The Rh factor distinguishes between Rh-positive and Rh-negative blood types based on the presence or absence of a specific protein. While this difference is largely inconsequential in daily life, it carries significant medical implications, particularly concerning pregnancy. The uneven distribution of Rh-negative blood across populations and its associated reproductive cost have led scientists to investigate when this ancient variation first arose in the human lineage.
Defining Rh-Positive and Rh-Negative Blood
The designation of Rh-positive or Rh-negative hinges on the presence or absence of the D antigen, a protein located on the surface of red blood cells. This characteristic is governed by the RHD gene, situated on chromosome 1. An individual is Rh-positive if the D antigen is present, and Rh-negative if it is absent. For most people of European descent, Rh-negative status results from a complete deletion of the RHD gene. Since the D antigen is genetically dominant, a person must inherit two copies of the non-functioning RHD gene, one from each parent, to be Rh-negative.
Geographical Distribution of Rh-Negative Blood
The Rh-negative blood type is unevenly distributed across the global population, providing a significant clue to its ancient origins. Globally, the frequency is low, affecting approximately 6% of people worldwide. However, its prevalence is dramatically higher in Europe, where 15% to 17% of the population is Rh-negative, the highest concentration found in any continent.
The most striking concentration occurs among the Basque people, where the frequency can reach between 21% and 36%. Other European areas, such as Ireland and Scotland, also exhibit higher-than-average rates.
Outside of Europe, the Rh-negative type is extremely rare in East Asian and Indigenous American populations, often falling below 1%. Pockets of high prevalence do exist in isolated groups, such as one group in the High Atlas region of Morocco, where rates have been reported at 29%.
Evolutionary Hypotheses for the Origin of Rh-Negative Blood
Genetic evidence suggests the mutation responsible for the European Rh-negative blood type—the deletion of the RHD gene—is ancient. Many geneticists theorize this deletion first occurred in Africa, possibly over 100,000 years ago, before the major migration of modern humans out of the continent. This specific RHD deletion is found in African populations, albeit at a very low frequency of 1% to 3%, supporting the idea that the mutation was carried out of Africa by early modern humans.
The subsequent high frequency of Rh-negative blood in Europe is attributed not to a new mutation, but to genetic drift or a founder effect. As small groups of early modern humans migrated into Europe and became geographically isolated, chance events caused the recessive Rh-negative trait to become much more concentrated. The Basque population, which remained genetically distinct from later migrants, is considered a relic of these early European inhabitants, retaining and amplifying the ancient Rh-negative frequency.
The reproductive cost of the Rh-negative trait, where a pregnant Rh-negative mother can develop antibodies against an Rh-positive fetus, suggests a counteracting selective advantage must have existed. This advantage is speculative, but one theory proposes that Rh-negative status conferred resistance to certain ancient pathogens, such as parasitic infections or smallpox. Such a survival benefit could outweigh the reproductive disadvantage over thousands of years, particularly in areas with high pathogen loads.
The popular Neanderthal origin hypothesis posits that the Rh-negative trait was acquired through interbreeding between early Homo sapiens and Neanderthals. Studies show Neanderthals possessed diverse Rh variants, but the consensus is that the specific deletion causing the common European Rh-negative type did not originate from this interbreeding. The presence of the Rh-negative deletion in Africa before these interbreeding events makes Neanderthals an unlikely source. However, genetic mixing may have introduced other blood group complexities or contributed to the decline of the Neanderthal population due to Rh incompatibility in hybrid offspring.
Clinical Significance of Rh Incompatibility
The evolutionary persistence of the Rh-negative trait has important clinical implications. When an Rh-negative mother carries an Rh-positive fetus, their blood types are incompatible, potentially leading to Hemolytic Disease of the Fetus and Newborn (HDFN). This problem begins when the baby’s Rh-positive red blood cells enter the mother’s bloodstream, a process called sensitization.
The mother’s immune system recognizes the D antigen as foreign and produces anti-D antibodies. These antibodies typically do not affect the first Rh-positive pregnancy, but in subsequent pregnancies, they can cross the placenta and attack the red blood cells of the fetus. This destruction can cause severe anemia, jaundice, or death for the infant.
Modern medicine has largely mitigated the risk of HDFN using Rho(D) Immune Globulin, often known as RhoGAM. This medication, a solution of anti-D antibodies, is given to the Rh-negative mother, typically around 28 weeks of pregnancy and again after delivery. The injected antibodies clear any fetal Rh-positive cells in the mother’s circulation before her immune system can initiate a long-term response. This preventative measure has significantly reduced the rate of Rh isoimmunization in at-risk pregnancies.