RESUMEN
In this study, we introduce a new web-based simulation framework ("MoBPSweb") that combines a unified language to describe breeding programs with the simulation software MoBPS, standing for "Modular Breeding Program Simulator." Thereby, MoBPSweb provides a flexible environment to log, simulate, evaluate, and compare breeding programs. Inputs can be provided via modules ranging from a Vis.js-based environment for "drawing" the breeding program to a variety of modules to provide phenotype information, economic parameters, and other relevant information. Similarly, results of the simulation study can be extracted and compared to other scenarios via output modules (e.g., observed phenotypes, the accuracy of breeding value estimation, inbreeding rates), while all simulations and downstream analysis are executed in the highly efficient R-package MoBPS.
Asunto(s)
Endogamia , Programas Informáticos , Simulación por Computador , Internet , Modelos Genéticos , FenotipoRESUMEN
Modern animal breeding programmes are constantly evolving with advances in breeding theory, biotechnology and genetics. Surprisingly, there seems to be no generally accepted succinct definition of what exactly a breeding programme is, neither is there a unified language to describe breeding programmes in a comprehensive, unambiguous and reproducible way. In this work, we try to fill this gap by suggesting a general definition of breeding programmes that also pertains to cases where genetic progress is not achieved through selection, but, for example, through transgenic technologies, or the aim is not to generate genetic progress, but, for example, to maintain genetic diversity. The key idea of the underlying concept is to represent a breeding programme in modular form as a directed graph that is composed of nodes and edges, where nodes represent cohorts of breeding units, usually individuals, and edges represent breeding activities, like "selection" or "reproduction." We claim, that by defining a comprehensive set of nodes and edges, it is possible to represent any breeding programme of arbitrary complexity by such a graph, which thus comprises a full description of the breeding programme. This concept is implemented in a web-based tool (MoBPSweb, available at www.mobps.de) and has a link to the R-package MoBPS (Modular Breeding Program Simulator) to simulate the described breeding programmes. The approach is illustrated by showcasing three different breeding programmes of increasing complexity. The concept allows a formal description of breeding programmes, which is requested, for example, in legal regulations of the European Union, but so far cannot be provided in a standardized format. In the discussion, we point out potential limitations of the concept and argue that the general approach can be easily extended to account for novel breeding technologies, to breeding of crops or experimental species, but also to modelling diversity dynamics in natural populations.
Asunto(s)
Fitomejoramiento , Reproducción , Animales , Biotecnología , Productos AgrícolasRESUMEN
Studies of genomic instability have historically focused on intrinsic mechanisms rather than extrinsic mechanisms based in the tumor microenvironment (TME). TGFß is the most abundantly secreted cytokine in the TME, where it imparts various aggressive characteristics including invasive migration, drug resistance, and epithelial-to-mesenchymal transition (EMT). Here we show that TGFß also promotes genomic instability in the form of DNA double strand breaks (DSB) in cancer cells that lack the tumor suppressor gene RUNX3 Loss of RUNX3 resulted in transcriptional downregulation of the redox regulator heme oxygenase-1 (HO-1 or HMOX1). Consequently, elevated oxidative DNA damage disrupted genomic integrity and triggered cellular senescence, which was accompanied by tumor-promoting inflammatory cytokine expression and acquisition of the senescence-associated secretory phenotype (SASP). Recapitulating the above findings, tumors harboring a TGFß gene expression signature and RUNX3 loss exhibited higher levels of genomic instability. In summary, RUNX3 creates an effective barrier against further TGFß-dependent tumor progression by preventing genomic instability. These data suggest a novel cooperation between cancer cell-extrinsic TGFß signaling and cancer cell-intrinsic RUNX3 inactivation as aggravating factors for genomic instability.Significance: RUNX3 inactivation in cancer removes an antioxidant barrier against DNA double strand breaks induced by TGFß expressed in the tumor microenvironment. Cancer Res; 78(1); 88-102. ©2017 AACR.