Biology subjects

Shohat, S.

Publications and source records attributed to Shohat, S..

4 recordsLinked to original sources

bioRxiv2025

The Quest for a Universal Parkinson's Transcriptomics Signature is Derailed by Inherent Variability between Patients

ObjectiveTo systematically evaluate the reproducibility and clinical utility of published blood mRNA-based gene signatures for classifying PD from healthy controls, and to uncover the pitfalls that limit their performances. MethodsWe validated the classification performance of 13 gene signatures unique for PD (published 2015-2025) using the Parkinsons Progression Markers Initiative (PPMI) database. We further validated classification performance on data collected in a prospective clinical trial where demographic and clinical parameters were minimized and environmental confounders were strictly controlled. Sources of gene expression variability were studied by mean pairwise distance analysis. ResultsGene overlap between signatures was low (11/411, 2.7%) but statistically significant (P<0.001) and enriched with genes involved in lipid metabolism. The majority (10/13) of these signatures retained statistical significance when tested on the PPMI dataset, but their classification performance was modest (median AUC 59.7%), substantially lower than originally reported. Classification performance improved when comparing GBA1-associated PD to controls (median AUC 65.4%, P=0.006). A prospective trial (16 PD patients, 14 controls) with rigorous environmental standardization did not improve classification accuracy. Inter-individual expression variability is the dominant limiting factor in classifier performance. Variability was not impacted by long-term levodopa therapy. InterpretationWhile blood transcriptomic signatures unique to PD are reproducible and may elucidate PD pathophysiology, their broad clinical utility remains severely limited by inherent inter-individual variability. Future research should prioritize biomarkers of divergence rather than the pursuit of a universal PD signature.

bioinformatics↗

bioRxiv2021

Gene essentiality in cancer cell lines is modified by the sex chromosomes

Human sex differences are thought to arise from gonadal hormones and genes on the sex chromosomes. Here we studied how sex and the sex chromosomes can modulate the outcome of mutations across the genome. We used the results of genome-wide CRISPR-based screens on 306 female and 396 male cancer cell lines to detect differences in gene essentiality between the sexes. By exploiting the tendency of cancer cells to lose or gain sex chromosomes, we were able to dissect the contribution of the Y and X chromosomes to variable gene essentiality. Using this approach, we identified 178 differentially essential genes that depend on the biological sex or the sex chromosomes. Integration with sex bias in gene expression and the rate of somatic mutations in human tumors highlighted genes that escape from X-inactivation, cancer-testis antigens, and Y-linked paralogs as central to the functional genetic differences between males and females.

genomics↗

bioRxiv2021

Genetic mechanisms for tissue-specific essential genes

Genetic diseases often manifest in specific tissues despite having the genetic risk variants in all cells. The most commonly assumed mechanism is selective expression of the causal gene in the pathogenic tissues, but other mechanisms are less explored. Using CRISPR screens from 789 cell lines and 27 lineages, we identified 1274 lineage-specific essential genes (LSEGs). We show that only a minority of LSEGs are explained by preferential expression (n = 115), and a big proportion of them (n = 509) is explained by lineage-specific gene amplification. Three other mechanisms were identified by genome-wide expression analysis. First, lineage-specific expression of paralogs leads to reduced functional redundancy and can account for 153 LSEGs. Second, for 45 LSEGs, the paralog expression increases vulnerability, implying functional codependency. Third, we suggest that the transfer of small molecules to mutant cells could explain blood-specific essentiality. Overall, LSEGs were more likely to be associated with human diseases than common essential genes, were highly intolerant to mutations and function in developmental pathways. Analysis of diverse human cell types found that the expression specificity of LSEGs and their paralogs is consistent with preferential expression and functional redundancy being a general phenomenon. Our findings offer important insights into genetic mechanisms for tissue specificity of human diseases.

genetics↗

bioRxiv2019

Genes essential for embryonic stem cells are associated with neurodevelopmental disorders

Mouse embryonic stem cells (mESCs) are a key component in generating mouse models for human diseases and performing basic research on pluripotency, but how many genes are essential for mESCs is still unknown. We performed a genome-wide screen for essential genes in mESCs and compared it to human cells. We found that essential genes are enriched for basic cellular functions, are highly expressed in mESCs, and tend to lack paralog genes. Notably, we discovered that genes that are essential specifically in mESCs play a role in pathways associated with their pluripotent state. We show that 25% of human genes that are intolerant to loss-of-function mutations are essential in mouse or human ESCs and that the human phenotypes most significantly associated with essential genes are neurodevelopmental. Our results provide insights into essential genes in the mouse, the pathways which govern pluripotency, and suggest that many genes associated with neurodevelopmental disorders are essential at very early embryonic stages.

genomics↗