Project description:Pancreatic cancer is among the deadliest cancers that affects almost 54,000 patients in United States alone, with 90% of them succumbing to the disease. Lack of early detection is considered to be the foremost reason for such dismal survival rates. Our study shows that resident gut microbiota is altered at the early stages of tumorigenesis much before development of observable tumors in a spontaneous, genetically engineered mouse model for pancreatic cancer. In the current study, we analyzed the microbiome of in a genetic mouse model for PDAC (KRASG12DTP53R172HPdxCre or KPC) and age-matched controls using WGS at very early time points of tumorigenesis. During these time points, the KPC mice do not show any detectable tumors in their pancreas. Our results show that at these early time points, the histological changes in the pancreas correspond to a significant change in certain gut microbial population. Our predictive metabolomic analysis on the identified bacterial species reveal that the primary microbial metabolites involved in progression and development of PDAC tumors are involved in polyamine metabolism.
Project description:We harvested and sequenced the spontaneous pancreatic tumor generated by a 6-month-old KPC mouse (KrasLSL-G12D; Trp53LSL-R172H; Ptf1a-Cre).
Project description:Epimutations are changes in chromatin modifications, such as DNA methylation or histone modifications. Some of these epigenetic changes can be inherited for several generations, and thus could contribute to evolutionary processes. Estimates of epimutation rates now exists in a few species, but epigenetic mechanism are not conserved across all life, and epigenetic marks funtion differently in different species. To understand the properties of epimutations in fungi, we performed a mutation accumulation experiment with the filamentous fungus Neurospora crassa and investigated spontaneous DNA methylation and trimethylation of lysine 9 on histone H3 (H3K9me3) changes in the mutation accumulation lines. We observed that centromeric regions are hotspots of spontaneous DNA methylation changes in N. crassa. In these hotspot regions, DNA methylation changes were transmitted across mitoses, but changes occurring in euchromatin were not maintained. The rate of DNA methylation changes was more than 10 000-fold faster than the genetic mutation rate. We did not observe spontaneous changes in H3K9me3 that were transmitted across mitoses. Our results show that while spontaneous epimutations occur in this species, they occur predominantly in gene poor heterochromatic regions, so their impact for evolutionary adaptation may be limited.
Project description:We have conducted a genome-wide analysis of spontaneous copy number variation (CNV) in the laboratory mouse. We used high resolution microarrays to identify 38 CNVs between 14 colonies of the C57BL/6 strain spanning ~967 generations of inbreeding, and examined these loci in 12 additional strains. It is clear from our results that many CNVs arise through a highly non-random process: 18 of 38 were the product of recurrent mutation, and rates of change vary roughly four orders of magnitude across different loci. These recurrent CNVs are distributed throughout the genome, affect 43 genes, and fluctuate in copy number over mere hundreds of generations, observations that raise questions about their contribution to natural variation. Keywords: comparative genomic hybridization, DNA copy number variation, structural variation, inbred mice, spontaneous mutation rate