Predicting genetic modifier loci using functional gene networks.
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.
Lee
Insuk
I
Department of Biotechnology, College of Life science and Biotechnology, Yonsei University, Seodaemun-ku, Seoul 120-749, South Korea. insuksysbio@gmail.com
Lehner
Ben
B
Vavouri
Tanya
T
Shin
Junha
J
Fraser
Andrew G
AG
Marcotte
Edward M
EM
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics; D053263:Gene Regulatory Networks; D056426:Genetic Loci; D008957:Models, Genetic; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods*; D015398:Signal Transduction / Q000235:genetics