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

TLDR

Humans lack the sialic acid Neu5Gc due to a CMAH gene inactivation that arose after the last common ancestor with bonobos and chimpanzees, and Neu5Gc expression is markedly reduced in the brain. The study aims to pinpoint the timing of the CMAH inactivation relative to human evolutionary milestones. Researchers combined bone sialic acid extraction, dating of a human‑specific Alu Y insertion adjacent to CMAH, and molecular‑clock analyses of ape CMAH genes to estimate the mutation’s age. These analyses place the CMAH inactivation at approximately 2.7–2.8 million years ago, shortly before the onset of brain expansion around 2.1–2.2 million years ago.

Abstract

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 Neandertal fossils studied had clearly detectable Neu5Ac but no Neu5Gc, indicating that the CMAH mutation predated the common ancestor of humans and Neandertals, ≈0.5–0.6 million years ago (mya). Second, we date the insertion event of the inactivating human-specific sah Alu Y element that replaced the ancestral Alu Sq 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 sah Alu Y insertion time at ≈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 ≈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, ≈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.