Biology subjects

Antal, T.

Publications and source records attributed to Antal, T..

4 recordsLinked to original sources

bioRxiv2025

Age distinguishes selection from causation in cancer genomes

Cancer genome sequencing efforts have revealed hundreds of genes under positive selection, many of which are now being developed as therapeutic targets. However, positively selected mutations also populate our aging tissues in the absence of cancer. For most mutations, it is currently unknown whether they are recurrently found in cancer genomes because they cause cancer or because they expand during normal tissue evolution and are passively inherited. Here, we develop a mathematical and statistical framework that distinguishes these two factors. We discover - across thousands of cancer and normal tissue genomes - that mutations that most strongly increase cancer risk are enriched in younger patients cancers, whereas mutations that are positively selected in normal tissue without causing cancer are enriched in older patients. Focusing on a particularly data-rich cancer type, acute myeloid leukemia, we show that genetic differences between young- and adult-onset cancers can largely be explained by the cumulative effects of normal tissue evolution, contradicting the long-standing notion that childhood cancers require a distinct set of causal mutations. Our framework establishes patient age as a powerful resource for clarifying whether positively selected mutations in cancer genomes are truly disease-promoting.

cancer biology↗

bioRxiv2024

Quantifying "just-right" APC inactivation for colorectal cancer initiation

Dysregulation of the tumour suppressor gene Adenomatous Polyposis Coli (APC) is a canonical step in colorectal cancer development. Curiously, most colorectal tumours carry biallelic mutations that result in only partial loss of APC function, suggesting that a just-right level of APC inactivation, and hence Wnt signalling, provides the optimal conditions for tumorigenesis. Mutational processes act variably across the APC gene, which could contribute to the bias against complete APC inactivation. Thus the selective consequences of partial APC loss are unclear. Here we propose a mathematical model to quantify the tumorigenic effect of biallelic APC genotypes, controlling for somatic mutational processes. Analysing sequence data from >2500 colorectal cancers, we find that APC genotypes resulting in partial protein function confer about 50 times higher probability of progressing to cancer compared to complete APC inactivation. The optimal inactivation level varies with anatomical location and additional mutations of Wnt pathway regulators. We use this context dependency to assess the regulatory effect of secondary Wnt drivers in combination with APC in vivo, and provide evidence that mutant AMER1 combines with APC genotypes that lead to relatively low Wnt. The fitness landscape of APC inactivation is consistent across microsatellite unstable and POLE-deficient colorectal cancers and tumours in patients with Familial Adenomatous Polyposis suggesting a general just-right optimum, and pointing to Wnt hyperactivation as a potential cancer vulnerability.

cancer biology↗

bioRxiv2018

Interference with HIV infection of the first cell is essential for viral clearance in a pre-exposure prophylaxis model

Pre-exposure prophylaxis (PrEP) uses relatively weak HIV inhibition to reduce transmission between individuals. Why this approach is successful is unclear. Here we derive and experimentally validate a mathematical model for predicting infection clearance with PrEP based on the measured effect of a drug on the HIV replication ratio and number of initial infected cells. We tested the model by inhibiting low dose HIV infection with tenofovir, which reduces infection frequency per cell, and atazanavir, which reduces the cellular burst size of viable virions. Both drugs were at concentrations which allowed similar HIV replication. Reducing infection frequency dramatically increased infection clearance, while reducing burst size did not. This indicates that initial infection is vulnerable to inhibition before it infects the first cell, but not thereafter. Our model explains why PrEP is potent at drug concentrations which are ineffective against established infection, and provides a framework to test drug effectiveness for PrEP.

bioinformatics↗

bioRxiv2018

Competing paths over fitness valleys in growing populations

Investigating the emergence of a particular cell type is a recurring theme in models of growing cellular populations. The evolution of resistance to therapy is a classic example. Common questions are: when does the cell type first occur, and via which sequence of steps is it most likely to emerge? For growing populations, these questions can be formulated in a general framework of branching processes spreading through a graph from a root to a target vertex. Cells have a particular fitness value on each vertex and can transition along edges at specific rates. Vertices represents cell states, say genotypes or physical locations, while possible transitions are acquiring a mutation or cell migration. We focus on the setting where cells at the root vertex have the highest fitness and transition rates are small. Simple formulas are derived for the time to reach the target vertex and for the probability that it is reached along a given path in the graph. We demonstrate our results on several scenarios relevant to the emergence of drug resistance, including: the orderings of resistance-conferring mutations in bacteria and the impact of imperfect drug penetration in cancer.

evolutionary biology↗