Systems genetic analysis of binge-like eating in a C57BL/6J x DBA/2J-F2 cross

ABSTRACTObjectiveBinge eating is a heritable quantitative trait associated with eating disorders (ED) and refers to the rapid consumption of a large quantity of energy-dense food that is associated with loss of control, anxiety, and depression. Binge Eating Disorder is the most common ED in adults in the US; however, the genetic basis is unknown. We previously identified robust mouse inbred strain differences between C57BL/6J and DBA/2J in binge-like eating (BLE) of sweetened palatable food (PF) in an intermittent access, conditioned place preference paradigm.MethodsTo map the genetic basis of BLE, we phenotyped and genotyped 128 C57BL/6J x DBA/2J-F2 mice.ResultsWe identified a quantitative trait locus (QTL) on chromosome 13 influencing progressive changes in body weight across training days (LOD = 5.5; 26-39 cM). We also identified two sex-combined QTLs influencing PF intake on chromosome 5 (LOD = 5.6; 1.5-LOD interval = 21-28 cM) and 6 (LOD = 5.3; 1.5-LOD interval = 50-59 cM). Furthermore, sex-specific analyses revealed that the chromosome 6 locus was driven by males (1.5-LOD interval: 52-59 cM) and identified a female-selective QTL for BLE on chromosome 18 (LOD = 4.1; 1.5-LOD interval: 23-35 cM). Systems genetic analysis of the chromosome 6 locus for BLE using GeneNetwork legacy trait datasets from BXD recombinant inbred strains identified Adipor2 and Plxnd1 as two positional, functional, biological candidate genes.DiscussionWe identified genetic loci influencing BLE. Future studies will phenotype BXD recombinant inbred strains to fine map loci and support candidate gene nomination and validation.

A Natural Occurring Mouse Model with Adgrv1 Mutation of Usher Syndrome 2C and Characterization of its Recombinant Inbred Strains

Background/Aims: Our laboratory discovered a Kunming mouse with enormous electroretinogram (ERG) defects. Its auditory brainstem response (ABR) threshold was significantly elevated and closely resembled the features of Usher syndrome (USH). This study sought to cross these USH-like mice (named KMush/ush mice) with CBA/CaJ mice to establish recombinant inbred strains and identify their phenotypes and genotypes. Methods: KMush/ush mice were crossed with CBA/CaJ mice to establish inbred strains by sibling mating. ERG, ABR, ocular fundus morphology, histological examinations of the retina and inner ear, quantitative real-time polymerase chain reaction, western blotting, and exon sequencing were performed to assess the phenotypes and genotypes of the offspring strains. Results: The F1 hybrids from crossing KMush/ush and CBA/CaJ mice had normal ERG and ABR responses. The F2 offspring from intercrossing the F1 mice showed a segregation of the retinitis pigmentosa (RP) and hearing loss phenotypes. The CBA-1ush/ush mice had an RP phenotype that was characterized by a vanished ERG waveform and loss of the outer nuclear layer. Their Pde6b gene had a nonsense mutation that resulted in the failure of protein production in western blotting. However, the ABR threshold of this strain of mice was normal. The CBA-2ush/ush mice had normal retinal function and architecture. Their ABR threshold was increased, with a dramatic degeneration of the stereocilia bundles in the outer hair cells of the inner ear. Whole exome sequencing and exon sequencing revealed a deletion of one base pair in exon 31 of the Adgrv1 gene, which would result in the premature termination of protein encoding. The level of Adgrv1 mRNA was reduced in the CBA-2ush/ush mice. The CBA-3ush/ush mice had phenotypes of RP, elevated ABR threshold, and degeneration of the stereocilia bundles in the outer hair cells. They were closely associated with the nonsense mutations of Pde6b and Adgrv1, respectively. Conclusion: We isolated a mouse strain with hearing loss from inbred mice with retinal degeneration and established it as a recombinant inbred strain with a spontaneous mutation in Adgrv1, the human Usher syndrome 2C gene. The retinal degeneration was cause by a mutation in Pde6b, while the hearing loss was caused by a mutation in Adgrv1.