Genomic variants in an inbred mouse model predict mania-like behaviors.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Bipolar Disorder/*genetics ; Mice, Inbred Strains/*genetics ; Polymorphism, Genetic/*genetics; Alleles ; Animals ; Basic Helix-Loop-Helix Transcription Factors/genetics ; DNA Helicases/genetics ; Disease Models, Animal ; Female ; Male ; Mice ; Mice, Inbred ICR/genetics ; Mice, Inbred Strains/psychology ; Nerve Tissue Proteins/genetics ; Nuclear Proteins/genetics ; Sequence Alignment ; Sequence Analysis, DNA ; TRPV Cation Channels/genetics ; Transcription Factors/genetics

Contemporary rodent models for bipolar disorders split the bipolar spectrum into complimentary behavioral endophenotypes representing mania and depression. Widely accepted mania models typically utilize single gene transgenics or pharmacological manipulations, but inbred rodent strains show great potential as mania models. Their acceptance is often limited by the lack of genotypic data needed to establish construct validity. In this study, we used a unique strategy to inexpensively explore and confirm population allele differences in naturally occurring candidate variants in a manic rodent strain, the Madison (MSN) mouse strain. Variants were identified using whole exome resequencing on a small population of animals. Interesting candidate variants were confirmed in a larger population with genotyping. We enriched these results with observations of locomotor behavior from a previous study. Resequencing identified 447 structural variants that are mostly fixed in the MSN strain relative to control strains. After filtering and annotation, we found 11 non-synonymous MSN variants that we believe alter protein function. The allele frequencies for 6 of these variants were consistent with explanatory variants for the Madison strain's phenotype. The variants are in the Npas2, Cp, Polr3c, Smarca4, Trpv1, and Slc5a7 genes, and many of these genes' products are in pathways implicated in human bipolar disorders. Variants in Smarca4 and Polr3c together explained over 40% of the variance in locomotor behavior in the Hsd:ICR founder strain. These results enhance the MSN strain's construct validity and implicate altered nucleosome structure and transcriptional regulation as a chief molecular system underpinning behavior.

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R01 MH085642 United States MH NIMH NIH HHS

0 (Basic Helix-Loop-Helix Transcription Factors)
0 (Nerve Tissue Proteins)
0 (Npas2 protein, mouse)
0 (Nuclear Proteins)
0 (TRPV Cation Channels)
0 (TRPV1 protein, mouse)
0 (Transcription Factors)
EC 3.6.1.- (Smarca4 protein, mouse)
EC 3.6.4.- (DNA Helicases)

Date Created: 20180517 Date Completed: 20181211 Latest Revision: 20201214

20250114

PMC5955540

10.1371/journal.pone.0197624

29768498