Biology subjects

Ko, J. M.

Publications and source records attributed to Ko, J. M..

6 recordsLinked to original sources

bioRxiv2023

Mechanistic Regulation of Planarian Shape During Growth and Degrowth

Adult planarians can grow when fed and degrow (shrink) when starved while maintaining their whole-body shape with correct proportions. Different planarian morphogens are expressed at the anterior-posterior poles, medio-lateral border, and midline to provide positional information signals for the specification of different tissues at the right locations. However, it is currently unknown how these signals are coordinated together during feeding or starvation and how they modulate the differential tissue growth or degrowth necessary to form correct whole-body shapes. Here we investigate the dynamics of planarian shape during growth and degrowth together with a theoretical study to evaluate the mechanisms that regulate whole-body proportions and shape. We found that the planarian body proportions scale isometrically following similar linear rates during growth and degrowth, but that fed worms are significantly wider than starved worms. By combining a descriptive model of planarian shape and size with a mechanistic model of anterior-posterior and medio-lateral signaling calibrated with a novel machine learning methodology, we demonstrate that the feedback loop between these positional information signals and the shape they control can regulate the planarian whole-body shape during growth. Furthermore, the model can predict the correct shape and size dynamics during degrowth due to an increase in apoptosis rate and pole signal during starvation. These results offer mechanistic insights into planarian shape and size dynamics and the regulation of whole-body morphologies.

developmental biology↗

bioRxiv2023

Systematic analysis of disease-linked rare germline variants reveals new classes of cancer predisposing genes

Despite recent insights into cancer predisposition genes (CPGs), the contribution of rare germline variants to carcinogenesis remains unclear. Here, we examine the enrichment of rare germline variants in Mendelian disease-associated genes using PCAWG and the 1,000 Genomes Project. Using an integrative approach that considers disease classes, cellular pathways, and tissue expression profiles, we find that subsets of Online Mendelian Inheritance in Man (OMIM) genes are strong candidate CPGs. These genes were classified into five clusters suggesting diverse mechanisms underlie tumor progression. We further analyzed PAH gene which shows the strongest prevalence of rare germline variants in cancers (2.2%) compared to controls (0.7%). This enrichment was validated in two independent cancer cohorts and present the possibility of tumorigenesis by contributing immune-associated pathways. Our data argue that rare germline variants of Mendelian disease-associated genes contribute to cancer progression and suggest new CPG classifications that may underlie diverse tumorigenesis mechanisms.

bioinformatics↗

bioRxiv2022

Integrated single-cell chromatin and transcriptomic analyses of human scalp reveal etiological insights into genetic risk for hair and skin disease

Genome-wide association studies (GWAS) of hair and skin disease have identified many genetic variants associated with disease phenotypes, but identifying causal variants and interpreting their function requires deciphering gene-regulatory networks in disease-relevant cell types. To this end, we generated matched scRNA- and scATAC-seq profiles of human scalp biopsies, identifying diverse cell types of the hair follicle niche. By interrogating the integrated datasets across multiple levels of cellular resolution, we infer 50-100% more enhancer-gene links than prior approaches, and show that the aggregate accessibility at linked enhancers for highly-regulated genes predicts expression. We use these gene-regulatory maps to prioritize cell types, genes, and causal variants implicated in the pathobiology of androgenetic alopecia (AGA), eczema, and other complex traits. AGA GWAS signals are strongly and specifically enriched in dermal papilla cell open chromatin regions, supporting the role of these cells as key drivers of AGA pathogenesis. Finally, we trained machine-learning models to nominate SNPs that affect gene expression through disruption of specific transcription factor binding motifs, identifying candidate functional SNPs linked to expression of WNT10A in AGA and IL18RAP in eczema. Together, this work reveals principles of gene regulation and identifies gene regulatory consequences of natural genetic variation in complex skin and hair diseases.

genomics↗

bioRxiv2019

Continuous dynamic modeling of regulated cell adhesion

Cell-cell adhesion is essential for tissue growth and multicellular pattern formation, and crucial for the cellular dynamics during embryogenesis and cancer progression. Understanding the dynamical gene regulation of cell adhesion molecules (CAMs) responsible for the emerging spatial tissue behaviors is a current challenge due to the complexity of these non-linear interactions and feedback loops at different levels of abstraction--from genetic regulation to whole-organism shape formation. Continuous mathematical models of cell adhesion are ideal for the modeling of the spatial dynamics of large cell populations, where different cell types define inherent adhesion strengths. However, biologically the adhesive properties of the cell arise dynamically from differential expression of CAMs, which are precisely regulated during development and cancer progression. To extend our understanding of cell and tissue behaviors due to the regulation of adhesion molecules, here we present a novel model for the spatial dynamics of cellular patterning, growth, and shape formation due to the differential expression of CAMs and their regulation. Capturing the dynamic interplay between genetic regulation, CAM expression, and differential cell adhesion, the proposed continuous model can recapitulate the complex and emergent spatial behaviors of cell populations that change their adhesion properties dynamically due to inter- and intracellular genetic regulation. This approach can demonstrate the mechanisms responsible for classical cell sorting behaviors, cell intercalation in proliferating populations, and the involution of germ layer cells induced by a diffusing morphogen during gastrulation. Integrating the emergent spatial tissue behaviors with the regulation of genes responsible for essential cellular properties such as adhesion will pave the way towards understanding the genetic regulation of large-scale complex patterns and shapes formation in developmental, regenerative, and cancer biology.

biophysics↗

bioRxiv2018

Somatic uniparental disomy with a rare EFL1 variant causes Shwachman-Diamond syndrome through dysregulating ribosomal protein synthesis

Shwachman-Diamond syndrome (SDS; OMIM: #260400) is caused by variants in SBDS (Shwachman-Bodian-Diamond syndrome gene), which encodes a protein that plays an important role in ribosome assembly. Recent reports suggest that recessive variants in EFL1 are also responsible for SDS. However, the precise genetic mechanism that leads to EFL1-induced SDS remains incompletely understood. Here we present three unrelated Korean SDS patients that carry biallelic pathogenic variants in EFL1 with biased allele frequencies, resulting from a bone marrow-specific somatic uniparental disomy (UPD) in chromosome 15. The recombination events generated cells that were homozygous for the relatively milder variant, allowing for the evasion of catastrophic physiological consequences. Still, the milder EFL1 variant was solely able to impair 80S ribosome assembly and induce SDS features in cell line, zebrafish, and mouse models. The loss of EFL1 resulted in a pronounced inhibition of terminal oligo-pyrimidine element-containing ribosomal protein transcript 80S assembly. Therefore, we propose a more accurate pathogenesis mechanism of EFL1 dysfunction that eventually leads to aberrant translational control and ribosomopathy.

genetics↗

bioRxiv2018

Comprehensive genetic analysis by whole exome sequencing in 352 Korean pediatric patients with unknown neurodevelopmental disorders

ImportanceAccurate diagnosis of pediatric patients with complicated neurological problems demands a well-coordinated combination of robust genetic analytic capability and delicate clinical evaluation. It should be tested whether this challenge can be augmented by whole exome sequencing (WES).\n\nObjectiveTo evaluate the utility of WES-based diagnosis and discovery of novel variants of undiagnosed patients with complex neurodevelopmental problems in a country with a centralized medical system.\n\nDesign, setting, and participantsA cohort of 352 Korean patients, believed to cover a major portion of the entire country from July 2014 to April 2017, with a broad spectrum of neurodevelopmental disorders without any pathogenic variants revealed by conventional methods were evaluated by trio-based WES at Seoul National University Childrens Hospital.\n\nExposuresWES of patients and parents and subsequent evaluation of genetic variants.\n\nMain outcomes and measuresGenetic variants from each patient were evaluated for known disease association and novel variants were assessed for possible involvement with neurodevelopment process.\n\nResultsWe identified disease-causing variants, including newly discovered variants, in 57.4% of the probands, who had underwent a mean of 5.6 years of undiagnosed periods and visited mean of 2.3 tertiary hospitals. The cohort included 112 patients with variants that were previously reported as pathogenic (31.8%), 16 patients with copy number variants (4.5%) and 27 patients with variants that were associated with different clinical symptoms (7.7%). We also discovered potentially pathogenic variants from 47 patients that required further functional assessments (13.4%) and demonstrated potential implications in neurodevelopmental disorders. Following the genetic analysis, we provided more precise treatments to selected patients. A few clinical vignettes are presented that illuminate the potential diagnostic pitfalls that one could have encountered without this approach.\n\nConclusions and relevanceOur results highlight the utility of WES-based diagnosis for improved patient care in a country with a centralized medical system and discovery of novel pathophysiology mechanisms.\n\nKey pointsO_ST_ABSQuestionC_ST_ABSWhat is the advantage of whole exome sequencing based diagnosis of pediatric neurology patients with unknown rare symptoms in a large tertiary clinic in a country with a centralized medical system?\n\nFindingsWhole exome sequencing of 352 Korean patients, with a mean of 5.7 years of undiagnosed period, yielded 44.0% of conservative diagnostic yield. A number of cases were directly benefitted by trio-based WES via termination of diagnostic odyssey, genetic counseling for next offspring, or suggestion of more effective and customized treatment options.\n\nMeaningWe report on the establishment of a national-level whole exome-based diagnosis system, with emphasis on deliberate integration of clinical interpretation and genetic analysis. Whole exome sequencing should be a choice of diagnostic tools for pediatric neurologic patients with ambiguous symptoms.

genetics↗