Figure 1.
Genotype configurations and Gene Key.
A. The different Gene Abstractions were placed into chromosomes in three different configurations. This led to different kinds of linkages between the Genes. B. For the notation of different genotypes, we have used the following key: (Number of Division Genes, Number of Death Genes, Number of Segregation Genes). The initial Genotype in every simulation is a diploid genome: (2,2,2). To better understand the proportions of the genes in a given phenotype, we have used the RGB model to represent the number of division genes as red, the number of death genes as green and the number of segregation genes as blue See Methods, Genotype Key).
Figure 2.
A. The three genetic arrangements, in simulated diploid chromosomes. Key measurements of each configuration are represented in Broom Diagrams. B. Aspects of each simulation, from total number of cells to genetic diversity are represented as line of different colour, with the median as a thick, black line (calculated until one of the simulations came to an end). The behaviour observed for Gene Configuration A is a homeostatic one. Configurations B and C displayed an over-proliferative behaviour. This is due to the genetic up and down regulation reflected by the change in the average number of key genes across time. C. The average number of Division Genes. D. The average number of Apoptosis Genes. E. The average number of Segregation Genes. F. The genetic diversity, liked to the number of Segregation genes, had a profound effect on the Genotypic Diversity, being greatest in Configuration C. Colours are purely used to distinguish runs and do not denote genetic distribution.
Figure 3.
A. The two over-proliferative genetic arrangements, in simulated diploid chromosomes, and the RGB key in the middle. We have used the RGB colour model to visually describe the different genotypes that evolve in the system by normalizing the maximum observed Genotype State (See Methods, RGB Key). We have assigned a colour to each of the abstracted genes: Red for division, green for death and blue for segregation. By comparing via an RGB system the colours assigned to a given genotype, we are able to tell visually the proportions in which the genes are distributed, with intensity values corresponding to the number of genes: (0,0,0) being black, the initial genotype (2, 2, 2) being dark grey and the maximum observed genotype (5, 5, 5) being white. B. Representative Marble Diagram for a simulation with the Model. These diagrams display the stacked percentage of Genetic Diversity across time for a representative simulation of Gene Configurations B and C across different scenarios. The beginning of therapies (when reaching 1000 cells) are marked with a black vertical line, while relapse times (when reaching again 1000 cells) are marked using a dashed line. C. Representative Marble Diagram for a Simulation of Surgery. D. Representative Marble Diagram for a Simulation of Chemotherapy. E. Representative Marble Diagram of a therapy combination of Surgery followed by Chemotherapy.
Figure 4.
Distribution of the response to treatments under different scenarios.
The histograms correspond to a measure of the distribution of the relapse times (the time it took each simulation to grow back to 1000 cells after treatment) for 100 simulations of each gene configuration under three different therapy scenarios: A. Surgery Scenario, B. Chemotherapy Scenario and C. Combination of both treatments (Surgery followed by Chemotherapy).
Figure 5.
The average ratio of apoptosis to division genes.
These graphs show the tendency of reducing the number of apoptosis genes and increasing the number of division genes with respect to time across different scenarios: A. Surgery Scenario, B. Chemotherapy Scenario and C. Combination of both treatments (Surgery followed by Chemotherapy). The dark line is the median of the samples and the shadowed area represents the variance. Interventions were carried out at time step zero. The reported slopes were measured taking into account 25 time steps after each therapy.