Know Your Model: Why mouse inbred strain contribution matters

Perry, Michelle N.; Bello, Susan M.; Smith, Cynthia L.

doi:10.1038/s41684-020-0525-1

Cited by 3 publications

(2 citation statements)

References 13 publications

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“…The term “modifier gene” defines genetic variants which alter the phenotypic outcome of an independent locus, but which have no phenotypic consequence of their own [ 19 , 20 ]. Strain-specific morphological, physiological, and behavioural differences are well recognised, but the mechanisms underlying inter-strain variation and the causative modifier loci remain largely uncharacterised due to technical and practical limitations.…”

Section: Introductionmentioning

confidence: 99%

Strain-Specific Epigenetic Regulation of Endogenous Retroviruses: The Role of Trans-Acting Modifiers

Elmer

Ferguson‐Smith

2020

Viruses

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Approximately 10 percent of the mouse genome consists of endogenous retroviruses (ERVs), relics of ancient retroviral infections that are classified based on their relatedness to exogenous retroviral genera. Because of the ability of ERVs to retrotranspose, as well as their cis-acting regulatory potential due to functional elements located within the elements, mammalian ERVs are generally subject to epigenetic silencing by DNA methylation and repressive histone modifications. The mobilisation and expansion of ERV elements is strain-specific, leading to ERVs being highly polymorphic between inbred mouse strains, hinting at the possibility of the strain-specific regulation of ERVs. In this review, we describe the existing evidence of mouse strain-specific epigenetic control of ERVs and discuss the implications of differential ERV regulation on epigenetic inheritance models. We consider Krüppel-associated box domain (KRAB) zinc finger proteins as likely candidates for strain-specific ERV modifiers, drawing on insights gained from the study of the strain-specific behaviour of transgenes. We conclude by considering the coevolution of KRAB zinc finger proteins and actively transposing ERV elements, and highlight the importance of cross-strain studies in elucidating the mechanisms and consequences of strain-specific ERV regulation.

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Section: Introductionmentioning

confidence: 99%

Strain-Specific Epigenetic Regulation of Endogenous Retroviruses: The Role of Trans-Acting Modifiers

Elmer

Ferguson‐Smith

2020

Viruses

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“…Mutations may be hypomorphic, gain or loss of function or even silent in the absence of an inducer or stressor. Phenotypic variability due to strain-specific variants in the mouse experimental genetic background can contribute to conflicting results when the data is inferred at the gene level ( Perry et al 2020 ). Genetic sex, microbiota, and parental origin (imprinting) can also influence phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Biochemical pathways represented by Gene Ontology-Causal Activity Models identify distinct phenotypes resulting from mutations in pathways

Hill,

Drabkin,

Smith

et al. 2023

Genetics

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Gene inactivation can affect the process(es) in which that gene acts and causally downstream ones, yielding diverse mutant phenotypes. Identifying the genetic pathways resulting in a given phenotype helps us understand how individual genes interact in a functional network. Computable representations of biological pathways include detailed process descriptions in the Reactome Knowledgebase, and causal activity flows between molecular functions in Gene Ontology-Causal Activity Models (GO-CAMs). A computational process has been developed to convert Reactome pathways to GO-CAMs. Laboratory mice are widely used models of normal and pathological human processes. We have converted human Reactome GO-CAMs to orthologous mouse GO-CAMs, as a resource to transfer pathway knowledge between humans and model organisms. These mouse GO-CAMs allowed us to define sets of genes that function in a causally connected way. To demonstrate that individual variant genes from connected pathways result in similar but distinguishable phenotypes, we used the genes in our pathway models to cross-query mouse phenotype annotations in the Mouse Genome Database (MGD). Using GO-CAM representations of two related but distinct pathways, gluconeogenesis and glycolysis, we show that individual causal paths in gene networks give rise to discrete phenotypic outcomes resulting from perturbations of glycolytic and gluconeogenic genes. The accurate and detailed descriptions of gene interactions recovered in this analysis of well-studied processes suggest that this strategy can be applied to less well-understood processes in less well-studied model systems to predict phenotypic outcomes of novel gene variants and to identify potential gene targets in altered processes.

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Biochemical Pathways Represented by Gene Ontology Causal Activity Models Identify Distinct Phenotypes Resulting from Mutations in Pathways

Hill

Drabkin

Smith

et al. 2023

Preprint

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Gene inactivation can affect the process(es) in which that gene acts and causally downstream ones, yielding diverse mutant phenotypes. Identifying the genetic pathways resulting in a given phenotype helps us understand how individual genes interact in a functional network. Computable representations of biological pathways include detailed process descriptions in the Reactome Knowledgebase, and causal activity flows between molecular functions in Gene Ontology-Causal Activity Models (GO-CAMs). A computational process has been developed to convert Reactome pathways to GO-CAMs. Laboratory mice are widely used models of normal and pathological human processes. We have converted human Reactome GO-CAMs to orthologous mouse GO-CAMs, as a resource to transfer pathway knowledge between humans and model organisms. These mouse GO-CAMs allowed us to define sets of genes that function in a connected and well-defined way. To test whether individual genes from well-defined pathways result in similar and distinguishable phenotypes, we used the genes in our pathway models to cross-query mouse phenotype annotations in the Mouse Genome Database (MGD). Using GO-CAM representations of two related but distinct pathways, gluconeogenesis and glycolysis, we can identify causal paths in gene networks that give rise to discrete phenotypic outcomes for perturbations of glycolysis and gluconeogenesis. The accurate and detailed descriptions of gene interactions recovered in this analysis of well-studied processes suggest that this strategy can be applied to less well-understood processes in less well-studied model systems to predict phenotypic outcomes of novel gene variants and to identify potential gene targets in altered processes.

show abstract

Know Your Model: Why mouse inbred strain contribution matters

Cited by 3 publications

References 13 publications

Strain-Specific Epigenetic Regulation of Endogenous Retroviruses: The Role of Trans-Acting Modifiers

Strain-Specific Epigenetic Regulation of Endogenous Retroviruses: The Role of Trans-Acting Modifiers

Biochemical pathways represented by Gene Ontology-Causal Activity Models identify distinct phenotypes resulting from mutations in pathways

Biochemical Pathways Represented by Gene Ontology Causal Activity Models Identify Distinct Phenotypes Resulting from Mutations in Pathways

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