Saudi Gene Hunters Comb Country’s DNA to Prevent Rare Diseases

December 18, 2016

by Jocelyn Kaiser at Science Magazine

In a hospital conference room here in Saudi Arabia’s capital, a lieutenant colonel in the Saudi army, dressed in fatigues and a black beret, stoically tells a story of genetic casualties. His and his wife’s first child, born in 2004, seemed healthy at first, but at 6 months old the baby girl could not yet sit up and barely cried. Doctors in France, where the family was living at the time, found no explanation. “We were sure that lack of oxygen” during delivery had caused brain damage, the father says.

Although their next baby, a boy, was healthy, a second girl born 5 years later had similar developmental delays. Meanwhile, the officer’s sister had given birth to six children, two healthy but four with similar medical problems: Each had crossed eyes and an IQ below 70, didn’t talk, and didn’t walk until about age 5.

Both the lieutenant colonel, who asked not to be identified, and his sister had married first cousins, who were also related. Suspicions that this close kinship played some role in their kids’ problems led the two families to this clinic at King Faisal Specialist Hospital and Research Centre (KFSHRC) and into the care of Fowzan Alkuraya, a young Saudi geneticist who had recently returned from the United States. Some months after the families gave him DNA samples, Alkuraya delivered the results: All four parents carried one copy of the exact same disease mutation, a change of a single DNA base in a gene called ADAT3. Although the mutation was harmless to the parents because each retained a working copy of the gene, their severely disabled children had inherited two faulty copies. As a result, their cells couldn’t make an enzyme that helps translate DNA into proteins.

Alkuraya’s news brought the families some measure of comfort, and hope. “It was a big relief for my wife, for me, for my sister, for everyone” to know what had gone wrong, the officer says. Hoping to break their bad genetic luck, he and his wife decided they would turn to in vitro fertilization (IVF) and use preimplantation genetic diagnosis to select embryos that inherited no ADAT3 mutation. They now have 2-year-old twins, a boy and a girl. “And they are perfectly healthy,” the father says.

The officer’s family is one of hundreds that have come to Alkuraya, 39, who may be the country’s leading genetics sleuth. His work is part of a boom in human genetics research in Saudi Arabia over the past decade, which has culminated in a Saudi version of a human genome project, called the Saudi Human Genome Program (SHGP). Largely because many Arabs marry cousins or other close relatives, the country, like others in the Middle East, has an increased rate of inherited genetic diseases—nearly double the rate in Europe and the United States and 10 times higher for certain disorders, according to some estimates. As a result, the country has long drawn Western scientists eager to bag disease genes new to science. But Alkuraya and other geneticists here at KFSHRC are bringing such research home.

They are harnessing cheap, next-generation DNA sequencing to pin down mutations underlying unexplained diseases, cranking through more than 10,000 cases in the past 5 years. Although most of the solved cases involve known mutations, some have yielded novel disease genes— more than 200 from Alkuraya’s group alone, including ADAT3. The output of the relatively small team rivals that of larger groups of disease gene hunters in the United States and Europe, colleagues say. “I am very impressed with what [Alkuraya] has achieved in Saudi Arabia,” says Joris Veltman, a human geneticist at Radboud University Medical Center in Nijmegen, the Netherlands.

Alkuraya and his colleagues hope the growing catalog of disease mutations they have found will not only help individual families with inherited diseases have healthy babies, but lead to premarriage DNA tests for young people that could bring down the high rate of those diseases here. The broader sequencing effort could also have payoffs beyond the Middle East. The country’s closely related population should make it easier to identify “healthy knockouts”—people who lack both copies of a specific gene yet remain healthy and even gain protection against disease, providing clues to new drugs. “If there’s any place they should be discovered, it’s here,” Alkuraya says.

But first, Saudi geneticists will have to get past the worsening budget crisis here triggered by the global drop in oil prices. Funding is on hold for the next phase of the overall genome project, and even ongoing research grants, including Alkuraya’s, have been slashed this year. It’s vital that his gene sleuthing and other genomics efforts in the country don’t stall out, observers say. As human geneticist Daniel MacArthur of the Broad Institute in Cambridge, Massachusetts, notes, “There’s no question the opportunities there are massive.”

When DNA and culture clash

Outside the research wing of KFSHRC on the traffic-clogged streets here, women cannot mingle with unrelated men and must wear a loose black robe called an abaya. But in this surprisingly cosmopolitan space, women swap their abayas for lab coats and work side by side with male staff. Some take off their head scarves, but others retain their black face veils, known as niqabs, even in the lab.

Such adherence to tradition helps explain why about 40% or more of native Saudis—two-thirds of the country’s 30 million people—still marry first cousins or other close relatives. The practice, once common in Europe, lives on in much of the Middle East today, helping preserve wealth and tribal ties. But the downside of consanguineous marriage is a relatively high risk for recessive genetic diseases, which develop when both the maternal and paternal copy of a gene are faulty. If both parents carry the same recessive disease mutation, their children have a 25% chance of inheriting two copies and developing the disease; and in the large families still common in Saudi Arabia, the genetic dice are rolled repeatedly. By one estimate, 8% of babies in Saudi Arabia are born with a genetic or partly genetic disease, compared with 5% in most high-income countries.

Often the diseases have never been seen before. For decades, Middle Eastern clinicians puzzled by these cases have called in European or U.S. scientists, who collected DNA samples from the afflicted families and claimed lead authorship on papers describing new disease genes. After the draft human genome was unveiled in 2001, the country’s homogeneous population—made up of about two dozen major tribes descended from a small number of founders— also attracted broader genetics efforts. Brian Meyer, an Australian expat scientist who has long worked in Saudi Arabia and now chairs the KFSHRC genetics department, recalls a proposal from genome sequencing pioneer Craig Venter to launch a company modeled after Iceland’s deCODE, which would have mined the DNA of Saudis for drug targets. The plan fizzled out because of local concerns about privacy and exporting genetic data for commercial purposes, however.

“The population wasn’t ready,” Meyer says. Saudi Arabia also declined to contribute DNA samples to HapMap, an international effort to map human genetic diversity that began in 2002. Middle Easterners are still virtually missing from human genome reference databases, a problem some Arab scientists are now trying to remedy.

In the late 1990s, however, the seeds of a Saudi genome effort began to take root. After finding that the mutations causing cystic fibrosis in Saudis were different from those in Europeans, KFSHRC geneticists began to do their own disease gene hunting. Alkuraya soon joined the chase.


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