The “+” or “-” following the ABO blood type indicates the presence or absence of a protein on the surface of human red blood cells (RBCs) that is referred to as the “Rh factor” (Rh for Rhesus); however, this protein is not found on the surface of Rhesus monkey RBCs. The human protein was renamed to “D antigen” over fifty years ago, but the original term and its connotations of a factor specifically shared between Rhesus monkeys and some humans have remained in use, despite the inaccuracy. The function of this protein was not immediately apparent, and there is a great deal of speculation on the implications of being Rh-negative versus Rh-positive. These include: nonhuman/extraterrestrial ancestors, associations with physical traits, high IQ, sensitivity to psychic/paranormal phenomena, and disease resistance. The sense that Rh-negative individuals are special persists despite the lack of scientific data. My goal in this article is to address various claims regarding being Rh-negative.
Associations between Rh-Negative Blood Type and Physical Traits
Websites discussing the Rh-negative blood type have a general list of “known” associations: blue, green, or hazel eyes; red or reddish hair; low body temperature; low pulse; low (or high) blood pressure; extra rib or vertebrae; vestigial tail; larger than average head/forehead; unexplained body scars; unclonable blood; heightened senses; sensitivity to heat/sunlight; and the ability to disrupt electrical appliances. I have not found any scientific articles that corroborate these “known” associations. As I’ll demonstrate, a founder effect likely played a role in the greater proportion of Rh-negative individuals in European populations, and it is possible this also influenced the prevalence of other traits.
Red hair in humans is associated with changes in the melanocortin 1 receptor (MC1R) gene. MC1R plays a role in the relative expression of the pigments eumelanin (brown/black) and pheomelanin (red/yellow), and thus far it is the only gene that explains the normal variation in human pigmentation (Valverde et al. 1995; Rees 2000). Low eumelanin compared to pheomelanin is also responsible for fair skin that tans poorly, which reflects a decreased need for protection from ultraviolet radiation in climates with less sunlight and an increased need to absorb sunlight for Vitamin D production. The genetics of MC1R in hair and skin color have been reviewed (Rees 2003), and the variants conferring red hair occurred up to 80,000 years ago (Harding et al. 2000). Some Neanderthals had MC1R alleles that would have resulted in fair skin and red hair; one is likely Neanderthal specific (Lalueza-Fox et al. 2007), while another is shared with modern humans and may have originated in Neanderthals (Ding et al. 2014).
The major gene involved in blue vs. brown eye color is OCA2, which encodes a protein important for normal pigmentation. There are many variations affecting eye color, but a specific single nucleotide change in the upstream HERC2 gene inhibits OCA2 expression in the iris, leading to blue eyes. Nearly all blue-eyed individuals have this mutation, which may go back to a single individual in the Black Sea region living 6,000 to 10,000 years ago (Eiberg et al. 2008). Several other genes contribute to variation in eye color (none as influential as HERC2-OCA2), and a recent study shows positive selection for lighter skin, hair, and eyes in Europeans over the past 5,000 years (Wilde et al. 2014).
The perceived association between Rh-negative blood type and red hair, light eyes, and sensitivity to sunlight is probably due to shared European ancestry. An association between traits does not imply that one causes the other. A recent study of blood type, hair color, and eye color in relation to sexual orientation found that both male and female homosexuals are more likely to be Rh-negative, although the statistical test fell just short of significance (p=0.06). The conclusion is not that these two traits have a direct connection but that some genes influencing sexual orientation may be on the same chromosome as the D antigen (Ellis et al. 2008).
Associations between Rh-Negative Blood Type and Cognitive or Personality Traits
There are also “known” cognitive and personality trait associations: high IQ; a truth-seeking nature; a compassionate/empathetic nature; tendency toward empathetic illnesses (manifesting another person’s symptoms); tendency toward healing professions; a sense of having a “mission” in life; a sense of not belonging/otherworldly feeling; tendency to have paranormal experiences; tendency to be easily shocked/scared; and an interest in space or science. As with the physical traits, I found very little information in the literature to support these claims. Two early studies showed no association between Rh and personality factors (Mai and Pike 1970) or between any blood type and IQ (Owen 1972). A more recent study of over 3,000 Czech draftees (males about twenty years old) showed that Rh-negative individuals scored lower for novelty seeking and higher for persistence; the study also showed a greater effect of age and smoking on some personality and health factors in Rh-negative individuals (Flegr et al. 2012). Although addiction is not mentioned on websites, a study showed that the AB and Rh-negative blood types were independently more frequent in opioid addicts vs. controls (Aflatoonian et al. 2011). IQ and personality traits require professional evaluation—there are multiple metrics available and interpretation is not straightforward. Self-reporting of these traits is problematic because standards are not well defined, and individuals may interpret these traits differently.
Electromagnetic hypersensitivity (EHS) refers to the development of symptoms when exposed to low/background levels of electromagnetic fields (EMFs); EM sensibility is sometimes used to describe the ability to perceive low EMF levels, with or without symptom development. EHS is suggested as one explanation for some “paranormal” events as well as being a wider health concern. A meta-analysis concluded that most self-identified EHS individuals cannot perceive low-level EMFs under laboratory conditions, and there is no evidence that short-term exposure causes non-specific symptoms (Röösli 2008). Individuals who can perceive low-level EMFs may exist, but they haven’t been identified or investigated for blood type.
Associations between Rh-Negative Blood Type and Disease Resistance
While interesting, most of the “known” associations have limited implications. In contrast, “known” associations with disease resistance can be dangerous, especially when there is no scientific evidence to support them. The most common claim is that Rh-negative individuals are immune to HIV infection, based on the presence of either HLA-B27 or the CCR5delta32 allele.
Human leukocyte antigen (HLA) genes encode surface proteins involved in presenting peptide antigens to T cells. These molecules are also called major histocompatibility complex (MHC) proteins. HLA-A, B, and C alleles encode class I MHC proteins that are found on all nucleated cells (this means they are not present on RBCs). Each individual has two HLA-A, HLA-B, and HLA-C alleles that are designated by group numbers (e.g., HLA-B*27). This group may contain proteins with amino acid changes that don’t impact serological reactions, designated with another set of numbers (e.g., HLA-B*27:05). Alleles with a different nucleotide sequence, but no amino acid changes, get a third set of numbers (e.g., B*27:05:01). B*27 allele variants have been associated with protection against some viral infections (including HIV), susceptibility to malaria and tuberculosis, and a predisposition for ankylosing spondylitis (an autoimmune chronic inflammatory disease). HLA-B27 associations are reviewed elsewhere (Sheehan 2010) and potential mechanisms have been described (Neumann-Haefelin 2013). While there is evidence for the association of the HLA-B27 allele with HIV protection, this protection is not absolute. Further, there is no evidence of association between HLA-B27 and Rh-negative blood type. Websites I examined that make this claim have a single source: “According to Randall Johnson at the Baylor College of Medicine in Houston, ‘Only 7% of the US population tests positive for the HLA-B27 gene; this gene, found only in persons with Rh-Negative blood, can trigger the immune system to operate overtime at WARP SPEED in times of medical emergency.’”
This statement has not been verified, and I was unable to locate the Randall Johnson named; Randy L. Johnson, PhD, at the University of Texas is not the source for this quote (personal communication). These genes are not on the same chromosome (HLA genes are on chromosome 6, RHD and RHCE are on chromosome 1), and to reiterate, there is no association between being Rh-negative and having HLA-B27, and no resistance to viral infection conferred by being Rh-negative.
C-C chemokine receptor 5 (CCR5) encodes a protein expressed on the surface of some white blood cells that allows them to respond to certain signals. It is also used as a co-receptor by some strains of HIV (R5 strains). The delta32 mutation results in a nonfunctional receptor, so R5 strains are not able to infect the cells; however, HIV strains that use the CXCR4 receptor are not impacted by this mutation. The CCR5delta32 mutation may also reduce risk of cardiovascular disease. These associations have been discussed (Jones et al. 2011). As with HLA-B27, the genes encoding the D antigen and CCR5 are on separate chromosomes, and there is no association between the two.
A disease that gets much less attention on the Rh-negative websites is toxoplasmosis, an infection caused by the parasite Toxoplasma gondii. The prevalence varies geographically, with approximately one third of people in developed countries having the infection. In most cases, the infection is latent and clinically asymptomatic; individuals with latent infections will generally have antibodies to the parasite and may have dormant cysts in neural and/or muscle tissues. Although asymptomatic, Toxoplasma-infected individuals may show some gender and age-related changes in personality traits as well as poorer performance on reaction time tests and a greater incidence of traffic accidents. Rh status seems to modulate many of these changes in a complex way, with a heterozygote advantage observed for some traits (Flegr 2013; Flegr et al. 2010). A recent questionnaire study by the same group showed a higher prevalence of self-reported digestive disorders, cardiovascular diseases, immunity disorders, and fatigue, as well as more prescribed medications among Rh-negative respondents (Flegr et al. 2015). These results may form a basis for studies investigating significant associations with disease outcomes other than those due to toxoplasmosis.
How the Rh Factor Was Named
Two major findings led to the name of the Rh factor: (1) A blood group O woman who received type O blood from her husband had a severe transfusion reaction. The transfusion was required following delivery of a stillborn fetus with hemolytic disease of the newborn. Her serum was subsequently shown to agglutinate (a reaction visualized by clumping of RBCs) 80 percent of O samples tested, independent of other known blood factors (Levine and Stetson 1939). (2) Some rabbit sera produced following immunization with blood from Rhesus monkeys agglutinated 87 percent of human blood samples. Since this agglutination was also independent of other known factors, the property detected was called Rh to reflect the response to Rhesus monkey antigens (Landsteiner and Wiener 1940). The component responsible for the transfusion reactions seemed to be the same as the Rh factor detected by the rabbit (and guinea pig) sera; however, differences in degree of agglutination were noted between sera from transfusion recipients, rabbits, and guinea pigs (Landsteiner and Wiener 1941). The observation that human anti-Rh serum did not agglutinate RBCs from Rhesus monkeys also suggested the antigens were different (Fisk and Foord 1942). Research over the next two decades refined human blood groups and their detection. Eventually, it became clear that human anti-Rh sera and rabbit/guinea pig anti-Rh sera were not recognizing the same antigen. Human anti-Rh sera recognized the D antigen (Rh-negative implies absence of the D antigen) while the antigen recognized by rabbit/guinea pig sera was renamed “LW” in honor of Landsteiner and Wiener (Levine et al. 1963). The LW antigen is expressed by both humans and Rhesus monkeys and is not part of the Rh blood system. (I discuss the basis for this initial confusion further below.) Rhesus monkeys do not express the D antigen and are therefore “Rh-negative.”
Rh-Negative Individuals Do Not Have a Separate Evolutionary History
The D antigen expressed by Rh-positive individuals is encoded by the RHD gene. This gene is the result of a duplication of the RHCE gene (Wagner and Flegel 2002) that occurred approximately 8.5 (± 3.4) million years ago, prior to the divergence of humans, gorillas, and chimpanzees (Matassi et al. 1999). Duplication events are fairly common evolutionarily; sometimes an entire genome is duplicated. A duplicated gene is often free from the selective pressures acting on the original. Over time, the protein encoded by the duplicate gene may become nonfunctional or change its function. If the original gene product had more than one function, duplication may result in division of these functions.
The proteins encoded by the RHCE and RHD genes are very similar but can be differentiated serologically using antibodies. The RHCE gene encodes the RhCE protein that includes two antigens with two forms of each: C/c and E/e. The RHD gene encodes the RhD protein that includes the D antigen recognized by anti-D antibodies, such as those found in the serum of the transfusion patient reported in 1939. These proteins have a structural role in the Rh complex found in the RBC membrane, and at least one of these is required for maintaining proper RBC shape—individuals lacking D (Rh-negative) or CE antigens have no RBC abnormalities, but individuals lacking both D and CE (Rhnull) have abnormal RBC morphology (Sturgeon 1970). Since the D antigen is found in the RBC membrane and there are some differences in interactions with the Rh complex containing the D polypeptide vs. the CcEe polypeptide (Beckmann et al. 2001), there may be a basis for differences in blood pressure or other blood properties based on membrane differences. Thus far, this has not been addressed.
The Rh complex includes two other proteins of importance to this discussion: Rh-associated glycoprotein (RhAG) and intercellular adhesion molecule-4 (ICAM-4). RhAG is a CO2 channel in the RBC membrane that is required for expression of RhCE/RhD and proper assembly of the Rh complex (Burton and Anstee 2008); defects in expression of RhAG result in one type of the Rhnull phenotype (Huang 1998). ICAM-4 includes the LW antigen recognized by the antibodies produced in rabbit and guinea pig in response to Rhesus monkey RBCs. Rh-positive cells show higher expression of LW, which caused the initial confusion between the LW and D antigens (Bailly et al. 1995).
Rh-positive individuals express the RhD protein encoded by the duplicated gene, RHD. In most cases, they are also expressing the RhCE protein and can be serologically typed for the C/c and E/e antigens. Unlike the D antigen, C and c (and E and e) are variants of the expressed antigens (upper and lower case do not indicate presence vs. absence of a single antigen). Rh-negative individuals do not express the D antigen (sometimes written as “d”). I suspect the notion of “unclonable blood” is due to a misunderstanding—molecular cloning involves expression of genes, and there is no “Rh-negative” gene. There is currently not a practical alternative to blood donation, but Rh-negative blood does not likely pose a greater technological challenge than Rh-positive blood.
Most Rh-negative individuals have a complete deletion of the RHD gene. Some of the mystique surrounding the Rh-negative blood type derives from claims that science can’t explain how the “Rh factor” was “lost” in some people. The mechanism for RHD deletion involves unequal crossing over between two highly homologous sequences called “Rhesus boxes” that bracket the RHD gene (Wagner and Flegel 2000). The deletion of the RHD gene probably occurred prior to migration out of Africa but was not present in a large number of people. Anatomically modern humans have lived in Europe since about 45,000 years ago, overlapping with the Neanderthals for about 15,000 years. Genes from Neanderthals represent approximately 2 percent of the genome of modern Eurasians and seem to result from multiple encounters with different non-African populations: (1) with modern humans shortly after they left Africa, which contributed Neanderthal genes to modern Europeans, Asians, and Melanesians; (2) with the ancestors of Eurasians—the ancestors of the Melanesians split from the ancestors of Eurasians, and modern Melanesians show a contribution from Denisovans (an extinct species of human different from the Neanderthals) rather than additional Neanderthal DNA; and (3) with the ancestors of East Asians after divergence from Europeans (Gibbons 2016; Vernot et al. 2016). Although non-Africans have some Neanderthal and possible Denisovan DNA, evidence available in the Ancient Genome Browser shows these populations were Rh-positive (Max Planck Institute for Evolutionary Anthropology 2016).
The last glacial maximum in Europe lasted from 25,000 to19,000 years ago and resulted in the population of Europe compressing into a few refuge areas (modern-day northern Spain/southern France, the Balkan peninsula, and the Ukraine). This led to a founder effect when the region was recolonized following deglaciation, increasing the Rh-negative phenotype as humans migrated out of the refuges and then mixed with Neolithic populations migrating from the Near East. The area of northern Spain/southern France that was a refuge during the last glacial maximum (sometimes called the Franco-Cantabrian refuge or the Iberian refuge) is also home to the Basques, who have an unusually high percentage of Rh-negative individuals (Mourant 1947).
Complete deletion of the RHD gene is the most common reason for testing Rh-negative; however, there are other gene variations that can result in a negative serological reaction as well as more than 200 alleles that are broadly classified into three groups based on serological reactivity patterns: weak D, partial D, and DEL. Some alleles are more common in specific ethnic populations, and although certain subtypes have clinical implications (e.g., transfusions), genotyping of patients is rarely performed (Sandler et al. 2015). A complete discussion of D antigen variants and the Rh blood system is outside the scope of this article, but it should now be clear that science can explain why some people are Rh-negative, and further that this explanation is more plausible than Rh-negative individuals being descended from an ancient reptilian race, extra-terrestrials, the Nephilim, etc. Also, for clarification, Rh-negative individuals are not more closely related to Rhesus macaques because they are both Rh-negative. Monkeys are Rh-negative because they never had the RHD gene; humans are Rh-negative because their evolutionary history includes the duplication event leading to expression of the antigen followed by a much later deletion or mutation of that gene in an ancestor.
There is a great deal of misunderstanding regarding the Rh-negative blood type, including the relationship of the Rh factor to Rhesus macaque proteins. Most claims of “known” associations with the Rh-negative blood type have no supporting evidence. Associations that have been shown do not necessarily reflect a role for the D antigen in the correlated trait but may reflect involvement of genes on the same chromosome that are co-inherited. Rh-positive individuals express the D antigen as a result of a gene duplication event that occurred prior to divergence from gorillas and chimpanzees. Rh-negative individuals do not express this antigen primarily as a result of a later gene deletion event in modern humans.
- Aflatoonian, Mohammad Reza, et al. 2011. Possible association between human blood types and opioid addiction. The American Journal on Addictions 20: 581–84.
- Bailly, Pascal, et al. 1995. The red cell LW blood group protein is an intercellular adhesion molecule which binds to CD11/CD18 leikocyte antigens. European Journal of Immunology 25: 3316–20.
- Beckmann, Roland, et al. 2001. Coexpression of band 3 mutants and Rh polypeptides: Differential effects of band 3 on the expression of the Rh complex containing D polypeptide and the Rh complex containing the CcEe polypeptide. Blood 97(8): 2496–505.
- Burton, Nicholas M., and David J. Anstee. 2008. Structure, function and significance of Rh proteins in red cells. Current Opinion in Hematology 15: 625–30.
- Ding, Qiliang, et al. 2014. Neanderthal origin of the haplotypes carrying the functional variant Val92Met in the MC1R in modern humans. Molecular Biology and Evolution 31(9): 1994–2003.
- Eiberg, Hans, et al. 2008. Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located with the HERC2 gene inhibiting OCA2 expression. Human Genetics 123: 177–87.
- Ellis, Lee, et al. 2008. Eye color, hair color, blood type, and the Rhesus factor: Exploring possible genetic links to sexual orientation. Archives of Sexual Behavior 37: 145–49.
- Fisk, Roy T., and Alvin G. Foord. 1942. Observations on the Rh agglutinogen of human blood. American Journal of Clinical Pathology 12: 545–52.
- Flegr, Jaroslav. 2013. Influence of latent Toxoplasma infection on human personality, physiology and morphology: Pros and cons of the Toxoplasma-human model in studying the manipulation hypothesis. The Journal of Experimental Biology 216: 127–33.
- Flegr, Jaroslav, Jan Geryk, et al. 2012. Rhesus factor modulation of effects of smoking and age on psychomotor performance, intelligence, personality profile, and health in Czech soldiers. PLoS ONE 7 (11): e49478.
- Flegr, Jaroslav, Rudolf Hoffman, et al. 2015. Worse health status and higher incidence of health disorders in Rhesus negative subjects. PLoS ONE 10 (10): e0141362.
- Flegr, Jaroslav, M. Novotná, et al. 2010. The influence of RhD phenotype on toxoplasmosis and age-associated changes in personality profile of blood donors. Folia Parasitologica 57(2): 143–50.
- Gibbons, Ann. 2016. Five matings for moderns, Neandertals. Science 351 (6279): 1250–51.
- Harding, Rosalind M., et al. 2000. Evidence for variable selective pressures at MC1R. American Journal of Human Genetics 66: 1351–61.
- Huang, Cheng-Han. 1998. The human Rh50 glycoprotein gene. The Journal of Biological Chemistry 273(4): 2207–13.
- Jones, K. L., et al. 2011. Chemokine receptor CCR5: From AIDS to atherosclerosis. British Journal of Pharmacology 162: 1453–69.
- Lalueza-Fox, Carles, et al. 2007. A melanocortin 1 receptor allele suggests varying pigmentation among Neanderthals. Science 318(5855): 1453–55.
- Landsteiner, Karl, and Alexander S. Wiener. 1940. An agglutinable factor in human blood recognized by immune sera for rhesus blood. Proceedings of the Society for Experimental Biology and Medicine 43: 223.
- ———. 1941. Studies on an agglutinogen (Rh) in human blood reacting with anti-Rhesus sera and with human isoantibodies. Journal of Experimental Medicine 74: 309–20.
- Levine, Philip, M.J. Celano, et al. 1963. A human “D-like” antibody. Nature 198: 596–97.
- Levine, Philip, and Rufus E. Stetson. 1939. An Unusual Case of Intra-group Agglutination. Journal of the American Medical Associations 113:126–27.
- Mai, F.M.M., and Anne Pike. 1970. Correlation of Rhesus (Rh) and personality factors. The British Journal of Social and Clinical Psychology 9: 83–84.
- Matassi, Giorgio, et al. 1999. The members of the RH gene family (RH50 and RH30) followed different evolutionary pathways. Journal of Molecular Evolution 48: 151–59.
- Max Planck Institute for Evolutionary Anthropology. 2016. “Ancient Genome Browser, RHD region on Chromosome 1.” Available online at https://bioinf.eva.mpg.de/jbrowse/?loc=1%3A25526458..25634183&tracks=Altai%2CDenisova%2Chg19_1000g%2CENSEMBL67&highlight=.
- Mourant, A.E. 1947. The blood groups of the Basques. Nature 160(4067): 505–06.
- Neumann-Haefelin, Christoph. 2013. HLA-B27-mediated protection in HIV and hepatitis C infection and pathogenesis in spondyloarthritis: Two sides of the same coin? Curent Opinion in Rheumatology 25(4): 426–33.
- Owen, David R. 1972. Blood type gene frequency and mental ability: Premature conclusions? Psychological Reports 31: 835–39.
- Rees, Jonathan L. 2000. The melanocortin 1 receptor (MC1R): More than just red hair. Pigment Cell Research 13: 135–40.
- ———. 2003. Genetics of hair and skin color. Annual Reviews in Genetics 37: 67–90.
- Röösli, Martin. 2008. Radiofrequency electromagnetic field exposure and non-specific symptoms of ill health: A systematic review. Environmental Research 107: 277–87.
- Sandler, S. Gerald, et al. 2015. It’s time to phase in RHD genotyping for patients with a serologic weak D phenotype. Transfusion 55: 680–89.
- Sheehan, Nicholas J. 2010. HLA-B27: What’s new? Rheumatology 49: 621–31.
- Sturgeon, Phillip. 1970. Hematological observations on the anemia associated with blood type Rhnull. Blood 36(3): 310–20.
- Valverde, Paloma, et al. 1995. Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nature Genetics 11: 328–30.
- Vernot, Benjamin, et al. 2016. Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals. Science 352(6282): 235–39.
- Wagner, Franz F., and Willy A. Flegel. 2000. RHD gene deletion occurred in the Rhesus box. Blood 95(12): 3662–68.
- ———. 2002. RHCE represents the ancestral RH position, while RHD is the duplicated gene. Blood 99(6): 2272–73.
- Wilde, Sandra, et al. 2014. Direct evidence for positive selection of skin, hair, and eye pigmentation in Europeans during the last 5,000 y. PNAS 111(13): 4832–37.