia and Genomics in the Middle East


DrFahd.jpgName: Fahd Al-Mulla

Title: Head of Molecular Pathology, Kuwait University

Education: PhD and MBChB, Glasgow University, UK

"Genome Arabia, At Last," was the title of Fahd Al-Mulla's talk at the joint Human Genome Meeting and International Congress of Genetics, held earlier this month in Singapore. According to Al-Mulla, Southwest Asian populations have to date been left out of most efforts to catalog human genetic variation, from the Human Genome Project to the 1000 Genomes Project.

To remedy this gap, Al-Mulla has teamed up with researchers from seven countries in the Middle East to sequence up to 500 individuals, obtaining data that will be used to build future generations of genotyping arrays optimized for studying Middle Eastern populations (see related story, this issue). The Qatar National Research Foundation in November awarded the group $1.1 million to commence the project, which is called Genome Arabia, and Al-Mulla said it will soon add new countries and obtain more funding.

At the conference, Al-Mulla spoke with BioArray News about Genome Arabia and the challenges of undertaking genomic research and medicine in a region where many are reluctant to share the genetic codes of the local populations with the outside world. Below is an edited transcript of that interview.

You called your talk 'Genome Arabia, At Last.' How long have you been working toward this project?

I wanted to make a statement, and the statement is that the Arabian genome has been ignored by everybody. The Human Genome Project had Nigerians, Chinese, Caucasians, Japanese, [but] no Arabs. Then there was the HapMap, but there was nothing about Arabs. Then there was HapMap II and III, and there was nothing about Arabs. In 2000, I introduced genetics and genomics to the pathology field in the form of a laboratory based at the Faculty of Medicine in Kuwait University. The laboratory specializes in molecular diagnostics and theranostics. In a few years, I started to find new DNA changes and I did not know if they were causative of the disease or are common in our population. Therefore, I decided to look closely and initiated [Genome Arabia] with my colleagues.

Why do you think that these earlier projects ignored Middle Eastern populations?

We can postulate that researchers were contacted but they did not answer or had little funding for this or had poor research facility infrastructures to contribute meaningfully. I have also heard, [but] don't believe, that there could have been a politically motivated intention not to study the Arab genome on the fear, that if they know about us, they can make SNP-specific weapons. I think this has its roots in the idea of germ-specific warfare. It probably had its origin in Egypt in the 1970s and 1980s, that Israel might deploy something like that.

In the Arab world, there is something that is sacred about the genome, that we shouldn't share it because people will use it against us. And policymakers, decision makers in our governments, are not well-read and they are ill-advised. This is across the region. And so it has been difficult to obtain funding. While people in the West invest, our policymakers think about short-term gains. This is the culture. Building a concrete building gives you rent and makes you money within a few years. A science project is risky and long-term, and therefore is likely avoided. My job is to change these points of view and demonstrate to the policymakers that without knowing our genetic variations, it will be impossible to practice evidence-based medicine now and in the future.

At the same time, you said there is a need for these kinds of projects, especially in the Middle East, because of the high-rate of consanguinity.

I think the statistic that 50 to 70 percent of marriages are between first cousins has been published, and it is variable, but it is not theoretical, it is a fact. In some areas, you will find it lower, maybe 25 percent, but in Saudi Arabia, Kuwait, United Arab Emirates, you will find it as high as 75 percent of marriages. This means that, at one particular time, you are going to share the genetic material from your ancestor. You and your cousin already share this material, but now a child is going to get one chromosome from this ancestor through the father and the same chromosome from his ancestor through his mother. At one point, he or she is going to have what we call a homozygosity stretch, which means the two sequences on both alleles of a chromosome have exactly the same DNA sequence. There is no variation. It is the same sequence. It is most likely that the genetic causes of diseases lie in these regions and we can find the genes associated with these diseases and Mendelian inheritance. If something is inherited in an autosomal recessive manner, it is more likely that when you marry your cousin one in four of your children will be affected, one in four will be normal, and two in four will be carriers. And so, at one point in time, you will realize that a lot of your population is carrying this disorder. So, that is the immediate impact [in terms of the] expression of the genetic diseases.

I think about this differently. I think this may have some benefit in the long run because it [enables] natural selection. In one way, it gives researchers the opportunity to identify a gene associated with a disease. And, in the long term, if you model this with a computer, over thousands of years, these harmful gene mutations may disappear from the population. We see this in the lack of BRCA 1 and 2 mutations in breast cancers in our women. Another example is cystic fibrosis, which is an autosomal recessive disease. Why isn't it common in Kuwait?

Do you have good quality records so that you can trace certain diseases?

Yes, we have good quality records, and these can be found in the Center for Arab Genomic Studies, CAG, [the council] of which I am a member. CAG, which is based in Dubai, UAE, decided to gather the scientists and database all of the genetic mutations from the publications, and catalogue all of these mutations in one database.

Most of the countries involved have really good genetic centers. But the problem is that it's not only about diagnosis. It is mainly about research and finding new things using new approaches. Our defect in the Arab world stems from the lack of vision based on the education system. For example, Kuwait University to this day does not have a department of genetics in the university. Molecular pathology is different; I am trying to get genetics through the backdoor. We tried to establish a genetics department, but it was resisted furiously, for reasons I do not completely know. I asked a question to all medical students, "What is homozygosity?" Not one answered. And so, it has to go back to the education system where we do not teach our students the importance of genetics, and we therefore do not graduate doctors specialized in medical genetics. We do not have enough clinical geneticists or good ones, and we do not recognize clinical molecular genetics, molecular pathology, or genomic medicine as clinical disciplines. They do not recognize me as a clinician, for example. I have a [bachelor of medicine and bachelor of surgery], but they see me as a scientist. My degree is translated as a degree in philosophy, while Glasgow University, where I graduated from, recognizes me as a clinician. However, in the eyes of Kuwait University, I am purely involved in research. We need to recognize genomic medicine as a clinical discipline.

But you are moving forward with this project.

Yes, now we have decided that we really need to look at normal Arabs. So together with CAG, who initially wanted to fund this, and I hope they do fund the database, I applied to the Qatar National Research Fund, and we got funded. I think Qatar National Research Foundation is a huge leap forward in the development of a research culture in the Arab world. Now we are sequencing around 120 whole genomes and 240 exomes from normal Arabs. We may increase the number to 500, because the prices are dropping.

We need to study these populations to understand what is normal, so that we can decide what is a mutation and what is a neutral genetic change (polymorphic changes). For example, in the West you will find type 2 diabetes in [up to] 7 percent of the population. In Bahrain and other Gulf States, 35 percent of the population has type 2 diabetes. If you look at this disease, each patient will cost you hundreds of thousands of dollars, because it is a chronic disease. This will bring the economy on its knees, and this is my prediction, within the next 20 to 30 years.

You mentioned in your talk that you had the SNP Array 6.0 set up. How is that going to come into play?

The Pan Asian Population Genetics Initiative [is] also doing sequencing first and then they are validating the data with chips. I have done it the other way around. Few years ago, the SNP 6 had just come out, so we decided to look at 100 samples of normal Arabs given to me by Suzanne Al-Bustan from Kuwait University. SNP 6.0 contains less than a million SNPs and about a million copy number probes. We had the SNPs, but we shared the data with Shuhua Xu, a professor of population genetics in China, to see if he could find some similarities with the Chinese population, and I also shared it with Timothy Ravasi, [a professor of bioscience at King Abdulla University of Science and Technology in Saudi Arabia], to see if there are similarities between what we have and the Saudis. Of course, the idea is that my data will now migrate to the Far East. Let's collect all of the SNPs from these countries and see where the data takes us.

I have heard some researchers complain that the whole-genome genotyping arrays were optimized for use with European populations.

Correct. These were optimized from the HapMap, and, as I said, the HapMap did not include any Arabs. But it is still useful to know what is the minor allele frequency, and how many in your 100 samples have SNP X. You cannot use this tool to discover new polymorphisms, but with whole genome or exome sequencing you can.

You said that you will apply for more funding for Genome Arabia.

Right now there are seven countries involved — Qatar, Bahrain, Kuwait, Saudi Arabia, United Arab Emirates, Tunis, and Lebanon. But Egypt wants to join in and doesn't have any funds to do exome sequencing but we are not going to let them down. We have decided to file another application next year where Egypt and other countries will come and join the project. We have received additional funding from the Kuwait Foundation for the Advancement of Sciences to look at new breast cancer genes in the Arab population.

When will the array platform come back into the picture?

The SNP 6.0 is going to support our Genome Arabia.

Has Affymetrix expressed interest in putting together arrays that are focused on Arab populations.

Yes, I would like to discuss this with Affymetrix once we release the data. I would love for Affymetrix to make a SNP 6.0 enriched for Arabs. And arrays for diabetes [and] cancer. I think that this is how it is going to go from now on. Ultimately, and you may start with whole-genome sequencing or exome sequencing, [but] you are going to make a smaller chip, spot it, dot it, and use it for diagnostics. I don't know if sequencing will ever become so cheap so that you will just do everything anyway. Because, honestly, these chips are what, $360? It will cost me now between $1,000 and $2,000 to sequence the entire exome in an individual. In the future, the cost may become much, much cheaper.

During your talk you discussed creating something called Phenobook that would be like Facebook.

Yes. Everyone who attends HUGO is excited about genomic data. Here you want to solve the cancer problem, so you sequence it. But will that data allow you to identify, [subtype, or locate] the cancer? Phenotype is extremely important and it is naive to look at the genetics without looking at the phenotype. So, Phenobook is a great idea. A patient with a disease would go in, take a picture of it, upload it. Another patient would come in, a third one, a fourth one, and so now we would have a database from the population, from the people themselves and each one of them contributed his or her phenotype and genotype and a phenotype-genotype correlation may then be very informative.

Of course, there is the issue of confidentiality. I think the idea needs a lot of refinement, but I think the only way that doctors will be able to make major improvements in human health, will be when the public contributes information about their diseases/phenotypes, and the doctors will have access to it, then we will have solved a big problem. We think about this as a blood bank idea where people can contribute their data for the advancement of medicine and helping the sick. In Kuwait, Global Med Clinic has started a genomic medicine initiative called Genatak, which in Arabic means 'your genes,' to introduce genomics in the practice of medicine. This represents a huge leap towards improving health and saving treatment cost in the Arab world.

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