N-Glycolylneuraminic Acid Expression

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Human Uniqueness Compared to "Great Apes": 
Absolute Difference
Human Universality: 
Individual Universal (All Individuals Everywhere)
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Humans are deficient in a common mammalian cell surface sialic acid called N-Glycolylneuraminic Acid (Neu5Gc). This results from the human homozygous state for an Alu-replacement mediated inactivating mutation in the CMAH gene, which is responsible for generating Neu5Gc from its precursor N-Acetylneuraminic Acid (Neu5Ac). The Neu5Gc loss thus also results in an excess of cell surface Neu5Ac in humans. Human-specific differences from great apes in the structure, function and expression patterns of a family of genes called Siglecs may also be a consequence of this event. There are other implications for the human condition, ranging from susceptibility or resistance to some microbial pathogens that use sialic acids as sign-posts for invading pathogens; effects on the "set state" of reactivity of the immune system; the expression of Neu5Gc as a "foreign" antigen in cancers; the consequences of human dietary intake of Neu5Gc from certain animal foods; and potential effects on speciation of Homo, and on human brain evolution.

 

 

Timing

Timing of appearance of the difference in the Hominin Lineage as a defined date or a lineage separation event. The point in time associated with lineage separation events may change in the future as the scientific community agrees upon better time estimates. Lineage separation events are defined in 2017 as:

  • the Last Common Ancestor (LCA) of humans and old world monkeys was 25,000 - 30,000 thousand (25 - 30 million) years ago
  • the Last Common Ancestor (LCA) of humans and chimpanzees was 6,000 - 8,000 thousand (6 - 8 million) years ago
  • the emergence of the genus Homo was 2,000 thousand (2 million) years ago
  • the Last Common Ancestor (LCA) of humans and neanderthals was 500 thousand years ago
  • the common ancestor of modern humans was 100 - 300 thousand years ago

Possible Appearance: 
3,000 thousand years ago
Probable Appearance: 
2,000 thousand years ago
Definite Appearance: 
100 thousand years ago
Background Information: 

All cells in multi-cellular organisms are covered with a dense and complex coating of sugars that consists of several type of units called monosaccharides. These are usually strung together in chains (called oligosaccharides or glycan chains). These glycan chains are in turn typically attached to proteins (glycoproteins) or lipids (glycolipids) that comprise the cell surface. In all vertebrates, and in some "higher" invertebrates, the outermost ends of such glycan chains are often terminated by one or more units of a family of 9-carbon monosaccharides called sialic acids. One particular kind of sialic acid called N-glycolylneuraminic acid (Neu5Gc) is commonly expressed on mammalian cells. Sialic Acids have important functions within a multi-cellular organism that makes them. However, they are also the cell surface targets for a variety of microbial pathogens that attack such organisms. When animal serum containing Neu5Gc that is attached to serum glycoproteins or glycolipids is injected into adult humans for various therapeutic purposes, it frequently provokes an immune response, characterized by the production of antibodies against Neu5Gc, and a clinical syndrome called "serum sickness". This fact, together with previous studies analyzing the sialic acids of human tissues first raised the possibility that human might be deficient in this sialic acid.

The Human Difference: 

Analysis of multiple tissues and body fluids from many humans of diverse geographic origins showed that Neu5Gc is completely absent, or present in only trace amounts on human cells. In contrast, Neu5Gc comprises a major fraction of the total sialic acids in most tissues and body fluids from great apes. The human deficiency of Neu5Gc is explained by an inactivating mutation in the gene encoding CMP-N-acetylneuraminic acid hydroxylase (CMAH), an enzyme that is the rate-limiting factor in metabolic synthesis of Neu5Gc in the cells of other mammals. The CMAH gene is intact and functional in many other mammals studied to date, including mice, pigs, and "great apes". The human deficiency of Neu5Gc also results in an excess of another sialic acid called N-acetylneuraminic acid (Neu5Ac), which is the metabolic precursor of Neu5Gc. Thus, the total amount of sialic acids on cell surfaces does not appear to be altered in humans, when compared to the great apes.

Universality in Human Populations: 

The CMAH mutation appears to be identical in, and universal to, all human populations studied to date.  It is highly likely that this single specific mutation is fixed in humans.

Mechanisms Responsible for the Difference: 

The human-specific mutation in the CMAH gene is a deletion of a genomic segment including the 92-base pair sized exon 6. This results in a frame shift in the coding sequence of the messenger RNA generated by the gene. Thus, even if the messenger RNA were translated, the resulting protein would be very short (72 amino acids) and unlikely to have any enzymatic activity (the 92 bp deleted exon also happens to include the coding sequences for certain amino acids thought to be required for the activity of the enzyme). The genetic mechanism of the original exon deletion appears to have been a side effect of the replacement of an adjacent ancient "Alu" transposon element with a younger, human-specific Alu element.  

Possible Selection Processes Responsible for the Difference: 

The original selection mechanisms responsible for this human-specific mutation remain uncertain. A likely possibility is that an epidemic caused by a pathogenic microbial organism e.g. a form of malaria that required Neu5Gc for infecting cells may have eliminated individuals who did not have the homozygous CMAH mutation. Another possibility was that the CMAH mutation was positively selected for because the loss of Neu5Gc conferred some other functional advantage to such individuals.  Finally it possible that the mutation simply drifted to fixation in a small effective population. 

Implications for Understanding Modern Humans: 

1. INFECTIOUS DISEASES: The lack of cell surface Neu5Gc should render humans resistant to microbial pathogens that require cell surface Neu5Gc for invasion. This could explain the apparent lack of susceptibility of humans to certain domestic livestock pathogens and toxins that use Neu5Gc to invade human cells. Conversely, the excess of cell surface Neu5Ac in humans could render them more susceptible microbial pathogens that use Neu5Ac to support invasion. This appears to be the case for P.falciparum malaria.  In at least case though,  human incorporation of dietary Neu5Gc can render an individual susceptible to a Neu5Gc-preferring toxin.
2. IMMUNE SYSTEM: The functions of certain endogenous receptors for sialic acids in the immune system (called Siglecs) seem be altered by this difference. Most or all  adult humans also seem to have circulating antibodies directed against Neu5Gc containing glycans.
3. HUMAN DIETARY INTAKE OF Neu5Gc FROM ANIMAL-DERIVED FOODS: Despite the lack of any obvious alternate pathway for its synthesis, Neu5Gc is present in human tumors and in human fetal tissues, and small amounts have been detected in normal human tissues. The most likely explanation is that this represents accumulation of Neu5Gc from dietary sources of animal origin. In combination with the presence of circulating anti-Neu5Gc antibodies, this tissue accumulation could be related to some diseases associated with chornic inflammation, such as cancers.
4. BRAIN DEVELOPMENT/FUNCTION: Despite relatively high levels of Neu5Gc in many tissues of most mammals, all mammalian brains studied to date have very low levels of Neu5Gc. This appears to be due to reduced expression of the CMAH mRNA in the brains of non-human mammals. However, small amounts of Neu5Gc are still present in mammalian brains studied to date, presumably because complete suppression of expression of CMAH has not occurred. This raises the possibility that the human-specific mutation of this enzyme could have played a role in human brain evolution, by completely eliminating Neu5Gc from the brain.

 

Occurrence in Other Animals: 

Neu5Gc appears to be widely distributed in many animals that express sialic acids, ranging from sea urchins to mammals. However, there are significant inter-species variations in the level of expression of Neu5Gc in non-neural tissues. There is at least one other published instance of a species that produces an immune response to Neu5Gc - the domesticated chicken. Neu5Gc has not been found so far in the limited set of adult chicken tissues studied, and has also not been in many other bird and reptile tissues. The genetic basis of the apparent avian deficiency of Neu5Gc is not clear at this time, but it has even been suggested the entire sauropod lineage (the dinosaurs that gave rise ot modern birds and reptile may be deficient in CMAH.  It is likely that other taxa will be found that have independently eliminated Neu5Gc.  But the human event appears to be an independent and unique one among old world monkeys.

References

  1. N-glycolyl groups of nonhuman chondroitin sulfates survive in ancient fossils, Bergfeld, Anne K., Lawrence Roger, Diaz Sandra L., Pearce Oliver M. T., Ghaderi Darius, Gagneux Pascal, Leakey Meave G., and Varki Ajit , PNAS, 09/2017, (2017)
  2. Uniquely human evolution of sialic acid genetics and biology, Varki, A. , Proc Natl Acad Sci U S A, May 11, Volume 107 Suppl , p.8939-46, (2010)
  3. Multiple changes in sialic acid biology during human evolution., Varki, A. , Glycoconj J, 04/2009, Volume 26, Issue 3, p.231-45, (2009)
  4. Glycan-based interactions involving vertebrate sialic-acid-recognizing proteins., Varki, A. , Nature, 04/2007, Volume 446, Issue 7139, p.1023-9, (2007)