1. Effects of background mutations and single nucleotide polymorphisms (SNPs) on the Disc1 L100P behavioral phenotype associated with schizophrenia in mice
- Author
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Yosefu Arime, Ikuo Miura, Kazufumi Akiyama, Yoichi Gondo, Ryutaro Fukumura, Atsushi Yoshiki, Kazuyuki Mekada, and Shigeharu Wakana
- Subjects
Locomotor activity ,Male ,Cognitive Neuroscience ,Strain-specific SNPs ,Congenic ,Single-nucleotide polymorphism ,Nerve Tissue Proteins ,Biology ,Motor Activity ,medicine.disease_cause ,Disrupted-in-schizophrenia 1 (DISC1) ,Social interaction ,Polymorphism, Single Nucleotide ,Methamphetamine ,Behavioral Neuroscience ,DISC1 ,Mice ,Inbred strain ,medicine ,SNP ,Animals ,Whole-exome resequencing ,Exome ,Interpersonal Relations ,Biological Psychiatry ,Genetics ,Mutation ,Point mutation ,Research ,General Medicine ,Phenotype ,ENU mutagenesis ,Mice, Inbred C57BL ,Disease Models, Animal ,biology.protein ,Schizophrenia ,Central Nervous System Stimulants ,Female ,Schizophrenic Psychology - Abstract
Background Disrupted-in-schizophrenia 1 (DISC1) is a promising candidate susceptibility gene for psychiatric disorders, including schizophrenia, bipolar disorder and major depression. Several previous studies reported that mice with N-ethyl-N-nitrosourea (ENU)-induced L100P mutation in Disc1 showed some schizophrenia-related behavioral phenotypes. This line originally carried several thousands of ENU-induced point mutations in the C57BL/6 J strain and single nucleotide polymorphisms (SNPs) from the DBA/2 J inbred strain. Methods To investigate the effect of Disc1 L100P, background mutations and SNPs on phenotypic characterization, we performed behavioral analyses to better understand phenotypes of Disc1 L100P mice and comprehensive genetic analyses using whole-exome resequencing and SNP panels to map ENU-induced mutations and strain-specific SNPs, respectively. Results We found no differences in spontaneous or methamphetamine-induced locomotor activity, sociability or social novelty preference among Disc1 L100P/L100P, L100P/+ mutants and wild-type littermates. Whole-exome resequencing of the original G1 mouse identified 117 ENU-induced variants, including Disc1 L100P per se. Two females and three males from the congenic L100P strain after backcrossing to C57BL/6 J were deposited to RIKEN BioResource Center in 2008. We genotyped them with DBA/2 J × C57BL/6 J SNPs and found a number of the checked SNPs still remained. Conclusion These results suggest that causal attribution of the discrepancy in behavioral phenotypes to the Disc1 L100P mutant mouse line existing among different research groups needs to be cautiously investigated in further study by taking into account the effect(s) of other ENU-induced mutations and/or SNPs from DBA/2 J. Electronic supplementary material The online version of this article (doi:10.1186/1744-9081-10-45) contains supplementary material, which is available to authorized users.
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- 2014