Modifier Genes and the Plasticity of Genetic Networks in Mice

Abstract

Modifier genes are an integral part of the genetic landscape in both humans and experimental organisms, but have been less well explored in mammals than other systems. A growing number of modifier genes in mouse models of disease nonetheless illustrate the potential for novel findings, while new technical advances promise many more to come. Modifier genes in mouse models include induced mutations and spontaneous or wild-derived variations captured in inbred strains. Identification of modifiers among wild-derived variants in particular should detect disease modifiers that have been shaped by selection and might therefore be compatible with high fitness and function. Here we review selected examples and argue that modifier genes derived from natural variation may provide a bias for nodes in genetic networks that have greater intrinsic plasticity and whose therapeutic manipulation may therefore be more resilient to side effects than conventional targets.

Loss of lysophosphatidic acid receptor LPA1 alters oligodendrocyte differentiation and myelination in the mouse cerebral cortex

“…Reported neural defects in maLPA 1 -null mice have been suggested to implicate the specific interactions of the LPA 1 receptor with unknown genetic modifiers influencing ultimately, cortical development , adult neurogenesis , behavior (Santín et al 2009;Estivill-Torrús et al 2013) and, according to herein described, oligodendrocyte function and myelination. Genetic modifiers contribute to the phenotypic diversity, show clinical relevance in genetic disorders and, in relation with the present case, play a significant role in influencing the severity of a mutant phenotype (Hamilton and Yu 2012;Kearney 2011).…”

Cd72c Is a Modifier Gene that Regulates Faslpr-Induced Autoimmune Disease

“…As there is a functional difference between human CD72 haplotypes (38,39), CD72 polymorphism may play a crucial role in the regulation of penetrance and disease manifestations in ALPS. Modifier genes are extensively studied in various diseases including cystic fibrosis, arrhythmia, and cancer because modifier genes extensively regulate penetrance, severity, and manifestations of these diseases (1)(2)(3). Also, modifier genes can be a good target of therapy and prevention if it is difficult to correct the defect caused by disease-causing mutations.…”

“…odifier genes have been extensively studied in various diseases such as cancer, arrythmia, and cystic fibrosis, because penetrance and disease manifestations of the disease caused by disease-causing genes are extensively modified by modifier genes (1)(2)(3). In cystic fibrosis, contribution of modifier genes to the disease variability is almost equivalent to that of environmental factors.…”

Cryptic genetic variation: evolution's hidden substrate

“…Likewise, a mouse model for congenital heart disease caused by mutations in the gene Nkx2-5 mapped multiple modifiers that substantially affect risk 48 . These genetic modifiers have been explicitly defined using the same language as CGV: as loci that influence the action of a primary locus while remaining silent, or at least “quiet,” with respect to phenotype on their own 49 .…”