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Rare African genes might reduce risks to pregnant women and their infants

Khoe-SanWhen Hugo Hilton began working at Stanford as a young researcher several years ago, his supervisor set him to work on a minor problem so he could practice some standard lab techniques. His results, however, were anything but standard. His supervisor — senior research scientist Paul Norman — told him to do the work over, convinced the new guy had made a mistake. But Hilton, got the same result the second time, so Norman made him do it over again. And then again.

“This was Hugo’s first PCR reaction in our lab and I gave him the DNA,” recalled Norman, “and the very first one he did, he pulled out this mutation. I was convinced that he’d made a mistake.” Norman even quietly redid the work himself. But the gene variant was real.

Norman and colleagues had been studying the same group of immune genes for decades and he knew them like the back of his hand. Yet he was astonished by what Hilton had stumbled on — a mutation that switched a molecular receptor from one protein target to another. It would be as if you bent your house key ever so slightly and discovered it now opened the door to your neighbor’s apartment — but not yours.

And the mutation, far from causing some illness, might contribute to healthier mothers and babies. Parallel research at another institution suggests the odd gene most likely changes the placenta during early pregnancy, leading to better-nourished babies and a reduced risk of pre-eclampsia, a major cause of maternal death.

The surprising finding grew out of a long-term effort to understand how immune system genes make us reject organ transplants. A big part of that puzzle is understanding how much immune genes can vary. On the surfaces of ordinary cells are proteins called HLAs. Combinations of these proteins mark cells in a way that makes each person’s cells so nearly unique that the immune system can recognize cells as either self or not self. When a surgeon transplants a kidney, the recipient’s immune system can tell that the kidney is someone else’s — just from its cell surface HLA proteins. The patient’s immune system then signals its natural killer cells to attack the transplanted kidney. The key to all that specificity is the huge variation in the genes for the HLA proteins.

Hilton’s surprising gene showed up in blood samples donated by a group of Khoe-San, a people in southern African known for the unusual clicking sounds in their language. The Khoe-San, one of the oldest populations in the world, harbor unusually high genetic diversity; their population of 100,000 has 10 times the genetic diversity of Europeans. So it’s not surprising the population would have some unusual genes.

To identify cells, natural killer cells deploy receptor molecules that bind to the cells’ HLA proteins. In most people, one kind of receptor binds the “HLA C2” cell surface proteins, and another kind of receptor binds the “HLA C1” proteins. The newly discovered mutation makes the receptor that normally binds HLA C2 switch over to binding HLA C1 instead. The difference is critical to certain mothers and babies.

In the uterus, natural killer cells are involved in building the blood supply to the embryo. The action takes place in the placenta, the organ that supplies blood to the embryo and acts as a dynamic interface between mother and embryo. Early in pregnancy, when the placenta is forming, the mother’s natural killer cells can bind to the embryo’s placental cells. If the mother doesn’t have the gene for the C2 protein but the embryo does, the mother’s natural killer sees the embryonic cells as foreign and bind the C2-marked cells. And that’s not good for the embryo or the mother.

When natural killer cells attack embryonic cells in the placenta, the maternal arteries are constricted and deliver less blood under higher pressure. The embryo, and later the fetus, gets too little blood and misses out on nutrients it needs. Meanwhile, the mother suffers from high blood pressure, or pre-eclampsia, a condition that accounts for 14 percent of all maternal deaths worldwide. But in Khoe-San with the rare version of the gene that Hilton discovered, the natural killer cells pass by the C2-labeled cells and head for the C1-labeled cells instead.

Hilton and Norman are first and second authors on a paper describing how the mutated gene works to reduce binding to HLA C2 and increase binding to HLA C1, along with senior author Peter Parham, PhD, professor of structural biology and microbiology and immunology. Six other researchers contributed to the work. The paper appears online today at PLOS Genetics.

Previously: Revealed: Epic evolutionary struggle between reproduction and immunity to infectious disease and Genetic study supports single migratory origin for aboriginal Americans
Photo by Brenna Henn

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