Biology subjects

Chen, S.-F.

Publications and source records attributed to Chen, S.-F..

5 recordsLinked to original sources

bioRxiv2024

AoUPRS: A Cost-Effective and Versatile PRS Calculator for the All of Us Program

BackgroundThe All of Us (AoU) Research Program provides a comprehensive genomic dataset to accelerate health research and medical breakthroughs. Despite its potential, researchers face significant challenges, including high costs and inefficiencies associated with data extraction and analysis. AoUPRS addresses these challenges by offering a versatile and cost-effective tool for calculating polygenic risk scores (PRS), enabling both experienced and novice researchers to leverage the AoU dataset for significant genomic discoveries. ResultsAoUPRS is implemented in Python and utilizes the Hail framework for genomic data analysis. It offers two distinct approaches for PRS calculation: the Hail MatrixTable (MT) and the Hail Variant Dataset (VDS). The MT approach provides a dense representation of genotype data, while the VDS approach offers a sparse representation, significantly reducing computational costs. In performance evaluations, the VDS approach demonstrated a cost reduction of up to 99.51% for smaller scores and 85% for larger scores compared to the MT approach. Both approaches yielded similar predictive power, as shown by logistic regression analyses of PRS for coronary artery disease, atrial fibrillation, and type 2 diabetes. The empirical cumulative distribution functions (ECDFs) for PRS values further confirmed the consistency between the two methods. ConclusionsAoUPRS is a versatile and cost-effective tool that addresses the high costs and inefficiencies associated with PRS calculations using the AoU dataset. By offering both dense and sparse data processing approaches, AoUPRS allows researchers to choose the approach best suited to their needs, facilitating genomic discoveries. The tools open-source availability on GitHub, coupled with detailed documentation and tutorials, ensures accessibility and ease of use for the scientific community.

bioinformatics↗

bioRxiv2024

Structural basis of the human transcriptional Mediator complex modulated by its dissociable Kinase module

The eukaryotic Mediator, comprising a large Core (cMED) and a dissociable CDK8 kinase module (CKM), regulates RNA Polymerase II (Pol II)-dependent transcription. cMED recruits Pol II and promotes pre-initiation complex (PIC) formation in a manner inhibited by the CKM, which is also implicated in post-initiation control of gene expression. Herein we report cryo-electron microscopy structures of the human complete Mediator and its CKM, which explains the basis for CKM inhibition of cMED-activated transcription. The CKM binds to cMED through an intrinsically disordered region (IDR) in MED13 and HEAT repeats in MED12. The CKM inhibits transcription by allocating its MED13 IDR to occlude binding of Pol II and MED26 to cMED and further obstructing cMED-PIC assembly through steric hindrance with TFIIH and the +1 nucleosome. Notably, MED12 binds to the cMED Hook, positioning CDK8 downstream of the transcription start site, which sheds new light on its stimulatory function in post-initiation events.

biochemistry↗

bioRxiv2021

Rapid, Reference-Free Human Genotype Imputation with Denoising Autoencoders

Genotype imputation is a foundational tool for population genetics. Standard statistical imputation approaches rely on the co-location of large whole-genome sequencing-based reference panels, powerful computing environments, and potentially sensitive genetic study data. This results in computational resource and privacy-risk barriers to access to cutting-edge imputation techniques. Moreover, the accuracy of current statistical approaches is known to degrade in regions of low and complex linkage disequilibrium. Artificial neural network-based imputation approaches may overcome these limitations by encoding complex genotype relationships in easily portable inference models. Here we demonstrate an autoencoder-based approach for genotype imputation, using a large, commonly-used reference panel, and spanning the entirety of human chromosome 22. Our autoencoder-based genotype imputation strategy achieved superior imputation accuracy across the allele-frequency spectrum and across genomes of diverse ancestry, while delivering at least 4-fold faster inference run time relative to standard imputation tools.

bioinformatics↗

bioRxiv2021

The MAP3Ks DLK and LZK direct diverse responses to axon damage in zebrafish peripheral neurons

The MAP3Ks Dual Leucine Kinase (DLK) and Leucine Zipper Kinase (LZK) are essential mediators of axon damage responses, but their responses are varied, complex, and incompletely understood. To characterize their functions in axon injury, we generated zebrafish mutants of each gene, labeled motor neurons (MN) and touch-sensing neurons in live zebrafish, precisely cut their axons with a laser, and assessed the ability of mutant axons to regenerate. DLK and LZK were required redundantly and cell autonomously for axon regeneration in MNs, but not in larval Rohon-Beard (RB) or adult dorsal root ganglion (DRG) sensory neurons. Surprisingly, in dlk lzk double mutants, the spared branches of wounded RB axons grew excessively, suggesting that these kinases inhibit regenerative sprouting in damaged axons. Uninjured trigeminal sensory axons also grew excessively in mutants when neighboring neurons were ablated, indicating that these MAP3Ks are general inhibitors of sensory axon growth. These results demonstrate that zebrafish DLK and LZK promote diverse injury responses, depending on the neuronal cell identity and type of axonal injury. Significance statementThe MAP3Ks DLK and LZK are damage sensors that promote diverse outcomes to neuronal injury, including axon regeneration. Understanding their context-specific functions is a prerequisite to considering these kinases as therapeutic targets. To investigate DLK and LZK cell-type specific functions, we created zebrafish mutants in each gene. Using mosaic cell labeling and precise laser injury we found that both proteins were required for axon regeneration in motor neurons, but, unexpectedly, were not required for axon regeneration in Rohon-Beard or dorsal root ganglion (DRG) sensory neurons, and negatively regulated sprouting in the spared axons of touch-sensing neurons. These findings emphasize that animals have evolved distinct mechanisms to regulate injury site regeneration and collateral sprouting, and identify differential roles for DLK and LZK in these processes.

neuroscience↗

bioRxiv2020

Population genetic structure in the insular Ryukyu flying fox, Pteropus dasymallus

Small isolated populations are vulnerable to both stochastic events and the negative consequences of genetic drift. For threatened species, the genetic management of such populations has therefore become a crucial aspect of conservation. Flying foxes (Pteropus spp, Chiroptera) are keystone species with essential roles in pollination and seed dispersal in tropical and subtropical ecosystems. Yet many flying fox species are also of conservation concern, having experienced dramatic population declines driven by habitat loss and hunting. The Ryukyu flying fox (Pteropus dasymallus) ranges from Japan and Taiwan to the northern Philippines, and has undergone precipitous population crashes on several islands in recent decades. To assess population genetic structure and diversity in P. dasymallus, and its likely causes, we analyzed mitochondrial and microsatellite DNA. Both markers showed significant genetic differentiation among most island populations with patterns of isolation-by-distance. However, while mitochondrial haplotypes showed some mixing across the region, likely reflecting historical colonization and/or dispersal events, microsatellites markers showed clear subdivisions corresponding to the position of deep ocean trenches. The current distribution of P. dasymallus and its subspecific diversity therefore appears to have arisen through vicariance coupled with a long history of restricted gene flow across oceanic barriers. We conclude that isolated island subgroups should be managed separately, with efforts directed at reducing further declines.

ecology↗