Most human disease has a genetic basis in cause, susceptibility, or resistance. However, the genetic architectures for most disease phenotypes are only poorly understood and architectures of genetic plasticity - the ability to modify genetic networks to favor one trait without adversely affecting other traits that rely on the same underlying genes - are understood almost not at all. We have previously demonstrated through positional identification of a novel wild-derived modifier gene in mice one instructive example. The Mvb1 locus attenuates the effects of retroviral insertion mutations without apparent disruption of the host gene expression program. Indeed, the variant we identified shows hallmarks of positive selection in wild populations, consistent with a role in innate immunity to a pathogen. This competing renewal application continues our work to understand the mechanisms of genetic suppression mediated by alleles of the Nxf1 gene at the Mvb1 locus. This renewal supports development of new mouse models for human disease and therapy based on modulating gene expression levels to reflect therapies that increase or replace expression of genetic defects, analysis of the genetic networks of normal gene expression that might be affected by manipulating this pathway, and tests for effects of feedback regulation within the proposed network architecture.

Public Health Relevance

Understanding mechanisms through which gene expression networks have been modified by selective pressures or can be manipulated therapeutically to favor host gene expression programs over those of pathogens, including RNA viruses, and molecular parasites, including retrotransposons, has potential applications in infectious disease and cancer. Understanding the network architecture and properties of component proteins such as Nxf1 has applications for animal models of a wide range of genetic disease and genetic susceptibility to disease as well as providing new insight into basic mechanisms of RNA processing downstream of transcriptional initiation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Bender, Michael T
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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Hamilton, Bruce A (2013) Retrotransposon activates ectopic Ptf1 expression: a short tail. PLoS Genet 9:e1003331
Hamilton, Bruce A; Yu, Benjamin D (2012) Modifier genes and the plasticity of genetic networks in mice. PLoS Genet 8:e1002644
Concepcion, Dorothy; Johannes, Frank; Lo, Yuan Hung et al. (2011) Modifier genes for mouse phosphatidylinositol transfer protein * (vibrator) that bypass juvenile lethality. Genetics 187:1185-91