Mercer, K. L. | bioRxiv Science

bioRxiv2026

Murine osteosarcoma recapitulates the driver landscape and genomic complexity of osteosarcoma evolution in humans

Osteosarcoma (OS) genomes are characterized by complex genomic rearrangements (CGRs) that drive genomic instability and clonal diversification early in tumor evolution. As a result, OS tumors display high inter-patient variability, which has hindered molecular stratification and targeted therapeutic development. To study genomic complexity in OS and credential a genetically engineered mouse model of the disease (Sp7-Cre Trp53fl Rb1fl), we performed high-depth and multi-region whole genome sequencing (WGS) of 35 tumor samples from 24 mice. Similar to human OS, the murine OS tumors (mOS) had a high number of somatic structural variants (158 per tumor) with low tumor mutational burden of single nucleotide variants (0.87 mutations/MB). CGRs were identified in 63% (15/24) of mOS cases, most frequently affecting chromosome 15 (33%, 8/24 mice) and resulting in Myc amplification in 6 mice, ranging from 5 to 104 copies. Myc amplification was verified with DNA FISH, long-read sequencing and gene expression data, which revealed examples of Myc amplification in both extrachromosomal circular DNA (ecDNA) and in derivative chromosomes generated by CGRs. PTEN loss occurred frequently (59% 12/22 mice), and contributed to osteosarcomagenesis, as demonstrated by tumor initiation with in vivo CRISPR/Cas9-mediated deletion experiments (2 mice). Together, these results demonstrate that a preclinical model of osteosarcoma can generate the genomic heterogeneity and complexity of the human disease, thereby facilitating research into mechanisms of tumor initiation and drivers of progression and relapse.

cancer biology↗

bioRxiv2021

Environment of origin and domestication affect morphological, physiological, and agronomic response to water deficit in chile pepper (Capsicum sp.)

Global climate change is having a significant effect on agriculture by causing greater precipitation variability and an increased risk of drought. To mitigate these effects, it is important to identify specific traits, adaptations, and germplasm that improve tolerance to soil water deficit. Local varieties, known as landraces, have undergone generations of farmer-mediated selection and can serve as sources of variation, specifically for tolerance to abiotic stress. Landraces can possess local adaptations, where accessions adapted to a particular environment will outperform others grown under the same conditions. We explore adaptations to water deficit in chile pepper landraces from across an environmental gradient in Mexico, a center of crop domestication and diversity, as well in improved varieties bred for the US. In the present study, we evaluated 25 US and Mexico accessions in a greenhouse experiment under well-watered and water deficit conditions and measured morphological, physiological, and agronomic traits. Accession and irrigation regime influenced biomass and height, while branching, CO2 assimilation, and fruit weight were all influenced by an interaction between accession and irrigation. A priori group contrasts revealed possible adaptations to water deficit for primary branching, CO2 assimilation, and plant height associated with geographic origin, domestication level, and pepper species. Additionally, within the Mexican landraces, the number of primary branches had a strong relationship with precipitation from the environment of origin. This work provides insight into chile pepper response to water deficit and adaptation to drought and identifies possibly tolerant germplasm.

plant biology↗