Apolipoprotein E variation at the sequence haplotype level: implications for the origin and maintenance of a major human polymorphism.
Level 4 - case-series / case-control
Descriptive cross-sectional genomic sequencing study; level assigned by design analogy
PubMed 10986041 · doi:10.1086/303070
What was done
Researchers sequenced a 5.5-kb genomic DNA region encompassing the entire APOE locus and flanking regions in 96 individuals (192 chromosomes; 48 chromosomes per population) across four populations: Black individuals from Jackson, MS; Mayans from Campeche, Mexico; Finns from North Karelia, Finland; and non-Hispanic White individuals from Rochester, MN. They also sequenced the chimpanzee APOE gene to determine ancestral states and reconstruct haplotype relationships.
What was found
The 5.5-kb region contained 23 variable sites (21 single nucleotide polymorphisms, 1 diallelic indel, and 1 multiallelic indel), defining 31 distinct haplotypes across the 22 diallelic sites. Nucleotide diversity was 0.0005 +/- 0.0003. Chimpanzee APOE sequence was most closely related to human epsilon4 haplotypes, differing from human consensus at 67 synonymous fixed positions (54 substitutions, 13 indels) and 9 nonsynonymous fixed positions. Haplotype analysis indicated epsilon3 and epsilon2 alleles derived from ancestral epsilon4, with epsilon3 increasing in frequency relative to epsilon4 over the past 200,000 years, and revealed substantial sequence heterogeneity within all three protein isoform classes.
Why it matters
This study establishes that the Alzheimer- and cardiovascular-risk allele epsilon4 is the ancestral human APOE state and shows that major protein isoforms encompass hidden sequence-level haplotype diversity across human populations.
Limits
The sample size was small (96 individuals total, 24 per population), limiting identification of low-frequency haplotypes. The study was descriptive and evolutionary, without direct clinical, phenotypic, or functional assays linked to the specific sequence haplotypes.
Cited by
- contradicts The ApoE4 allele was the primordial human isoform present during roughly 96% of hominid evolution, whereas chimpanzees lack ApoE4.