The Apolipoprotein E (APOE) Gene Appears Functionally Monomorphic in Chimpanzees (Pan troglodytes)

Abstract

BackgroundThe human apolipoprotein E (APOE) gene is polymorphic, with three primary alleles (E2, E3, E4) that differ at two key non-synonymous sites. These alleles are functionally different in how they bind to lipoproteins, and this genetic variation is associated with phenotypic variation for several medical traits, including cholesterol levels, cardiovascular health, Alzheimer’s disease risk, and longevity. The relative frequencies of these alleles vary across human populations, and the evolution and maintenance of this diversity is much debated. Previous studies comparing human and chimpanzee APOE sequences found that the chimpanzee sequence is most similar to the human E4 allele, although the resulting chimpanzee protein might function like the protein coded for by the human E3 allele. However, these studies have used sequence data from a single chimpanzee and do not consider whether chimpanzees, like humans, show intra-specific and subspecific variation at this locus.Methodology and Principal FindingsTo examine potential intraspecific variation, we sequenced the APOE gene of 32 chimpanzees. This sample included 20 captive individuals representing the western subspecies (P. troglodytes verus) and 12 wild individuals representing the eastern subspecies (P. t. schweinfurthii). Variation in our resulting sequences was limited to one non-coding, intronic SNP, which showed fixed differences between the two subspecies. We also compared APOE sequences for all available ape genera and fossil hominins. The bonobo APOE protein is identical to that of the chimpanzee, and the Denisovan APOE exhibits all four human-specific, non-synonymous changes and appears functionally similar to the human E4 allele.ConclusionsWe found no coding variation within and between chimpanzee populations, suggesting that the maintenance of functionally diverse APOE polymorphisms is a unique feature of human evolution.

ApoE4 upregulates the activity of mitochondria‐associated ER membranes

“…We also note that from an evolutionary point of view, the ApoE4 genotype is apparently present only in the primate line, including ancestors to humans 59, implying that the maintenance of the ε4 allele in this genus may actually confer a selective advantage. Besides the aforementioned role of ApoE4 in apoptosis 20 (a MAM‐mediated function 60), another possible advantage might be in resistance to infection 61, 62.…”

Insulin resistance and cognitive dysfunction

“…ApoE is a polymorphic protein with common variants known as E2, E3, and E4 that are encoded by the ε2, ε3, and ε4 alleles, respectively, with population frequencies of approximately 8, 77 and 15%, respectively [97][98][99]. ApoE4 has been confirmed as an important factor for dementia and progress of cognitive impairment in the elderly [100,101].…”

Exercise, APOE genotype, and the evolution of the human lifespan

“…Even after the evolution of other alleles, ε4 remained present in our ancestors, given that McIntosh et al [67] showed that the Denisovan hominin (30 000–80 000-years old) appears to have had the ε4 allele. Although direct measures of lipid binding have not been assessed, living chimpanzees have a form of the APOE gene that is believed to be functionally similar to the human APOE ε3 allele based on amino acid predictions, and the chimpanzee APOE amino acid sequence is monomorphic [67], suggesting the ε4 allele was an evolutionary novelty during human evolution (Box 2). …”