Edgetic perturbation models of human inherited disorders.
Cellular functions are mediated through complex systems of macromolecules and metabolites linked through biochemical and physical interactions, represented in interactome models as 'nodes' and 'edges', respectively. Better understanding of genotype-to-phenotype relationships in human disease will require modeling of how disease-causing mutations affect systems or interactome properties. Here we investigate how perturbations of interactome networks may differ between complete loss of gene products ('node removal') and interaction-specific or edge-specific ('edgetic') alterations. Global computational analyses of approximately 50,000 known causative mutations in human Mendelian disorders revealed clear separations of mutations probably corresponding to those of node removal versus edgetic perturbations. Experimental characterization of mutant alleles in various disorders identified diverse edgetic interaction profiles of mutant proteins, which correlated with distinct structural properties of disease proteins and disease mechanisms. Edgetic perturbations seem to confer distinct functional consequences from node removal because a large fraction of cases in which a single gene is linked to multiple disorders can be modeled by distinguishing edgetic network perturbations. Edgetic network perturbation models might improve both the understanding of dissemination of disease alleles in human populations and the development of molecular therapeutic strategies.
Zhong
Quan
Q
Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Simonis
Nicolas
N
Li
Qian-Ru
QR
Charloteaux
Benoit
B
Heuze
Fabien
F
Klitgord
Niels
N
Tam
Stanley
S
Yu
Haiyuan
H
Venkatesan
Kavitha
K
Mou
Danny
D
Swearingen
Venus
V
Yildirim
Muhammed A
MA
Yan
Han
H
Dricot
Amélie
A
Szeto
David
D
Lin
Chenwei
C
Hao
Tong
T
Fan
Changyu
C
Milstein
Stuart
S
Dupuy
Denis
D
Brasseur
Robert
R
Hill
David E
DE
Cusick
Michael E
ME
Vidal
Marc
M
D000483:Alleles; D004194:Disease / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics