Biology subjects

Martin, N. S.

Publications and source records attributed to Martin, N. S..

6 recordsLinked to original sources

bioRxiv2025

Combined inhibition of NAD synthesis and C-terminal binding protein cooperatively induce cell death and inhibit growth of High Grade Serous Ovarian Carcinoma

The transcriptional scaffolds C-terminal Binding Proteins (CtBP) 1 and 2 are overexpressed and act as oncogenic dependencies in multiple cancers but importantly encode a chemically targetable dehydrogenase domain. CtBP promotes survival of high grade serous ovarian carcinoma (HGSOC) cells by repressing expression of Death Receptors (DR) 4 and 5, which activate caspase 8-dependent apoptosis. We have previously developed a series of substrate competitive CtBP dehydrogenase inhibitors active in multiple cell and preclinical solid tumor models. In the current study, we validated CtBP 1 and 2 overexpression in a longitudinal series of primary and metastatic/recurrent HGSOC cases. Furthermore, our lead CtBP dehydrogenase inhibitor, JW-98 induced apoptosis and exhibited variable single agent IC50 values in HGSOC cell lines, but depletion of nicotinamide adenine dinucleotide (NAD) using the NAD synthesis inhibitor GMX1778 strikingly sensitized tumor cells to JW-98 treatment. Mechanistically, the JW-98/GMX-1778 combination effectively disrupted CtBP dimerization that requires stoichiometric levels of intracellular NAD and is required for oncogenic transcriptional activities. Highlighting the translational potential of this combination, combined JW-98/GMX1778 treatment of OVCAR3 HGSOC xenografts in immunodeficient mice abrogated tumor growth without observable toxicity. CtBP/NAD combined inhibition represents a novel therapeutic strategy that could improve outcomes in chemoresistant HGSOC.

cancer biology↗

bioRxiv2025

Predicting the topography of fitness landscapes from the structure of genotype-phenotype maps

Ruggedness, the prevalence of fitness peaks, and navigability, the existence of fitness-increasing paths to a target, are key factors affecting evolution on fitness landscapes. We analytically predict landscape ruggedness for genotype-phenotype maps with randomly assigned fitness, using only the sizes of neutral components - mutationally connected genotype sets sharing the same phenotype- and their evolvabilities, the number of neighbouring phenotypes. Further, more evolvable peaks tend to have higher fitness and a minimal evolvability is required for navigability.

evolutionary biology↗

bioRxiv2023

Non-Poissonian bursts in the arrival of phenotypic variation can strongly affect the dynamics of adaptation

The introduction of novel phenotypic variation in a population through random mutations plays a crucial role in evolutionary dynamics. Here we show that, when the probability that a sequence has a particular phenotype in its 1-mutational neighbourhood is low, statistical fluctuations imply that in the weak-mutation or monomorphic regime, novel phenotypic variation is not introduced at a constant rate, but rather in non-Poissonian "bursts". In other words, a novel phenotype appears multiple times in quick succession, or not at all for many generations. We use the RNA secondary-structure genotype-phenotype map to explore how increasing levels of heterogeneity in mutational neighbourhoods strengthen the bursts. Similar results are obtained for the HP model for protein tertiary structure and the Biomorphs model for morphological development. Burst can profoundly affect adaptive dynamics. Most notably, they imply that differences in arrival rates of novel variation can influence fixation rates more than fitness differences do.

evolutionary biology↗

bioRxiv2023

Bias in the arrival of variation can dominate over natural selection in Richard Dawkins' biomorphs

Biomorphs, Richard Dawkins iconic model of morphological evolution, are traditionally used to demonstrate the power of natural selection to generate biological order from random mutations. Here we show that biomorphs can also be used to illustrate how developmental bias shapes adaptive evolutionary outcomes. In particular, we find that biomorphs exhibit phenotype bias, a type of developmental bias where certain phenotypes can be many orders of magnitude more likely than others to appear through random mutations. Moreover, this bias exhibits a strong Occams-razor-like preference for simpler phenotypes with low descriptional complexity. Such bias towards simplicity is formalised by an information-theoretic principle that can be intuitively understood from a picture of evolution randomly searching in the space of algorithms. By using population genetics simulations, we demonstrate how moderately adaptive phenotypic variation that appears more frequently upon random mutations will fix at the expense of more highly adaptive biomorph phenotypes that are less frequent. This result, as well as many other patterns found in the structure of variation for the biomorphs, such as high mutational robustness and a positive correlation between phenotype evolvability and robustness, closely resemble findings in molecular genotype-phenotype maps. Many of these patterns can be explained with an analytic model based on constrained and unconstrained sections of the genome. We postulate that the phenotype bias towards simplicity and other patterns biomorphs share with molecular genotype-phenotype maps may hold more widely for developmental systems, which would have implications for longstanding debates about internal versus external causes in evolution.

evolutionary biology↗

bioRxiv2023

The non-deterministic genotype-phenotype map of RNA secondary structure

Selection and variation are both key aspects in the evolutionary process. Previous research on the mapping between molecular sequence (genotype) and molecular fold (phenotype) has shown the presence of several structural properties in different biological contexts, implying that these might be universal in evolutionary spaces. The deterministic genotype-phenotype (GP) map that links short RNA sequences to minimum free energy secondary structures has been studied extensively because of its computational tractability and biologically realistic nature. However, this mapping ignores the phenotypic plasticity of RNA. We define a GP map that incorporates non-deterministic phenotypes, and take RNA as a case study; we use the Boltzmann probability distribution of folded structures and examine the structural properties of non-deterministic (ND) GP maps for RNA sequences of length 12 and coarse-grained RNA structures of length 30 (RNAshapes30). A framework is presented to study robustness, evolvability and neutral spaces in the non-deterministic map. This framework is validated by demonstrating close correspondence between the non-deterministic quantities and sample averages of their deterministic counterparts. When using the non-deterministic framework we observe the same structural properties as in the deterministic GP map, such as bias, negative correlation between genotypic robustness and evolvability, and positive correlation between phenotypic robustness and evolvability.

biophysics↗

bioRxiv2023

The Boltzmann distributions of folded molecular structures predict likely changes through random mutations

New folded molecular structures can only evolve after arising through mutations. This aspect is modelled using genotype-phenotype (GP) maps, which connect sequence changes through mutations to changes in molecular structures. Previous work has shown that the likelihood of appearing through mutations can differ by orders of magnitude from structure to structure and that this can affect the outcomes of evolutionary processes. Thus, we focus on the phenotypic mutation probabilities{phi} qp, i.e. the likelihood that a random mutation changes structure p into structure q. For both RNA secondary structures and the HP protein model, we show that a simple biophysical principle can explain and predict how this likelihood depends on the new structure q:{phi} qp is high if sequences that fold into p as the minimum-free-energy structure are likely to have q as an alternative structure with high Boltzmann frequency. This generalises the existing concept of plastogenetic congruence from individual sequences to the entire neutral spaces of structures. Our result helps us understand why some structural changes are more likely than others, can be used as a basis for estimating these likelihoods via sampling and makes a connection to alternative structures with high Boltzmann frequency, which could be relevant in evolutionary processes.

biophysics↗