Scientists finally crack a blood type mystery that began in 1972

In 1972, a doctor drew blood from a pregnant woman and found something that did not match any known blood type on record. Her red cells lacked a marker nearly every other human being carries, and for the next 50 years nobody could say why. Researchers at the University of Bristol and NHS Blood and Transplant have now traced that missing marker to a single gene, closing a case that outlasted the careers of the scientists who first opened it.

Tracking a 1972 antigen to the MAL gene

The marker in question is called AnWj, an antigen sitting on the surface of red blood cells that more than 99.9% of people carry. A tiny fraction of people are born without it, a trait geneticists had documented since that original 1972 case but had never been able to explain at the genetic level. Louise Tilley, a senior research scientist at NHS Blood and Transplant’s International Blood Group Reference Laboratory, spent close to two decades of her career chasing the cause. “The genetic background of AnWj has been a mystery for more than 50 years,” she said, calling the resolution “the culmination of a long team effort.”

Working with Ash Toye, a professor of cell biology at the University of Bristol who directs a national blood and transplant research unit, Tilley’s team sequenced the genomes of five genetically AnWj-negative people, including members of an Arab-Israeli family whose case had puzzled specialists for years. Every one of them carried homozygous deletions affecting the same gene, called MAL, which had never before been linked to a blood group at all.

The 47th blood group system, and why it took so long

The discovery, published in the journal Blood, made MAL the 47th officially recognized blood group system, joining a list that already accounted for more than 360 distinct blood antigens across the ABO, Rh and dozens of smaller systems. The reason AnWj resisted explanation for so long, according to the University of Bristol’s own account of the research, is that the MAL protein is so small and so tightly bound to the cell membrane that standard laboratory techniques could not isolate enough of it to study directly, even as separate techniques repeatedly confirmed AnWj existed on red cells.

Only sequencing whole genomes and comparing them against people known to lack the antigen made the connection visible. AnWj-negative status turned out to be more layered than researchers expected: most cases trace back to blood disorders that suppress MAL expression rather than genetic deletion, and only the small subset with an inherited, permanent absence of the gene need the kind of specialized testing the Bristol team’s genotyping method now allows.

Earlier generations of researchers had tried and failed to pin down AnWj using the tools available to them at the time. Serology, the decades-old method of testing how red cells react to different antibodies, could confirm that AnWj-negative blood behaved differently but could not point to a gene, because the antigen sits on a protein too small and too embedded in the cell membrane for older biochemical extraction methods to isolate in useful quantities. It took the falling cost of whole-genome sequencing, applied to rare families rather than large populations, to finally connect the antigen to MAL.

What a rare blood type means at the transfusion bench

The stakes are not abstract. Someone who is AnWj-negative and receives AnWj-positive blood, whether through transfusion or during pregnancy, risks an immune reaction as the body attacks the mismatched antigen it does not recognize. Because AnWj-negative status had no known genetic test until now, hospitals could only catch it after a reaction had already occurred, typically during a transfusion crisis when there was no time to investigate why a patient’s blood was reacting badly. Bristol’s Infection and Immunity Research Network credits the finding with opening the door to routine genetic screening for the trait before it ever becomes an emergency.

Toye said the practical payoff is identifying people who need it most: the discovery “will help identify these rare donors and help patients in the future,” giving blood banks a tool to flag AnWj-negative units and match them to the rare patients who require them. Nicole Thornton, who heads the reference laboratory where Tilley works, has described the case as one of the longest-running unsolved puzzles in modern transfusion medicine, one that a genetics lab in 1972 simply did not have the tools to answer.

Independent science outlets tracking the paper, including Sci.News and Interesting Engineering, have noted that MAL’s small size likely means it will not be the last blood group system hiding in plain sight; researchers already suspect a handful of other rare, unexplained antigen reactions could trace back to similarly overlooked membrane proteins once genome sequencing is applied the way it was here.

How many people worldwide carry an undiagnosed AnWj-negative status, and how many past transfusion reactions it explains, remains an open question the Bristol and NHS Blood and Transplant teams have not yet answered.

This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.

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