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

Authors:
Friederike Flachsbart, Michael Möller, Carolin Däumer, Liljana Gentschew, Rabea Kleindorp, Michael Krawczak, Amke Caliebe, Stefan Schreiber, Almut Nebel
Year of publication:
2013
Volume:
21
Issue:
2
Issn:
1018-4813
Journal title abbreviated:
EUR J HUM GENET
Journal title long:
European journal of human genetics
Impact factor:
4.580
Abstract:
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.