Biology subjects

Morton, S. U.

Publications and source records attributed to Morton, S. U..

6 recordsLinked to original sources

bioRxiv2026

A Large-Scale Deep Normative Modeling of Primary Sulcal Patterns Reveals Deviations in a Spectrum of Disorders

Primary sulcal patterns, the spatial arrangement of the earliest cortical folds, emerge prenatally and remain essentially stable after birth. Alterations are associated with cognitive outcomes and hold promise as clinical biomarkers. However, detecting abnormalities is challenging due to the high topological variability and complexity of normal individual sulcal patterns. Here, we introduce an unsupervised generative model that quantifies individual sulcal pattern deviations against a normative baseline learned from 10,349 typically developing subjects spanning early childhood through adulthood. We combine a generative reconstruction error with a discriminator trained on diffusion-generated pseudo-atypical graphs to leverage their complementary strengths in sensitivity and robustness. The discriminator captures subtle anomalies and is robust to demographic and data quality variations, whereas the generative model enables severity stratification and demonstrates cross-site generalizability. Across two clinical cohorts spanning subtle to overt sulcal abnormalities (congenital heart disease and polymicrogyria), our model captured global and localized condition-related deviations and linked them to neurodevelopmental outcomes. By enabling population-scale, individualized quantification of sulcal deviations, this framework provides a foundation for future clinical risk stratification.

neuroscience↗

bioRxiv2026

Removing an S-layer enables endolysin-derived probes to detect Paenibacillus thiaminolyticus in mixed bacterial populations

The emerging neonatal bacterial pathogen Paenibacillus thiaminolyticus causes sepsis and postinfectious hydrocephalus, yet few tools are available to study or specifically detect it. We developed fluorescent probes based on cell wall-binding domains (CBDs) from bacteriophage-derived cell-wall hydrolases. CBDs can target structurally conserved cell-wall glycans, making them attractive affinity reagents for bacterial detection. None of the 11 probes we designed labeled intact cells under standard conditions, and we identified a surface layer (S-layer) that prevented access to their cell-wall targets. Brief acidic treatment (pH 2.0) released abundant high-molecular-mass proteins from the cell surface and enabled labeling by five distinct CBD probes, each containing a single C-terminal S-layer homology domain. Mass spectrometry identified the main released protein as an ortholog of the P. alvei SpaA S-layer protein, which we designate SlsA. Across 26 surveyed P. thiaminolyticus genomes, we identified four distinct SlsA variants with 58-79% pairwise amino acid identity, encoded within a conserved cluster homologous to the P. alvei S-layer-associated locus. After either the acidic treatment or a quick flame fixation, the lead probe mGL-BDPt9 labeled six P. thiaminolyticus strains, including three Ugandan clinical isolates, as well as a P. dendritiformis clinical isolate from a US infant, and three additional Paenibacillus species. mGL-BDPt9 also distinguished P. thiaminolyticus from five gram-positive sepsis pathogens in pairwise mixtures and detected it in a five-species suspension. Together, these findings establish the presence of an S-layer in P. thiaminolyticus and provide a rapid fluorescent labeling strategy for multiple Paenibacillus pathogens associated with neonatal paenibacilliosis.

microbiology↗

bioRxiv2025

Dosage-sensitive RBFOX2 autoregulation promotes cardiomyocyte differentiation through transcriptome maturation

Haploinsufficiency of the RNA splicing regulator, RBFOX2, is linked to congenital heart disease (CHD), yet its pathogenic mechanisms remain unclear. Here, we demonstrate that RBFOX2 is essential for progressing cardiomyocyte (CM) differentiation by shifting exon usage profiles to more mature patterns in sarcomere, cytoskeletal, and focal adhesion genes, including alpha-actinin-2 (ACTN2). This maturation program is initiated by critical levels of RBFOX2 that facilitate autoregulatory splicing at mutually exclusive exons encoding early and late isoforms with distinct functional roles. In heterozygous CMs, autoregulation is disrupted, which skews isoform ratios and generates a dominant-negative product caused by exon co-inclusion. Finally, we demonstrate that overexpression of ACTN2 rescues heterozygous, but not null, phenotypes by restoring contractility, which triggers a mechanosensing feedback loop involving upregulation of RBFOX2 from the wildtype allele and transcriptome maturation. Our data suggest that decreased RBFOX2 dosage and autoregulation impair CM differentiation, contributing to CHD pathogenesis and heart failure susceptibility.

developmental biology↗

bioRxiv2022

Type IV pili is a critical virulence factor in clinical isolates of Paenibacillus thiaminolyticus

Hydrocephalus, the leading indication for childhood neurosurgery worldwide, is particularly prevalent in low-and-middle-income countries (LMICs). Hydrocephalus preceded by an infection, or postinfectious hydrocephalus (PIH), accounts for up to 60% of hydrocephalus in LMICs. Since many children with hydrocephalus suffer poor long-term outcomes despite surgical intervention, prevention of hydrocephalus remains paramount. Our previous studies implicated a novel bacterial pathogen, Paenibacillus thiaminolyticus, as a contributor to PIH in Uganda. Here we report the isolation of three P. thiaminolyticus strains, Mbale, Mbale2, and Mbale3, from patients with PIH and the demonstration that the three clinical isolates exhibit virulence in mice while P. thiaminolyticus type strain, B-4156, does not. We constructed complete genome assemblies of the clinical isolates as well as the reference strain and performed comparative genomics and proteomics analyses to identify potential virulence factors. One candidate virulence factor is a cluster of genes carried on a mobile genetic element that encodes a type IV pilus and is present in all three PIH patient strains but absent in the type strain. Proteomic and transcriptomic data confirmed the expression of this cluster of genes in the Mbale strain, while CRISPR-mediated deletion of the gene cluster substantially reduced the virulence of this strain. Our comparative proteogenomic analysis also identified various antibiotic resistance loci in the virulent strains. These results provide insight into the mechanism of virulence of Paenibacillus thiaminolyticus and suggest avenues for the diagnosis and treatment of this novel bacterial pathogen. Author SummaryPostinfectious hydrocephalus (PIH), a devastating sequela of neonatal infection, is associated with increased childhood mortality and morbidity. Paenibacillus thiaminolyticus was recently identified as the dominant organism highly associated with PIH in an African cohort. Our whole-genome sequencing, RNA sequencing and proteomics of three clinical isolates and a type strain in combination with CRISPR editing has revealed the type IV pili (T4P), encoded in a mobile genetic element, as a critical virulence factor for P. thiaminolyticus infection. Given the widespread presence of T4P in pathogens, the presence of T4P operon could serve as an important diagnostic and therapeutic target in P. thiaminolyticus and related bacteria.

microbiology↗

bioRxiv2019

Early post-zygotic mutations contribute to congenital heart disease

BackgroundThe contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined.\n\nResultsWe developed a computational method, Expectation-Maximization-based detection of Mosaicism (EM-mosaic), to analyze mosaicism in exome sequences of 2530 CHD proband-parent trios. EM-mosaic detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The frequency of mosaic variants above 10% mosaicism was 0.13/person in blood and 0.14/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction.\n\nConclusionsWe estimate that ~1% of CHD probands have a mosaic variant detectable in blood that could contribute to cardiac malformations, particularly those damaging variants expressed at higher allele fraction compared to benign variants. Although blood is a readily-available DNA source, cardiac tissues analyzed contributed ~5% of somatic mosaic variants identified, indicating the value of tissue mosaicism analyses.

bioinformatics↗

bioRxiv2017

Paternal-age-related de novo mutations and risk for five disorders

BackgroundThere are well-established epidemiologic associations between advanced paternal age and increased offspring risk for several psychiatric and developmental disorders. These associations are commonly attributed to age-related de novo mutations. However, the actual magnitude of risk conferred by age-related de novo mutations in the male germline is unknown. Quantifying this risk would clarify the clinical and public health significance of delayed paternity.\n\nMethodsUsing results from large, parent-child trio whole-exome-sequencing studies, we estimated the relationship between paternal-age-related de novo single nucleotide variants (dnSNVs) and offspring risk for five disorders: autism spectrum disorders (ASD), congenital heart disease (CHD), neurodevelopmental disorders with epilepsy (EPI), intellectual disability (ID), and schizophrenia (SCZ). Using Danish national registry data, we then investigated the degree to which the epidemiologic association between each disorder and advanced paternal age was consistent with the estimated role of de novo mutations.\n\nResultsIncidence rate ratios comparing dnSNV-based risk to offspring of 45 versus 25-year-old fathers ranged from 1.05 (95% confidence interval 1.01-1.13) for SCZ to 1.29 (95% CI 1.13-1.68) for ID. Epidemiologic estimates of paternal age risk for CHD, ID and EPI were consistent with the dnSNV effect. However, epidemiologic effects for ASDs and SCZ significantly exceeded the risk that could be explained by dnSNVs alone (p<2e-4 for both comparisons).\n\nConclusionIncreasing dnSNVs due to advanced paternal age confer a small amount of offspring risk for psychiatric and developmental disorders. For ASD and SCZ, epidemiologic associations with delayed paternity largely reflect factors that cannot be assumed to increase with age.

genetics↗