FOXO3B

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box protein O3B

Publications[править]

Genetic investigation of FOXO3A requires special attention due to sequence homology with FOXO3B.

Our study demonstrates that the genetic investigation of forkhead box O3A gene (FOXO3A), a validated human longevity gene, is greatly hampered by the fact that its exonic regions have 99% sequence homology with the FOXO3B pseudogene. If unaccounted for, this high degree of homology can cause serious genotyping or sequencing errors. Here, we present an experimental set-up that allows reliable data generation for the highly homologous regions and that can be used for the evaluation of assay specificity. Using this design, we exemplarily showed FOXO3A-specific results for two single-nucleotide polymorphisms (SNPs) (rs4945816 and rs4946936) that are significantly associated with longevity in our centenarian-control sample (P(each)=0.0008). Because both SNPs are located in the 3' untranslated region of FOXO3A, they could be of functional relevance for the longevity phenotype. Our experimental set-up can be used for reliable and reproducible data generation for further sequencing and genotyping studies of FOXO3A with the aim of discovering new SNPs of functional relevance.

MeSH Terms

  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Genotype
  • Humans
  • Longevity
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Pseudogenes
  • Sequence Homology


FOXO3 gene variants and human aging: coding variants may not be key players.

FOXO3 is generally recognized as a "master" gene in aging since its association with longevity has been replicated in multiple organisms and human populations. A group of single nucleotide polymorphisms in linkage disequilibrium with a coding region has been associated with human longevity, but the actual functional variant is unidentified. Therefore, we sequenced the coding region in our long-lived Japanese American population in order to enhance resources for fine mapping this region. We demonstrate that of 38 published variants, 6 are misalignments with homologous nonallelic sequences from FOXO3B (ZNF286B), a pseudogene on a different chromosome; 2 are attributable to ZNF286B only, and the remaining 30 were unconfirmed, indicating that they are very rare and not likely involved in longevity. Furthermore, we identified a novel, unique, nonsynonymous coding variant in exon 3 (Gly566Ala; rs138174682) that is prevalent in multiple ethnic groups but appeared too rare for major longevity effects in our study populations.

MeSH Terms

  • Aged
  • Aged, 80 and over
  • Aging
  • Alleles
  • Asian Americans
  • Case-Control Studies
  • Chromosome Mapping
  • Cohort Studies
  • European Continental Ancestry Group
  • Female
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Genetic Variation
  • Humans
  • Longevity
  • Male
  • Middle Aged
  • Open Reading Frames
  • Polymorphism, Single Nucleotide
  • Sensitivity and Specificity