Biology subjects

Chan, A.

Publications and source records attributed to Chan, A..

5 recordsLinked to original sources

bioRxiv2018

Fallen Pillars: The Past, Present, and Future Population Dynamics of a Rare, Specialist Coral-Algal Symbiosis

Rare and ecologically specialized species are at greater risk of extinction. Rarity in terms of low genotypic diversity may be obscured in sessile foundation species that can reproduce asexually. Asexual propagules are often only distinguishable from sexual recruits through molecular tools. Thus, molecular markers are necessary to assess genotypic variation and population structure in clonal organisms such as corals. The global decline of corals has necessitated marker development for improved conservation of rare coral species. We infer past demographic changes, describe modern population structure, and quantify asexual reproduction of the uncommon Caribbean pillar coral, Dendrogyra cylindrus and its endosymbiotic dinoflagellate, Symbiodinium dendrogyrum using de novo microsatellite markers. Results show that D. cylindrus comprises three distinct populations in the Caribbean whereas the symbiont was differentiated into four populations. Thus, barriers to gene flow differ between host and symbiont. In Florida, host and symbiont reproduced mainly asexually, yielding lower genotypic diversity than predicted from census size. Models of past demographic events revealed no evidence of historical changes in population size, consistent with the geological record of D. cylindrus indicating it has been rare for hundreds of thousands of years. The most recent global thermal stress event triggered a severe disease outbreak among D. cylindrus in Florida, resulting in a precipitous population decline. Projections indicate a high likelihood that this species may become locally extinct within the coming decades. The ecosystem consequences of losing rare coral species and their symbionts with increasingly frequent extreme warming events are not known but require urgent study.

genetics↗

bioRxiv2018

Endothelia extrude apoptotic cells to maintain a constant barrier

The vascular system is lined with endothelial cells that, although only existing in a single monolayer, are key in the regulation of vascular barrier function. One of the major challenges these cells face is a routine exposure to environmental stressors that can induce apoptosis. Uncontrolled apoptosis in the endothelial monolayer threatens the ability of the cells to maintain their barrier function, resulting in vascular dysfunction. Therefore, we sought to identify ways in which endothelia maintain a cohesive monolayer during apoptotic events. We found that endothelial cells fated die will undergo a process of apoptotic cellular extrusion, similar to what has been described in the epithelium. We further show that endothelial extrusion uses a conserved S1P-S1PR2-RhoA signaling pathway in order to induce the formation of an actin ring that contracts closed, forcing the dying cell out of the monolayer while simultaneously filling in the gap left behind. Thus, endothelial extrusion successfully removes an apoptotic cell before it compromises the monolayer, preserving the barrier function.

cell biology↗

bioRxiv2017

RNA helicase, DDX27 regulates proliferation and myogenic commitment of muscle stem cells

Developmental processes depend on the combined efforts of epigenetic, transcriptional and post-transcriptional processes that lead to the production of specific proteins that are important determinants of cellular identity and developmental processes. Ribosomes are a central component of the protein biosynthesis machinery in cells; however, their regulatory roles in the translational control of gene expression in an organ specific context during development remain to be defined. In a genetic screen to identify critical regulators of myogenesis, we identified a DEAD-Box RNA helicase, DDX27, that is required for the proliferation and myogenic commitment of skeletal muscle stem cells. DDX27 deficient skeletal muscle exhibits hypotrophy and impaired regeneration potential. We demonstrate that DDX27 regulates ribosomal RNA (rRNA) maturation, and thereby the ribosome biogenesis and the translation of specific transcripts that are required to maintain pluripotency and myogenic differentiation of satellite cells. These findings provide insight into the translational regulation of gene expression in myogenesis and suggest novel functions for ribosomes in regulating gene expression during skeletal muscle development.\n\nAUTHOR SUMMARYInherited skeletal muscle diseases are the most common form of genetic disorders with primary abnormalities in the structure and function of skeletal muscle resulting in the impaired locomotion in affected patients. A major hindrance to the development of effective therapies is a lack of understanding of biological processes that promote skeletal muscle growth. By performing a forward genetic screen in zebrafish we have identified mutation in a RNA helicase that leads to perturbations of ribosomal biogenesis pathway and impairs skeletal muscle growth and regeneration. Therefore, our studies have identified novel ribosome-based disease processes that may be therapeutic modulated to restore muscle function in skeletal muscle diseases.

genetics↗

bioRxiv2016

Discovery of an autoimmunity-associated IL2RA enhancer by unbiased targeting of transcriptional activation

The majority of genetic variants associated with common human diseases map to enhancers, non-coding elements that shape cell type-specific transcriptional programs and responses to specific extracellular cues 1-3. In order to understand the mechanisms by which non-coding genetic variation contributes to disease, systematic mapping of functional enhancers and their biological contexts is required. Here, we develop an unbiased discovery platform that can identify enhancers for a target gene without prior knowledge of their native functional context. We used tiled CRISPR activation (CRISPRa) to synthetically recruit transcription factors to sites across large genomic regions (>100 kilobases) surrounding two key autoimmunity risk loci, CD69 and IL2RA (interleukin-2 receptor alpha; CD25). We identified several CRISPRa responsive elements (CaREs) with stimulation-dependent enhancer activity, including an IL2RA enhancer that harbors an autoimmunity risk variant. Using engineered mouse models and genome editing of human primary T cells, we found that sequence perturbation of the disease-associated IL2RA enhancer does not block IL2RA expression, but rather delays the timing of gene activation in response to specific extracellular signals. This work develops an approach to rapidly identify functional enhancers within non-coding regions, decodes a key human autoimmunity association, and suggests a general mechanism by which genetic variation can cause immune dysfunction.

genetics↗

bioRxiv2016

A comprehensive survey of genetic variation in 20,691 subjects from four large cohorts

The Nurses Health Study (NHS), Nurses Health Study II (NHSII), Health Professionals Follow Up Study (HPFS) and the Physicians Health Study (PHS) have collected detailed longitudinal data on multiple exposures and traits for approximately 310,000 study participants over the last 35 years. Over 160,000 study participants across the cohorts have donated a DNA sample and to date, 20,691 subjects have been genotyped as part of genome-wide association studies (GWAS) of twelve primary outcomes. However, these studies utilized six different GWAS arrays making it difficult to conduct analyses of secondary phenotypes or share controls across studies. To allow for secondary analyses of these data, we have created three new datasets merged by platform family and performed imputation using a common reference panel, the 1,000 Genomes Phase I release. Here, we describe the methodology behind the data merging and imputation and present imputation quality statistics and association results from two GWAS of secondary phenotypes (body mass index (BMI) and venous thromboembolism (VTE)).\n\nWe observed the strongest BMI association for the FTO SNP rs55872725 ({beta}=0.45, p=3.48x10-22), and using a significance level of p=0.05, we replicated 19 out of 32 known BMI SNPs. For VTE, we observed the strongest association for the rs2040445 SNP (OR=2.17, 95% CI: 1.79-2.63, p=2.70x10-15), located downstream of F5 and also observed significant associations for the known ABO and F11 regions. This pooled resource can be used to maximize power in GWAS of phenotypes collected across the cohorts and for studying gene-environment interactions as well as rare phenotypes and genotypes.

epidemiology↗