Biology subjects

Rago, A.

Publications and source records attributed to Rago, A..

5 recordsLinked to original sources

bioRxiv2022

TP53 knockout in MCF7 breast cancer cells induces sensitivity to fluoropyrimidine drugs.

TP53 mutations are present in all molecular subtypes of breast cancer and often correlate with decreased survival; however, few therapeutic options exist for patients with TP53-mutant breast cancers. To discover therapeutic strategies for these patients, we investigated the sensitivity of 129 FDA-approved chemotherapies to TP53-KO and TP53-WT MCF7 breast adenocarcinoma cells and found p53 loss to confer sensitivity to 5-fluorouracil (5-FU). We then treated the p53-null cells and isogenic controls with F10, a second-generation polymeric fluoropyrimidine, and found this preferential cytotoxicity of TP53-KO cells to be significantly magnified. F10 killing could only minimally be rescued by addition of exogenous uridine, whereas it was completely abrogated by addition of exogenous thymidine, suggesting DNA incorporation to be central to the cytotoxic mechanism of action. Furthermore, F10 killing of p53-null cells was persistent even in heterogeneous cellular mixtures more reflective of natural tumor evolution. Together, our results suggest F10 may widen the therapeutic window for TP53-mutant breast cancer by enhancing genotoxicity in cells resistant to apoptosis.

cancer biology↗

bioRxiv2020

Developmental models reveal the role of phenotypic plasticity in explaining genetic evolvability

Biological evolution exhibits an extraordinary capability to adapt organisms to their environments. The explanation for this often takes for granted that random genetic variation produces at least some beneficial phenotypic variation for natural selection to act on. Such genetic evolvability could itself be a product of evolution, but it is widely acknowledged that the immediate selective gains of evolvability are small on short timescales. So how do biological systems come to exhibit such extraordinary capacity to evolve? One suggestion is that adaptive phenotypic plasticity makes genetic evolution find adaptations faster. However, the need to explain the origin of adaptive plasticity puts genetic evolution back in the driving seat, and genetic evolvability remains unexplained. To better understand the interaction between plasticity and genetic evolvability, we simulate the evolution of phenotypes produced by gene-regulation network-based models of development. First, we show that the phenotypic variation resulting from genetic and environmental change are highly concordant. This is because phenotypic variation, regardless of its cause, occurs within the relatively specific space of possibilities allowed by development. Second, we show that selection for genetic evolvability results in the evolution of adaptive plasticity and vice versa. This linkage is essentially symmetric but, unlike genetic evolvability, the selective gains of plasticity are often substantial on short, including within-lifetime, timescales. Accordingly, we show that selection for phenotypic plasticity is, in general, the most efficient and results in the rapid evolution of high genetic evolvability. Thus, without overlooking the fact that adaptive plasticity is itself a product of genetic evolution, this shows how plasticity can influence adaptive evolution and helps explain the genetic evolvability observed in biological systems.

evolutionary biology↗

bioRxiv2019

Sex biased expression and co-expression networks in development, using the hymenopteran Nasonia vitripennis

Sexual dimorphism requires gene expression regulation in developing organisms. Differential expression, alternative splicing and transcript-transcript interactions all contribute to developmental differences between the sexes. However, few studies have described how these processes change across developmental stages, or how they interact to form co-expression networks. We compare the dynamics of all three regulatory processes in the sexual development of the model parasitoid wasp Nasonia vitripennis, a system that permits genome wide analysis of sex bias from early embryos to adults. We find relatively little sex-bias in embryos and larvae at the whole-gene level, but several sub-networks show sex-biased transcript-transcript interactions in early developmental stages. These provide new candidates for hymenopteran sex determination, including histone modification genes. In contrast, sex-bias in pupae and adults is driven by whole-gene differential expression. We observe sex-biased splicing consistently across development, but mostly in genes that are already biased at the whole-gene level. Finally, we discover that sex-biased networks are enriched by genes specific to the Nasonia clade, and that those genes possess the topological properties of key regulators. These findings suggest that regulators in sex-biased networks evolve more rapidly than regulators of other developmental networks.

evolutionary biology↗

bioRxiv2018

How adaptive plasticity evolves when selected against

Adaptive plasticity allows organisms to cope with environmental change, thereby increasing the populations long-term fitness. However, individual selection can only compare the fitness of individuals within each generation: if the environment changes more slowly than the generation time (i.e., a coarse-grained environment) a population will not experience selection for plasticity even if it is adaptive in the long-term. How does adaptive plasticity then evolve? One explanation is that, if competing alleles conferring different degrees of plasticity persist across multiple environments, natural selection between lineages carrying those alleles could select for adaptive plasticity (lineage selection).\n\nWe show that adaptive plasticity can evolve even in the absence of such lineage selection. Instead, we propose that adaptive plasticity in coarse-grained environments evolves as a by-product of inefficient short-term natural selection. In our simulations, populations that can efficiently respond to selective pressures follow short-term, local, optima and have lower long-term fitness. Conversely, populations that accumulate limited genetic change within each environment evolve long-term adaptive plasticity even when plasticity incurs short-term costs. These results remain qualitatively similar regardless of whether we decrease the efficiency of natural selection by increasing the rate of environmental change or decreasing mutation rate, demonstrating that both factors act via the same mechanism. We demonstrate how this mechanism can be understood through the concept of learning rate.\n\nOur work shows how plastic responses that are costly in the short term, yet adaptive in the long term, can evolve as a by-product of inefficient short-term selection, without selection for plasticity at either the individual or lineage level.

evolutionary biology↗

bioRxiv2018

FESTA: Flexible Exon-based Splicing and Transcription Annotation

We introduce FESTA, an R based algorithm that allows detection of alternative splicing based on experiment-specific exon expression data. FESTA disentangles alternative splicing signal from whole-gene transcription, facilitating the discovery and characterization of novel regulatory events even in the absence of transcript annotations or paired-end data. We also include customization options to increase its applicability on different platforms and experimental designs as well as a tool for the conversion from transcript expression to inclusion ratios.

bioinformatics↗