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

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, Ϸ0.5-0.6 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 Ϸ2.7 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 Ϸ2.8 mya. Taken together, these studies indicate that the CMAH gene was inactivated shortly before the time when brain expansion began in humankind's ancestry, Ϸ2.1-2.2 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. hominid evolution ͉ sialic acids ͉ Alu sequences

Large-scale sequencing of the CD33-related Siglec gene cluster in five mammalian species reveals rapid evolution by multiple mechanisms

“…This evolutionary change occurred in the human lineage after our last common ancestor with the chimpanzee and bonobo (10,11), allowing recognition of N-acetylneuraminic acid, which, being a precursor to Neu5Gc accumulates at higher levels in humans (12). These data favor the hypothesis that CD33rSiglecs function primarily as self-recognition receptors for endogenous Sia ligands.…”

DNA sequence and comparative analysis of chimpanzee chromosome 22

“…If we could determine the oldest expansion event through genomic comparison, we might be able to identify whether such an Alu burst was the driving force for speciation between the two species from the common ancestor. Amplification of Alu elements during the evolution of primates and alteration of gene functions through the insertion of repetitive elements has been discussed in many previous studies [25][26][27][28][29][30][31][32][33][34] . However, further wide-ranging analyses comparing the chimpanzee and other primate genomes is necessary to clarify these points.…”

Inviting instability: Transposable elements, double-strand breaks, and the maintenance of genome integrity

“…While a number of TE-related rearrangement events have resulted in key innovations during evolution (e.g. [1,2]), it is nevertheless the case that these events are more frequently neutral or deleterious in terms of organismal fitness. The negative consequences of instability are perhaps best illustrated by the 25 distinct human genetic diseases that are attributable to TE-related rearrangements [3].…”