In 1972, a routine blood test on a pregnant woman returned a result that baffled hematologists. Her red blood cells were missing a surface molecule, an antigen, that appeared to be universal in every other human blood sample ever tested. For more than half a century, the genetic basis of this anomaly remained unknown. Now, an international research team led by the UK’s NHS Blood and Transplant (NHSBT) and the University of Bristol has finally identified the gene responsible, establishing an entirely new blood group system called MAL.
The 1972 Anomaly That Launched a 50-Year Quest
The story begins with a single blood sample. Clinicians noticed that the pregnant woman’s red blood cells lacked a specific surface marker, which they later named the AnWj antigen, after the first two patients, Anton and Wj, who produced antibodies against it. At the time, every known human red blood cell carried this molecule, making its absence deeply puzzling.
For decades, hematologists could detect the antigen, or its absence, but could not trace it to any known gene. “It represents a huge achievement, and the culmination of a long team effort, to finally establish this new blood group system and be able to offer the best care to rare, but important, patients,” said lead author and NHSBT hematologist Louise Tilley, who devoted nearly 20 years of her career to solving the puzzle.
The breakthrough, published in the journal Blood in late 2024, marks the first new blood group system to be formally recognized in years and brings the total number of known human blood group systems to 47.
What Is the MAL Blood Group?
The MAL blood group system is defined by the presence or absence of the AnWj antigen on the surface of red blood cells. This antigen is carried by a protein called “Mal,” short for myelin and lymphocyte-associated protein, which gives the system its name.
Mal is a small, multi-pass membrane protein that plays important roles in cell membrane stability and cellular transport. In more than 99.9% of the global population, full-length Mal protein is expressed on red blood cell membranes, making those individuals AnWj-positive.
Only a tiny fraction of people, those with specific mutations in both copies of the MAL gene, are AnWj-negative.
The table below situates MAL among other major and recently discovered blood group systems:
| Blood Group System | Year Discovered | Gene | Key Antigen(s) | Prevalence of Negative Phenotype |
|---|---|---|---|---|
| ABO | 1900 | ABO | A, B, H | Varies by population |
| Rh | 1940 | RHD, RHCE | D, C, c, E, e | ~15% (RhD-negative in Caucasians) |
| Kell | 1946 | KEL | K, k, Kpa, Kpb | ~91% are K-negative |
| Duffy | 1950 | ACKR1 | Fya, Fyb | ~68% of African ancestry are Fy(a−b−) |
| Kidd | 1951 | SLC14A1 | Jka, Jkb | Rare (Jk null <0.01%) |
| MNS | 1927 | GYPA, GYPB | M, N, S, s | Rare |
| Er | 2022 | PIEZO1 | Era, Erb | Extremely rare |
| MAL | 2024 | MAL | AnWj | <0.01% (inherited form) |
The Genetic Detective Work: How Scientists Cracked the Case
Solving the AnWj mystery required a combination of cutting-edge genetic tools and old-fashioned scientific persistence. The research team, which included collaborators from Israel, used whole exome sequencing, a technique that analyzes all protein-coding regions of DNA to compare the genomes of AnWj-negative individuals with those of their AnWj-positive family members.
The result was definitive. Every person with the inherited AnWj-negative phenotype carried the same genetic signature: a 6,646-base-pair deletion in the MAL gene. This deletion removes critical sections called exons, preventing cells from producing functional Mal protein. Without Mal, the AnWj antigen simply never appears on red blood cell surfaces.
The inheritance pattern is autosomal recessive, meaning a person must inherit the deleted gene from both parents to be AnWj-negative. Family members with only one mutated copy still produce enough Mal protein to display the antigen normally.
To confirm the link beyond any doubt, the team performed an elegant experiment. They inserted a normal MAL gene into cultured AnWj-negative blood cells. The missing AnWj antigen promptly appeared on the cell surface. When they repeated the experiment with the mutated version of the gene, no antigen appeared. “Mal is a very small protein with some unusual properties, which meant we needed to pursue multiple lines of evidence to build a definitive proof,” noted Tim Satchwell, a cell biologist at the University of the West of England and co-author of the study.
Interestingly, the MAL gene was not the first suspect. Earlier research had pointed toward two other genes, CD44 and SMYD1, as possible carriers of the AnWj antigen. The new study definitively ruled both out, closing a long-running scientific dead end.
Just How Rare Is MAL-Negative Blood?
The inherited AnWj-negative blood type is among the rarest known. In their study, the researchers identified only five genetically AnWj-negative individuals worldwide, including members of an Arab-Israeli family. This places the inherited MAL-negative phenotype in the same extreme rarity category as the Rh-null (“golden blood”) type, of which fewer than 50 people are known globally.
For context, the three rarest blood types overall are:
- Rh-null: fewer than 50 known individuals worldwide; lacks all Rh antigens
- MAL-negative (AnWj-negative): only five confirmed genetic cases; the 47th and newest blood group system
- Kell-null (K0): extremely rare; lacks all Kell system antigens, making compatible donor blood exceptionally difficult to source
However, there is an important clinical distinction. Some people can become temporarily AnWj-negative due to an underlying illness, such as certain blood disorders or cancers that suppress Mal protein expression. In these cases, the antigen may return once the underlying condition is treated. The newly available genetic test helps doctors distinguish between the inherited form (permanent) and the acquired form (potentially reversible), which is critical for transfusion decisions.
Beyond ABO: Understanding the 47 Blood Group Systems
Most people learn about only two blood group systems: ABO (types A, B, AB, and O) and Rh (positive or negative). But human blood is far more complex, and researchers have even discovered ways to convert Type A blood into universal Type O using enzymes from gut microbes. The International Society of Blood Transfusion (ISBT) officially recognizes 47 distinct blood group systems, each defined by a specific gene and its associated antigens.
Together, these systems encompass more than 360 known red blood cell antigens: tiny proteins, glycoproteins, and glycolipids that decorate the surface of every red blood cell. They serve as identity tags that help the immune system distinguish “self” from “foreign.” When mismatched blood enters the body, the immune system may launch a dangerous attack.
For a new blood group to earn ISBT recognition, researchers must demonstrate three things: the antigen must be shown to be genetically determined, the responsible gene must be identified and sequenced, and the system must be distinct from all previously known groups. The MAL system cleared all three hurdles with the 2024 publication. While ABO and Rh remain the most clinically important systems for routine transfusions, which together produce the eight common blood types most people know (A+, A−, B+, B−, AB+, AB−, O+, and O−), each newly discovered group adds a layer of precision to transfusion medicine, particularly for patients with rare blood types who need precisely matched donations.
Notably, researchers continue to identify new antigens and systems. In 2022, the Er blood group system was discovered, linked to the PIEZO1 gene. The question of a potential 48th blood group system remains open, and with genomic technologies advancing rapidly, further discoveries are likely.
What the MAL Discovery Means for Transfusion Medicine
The immediate practical benefit of this discovery is improved transfusion safety. When an AnWj-negative person receives blood from an AnWj-positive donor, their immune system can produce antibodies against the unfamiliar antigen, triggering a transfusion reaction that ranges from mild to life-threatening.
Now that the genetic basis is known, laboratories can develop genotyping tests to screen for the MAL deletion. These tests can be integrated into existing blood typing platforms, allowing blood banks to identify AnWj-negative patients before they ever need a transfusion.
For the tiny number of people affected, this means matched blood can be sourced or manufactured in advance, a precaution that could be lifesaving during surgery, childbirth, or emergency treatment and complements other advancements like synthetic red blood cells that offer new options for patients with rare blood needs.
“The new test will make it easier to find blood for patients with this rare blood type and will also allow us to search for blood donors to keep a supply of this rare blood,” the NHSBT research team stated in their press release. The genetic test also helps clinicians determine whether a patient’s AnWj-negative status is inherited or the result of an underlying disease, a distinction that directly affects treatment decisions.
Beyond the immediate clinical applications, the MAL discovery demonstrates how persistent, long-term scientific investigation can resolve even the most stubborn biological mysteries and how each answer opens the door to better patient care.
Frequently Asked Questions
What is the 47th blood type?
The 47th officially recognized human blood group system is the MAL system, discovered in 2024 by researchers at NHS Blood and Transplant and the University of Bristol. It is defined by the presence or absence of the AnWj antigen, which is carried on the Mal protein and encoded by the MAL gene.
What two blood types don’t mix?
The most clinically important mismatch is between ABO blood types. Type A blood cannot receive type B blood (and vice versa) because the recipient’s antibodies will attack the foreign antigens. More broadly, any transfusion where the recipient has antibodies against a donor’s antigen can trigger a reaction, which is why the MAL discovery matters: AnWj-negative patients can react against AnWj-positive donor blood, even if their ABO and Rh types match.
What happens if someone receives mismatched blood?
A transfusion reaction occurs when the recipient’s immune system recognizes foreign antigens on donor red blood cells and attacks them. Symptoms range from fever, chills, and back pain to severe complications, including kidney failure, shock, and, in extreme cases, death. This is why identifying rare blood types like MAL-negative before transfusion is so important.
Can you be born without the AnWj antigen?
Interestingly, no. The AnWj antigen is absent at birth in all humans and typically develops within the first few weeks or months of life. However, people with the inherited MAL gene deletion never develop the antigen at all, making them permanently AnWj-negative. This developmental pattern is one of the unusual features of the Mal protein that made it difficult to study.
Is the MAL blood group inherited?
Yes. The inherited form of AnWj-negativity follows an autosomal recessive pattern. A person must inherit a mutated (deleted) copy of the MAL gene from both parents. Individuals with only one mutated copy are carriers who still produce enough Mal protein to be AnWj-positive.
What are the symptoms of being MAL-negative?
Being AnWj-negative causes no symptoms in daily life; individuals with this rare blood type are otherwise healthy. The Mal protein, despite its roles in cell membrane stability, does not appear to cause any health problems when absent. The only clinical risk arises during blood transfusions, where receiving AnWj-positive blood could trigger an immune reaction.
The Future of Blood Group Discovery
The resolution of the AnWj mystery closes one chapter but opens another. With whole exome sequencing and other genomic tools now widely available, the pace of blood group discovery may accelerate. Researchers are already investigating several other known but unexplained blood antigens, and the ISBT may not wait another 50 years to welcome its 48th system, especially as personalized medicine and gene editing accelerate the pace of discovery.
For the rare patients whose blood falls outside the familiar ABO and Rh categories, each new discovery brings them closer to a world where every transfusion is precisely matched and where no blood type remains a mystery.
