epistasis

Moore JH & Williams SM 2009 Epistasis and its implications for personal genetics. Am J Hum Genet 85:309-320.

  • genetic epidemiology has preferred Fisher's definition of epistasis to Bateson's
  • this has led to analytical approaches that significantly hurt our ability to model real genetic architecture
  • the historical sidetracking of Bateson's biological epistasis for Fisher's statistical definition, which he called "epistacy," has been noted
  • going from a population-level statistical summary of gene-gene interactions to inferences about the biological interactions occurring at the cellular level is a significant and difficult leap
  • translating our knowledge of gene networks and cellular function at the individual level to predictions about public health is equally difficult
  • systems biology holds the promise to help us traverse this conceptual and practical divide
  • Askland et al. recently showed that patterns of SNPs in biological pathways are more likely to replicate than individual SNPs in GWAS
  • Wilke et al. have suggested that we should not even begin to analyze a GWAS study until we have exhaustively studied each candidate gene and each pathway
  • only then will we have the appropriate knowledge base to make sense of GWAS results
  • there is a major shift in the field of genetic epidemiology away from the purely statistical approaches to more bioinformatic approaches that consider knowledge about gene function, gene networks, and biochemical pathways
  • 2009 perhaps marks the turning point toward more of a systems approach that recognizes the role of epistasis and other complexities in genetic architecture
  • pedigrees have been put aside in favor of large population-based case-control studies for GWAS
  • there will be a return to pedigree-based studies and other methods consistent with classical genetics
  • technology-centric approaches have significant shortcomings
  • one of the greatest contributions to our understanding of biological organisms was the merger of Darwin's evolution of species by natural selection and Mendel's principles of heredity
  • it paved the way for evolutionary and population genetics as we know them today
  • we are presently undergoing a "more modern" synsthesis that merges multiple disciplines into what has been referred to as systems biology
  • the vast divide between biological and statistical epistasis will only be narrowed by our success in applying systems biology to genetics problems