ABSTRACT
Genetic suppression occurs when the deleterious effects of a primary “query” mutation are rescued by a suppressor mutation elsewhere in the genome. To capture existing knowledge on suppression interactions between human genes, we examined 2,400 published papers for potential interactions identified through either genetic modification of cultured human cells or through association studies in patients. The resulting network encompassed 476 unique suppression interactions that often linked genes that function in the same biological process. The suppressor genes were strongly enriched for genes with a role in stress response or signaling, suggesting that deleterious mutations can often be buffered by modulating signaling cascades or immune responses. Suppressor mutations were frequently deleterious when they occurred in absence of the query mutation, in apparent contrast with their protective role in the presence of the query. We formulated and quantified mechanisms of genetic suppression that could explain 71% of interactions and provided mechanistic insight into disease pathology. Finally, we used these observations to predict suppressor genes among all genes in the human genome. The emerging frequency of suppression interactions and range of underlying mechanisms suggest that compensatory mutations may exist for the majority of genetic diseases.
Competing Interest Statement
The authors have declared no competing interest.
