Arginine residues at codons 112 and 158 in the apolipoprotein E gene correspond to the ancestral state in humans.

Apolipoprotein E is a secretory glycoprotein that associates with lipoprotein particles and is coded for by a single locus on chromosome 19. The three common allelic isoforms of this protein (apo E2, apo E3 and apo E4) are associated with distinct patterns of lipoprotein metabolism and variable risks for coronary artery disease. In addition, recent work has shown that the presence of the apo E4 isoform constitutes a major risk for developing late-onset Alzheimer's disease as well as hypercholesterolaemia. The only differences between these isoforms result from cysteine-arginine interchanges at codons 112 and 158. There is considerable disagreement in the literature concerning the identity of the ancestral allele. In order to resolve this, 24 chimpanzees and individuals from a number of other primate species were analysed. All were similar to apo E4. This suggests that apo E4 is the ancestral allele and that apo E2 and apo E3 arose after the split of the human and chimpanzee lineages.