Abstract
A genetic interaction (GI) is defined when the mutation of one gene modifies the phenotypic expression associated with the mutation of a second gene. Genome-wide efforts to map GIs in yeast revealed structural and functional properties of a GI network. This provided insights into the mechanisms underlying the robustness of yeast to genetic and environmental insults, and also into the link existing between genotype and phenotype. While a significant conservation of GIs and GI network structure has been reported between distant yeast species, such a conservation is not clear between unicellular and multicellular organisms. Structural and functional characterization of a GI network in these latter organisms is consequently of high interest. In this study, we present an in-depth characterization of ~1.5K GIs in the nematode Caenorhabditis elegans. We identify and characterize six distinct classes of GIs by examining a wide-range of structural and functional properties of genes and network, including co-expression, phenotypical manifestations, relationship with protein-protein interaction dense subnetworks (PDS) and pathways, molecular and biological functions, gene essentiality and pleiotropy. Our study shows that GI classes link genes within pathways and display distinctive properties, specifically towards PDS. It suggests a model in which pathways are composed of PDS-centric and PDS-independent GIs coordinating molecular machines through two specific classes of GIs involving pleiotropic and non-pleiotropic connectors. Our study provides the first in-depth characterization of a GI network within pathways of a multicellular organism. It also suggests a model to understand better how GIs control system robustness and evolution.
Highlights
The behaviour of biological systems and their adaptation to environmental changes depend on many factors on the path from genomic structure, through gene expression, molecular and functional interactions, to phenotypic manifestations
Considering that the function and the structure of genetic interaction networks are mainly unknown for multicellular organisms while being of increasing interest, we characterized a network composed of ~1,500 GIs of the nematode C. elegans
We showed that GIs form a heterogeneous group of entities with respect to attributes computed from expression, protein-protein interaction (PPI) and phenotype data
Summary
The behaviour of biological systems and their adaptation to environmental changes depend on many factors on the path from genomic structure, through gene expression, molecular and functional interactions, to phenotypic manifestations. Level III), the functional relationship between these elements (level IV), their biological and molecular function (level V) and the phenotypical manifestations (level VI). To simplify studies of these different levels of information, systems biologists may build a theoretical framework where biological systems are decomposed into six abstraction levels [1]: the genome structure (level I), the gene expression (level II), the physical interaction between systems elements Within this framework, genetic interactions (GIs) are located at the level IV together with signaling and metabolic pathways [1]. Mapping GIs in human recently emerged as a necessity to identify biomarkers from Genome-wide association studies (GWAS) and move the medical field towards a more personalized practice [2]
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