Predicting genetic modifier loci using functional gene networks

Insuk Lee, Ben Lehner, Tanya Vavouri, Junha Shin, Andrew G. Fraser, Edward M. Marcotte

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

Most phenotypes are genetically complex, with contributions from mutations in many different genes. Mutations in more than one gene can combine synergistically to cause phenotypic change, and systematic studies in model organisms show that these genetic interactions are pervasive. However, in human association studies such nonadditive genetic interactions are very difficult to identify because of a lack of statistical power - simply put, the number of potential interactions is too vast. One approach to resolve this is to predict candidate modifier interactions between loci, and then to specifically test these for associations with the phenotype. Here, we describe a general method for predicting genetic interactions based on the use of integrated functional gene networks. We show that in both Saccharomyces cerevisiae and Caenorhabditis elegans a single high-coverage, high-quality functional network can successfully predict genetic modifiers for the majority of genes. For C. elegans we also describe the construction of a new, improved, and expanded functional network, WormNet 2. Using this network we demonstrate how it is possible to rapidly expand the number of modifier loci known for a gene, predicting and validating new genetic interactions for each of three signal transduction genes. We propose that this approach, termed network-guided modifier screening, provides a general strategy for predicting genetic interactions. This work thus suggests that a high-quality integrated human gene network will provide a powerful resource for modifier locus discovery in many different diseases.

Original languageEnglish
Pages (from-to)1143-1153
Number of pages11
JournalGenome Research
Volume20
Issue number8
DOIs
Publication statusPublished - 2010 Aug

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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    Lee, I., Lehner, B., Vavouri, T., Shin, J., Fraser, A. G., & Marcotte, E. M. (2010). Predicting genetic modifier loci using functional gene networks. Genome Research, 20(8), 1143-1153. https://doi.org/10.1101/gr.102749.109