Project description:While BRCA-related cancers respond well to double-strand break (DSB) inducing agents, resistance is a serious clinical problem. One mechanism of resistance is reversion of the BRCA1 mutation, suggesting that BRCA1 function is required for resistance. Here we show that secondary Brca1 mutations are not always necessary, since residual activity of the mutant BRCA1 protein can be sufficient for tumor cells to withstand treatment. Genomic profiling and RAD51 foci formation are currently seen as potential biomarkers to stratify patients for therapies targeting homologous recombination deficiency (HRD). However, we show that while mouse mammary tumors with different Brca1 mutations have identical genomic profiles, they respond considerably different to HRD targeted therapy. It may therefore be useful to stratify patients according to functional assays and the underlying BRCA1 mutation. We performed aCGH on mammary tumor DNA from KB1(185stop)P (n=20), KB1(5382stop)P (n=20) and littermate KB1P (n=22). Spleen DNA of the same animal was used as control material.
Project description:Introgressed variants from other species can be an important source of genetic variation because they may arise rapidly, can include multiple mutations on a single haplotype, and have often been pretested by selection in the species of origin. Although introgressed alleles are generally deleterious, several studies have reported introgression as the source of adaptive alleles-including the rodenticide-resistant variant of Vkorc1 that introgressed from Mus spretus into European populations of Mus musculus domesticus. Here, we conducted bidirectional genome scans to characterize introgressed regions into one wild population of M. spretus from Spain and three wild populations of M. m. domesticus from France, Germany, and Iran. Despite the fact that these species show considerable intrinsic postzygotic reproductive isolation, introgression was observed in all individuals, including in the M. musculus reference genome (GRCm38). Mus spretus individuals had a greater proportion of introgression compared with M. m. domesticus, and within M. m. domesticus, the proportion of introgression decreased with geographic distance from the area of sympatry. Introgression was observed on all autosomes for both species, but not on the X-chromosome in M. m. domesticus, consistent with known X-linked hybrid sterility and inviability genes that have been mapped to the M. spretus X-chromosome. Tract lengths were generally short with a few outliers of up to 2.7 Mb. Interestingly, the longest introgressed tracts were in olfactory receptor regions, and introgressed tracts were significantly enriched for olfactory receptor genes in both species, suggesting that introgression may be a source of functional novelty even between species with high barriers to gene flow.