Alu -mediated inactivation of the human CMP- N -acetylneuraminic acid hydroxylase gene

Abstract

Inactivation of the CMP-N-acetylneuraminic acid hydroxylase gene has provided an example of human-specific genomic mutation that results in a widespread biochemical difference between human and nonhuman primates. We have found that, although a region containing a 92-bp exon and an AluSq element in the hydroxylase gene is intact in all nonhuman primates examined, the same region in the human genome is replaced by an AluY element that was disseminated at least one million years ago. We propose a mechanistic model for this Alu-mediated replacement event, which deleted the 92-bp exon and thus inactivated the human hydroxylase gene. It is suggested that Alu elements have played potentially important roles in genotypic and phenotypic evolution in the hominid lineage.

Fixation of the Human-Specific CMP-N-Acetylneuraminic Acid Hydroxylase Pseudogene and Implications of Haplotype Diversity for Human Evolution

“…This region is 8100 and 8099 bp long for the gorilla and the chimpanzee, respectively, but it varies from 7611 to 7637 bp in the human. The region contains a human-specific AluY that replaced a genomic region, including functionally important exon 6 (Hayakawa et al 2001). The AluY insertion is found in all human chromosomes examined, but not in the chimpanzee or in the gorilla.…”

“…Hayakawa et al (2001) studied the genomic sequences around exon 6 of various primate species and found that whereas the exon and a nearby AluSq element are present in all nonhuman primates, they are completely replaced by a young AluY element in humans. On the basis of the finding of a potential target-priming sequence by the Alu poly(A) tail located in the 59 region immediately adjacent to the upstream deletion boundary, an Alu-mediated replacement of a genomic region was proposed as the underlying molecular mechanism (Hayakawa et al 2001). Subsequently, Chou et al (2002) took multiple approaches to estimate the timing of this Alu-mediated replacement.…”

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

“…Inactivation of CMAH evidently involved replacement of an ancient AluSq present in the humanchimpanzee ancestral genome with a younger sahAluY (sialic acid hydroxylase AluY) that is related to the AluYb8 subfamily (18). We used the timing of human Alu integration events to calculate the inactivation time of CMAH.…”

“…This mutation is homozygous in all human populations but absent in great apes (3,5,18)-i.e., it occurred after our last common ancestor with chimpanzees but before the diaspora of present-day humans. This mutation was apparently caused by a human-specific sahAluY element that replaced an ancestral AluSq element found adjacent to exon 6 of the CMAH gene in the genomes of great apes (18).…”

“…Thus, we directly analyzed present-day human, great ape, and Neandertal and other fossil samples for the presence of Neu5Ac and Neu5Gc. Second, we estimated the timing of the Alu integration event that inactivated the human CMAH (18). Finally, because pseudogenes have different rates of nucleotide substitution as compared with active genes subject to selection, we used the molecular clock approach to date the mutation in the human CMAH gene (21).…”