Biology subjects

Robinette, M.

Publications and source records attributed to Robinette, M..

4 recordsLinked to original sources

bioRxiv2026

Suppressive Genetic Interactions Between Haploinsufficient Mitochondrial Genes Encoded in the 22q11.2 Microdeletion Locus Define Brain and Cardiac Phenotypes

Genomic copy number variations, such as the 22q11.2 microdeletion syndrome, cause pleiotropic disorders that affect diverse organ systems and disrupt neurodevelopment. Deletions of the 22q11.2 locus reduce the dosage of up to 46 protein coding genes, raising questions about the identity of haploinsufficient genes and their genetic interactions contributing to 22q11.2 phenotypes. Here, we dissect functional and molecular relationships between two genes encoded within the 22q11.2 locus: the mitochondrial ribosomal protein gene MRPL40 and the mitochondrial citrate transporter SLC25A1. We show that a MRPL40 null mutation disrupts mitochondrial translation, impairs respiration, and affects multiple components of the SLC25A1 interactome including factors required for lipid metabolism, mitochondrial ribosome subunits, and the mitochondrial RNA processing machinery. In silico coessentiality network analysis revealed correlated and anticorrelated fitness interactions linking MRPL40 and SLC25A1 to mitochondrial translation, intermediate carbon metabolism, and interferon signaling. We determined that Mrpl40-null mutations are embryonic lethal in mice, but Mrpl40-/+ mice are viable and displayed embryonic cardiac development and adult behavioral phenotypes. Similarly, Slc25a1+/- animals showed embryonic cardiac developmental defects but lacked the adult behavioral phenotypes observed in Mrpl40-/+ mice. Surprisingly, transheterozygotic Slc25a1+/-;Mrpl40-/+ mice suppressed or mitigated cardiac development, behavioral, and brain transcriptome phenotypes observed in single heterozygotic animals. These results reveal that MRPL40 and SLC25A1 are haploinsufficient genes within the 22q11.2 locus that genetically and biochemically interact to define tissue development and physiology. Our findings provide a framework for understanding the complexity and type of gene dosage interactions within the 22q11.2 deletion syndrome locus.

neuroscience↗

bioRxiv2025

Comparative Connectomics Highlights Conserved Architectural Synaptic Motifs in the Drosophila Mushroom Body

While the influence of synaptic plasticity on learning and memory has been extensively studied, the detailed patterns of synaptic connectivity remain incompletely mapped. Convergent synaptic motifs -- a tight grouping of at least two axons whose active zones are within 300nm and which are presynaptic to the same target -- are a common feature of neural circuits in the insect brain and are believed to serve as an important computational primitive in many brain areas. The Mushroom Body (MB) of Drosophila, for instance, is the center of associative learning and memory, where sensory information is conducted by Kenyon cells (KCs), the intrinsic neurons of the MB, and integrated by MB output neurons (MBONs). Indeed, the majority of KC-to-MBON synapses occur in a convergent motif. Nonetheless, the functional role of this convergent motif is not well studied. To gain insight into their potential role in the MB, we combine big-data network neuroscience tools with existing electron microscopy connectome datasets to detect and map the distribution of convergent synaptic motifs. We find that convergent motifs consistently occur across the MB in different individuals, including the -lobe where they were first quantified, and we report on both the variance and consistency in the formation of these motifs across different MB regions and individuals. Our discovery of multiply-convergent motifs -- where two KCs target multiple postsynaptic targets simultaneously -- reveals a previously unrecognized synaptic economy that may optimize information transfer while conserving neural resources. These stereotyped arrangements likely represent fundamental organizational principles underlying associative learning across species. Lastly, to our knowledge, this study offers the first and most extensive comparative analysis of synaptic motifs across Drosophila connectomes, establishing a framework for enabling systematic motif analysis of synapses across species.

neuroscience↗

bioRxiv2025

Using Random Forests to Infer Nonlinear Step Selection Effects

O_LIStep selection functions (SSFs) examine the factors that motivate animal movement by pairing observed steps with unobserved "comparison steps" and quantifying the effects of covariates corresponding to the values of the factors at each observed step. Traditionally, SSFs are fit with conditional logistic regression (CLR) models, which explicitly reflect how an animal must decide between an observed step and other available steps. These models, however, cannot infer nonlinear effects unless the specific parametric form (e.g., quadratic) of the nonlinear effect is specified. C_LIO_LITo enable more general inference of nonlinear effects, we propose replacing CLR with random forests (RFs). Using a fitted model, we also describe how to plot the relationship between changes in the value of a covariate upon the likelihood that the animal will select a given step with those covariate values (an "effect curve"). C_LIO_LITo evaluate our models and their corresponding effect curves, we simulated tracks with various nonlinear effects. RFs yield effect curves that closely resemble the specified nonlinear effect curves, achieving mean R2 = 0.953 and outperforming a CLR model with quadratic terms and spline-based generalized additive models. Additionally, we applied our best-performing RF to real wolf data (Barry et al., 2020). The resulting effect curves confirm the authors assumptions that their covariates affect wolf movement according to a step function. C_LIO_LIThese results suggest that RFs may be used either to discover unknown nonlinear step selection effects or to confirm previously hypothesized nonlinear effects. Going forward, we envision the use of RFs as an approach that complements existing SSF approaches, providing insights about nonlinear relationships between covariate values and the effects that they have on animal movement decisions. C_LI

ecology↗

bioRxiv2023

Cross-species transcriptomic analysis identifies mitochondrial dysregulation as a functional consequence of the schizophrenia-associated 3q29 deletion

Recent advances in the genetics of schizophrenia (SCZ) have identified rare variants that confer high disease risk, including a 1.6 Mb deletion at chromosome 3q29 with a staggeringly large effect size (O.R. > 40). Understanding the impact of the 3q29 deletion (3q29Del) on the developing CNS may therefore lead to insights about the pathobiology of schizophrenia. To gain clues about the molecular and cellular perturbations caused by the 3q29 deletion, we interrogated transcriptomic effects in two experimental model systems with complementary advantages: isogenic human forebrain cortical organoids and isocortex from the 3q29Del mouse model. We first created isogenic lines by engineering the full 3q29Del into an induced pluripotent stem cell line from a neurotypical individual. We profiled transcriptomes from isogenic cortical organoids that were aged for 2 months and 12 months, as well as day p7 perinatal mouse isocortex, all at single cell resolution. Differential expression analysis by genotype in each cell-type cluster revealed that more than half of the differentially expressed genes identified in mouse cortex were also differentially expressed in human cortical organoids, and strong correlations were observed in mouse-human differential gene expression across most major cell-types. We systematically filtered differentially expressed genes to identify changes occurring in both model systems. Pathway analysis on this filtered gene set implicated dysregulation of mitochondrial function and energy metabolism, although the direction of the effect was dependent on developmental timepoint. Transcriptomic changes were validated at the protein level by analysis of oxidative phosphorylation protein complexes in mouse brain tissue. Assays of mitochondrial function in human heterologous cells further confirmed robust mitochondrial dysregulation in 3q29Del cells, and these effects are partially recapitulated by ablation of the 3q29Del gene PAK2. Taken together these data indicate that metabolic disruption is associated with 3q29Del and is conserved across species. These results converge with data from other rare SCZ-associated variants as well as idiopathic schizophrenia, suggesting that mitochondrial dysfunction may be a significant but overlooked contributing factor to the development of psychotic disorders. This cross-species scRNA-seq analysis of the SCZ-associated 3q29 deletion reveals that this copy number variant may produce early and persistent changes in cellular metabolism that are relevant to human neurodevelopment.

genomics↗