Biology subjects

Willis, S.

Publications and source records attributed to Willis, S..

5 recordsLinked to original sources

bioRxiv2026

Developmental dysregulation of chandelier cell excitability in a mouse model of Dravet Syndrome

Chandelier cells (ChCs) are a rare and highly specialized sub-type of inhibitory neuron in the cerebral cortex that specifically and exclusively form synapses onto the axon initial segment of excitatory neurons and thereby exert powerful control of excitability. We applied a newly developed, cell type-specific enhancer element to label ChCs and assess their electrophysiological and morphological properties across development in Dravet Syndrome (Scn1a+/- mice), a prominent neurodevelopmental disorder defined by epilepsy and features of autism spectrum disorder. Dravet Syndrome is known to predominantly impact GABAergic interneurons. We found that ChCs from juvenile Scn1a+/- mice (postnatal day, P18-21) exhibit impaired excitability, and that deficits largely persist in young adulthood (P35-56). These findings are distinct from prior observations in the more common subtype of parvalbumin-positive interneurons, basket cells. We found no differences in the axonal or dendritic morphology of ChCs at either time point. Our results suggest a role for ChCs in the pathogenesis of Dravet Syndrome and constitute the first targeted study of ChC function in a specific genetically-defined neurodevelopmental disorder.

neuroscience↗

bioRxiv2025

De novo Genome Assemblies of Four Rainbow Trout Genetic Lines Reveal Structural Variants In Pursuit of a Pangenome Reference

Rainbow trout (Oncorhynchus mykiss) exhibit extensive genomic diversity shaped by domestication, life history, and geographic origin. To advance the development of a comprehensive pangenome reference, we present new de novo genome assemblies of two genetically and ecologically distinct lines: Whale Rock (WR; wild, landlocked, Central California) and Keithley Creek (KC; wild, resident, interior Columbia Basin), along with the previously published assemblies of the Arlee (domesticated, Northern California) and Swanson (semi-domesticated, resident, Alaska) lines. All assemblies provide nearly complete coverage of known genes (BUSCO 95.8-99.7%) and are similar in genome size ([~]2.3 Gb), with scaffold N50 values between 3.4 Mb (KC) and 52.4 Mb (Swanson). Comparative whole-genome alignments revealed high sequence conservation (97-98% identity) among assemblies, but also evidence of extensive structural variation of at least 50 bp in length. Structural variant (SV) profiling identified tens of thousands of deletions, insertions, and complex rearrangements largely in noncoding sequences. In an initial assessment of the utility of having multiple de novo genome assemblies for rainbow trout, we found that two strains (Arlee and Swanson; domesticated) share SVs enriched in genes linked with growth, reproduction, and adaptation to domestication, such as GTP binding and ECM-receptor interaction. In comparison, the other two strains (WR and KC; wild origin) share SVs associated with reproductive timing such as GnRH signaling pathway. Both Arlee and WR also have unique SVs potentially related to their geographic origin and unique life history. Additionally, we identified SVs in key regions, such as a QTL for fillet yield on Omy17 and the maturation-associated SIX6/ER{beta}-GPHB5 locus on Omy25q, suggesting the importance of considering SVs when investigating the genomics of complex traits. Together, these assemblies and comparative analyses establish a foundation for a rainbow trout pangenome reference, illuminating how they can be utilized to reveal the structural genomic basis of domestication, adaptation, and other complex traits in O. mykiss.

genomics↗

bioRxiv2023

A new codon adaptation metric predicts vertebrate body size and tendency to protein disorder

The nearly neutral theory of molecular evolution posits variation among species in the effectiveness of selection. In an idealized model, the census population size determines both this minimum magnitude of the selection coefficient required for deleterious variants to be reliably purged, and the amount of neutral diversity. Empirically, an "effective population size" is often estimated from the amount of putatively neutral genetic diversity and is assumed to also capture a species effectiveness of selection. A potentially more direct measure of the effectiveness of selection is the degree to which selection maintains preferred codons. However, past metrics that compare codon bias across species are confounded by among-species variation in %GC content and/or amino acid composition. Here we propose a new Codon Adaptation Index of Species (CAIS), based on Kullback-Leibler divergence, that corrects for both confounders. We demonstrate the use of CAIS correlations, as well as the Effective Number of Codons, to show that the protein domains of more highly adapted vertebrate species evolve higher intrinsic structural disorder

evolutionary biology↗

bioRxiv2020

Snx4-mediated nucleophagy targets transcription factors controlling ATG gene expression

Autophagy is controlled in part by the repression and activation of Autophagy-related (ATG) gene transcription. Here, we demonstrate that the conserved Cdk8 Kinase Module (CKM) of the mediator complex represses transcription of several ATG genes. To relieve this repression following nitrogen starvation, Med13 is rapidly degraded via a novel selective autophagy mechanism. This pathway requires the core autophagy machinery but is independent of known nucleophagy systems. It requires the cytosolic filament nucleoporin Gle1, the sorting nexin Snx4-Atg20 heterodimer, and the scaffold protein Atg17. This suggests a model where Med13 traverses through the nuclear pore complex, passing from Gle1 to Snx4. Snx4 then transports Med13 to autophagosomes by binding to Atg17. This previously unidentified nucleophagy pathway also mediates the autophagic degradation of two transcriptional activators of ATG genes (Rim15, Msn2) suggesting that this mechanism targets transcription factors that regulate ATG expression. This system provides a new level of selectivity, permitting the cell to fine-tune the autophagic response by controlling the turnover of both positive and negative ATG transcription factors.

cell biology↗

bioRxiv2017

Gene birth and constraint avoidance both contribute to structural disorder in overlapping genes

The same nucleotide sequence can encode two protein products in different reading frames. Overlapping gene regions encode higher levels of intrinsic structural disorder (ISD) than non-overlapping genes (39% vs. 25% in our viral dataset). This might be because of the intrinsic properties of the genetic code, because one member per pair was recently born de novo in a process that favors high ISD, or because high ISD relieves increased evolutionary constraint imposed by dual-coding. Here we quantify the relative contributions of these three alternative hypotheses. We estimate that the recency of de novo gene birth explains 32% or more of the elevation in ISD in overlapping regions of viral genes. While the two reading frames within a same-strand overlapping gene pair have markedly different ISD tendencies that must be controlled for, their effects cancel out to make no net contribution to ISD. The remaining elevation of ISD in the older members of overlapping gene pairs, presumed due to the need to alleviate evolutionary constraint, was already present prior to the origin of the overlap. Same-strand overlapping gene birth events can occur in two different frames, favoring high ISD either in the ancestral gene or in the novel gene; surprisingly, most de novo gene birth events contained completely within the body of an ancestral gene favor high ISD in the ancestral gene (23 phylogenetically independent events vs. 1). This can be explained by mutation bias favoring the frame with more start codons and fewer stop codons.

evolutionary biology↗