Biology subjects

Jamison, B.

Publications and source records attributed to Jamison, B..

5 recordsLinked to original sources

bioRxiv2026

Beyond the mean: genetic control of gene expression fidelity and dispersion

For decades, molecular biologists have interpreted gene regulation through measurements of mean gene expression, because they could not resolve regulatory variation among individual cells. The advent of single-cell genomics has now made that variation measurable, revealing pervasive differences in gene expression among apparently similar cells. Whether this variation mainly reflects stochastic noise or an informative regulatory property remains unclear. Here we show that mean-corrected gene expression dispersion is a reproducible and biologically structured feature of gene regulation that reflects regulatory fidelity. In heterogeneous differentiated cardiac cultures, genes with low dispersion are shared across cell types, enriched for housekeeping functions, depleted for expression quantitative trait loci, and more highly connected in transcriptional and protein interaction networks. In a comparative single-cell system spanning human, chimpanzee, and allotetraploid cells, a substantial subset of interspecies differences in regulatory dispersion persists in a shared trans environment, indicating that gene expression fidelity is often regulated in cis. Our findings establish gene expression dispersion as a genetically encoded dimension of gene regulation that is distinct from mean expression, and places dispersion along a fidelity-plasticity axis with implications for development, disease, and threshold-dependent cellular phenotypes.

genomics↗

bioRxiv2025

Single-cell multiomics of neuronal activation reveals context-dependent genetic control of brain disorders

Most causal variants for neuropsychiatric disorders (NPD) remain unknown. A major hurdle is that disease variants may act in specific contexts, such as during neuronal activation, which is difficult to study in vivo at the population level. We profiled single-nucleus neuron-activation multiomics in human induced pluripotent stem cell (iPSC)-derived neurons from 100 donors, revealing the NPD-relevant transcriptomic/epigenomic landscape of neuronal activation. We identified abundant genetic variants associated with activity-dependent gene expression (eQTL) and chromatin accessibility (caQTL), the latter explaining larger proportions of NPD heritability. Integrating multiomic data with genome-wide association studies (GWAS) further revealed NPD risk variants and genes with effects detected only upon stimulation, such as activity-dependent cholesterol metabolism. Our work highlights the power of cell stimulation to reveal context-specific "hidden" genetic effects.

neuroscience↗

bioRxiv2024

Scaled and Efficient Derivation of Loss of Function Alleles in Risk Genes for Neurodevelopmental and Psychiatric Disorders in Human iPSC

Translating genetic findings for neurodevelopmental and psychiatric disorders (NPD) into actionable disease biology would benefit from large-scale and unbiased functional studies of NPD genes. Leveraging the cytosine base editing (CBE) system, here we developed a pipeline for clonal loss-of-function (LoF) allele mutagenesis in human induced pluripotent stem cells (hiPSCs) by introducing premature stop-codons (iSTOP) that lead to mRNA nonsense-mediated-decay (NMD) or protein truncation. We tested the pipeline for 23 NPD genes on 3 hiPSC lines and achieved highly reproducible, efficient iSTOP editing in 22 NPD genes. Using RNAseq, we confirmed their pluripotency, absence of chromosomal abnormalities, and NMD. Interestingly, for three schizophrenia risk genes (SETD1A, TRIO, CUL1), despite the high efficiency of base editing, we only obtained heterozygous LoF alleles, suggesting their essential roles for cell growth. We replicated the reported neural phenotypes of SHANK3-haploinsufficiency and found CUL1-LoF reduced neurite branches and synaptic puncta density. This iSTOP pipeline enables a scaled and efficient LoF mutagenesis of NPD genes, yielding an invaluable shareable resource.

genetics↗

bioRxiv2022

Loss-of-function of OTUD7A in the schizophrenia-associated 15q13.3 deletion impairs synapse development and function in human neurons

Identifying causative gene(s) within disease-associated large genomic regions of copy number variants (CNVs) is challenging. Here, by targeted sequencing of genes within schizophrenia (SZ)-associated CNVs in 1,779 SZ cases and 1,418 controls, we identified three rare putative loss-of-function (LoF) mutations in OTU deubiquitinase 7A (OTUD7A) within the 15q13.3 deletion in cases, but none in controls. To tie OTUD7A LoF with any SZ-relevant cellular phenotypes, we modeled the OTUD7A LoF mutation, rs757148409, in human induced pluripotent stem cell (hiPSC)-derived induced excitatory neurons (iNs) by CRISPR/Cas9 engineering. The mutant iNs showed a [~]50% decrease in OTUD7A expression without undergoing nonsense-mediated mRNA decay. The mutant iNs also exhibited marked reduction of dendritic complexity, density of synaptic proteins GluA1 and PSD-95, and neuronal network activity. Congruent with the neuronal phenotypes in mutant iNs, our transcriptomic analysis showed that the set of OTUD7A LoF-downregulated genes was enriched for those relating to synapse development and function, and was associated with SZ and other neuropsychiatric disorders. These results suggest that OTUD7A LoF impairs synapse development and neuronal function in human neurons, providing mechanistic insight into the possible role of OTUD7A in driving neuropsychiatric phenotypes associated with the 15q13.3 deletion.

neuroscience↗

bioRxiv2020

Rapid self-selecting and clone free integration of transgenes into engineered CRISPR safe harbor locations in Caenorhabditis elegans

Precision genome editing for model organisms has revolutionized functional analysis and validation of a wide variety of molecular systems. To date, the capacity to insert transgenes into the model nematode Caenorhabditis elegans has focused on utilizing either transposable elements or CRISPR-based safe harbor strategies. These methods require laborious screening processes that often result in false positives from heritable extrachromosomal arrays or rely on co-CRISPR markers to identify likely edited individuals. As a result, verification of transgene insertion requires anti-array selection screening methods or extensive PCR genotyping respectively. These approaches also rely on cloning plasmids for the addition of transgenes. Here, we present a novel safe harbor CRISPR-based integration strategy that utilizes engineered insertion locations containing a synthetic guide RNA target and a split-selection system to eliminate false positives from array formation, thereby providing integration-specific selection. This approach allows the experimenter to confirm an integration event has taken place without molecular validation or anti-array screening methods, and is capable of producing integrated transgenic lines in as little as five days post-injection. To further increase the speed of generating transgenic lines, we also utilized the C. elegans native homology-based formation of extra-chromosomal arrays to assemble transgenes in-situ, removing the cloning step. We show that complete transgenes can be made and inserted into our split-selection safe harbor locations starting from PCR products, providing a clone-free and molecular-validation-free strategy for single-copy transgene integration. Overall, this combination of approaches provides an economical and rapid system for generating highly reproducible complex transgenics in C. elegans.

genetics↗