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Genome Arabia Project Launches to ID Disease-Causing Mutations in Middle Eastern Populations

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Located at the crossroads between Europe, Africa, and Asia, the populations of the Middle East have for too long been overlooked by major initiatives to catalogue human variation, maintains Fahd Al-Mulla, Kuwait University's head of molecular pathology.

"It's been ignored by everybody," said Al-Mulla, citing the absence of Arab participants in the Human Genome Project, the three phases of the Human HapMap Project, and the 1000 Genomes Project.

Recently, Al-Mulla and fellow researchers decided to address this issue by forming a project called Genome Arabia. In November, the Qatar National Research Fund awarded the research team $1.1 million, funding that Al-Mulla and fellow investigators plan to use to sequence up to 500 individuals from seven countries in the region — Qatar, Bahrain, Kuwait, United Arab Emirates, Tunisia, Lebanon, and Saudi Arabia — using next-generation technologies.

According to the abstract describing the three-year grant, the resulting Arab genome sequences will "stand alongside the 1000 Genomes Project" as an imputation resource to catalyze the discovery of low-frequency and rare genetic variants that influence complex disease risk, "empowering all West Asian case-control, cohort, and biobank studies." Researchers will also use the data to map Mendelian recessive diseases and to shed new light on the population genetics of the region.

And, according to Al-Mulla, who has Affymetrix's GeneChip platform set up in his laboratory in Kuwait, microarrays will also have a role to play in Genome Arabia once the group assembles the data.

"I would love for Affymetrix to make a SNP 6.0 enriched for Arabs, and arrays for diabetes [and] cancer," Al-Mulla told BioArray News. "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," he said.

Specific Needs

Al-Mulla discussed Genome Arabia in a talk at the joint Human Genome Meeting and International Congress of Genetics, held in Singapore earlier this month. In his talk and a subsequent interview with BioArray News (see Q&A, this issue), Al-Mulla discussed many different issues facing genomic research and medicine in the region.

One such issue is a regional tendency to view genomic information about the local populations as a private matter, as well as a vulnerability. Indeed, confusion about how such information could be used has made it more difficult for researchers in the region to obtain support, Al-Mulla claimed.

"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," said Al-Mulla. "And policymakers, decision makers in our governments, are not well-read and they are ill-advised," he said. "This is across the region. And so it has been difficult to obtain funding."

At the same time, he portrayed the Middle East as a region with a specific need for genomic research and medicine.

One variable impacting this need is a high degree of consanguinity, the result of generations of first-cousin marriages, mainly organized to consolidate wealth within families.

"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," said Al-Mulla. "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."

As a result, certain diseases that are common in European countries are absent in Arab populations, Al-Mulla said, while others are more prevalent in Arab populations than in other parts of the world, and put increasing strain on local healthcare systems.

"In Bahrain and other Gulf States, 35 percent of the population has type 2 diabetes," said Al-Mulla. "If you look at this disease, each patient will cost you hundreds of thousands of dollars, because it is a chronic disease."

At the same time, Al-Mulla said that the high degree of consanguinity, along with quality genetic records kept at Qatar's Center for Arab Genomics, should enable researchers to uncover disease-causing mutations specific to Middle Eastern populations with the hope that these markers can later be used to diagnose and treat different diseases and conditions.

The Right Tools

To date, Al-Mulla said it has been hard to get at the genetics underlying conditions common to Middle Eastern populations because available genotyping arrays were optimized using data from projects that did not cover Arab populations.

"These were optimized from the HapMap, and, as I said, the HapMap did not include any Arabs," Al-Mulla said of the available technology, though he has used the SNP 6.0 in a number of studies. "It is still useful to know what is the minor allele frequency, and how many in your 100 samples have SNP X," he said.

Array vendors have taken note of researchers needs for population-focused chips. Affymetrix, for instance, has a menu of arrays optimized for different populations. Illumina, too, has sold catalog population-focused arrays, such as its HumanOmniZhongHua BeadChip for studying Chinese populations (BAN 12/18/2012).

But, in general, Al-Mulla maintained that association studies have relied on arrays that "harbored SNPs that may have not been suitable to show genotype-phenotype association in our population," and "this is why we decided to whole-genome sequence Arabs, to find novel SNPs and frequencies of other SNPs in our population."

At the same time, he said that Genome Arabia does not view next-generation sequencing as the tool that will serve all of its needs.

"I don't know if sequencing will ever become so cheap so that you will just do everything anyway," said Al-Mulla, "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," he said.

To that end, Al-Mulla said that he and fellow researchers hope to make "representative arrays" in a second phase of the Genome Arabia Project to "aid in our push for implementing full-scale genomics in medical practice."

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