LONDON: Scientists have discovered a new human blood group system, solving a medical mystery that had remained unanswered for more than 50 years.
The newly identified MAL blood group system emerged after researchers finally determined the genetic basis of the mysterious AnWj blood group antigen, a marker on red blood cells first identified in 1972.
The discovery, led by scientists at NHS Blood and Transplant (NHSBT) and its International Blood Group Reference Laboratory (IBGRL) in Bristol, with collaborators including the University of Bristol, could improve the identification of people with this exceptionally rare blood phenotype and help transfusion specialists find compatible blood when it is needed.
A new blood group hidden inside an old mystery
For most people, blood type means A, B, AB or O, together with the familiar Rh-positive or Rh-negative designation.
But human blood is far more complex.
Red blood cells carry hundreds of molecular markers called antigens, and differences in these markers can become critically important when a person needs a blood transfusion.
The AnWj antigen had been known since 1972. What scientists did not know for decades was which gene produced it and what biological system it belonged to.
That mystery has now been solved.
Researchers established that AnWj is carried on the Mal protein, which is produced from the MAL gene. Their findings formed the basis for recognizing MAL as a distinct blood group system.
The mystery began in 1972
The AnWj antigen was first identified more than half a century ago.
But simply observing an antigen is not enough to establish its genetic identity. Researchers needed to determine what molecule carried it, what gene controlled its expression and why a tiny number of people lacked it.
That proved exceptionally difficult because inherited AnWj-negative individuals are extraordinarily rare.
The breakthrough came when researchers studied people with the persistent inherited form of the AnWj-negative phenotype and used whole-exome sequencing, a genetic technique that examines the DNA sequences responsible for producing proteins.
Instead of finding the answer in genes previously suspected of being involved, the team discovered the same large deletion in the MAL gene in multiple unrelated AnWj-negative individuals.
More than 99.9% of people have the AnWj antigen
The researchers found that more than 99.9% of people are AnWj-positive.
In these individuals, red blood cells carry the full-length Mal protein.
In people with the rare inherited AnWj-negative phenotype, the Mal protein is absent from the red-cell membrane because of changes affecting the MAL gene.
The study identified five genetically AnWj-negative individuals, including members of an Arab-Israeli family. Researchers also examined a blood sample donated in 2015 by the woman who had been the first AnWj-negative person identified in the 1970s.
That extraordinary rarity helps explain why the genetic mystery survived for so long.
Scientists had to prove MAL was actually responsible
Finding a mutation in a rare group of patients was only part of the puzzle.
The researchers conducted additional laboratory experiments to establish that the Mal protein was actually responsible for the AnWj antigen.
They demonstrated that AnWj-positive red blood cells expressed full-length Mal, while it was absent from AnWj-negative cells.
They then introduced the normal MAL gene into an erythroid cell line. The cells began expressing the AnWj antigen, providing evidence that Mal was both necessary and sufficient for AnWj expression.
That evidence allowed the researchers to move from an unexplained blood-cell characteristic to a defined genetic blood group system.
Why this rare blood group matters to transfusions
For the overwhelming majority of people, the discovery will not alter their everyday medical care.
But for an AnWj-negative person who develops anti-AnWj antibodies, the distinction can become clinically important.
An AnWj-negative patient receiving AnWj-positive blood in the presence of clinically significant antibodies can potentially experience a transfusion reaction.
The new genetic understanding therefore has a practical purpose: it could enable laboratories to develop genotyping tests capable of identifying genetically AnWj-negative patients and donors.
That could make it easier for transfusion services to recognize rare patients and locate compatible blood when conventional matching identifies an unusual antibody.
Not every AnWj-negative person has the rare inherited blood group
There is another surprising part of the discovery.
A person can be AnWj-negative because of an underlying illness, rather than because they inherited the rare MAL gene deletion.
The researchers reported that haematological disorders and some cancers can suppress expression of the AnWj antigen.
The inherited form is different. The exceptionally rare people with the genetic AnWj-negative phenotype carry changes in MAL and can otherwise be healthy.
This distinction is important for clinicians and transfusion specialists because the same blood-cell phenotype can have different biological explanations.
The scientist who spent nearly 20 years chasing the answer
For Louise Tilley, Senior Research Scientist at the International Blood Group Reference Laboratory at NHS Blood and Transplant, the discovery represented the culmination of nearly two decades of work.
Tilley said the genetic background of AnWj had remained a mystery for more than 50 years and that she had personally been trying to resolve it for almost 20 years of her career.
The rarity of genetic cases made the investigation particularly difficult.
The researchers also had to overcome another obstacle: the gene they eventually identified was not an obvious candidate, and relatively little was known about the Mal protein in red blood cells.
From mysterious antigen to officially recognized blood group
The findings established MAL as a distinct blood group system, with AnWj as its defining antigen.
The International Society of Blood Transfusion (ISBT) formally lists MAL as blood group system 047.
At the time of the discovery, MAL was described as the 47th recognized blood group system. The ISBT's current database, updated in September 2026, now lists 49 recognized blood group systems, 57 genes and 400 antigens, meaning MAL is no longer the newest system.
That distinction does not diminish the discovery. Instead, it places it within a rapidly expanding understanding of how extraordinarily complex human blood compatibility really is.
Indeed, the ISBT has continued adding blood group systems since MAL was recognized, with JAMA becoming the 49th system in 2026.
A 50-year question finally has an answer
The significance of the MAL discovery lies in the journey as much as the final genetic answer.
Scientists could see the AnWj antigen in human blood in 1972.
For more than five decades, they could not fully explain its genetic origin.
Then whole-exome sequencing, rare patient samples and laboratory experiments converged on a single answer: the MAL gene and its Mal protein.
That breakthrough has transformed AnWj from a mysterious blood marker into part of a formally recognized human blood group system.
And for the rare patients whose blood lacks AnWj, the discovery could eventually mean something far more important than a new entry in a scientific database.
It could help doctors identify their blood phenotype more accurately, find compatible donors more efficiently and reduce the risk of transfusion complications when compatible blood is urgently needed.
The discovery is therefore not simply about finding another name to add to the list of human blood groups.
It is about finally understanding a hidden difference in human blood that scientists first noticed more than half a century ago.
Scientific record
The research was led by Louise A. Tilley and colleagues and published in the peer-reviewed journal Blood under the title “Deletions in the MAL gene result in loss of Mal protein, defining the rare inherited AnWj-negative blood group phenotype.” The paper appeared online in 2024 and in the December 26, 2024 issue of Blood.
The research involved scientists from NHS Blood and Transplant, the University of Bristol, Rabin Medical Center, Tel Aviv University, Magen David Adom National Blood Services, Umm Al-Qura University and other collaborating institutions.
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