CMAH (cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMP-N-acetylneuraminate monooxygenase) pseudogene)

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Human Uniqueness Compared to "Great Apes": 
Absolute Difference
Human Universality: 
Individual Universal (All Individuals Everywhere)
MOCA Domain: 
MOCA Topic Authors: 

Sialic acids are sugars typically found at the outer terminal position of glycan chains that cover the surface of all vertebrate cells. The most commonly-expressed sialic acid is N-acetylneuraminic acid (Neu5Ac), which is the precursor for N-glycolylneuraminic acid (Neu5Gc) synthesis -  a conversion mediated by  action of the CMP-N-acetylneuraminic acid hydroxylase (CMAH) enzyme. While both Neu5Ac and Neu5Gc are found to be expressed in many mammals (including our closest evolutionary cousins, the great apes), the single-copy human CMAH gene was pseudogenized by an Alu-mediated deletion event, which seems to have occurred ~2-3 million years ago in our ancestors, and is now universal to the human population. This genetic loss has multiple consequences that are still being investigated, ranging from pathogen susceptibility to changes in the immune system. It may even have contributed to relative reproductive incompatibility that was involved in the origin of the genus Homo.


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 (Lineage Separation Event): 
Definite Appearance (Lineage Separation Event): 
Related MOCA Topics
Genetics Topic Attributes
Gene symbols follow the HUGO Gene Nomenclature Committee standard.
Gene Symbol Type of Human-Specific Changes
CMAH Pseudogenization


  1. Human-like Cmah Inactivation in Mice Increases Running Endurance and Decreases Muscle Fatigability: Implications for Human Evolution, Okerblom, JJ, Fletes W, Patel HH, Schenk S, Varki Ajit, and Breen EC , Proceedings of the Royal Society (Biological Sciences), 09/2018, Volume 285, Issue 1886, (2018)
  2. Sexual selection by female immunity against paternal antigens can fix loss of function alleles, Ghaderi, D., Springer S. A., Ma F., Cohen M., Secrest P., Taylor R. E., Varki Ajit, and Gagneux P. , Proc Natl Acad Sci U S A, Oct 25, Volume 108, Number 43, p.17743-8, (2011)
  3. Uniquely human evolution of sialic acid genetics and biology, Varki, Ajit , Proc Natl Acad Sci U S A, May 11, Volume 107 Suppl , p.8939-46, (2010)
  4. N-glycolylneuraminic acid deficiency in mice: implications for human biology and evolution., Hedlund, Maria, Tangvoranuntakul Pam, Takematsu Hiromu, Long Jeffrey M., Housley Gary D., Kozutsumi Yasunori, Suzuki Akemi, Wynshaw-Boris Anthony, Ryan Allen F., Gallo Richard L., et al. , Mol Cell Biol, 2007 Jun, Volume 27, Issue 12, p.4340-6, (2007)
  5. Fixation of the human-specific CMP-N-acetylneuraminic acid hydroxylase pseudogene and implications of haplotype diversity for human evolution, Hayakawa, T., Aki I., Varki Ajit, Satta Y., and Takahata N. , Genetics, Feb, Volume 172, Number 2, p.1139-46, (2006)
  6. Inactivation of CMP-N-acetylneuraminic acid hydroxylase occurred prior to brain expansion during human evolution, Chou, H. H., Hayakawa T., Diaz S., Krings M., Indriati E., Leakey M., Paabo S., Satta Y., Takahata N., and Varki Ajit , Proc Natl Acad Sci U S A, Sep 3, Volume 99, Number 18, p.11736-41, (2002)