Castro, L. A. | Search bioRxiv

bioRxiv2024

Manipulation of the Nuclear Envelope-Associated Protein SLAPDuring Mammalian Brain Development Affects Cortical Lamination and Exploratory Behavior

Here we report the first characterization of the effects resulting from the manipulation of Soluble-Lamin Associated Protein (SLAP) expression during mammalian brain development. We found that SLAP localizes to the nuclear envelope and when overexpressed causes changes in nuclear morphology and lengthening of mitosis. SLAP overexpression in apical progenitors of the developing mouse brain altered asymmetric cell division, neurogenic commitment and neuronal migration ultimately resulting in unbalance in the proportion of upper, relative to deeper, neuronal layers. Several of these effects were also recapitulated upon Cas9-mediated knock-down. Ultimately, SLAP overexpression during development resulted in a reduction in subcortical projections of young mice and, notably, reduced their exploratory behavior. Our study shows the potential relevance of the previously uncharacterized nuclear envelope protein SLAP in neurodevelopmental disorders.

developmental biology↗

bioRxiv2022

Recombination smooths the time-signal disrupted by latency in within-host HIV phylogenies

Within-host HIV evolution involves latency and re-activation of integrated provirus that has the potential to disrupt the temporal signal induced by the evolutionary race between host immune responses and viral evolution. Yet, within-host HIV phylogenies tend to show clear, ladder-like trees structured by the time of sampling. Recombination complicates this dynamic by allowing latent HIV viruses to re-integrate as fragments in the genomes of contemporary virus populations. That is, recombination violates the fundamental assumption made by the phylogenetic methods typically used to study within-host HIV sequence data that evolutionary history can be represented by a single bifurcating tree. In this paper we develop a coalescent-based simulator of within-host HIV evolution that includes, latency, recombination, and population dynamics that allows us to study the relationship between the true, complex genealogy of within-host HIV, encoded as an Ancestral Recombination Graph (ARG), and the observed phylogenetic tree. We show how recombination recovers the disruption of the temporal signal of within-host HIV evolution caused by latency by mixing fragments of ancestral, latent genomes into the contemporary population through recombination. In effect, recombination averages over extant heterogeneity, whether it stems from mixed time-signals or population bottlenecks. Further, we establish that the signals of latency and recombination can be observed in phylogenetic trees despite being an incorrect representation of the true evolutionary history. Using an Approximate Bayesian Computation method, we develop a set of statistical probes to tune our simulation model to nine longitudinally-sampled within-host HIV phylogenies, finding evidence for recombination rates at the lower end of published estimates and relatively small latent pool sizes ranging from about 1000 to 2500 cells.

evolutionary biology↗