Identification of molecular mechanisms acting at the jObes1 locus in the Berlin Fat Mouse with effect on juvenile fat deposition

• Applicant: Professorin Dr. Gudrun Brockmann
• Subject Area: Animal Breeding, Animal Nutrition, Animal Husbandry
• Term: from 2012 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 226367462

The aim of the project is the elucidation of the mechanism causing obesity in the Berlin Fat Mouse (BFMI). This mouse harbors a spontaneous mutation on mouse chromosome 3 (jObes1 locus) accounting for the high fat deposition particularly during puberty. Fine mapping, complementation tests and gene expression studies have identified the Bardet Biedl Syndrome 7 (Bbs7) gene as most likely candidate gene. Bbs7 contributes to the formation of cilia and mutations in this gene may cause the Bardet-Biedl-Syndrome in humans. Like humans, BFMI mice are overweight, have degraded retinae and alterations in the brain. The standard protein sequence of Bbs7 has been excluded as cause for the defects in BFMI mice. Sequence data and expression profiles provide evidence for regulatory acting sequence variants leading to alternative Bbs7 expression patterns. In addition, interactions between mutated DNA regions could affect the expression of Bbs7 as well as neighboring genes.To identify the mechanisms underlying the malfunction of different tissues, we intend to perform following studies: (1) The genomic region around Bbs7 will be sequenced to fill existing gaps and to allow the identification of single sequence variants or whole haplotypes that differ between BFMI and other mouse inbred lines and to test them in complementation tests. (2) The expression of Bbs7 transcript variants will be examined in different cell types and different genotypes to find an association between expression pattern and genotype. (3) The function of two potentially acting BFMI mutations will be tested in genetically modified mice. (4) Chromosome conformation capture studies will be performed to test the effect of mutations in the Bbs7 region on the expression of genes in this region.With the identified symptoms and the likely regulatory acting mutations, Bbs7 in the BFMI mouse is a suitable model for the elucidation of regulatory mechanisms leading to overweight and pleiotropic effects. The proposed examinations will improve our understanding on how regulatory sequence variants change trait variation.

• DFG Programme: Research Grants