Biology subjects

Kwong, A.

Publications and source records attributed to Kwong, A..

9 recordsLinked to original sources

bioRxiv2026

The Effects of Phosphorylation on the Structure and Function of Motif A, an Intrinsically Disordered Region within SIRT1

The NAD+ dependent deacetylase sirtuin-1 (SIRT1) is known to elicit cellular defenses against aging, cancer, and other aberrant pathologies. Previous studies have identified an intrinsically disordered region of SIRT1 comprised of N-terminal residues 1-52, herein referred to as motif A, which activates SIRT1 activity, likely through intramolecular interactions. Additionally, phosphorylation of N-terminal residues Ser27 and Ser47 has been shown to be important for regulating SIRT1 activity and stability. The lack of in vitro characterization of these effects hampers our further understanding of the role of motif A in SIRT1 regulation. In this study, we elucidate the role phosphorylation plays in motif As structure as well as its regulatory effects on SIRT1 activity against Ac-p65. We find that phosphomimetic mutation at Ser27 significantly increases the activation effect of motif A towards SIRT1. This result is supported by molecular dynamics simulations of the phosphomimetics, which reveal stabilization of different transient structures for motif A depending on whether Ser27 and Ser47 have been modified. A key finding suggested by this study is that phosphorylation of S27 appears to activate SIRT1 by causing motif A, which is intrinsically disordered in the WT, to fold into an ordered structure. This conclusion is based on both the experimental findings and simulation results. These findings contribute to our understanding of SIRT1 regulation, specifically the role played by phosphorylation within the N-terminal disordered region.

biochemistry↗

bioRxiv2025

A niche-dependent redox rheostat regulates epithelial stem cell fate in the distal colon

The niche environment surrounding intestinal stem cells (ISCs) varies along the length of intestine and provides key cues that regulate stem cell fate. Here, we investigated the role of cellular redox balance in colonic ISC function. We show that hypoxia and Wnt signaling synergize to restrict the reactive oxygen species (ROS) generating enzyme NADPH oxidase 1 (NOX1) to the crypt base in the distal colon. NOX1 function maintains a more oxidative cell state that licenses cell cycle entry, altering the balance of asymmetric stem cell self-renewal and directing lineage commitment. Mechanistically, cell redox state directs a self-reinforcing circuit that connects hypoxia inducible factor 1 (HIF1)-dependent signaling with regulation of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1). Our studies show that cellular redox balance is a central and niche-dependent regulator of epithelial homeostasis and regeneration and provide a basis for understanding disease propensity in the distal large intestine. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=176 SRC="FIGDIR/small/634856v2_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@107798aorg.highwire.dtl.DTLVardef@1bc9013org.highwire.dtl.DTLVardef@96d56aorg.highwire.dtl.DTLVardef@95268d_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIThe balance of cycling intestinal stem cells (ISCs) versus committed epithelial cells in the uniquely hypoxic niche of the distal colon is regulated by NADPH oxidase 1 (NOX1) dependent H2O2 both at homeostasis and during regeneration. C_LIO_LIPhysiological increase in cellular H2O2 favors maintenance of glycolysis in ISCs for self-renewal through regulation of isocitrate dehydrogenase 1 activity. C_LIO_LIMaintenance of the increased cellular oxidative state stabilizes HIF1 through a re-enforcing metabolic circuit. C_LIO_LIA shift from a relatively oxidative to a reductive cell environment in distal colonic ISCs leads to decreased progression through the cell cycle and altered cell fate determination. C_LI

cell biology↗

bioRxiv2023

Java sparrow song conforms to Mezerath's Law but not Zipf's Law of Abbreviation

Linguistic laws, which describe common statistical patterns in human language, are often studied in animal communication systems. Despite good evidence for adherence to these laws in non-human primate communication, there is still a paucity of data on other taxa. Birdsong is often used as a model for human language development due to similarities in vocal learning processes. Investigating whether birdsong also adheres to linguistic laws may provide further value or help determine the limitations of such comparisons. Here, we looked for patterns consistent with Menzeraths law, the tendency for longer sequences to be made up of smaller constituent parts, and Zipfs Law of Abbreviation, the tendency for more frequently used elements to be shorter in length, in the songs of Java sparrows (Padda oryzivora). We found that songs conformed to Menzeraths law at both the population and individual level; longer sequences were made up of shorter notes. This pattern was achieved through note type selection rather than the shortening of existing note types. Adherence to Menzeraths law may reflect species-specific constraints on song durations. We found no evidence to support adherence to Zipfs Law of Abbreviation, either at population or individual level; more frequently used notes were not shorter in length. However, as repertoire size in Java sparrows is small, we expect our power to detect Zipfs Law of Abbreviation to be weak. Whilst there may be some limitations in applying linguistic laws derived from human language to birdsong, especially Zipfs Law of Abbreviation, these laws may still provide insights into animal and human communication systems.

animal behavior and cognition↗

bioRxiv2023

Methodological Considerations When Using Polygenic Scores to Explore Parent-Offspring Genetic Nurturing Effects

BackgroundResearch has begun to explore the effects of parental genetic nurturing on offspring outcomes using polygenic scores (PGSs). However, there are concerns regarding potential biases due to confounding when mediating parental phenotypes are included. MethodsDepression, educational attainment and height PGSs were generated for 2680 biological parent-offspring trios using genome-wide association study (GWAS) meta-analysis summary statistics in a large population study: Generation Scotland. Regression and pathway models were estimated incorporating PGSs for both parents and offspring to explore direct (offspring PGS) and genetic nurturing (parental PGS) effects on psychological distress, educational attainment and height. Genetic nurturing via parental phenotypes were incorporated into the models. To explore sources of bias we conducted simulation analyses of 10,000 trios using combinations of PGS predictive accuracy and accounted variance. ResultsModels incorporating both offspring and parental PGSs suggested positive parental genetic nurturing effects on offspring educational attainment, but not psychological distress or height. In contrast, models additionally incorporating parental phenotypic information suggested positive parent phenotype mediated genetic nurturing effects were at play for all phenotypes explored as well as negative residual genetic nurturing effects for height. 10,000 parent-offspring trio effects (without genetic nurturing effects) were simulated. Simulations demonstrated that models incorporating parent and offspring PGSs resulted in genetic nurturing effects that were unbiased. However, adding parental phenotypes as mediating variables results in biased positive estimates of parent phenotype mediated genetic nurturing effects and negative estimates of residual genetic nurturing effects. Biased effects increased in magnitude as PGS accuracy and accounted variance decreased. These biases were only eliminated when PGSs were simulated to capture the entirety of trait genetic variance. ConclusionResults suggest that in the absence of PGSs that capture all genetic variance, parental phenotypes act as colliders in the same way as heritable environments. Relatively simple models combining parental and offspring PGSs can be used to detect genetic nurturing effects in complex traits. However, our findings suggest alternative methods should be utilised when aiming to identify mediating phenotypes and potentially modifiable parental nurturing effects.

genomics↗

bioRxiv2021

FIVEx: an interactive multi-tissue eQTL browser

SummaryExpression quantitative trait loci (eQTLs) characterize the associations between genetic variation and gene expression to provide insights into tissue-specific gene regulation. Interactive visualization of tissue-specific eQTLs can facilitate our understanding of functional variants relevant to disease-related traits. However, combining the multi-dimensional nature of eQTLs into a concise and informative visualization is challenging. Existing eQTL visualization tools provide useful ways to summarize the unprecedented scale of transcriptomic data but are not necessarily tailored to answer questions about the functional interpretations of trait-associated variants or other variants of interest. We developed FIVEx, an interactive eQTL browser with an intuitive interface tailored to the functional interpretation of associated variants. It features the ability to navigate seamlessly between different data views while providing relevant tissue- and locus-specific information to offer users a better understanding of population-scale multi-tissue transcriptomic profiles. Our implementation of the FIVEx browser on the Gene-Tissue Expression (GTEx) dataset provides important insights for understanding potential tissue-specific regulatory mechanisms underlying trait-associated signals. Availability and implementationA FIVEx instance visualizing GTEx v8 data can be found at https://eqtl.pheweb.org. The FIVEx source code is open source under an MIT license at https://github.com/statgen/fivex.

bioinformatics↗

bioRxiv2020

Robust, flexible, and scalable tests for Hardy-Weinberg Equilibrium across diverse ancestries

Traditional Hardy-Weinberg equilibrium (HWE) tests (the {chi}2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in datasets comprised of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence datasets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently amongst the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.

bioinformatics↗

bioRxiv2019

The GTEx Consortium atlas of genetic regulatory effects across human tissues

The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues, and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the v8 data, based on 17,382 RNA-sequencing samples from 54 tissues of 948 post-mortem donors. We comprehensively characterize genetic associations for gene expression and splicing in cis and trans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue-specificity of genetic effects, and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.

genetics↗

bioRxiv2018

Expanded genomic analyses for male voice-breaking highlights a shared phenotypic and genetic basis between puberty timing and hair colour

The timing of puberty is highly variable and has important consequences for long-term health. Most of our understanding of the genetic control of puberty timing is based on studies in women, as age at menarche is often recorded. Here, we report a multi-trait genome-wide association study for male puberty timing, based on recalled timing of voice breaking and facial hair, with an effective sample size of 205,354 men, nearly four-fold larger than previously reported. We identify 78 independent signals for male puberty timing, including 29 signals not previously associated with puberty in either sex. Novel mechanisms include an unexpected phenotypic and genetic link between puberty timing and natural hair colour, possibly reflecting common effects of pituitary hormones on puberty and pigmentation. Earlier male puberty timing is genetically correlated with several adverse health outcomes and, in Mendelian randomization analyses, shows causal relationships with higher risk of prostate cancer and shorter lifespan. These findings highlight the relationships between puberty timing and later health outcomes, and demonstrate the value of genetic studies of puberty timing in both sexes.

genomics↗

bioRxiv2017

Forward-reverse mutation cycles between stages of cancer development

Earlier, prominent occurrences of interstitial loss-of-heterozygosities (LOHs) were found in different cancers as a type of single-nucleotide-variations (SNVs), at rates far exceeding those of the commonly investigated gain-of-heterozygosities (GOHs) type of SNVs. Herein, such co-occurrences of LOHs and GOHs were confirmed in 102 cases of four cancer types analyzed with three different next-generation sequencing platforms, comparing non-tumor, paratumor, and tumor tissues with white-blood-cell controls; and in 246 pan-cancer cases of whole-genome tumor-control pairs. Unexpectedly, large numbers of SNVs enriched with CG>TG GOHs and copy-number-variations (CNVs) proximal to these GOHs were detected in the non-tumor tissues, which were extensively reversed in paratumors showing prominent TG>CG LOHs with proximal CNVs, and less so in tumors to form forward-reverse mutation cycles. Lineage effects in the reversions, likely resulting from directional selection, supported a sequential rather than parallel mode of evolution as described in a Stage Specific Populations model of cancer development.

cancer biology↗