Subscribe to the gold package and get unlimited access to Shamra Academy
Register a new userEvolution of intratumoral phenotypic heterogeneity: the role of trait inheritance
137
0
0.0
(
0
)
Ask ChatGPT about the research
No Arabic abstract
A tumor can be thought of as an ecosystem, which critically means that we cannot just consider it as a collection of mutated cells but more as a complex system of many interacting cellular and microenvironmental elements. At its simplest, a growing tumor with increased proliferation capacity must compete for space as a limited resource. Hypercellularity leads to a contact-inhibited core with a competitive proliferating rim. Evolution and selection occurs, and an individual cells capacity to survive and propagate is determined by its combination of traits and interaction with the environment. With heterogeneity in phenotypes, the clone that will dominate is not always obvious as there are both local interactions and global pressures. Several combinations of phenotypes can coexist, changing the fitness of the whole. To understand some aspects of heterogeneity in a growing tumor we build an off-lattice agent based model consisting of individual cells with assigned trait values for proliferation and migration rates. We represent heterogeneity in these traits with frequency distributions and combinations of traits with density maps. How the distributions change over time is dependent on how traits are passed on to progeny cells, which is our main inquiry. We bypass the translation of genetics to behavior by focussing on the functional end result of inheritance of the phenotype combined with the environmental influence of limited space.
rate research
Read More
The unwelcome evolution of malignancy during cancer progression emerges through a selection process in a complex heterogeneous population structure. In the present work, we investigate evolutionary dynamics in a phenotypically heterogeneous population of stem cells (SCs) and their associated progenitors. The fate of a malignant mutation is determined not only by overall stem cell and differentiated cell growth rates but also differentiation and dedifferentiation rates. We investigate the effect of such a complex population structure on the evolution of malignant mutations. We derive exact analytic results for the fixation probability of a mutant arising in each of the subpopulations. The analytic results are in almost perfect agreement with the numerical simulations. Moreover, a condition for evolutionary advantage of a mutant cell versus the wild type population is given in the present study. We also show that microenvironment-induced plasticity in invading mutants leads to more aggressive mutants with higher fixation probability. Our model predicts that decreasing polarity between stem and differentiated cells turnover would raise the survivability of non-plastic mutants; while it would suppress the development of malignancy for plastic mutants. We discuss our model in the context of colorectal/intestinal cancer (at the epithelium). This novel mathematical framework can be applied more generally to a variety of problems concerning selection in heterogeneous populations, in other contexts such as population genetics, and ecology.
We present a mathematical study of the emergence of phenotypic heterogeneity in vascularised tumours. Our study is based on formal asymptotic analysis and numerical simulations of a system of non-local parabolic equations that describes the phenotypic evolution of tumour cells and their nonlinear dynamic interactions with the oxygen, which is released from the intratumoural vascular network. Numerical simulations are carried out both in the case of arbitrary distributions of intratumour blood vessels and in the case where the intratumoural vascular network is reconstructed from clinical images obtained using dynamic optical coherence tomography. The results obtained support a more in-depth theoretical understanding of the eco-evolutionary process which underpins the emergence of phenotypic heterogeneity in vascularised tumours. In particular, our results offer a theoretical basis for empirical evidence indicating that the phenotypic properties of cancer cells in vascularised tumours vary with the distance from the blood vessels, and establish a relation between the degree of tumour tissue vascularisation and the level of intratumour phenotypic heterogeneity.
Species richness varies widely across the tree of life, and there is great interest in identifying ecological, geographic, and other factors that affect rates of species proliferation. Recent methods for explicitly modeling the relationships among character states, speciation rates, and extinction rates on phylogenetic trees- BiSSE, QuaSSE, GeoSSE, and related models - have been widely used to test hypotheses about character state-dependent diversification rates. Here, we document the disconcerting ease with which neutral traits are inferred to have statistically significant associations with speciation rate. We first demonstrate this unfortunate effect for a known model assumption violation: shifts in speciation rate associated with a character not included in the model. We further show that for many empirical phylogenies, characters simulated in the absence of state-dependent diversification exhibit an even higher Type I error rate, indicating that the method is susceptible to additional, unknown model inadequacies. For traits that evolve slowly, the root cause appears to be a statistical framework that does not require replicated shifts in character state and diversification. However, spurious associations between character state and speciation rate arise even for traits that lack phylogenetic signal, suggesting that phylogenetic pseudoreplication alone cannot fully explain the problem. The surprising severity of this phenomenon suggests that many trait-diversification relationships reported in the literature may not be real. More generally, we highlight the need for diagnosing and understanding the consequences of model inadequacy in phylogenetic comparative methods.
We discuss two different ways of chromosomes and genomes evolution. Purifying selection dominates in large panmictic populations, where Mendelian law of independent gene assortment is valid. If the populations are small, recombination processes are not effective enough to ensure an independent assortment of linked genes and larger clusters of genes could be inherited as the genetic units. There are whole clusters of genes which tend to complement in such conditions instead of single pairs of alleles like in the case of purifying selection. Computer simulations have shown that switching in-between complementation and purification strategies has a character of a phase transition. This is also responsible for specific distribution of recombination events observed along eukaryotic chromosomes - higher recombination rate is observed in subtelomeric regions than in central parts of chromosomes - for sympatric speciation and probably for non-monotonous relation between reproduction potential and genetic distance between parents.
Genetic studies of human traits have revolutionized our understanding of the variation between individuals, and opened the door for numerous breakthroughs in biology, medicine and other scientific fields. And yet, the ultimate promise of this area of research is still not fully realized. In this review, we highlight the major open problems that need to be solved to improve our understanding of the genetic variation underlying human traits, and by discussing these challenges provide a primer to the field. Our focus is on concrete analytical problems, both conceptual and technical in nature. We cover general issues in genetic studies such as population structure, epistasis and gene-environment interactions, data-related issues such as ethnic diversity and rare genetic variants, and specific challenges related to heritability estimates, genetic association studies and polygenic risk scores. We emphasize the interconnectedness of these open problems and suggest promising avenues to address them.
Log in to be able to interact and post comments
comments
Fetching comments
Sign in to be able to follow your search criteria
