Inactivation of CMP-N-acetylneuraminic acid hydroxylase occurred prior to brain expansion during human evolution

Bibliographic Collection: 
CARTA-Inspired Publication, APE
Publication Type: Journal Article
Authors: Chou, H. H.; Hayakawa, T.; Diaz, S.; Krings, M.; Indriati, E.; Leakey, M.; Paabo, S.; Satta, Y.; Takahata, N.; Ajit Varki
Year of Publication: 2002
Journal: Proc Natl Acad Sci U S A
Volume: 99
Edition: 2002/08/23
Number: 18
Pagination: 11736-41
Date Published: Sep 3
Type of Article: Research Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.
Publication Language: eng
ISBN Number: 0027-8424 (Print)0027-84
Accession Number: 12192086 PMID
Keywords: &, *Biological Evolution, Animals, Base Sequence, Brain/*enzymology/growth, Complementary, development, DNA, DNA Primers, Fossils, Gorilla gorilla/genetics, Hominidae/genetics, Humans, inhibitors, Mixed Function Oxygenases/*antagonists, Molecular S

Humans are genetically deficient in the common mammalian sialic acid N-glycolylneuraminic acid (Neu5Gc) because of an Alu-mediated inactivating mutation of the gene encoding the enzyme CMP-N-acetylneuraminic acid (CMP-Neu5Ac) hydroxylase (CMAH). This mutation occurred after our last common ancestor with bonobos and chimpanzees, and before the origin of present-day humans. Here, we take multiple approaches to estimate the timing of this mutation in relationship to human evolutionary history. First, we have developed a method to extract and identify sialic acids from bones and bony fossils. Two Neanderthal fossils studied had clearly detectable Neu5Ac but no Neu5Gc, indicating that the CMAH mutation predated the common ancestor of humans and the Neanderthal, approximately 0.5-0.6 million years ago (mya). Second, we date the insertion event of the inactivating human-specific sahAluY element that replaced the ancestral AluSq element found adjacent to exon 6 of the CMAH gene in the chimpanzee genome. Assuming Alu source genes based on a phylogenetic tree of human-specific Alu elements, we estimate the sahAluY insertion time at approximately 2.7 mya. Third, we apply molecular clock analysis to chimpanzee and other great ape CMAH genes and the corresponding human pseudogene to estimate an inactivation time of approximately 2.8 mya. Taken together, these studies indicate that the CMAH gene was inactivated shortly before the time when brain expansion began in humankind's ancestry, approximately 2.1-2.2 mya. In this regard, it is of interest that although Neu5Gc is the major sialic acid in most organs of the chimpanzee, its expression is selectively down-regulated in the brain, for as yet unknown reasons.


Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11736-41. Epub 2002 Aug 21

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Alternate Journal: Proceedings of the National Academy of Sciences of the United States of America
Author Address:

Glycobiology Research and Training Center, Department of Medicine, University of California at San Diego, La Jolla, CA 92093-0687, USA.