Biology subjects

Crowley, J.

Publications and source records attributed to Crowley, J..

4 recordsLinked to original sources

bioRxiv2023

Birth of an organelle: molecular mechanism of lipid droplet biogenesis

Lipid droplets (LDs) are cellular organelles regulating energy and lipid metabolism. Generated in the endoplasmic reticulum (ER) by phase separation of neutral lipids (e.g., triglycerides), nascent LDs resemble lens-shaped blisters, grow into spherical droplets, and eventually emerge from the ER membrane, generally towards the cytosol - a process known as budding. Images of both nascent and mature LDs are available, but the mechanism of biogenesis has never been observed experimentally. Here we identify the mechanism of the initial steps in LD biogenesis using computer simulations at the molecular level, emulating LD growth in ER-mimicking membranes. We find that LDs bud towards the cytosol only when sufficient asymmetry is generated between the two membrane leaflets: the budding transition is independent of membrane morphology, lipid composition, and LD size. Seipin, a protein essential for correct LD biogenesis, is per se not sufficient to promote budding, but it stabilizes LD-ER contact sites. Localization of triglyceride synthesis in the proximity of seipin is necessary to avoid nucleation of multiple LDs - a possible cause of aberrant phenotypes. In contrast, localization of phospholipid synthesis has no effect on the mechanism of budding. Our new methodology paves the way to simulations of organelle and cell biogenesis.

biophysics↗

bioRxiv2019

Characterization of single gene copy number variants in schizophrenia

Genetic studies of schizophrenia (SCZ) have now implicated numerous genomic loci that contribute to risk including several copy number variants (CNV) of large effect and hundreds of associated loci of small effect. However, in only a few cases has a specific gene been clearly identified. Rare CNV that affect only a single gene offer a potential avenue to discovering specific SCZ risk genes. Here, we use CNV generated from exome-sequencing of 4,913 SCZ cases and 6,188 controls in a homogenous Swedish cohort to assess the contribution of single-gene deletions and duplications to SCZ risk. As previously seen, we found an excess of rare deletions (p = 0.0004) and duplications (p = 0.0006) in SCZ cases compared to controls. When limiting to only single-gene CNV we identified nominally significant excess of deletions (p = 0.04) and duplications (p = 0.03). In an effort to increase the number of single-gene CNV, we reduced strict filtering criteria but required support from two independent CNV calling methods to create an expanded set that showed a significant burden of deletions in 11 out of 22 gene sets previously implicated in SCZ and in the combined set of genes across those sets (p = 0.008). Finally, for the significantly enriched set of voltage-gated calcium channels, we performed an extensive validation of all deletions generated from exome-sequencing as well as any deletion with evidence from previously analyzed genotyping arrays. In total, 4 exonic, single-gene deletions validated in cases and none in controls (p = 0.039), of which all were identified by exome-sequencing. Broadly, these results point to the potential contribution of single-gene CNV to SCZ and the added value of a deeper dive into CNV calls from exome-sequencing.

genetics↗

bioRxiv2017

Common Variant Associations with Fragile X Syndrome

Fragile X syndrome is a common cause of intellectual disability. It is usually caused by a de novo mutation which often occur on multiple haplotypes and should not be detectible using genome-wide association (GWA). We conducted GWA 89 male FXS cases and 266 male controls, and detected multiple genome-wide significant signals near FMR1 (odds ratio=8.10, P=2.5x10-10). These findings withstood robust attempts at falsification. Fine-mapping did not serve to narrow the interval (minimum P=1.13xl0-14), and functional genomic integration (including 5C data we generated for this region) did not provide a mechanistic hypothesis. Controls carrying a risk haplotype had significantly longer and more variable FMR1 CGG repeats than controls with the protective haplotype (P=4.75x10-5) which may predispose toward increases in CGG number to the pre-mutation range over many generations. This is a salutary reminder of the complexity of even \"simple\" monogenetic disorders.

genetics↗

bioRxiv2016

Genome-Wide Association Study Reveals First Locus for Anorexia Nervosa and Metabolic Correlations

Anorexia nervosa (AN) is a serious eating disorder characterized by restriction of energy intake relative to requirements, resulting in abnormally low body weight. It has a lifetime prevalence of approximately 1%, disproportionately affects females1,2, and has no well replicated evidence of effective pharmacological or psychological treatments despite high morbidity and mortality2. Twin studies support a genetic basis for the observed aggregation of AN in families3, with heritability estimates of 48%-74%4. Although initial genome-wide association studies (GWASs) were underpowered5,6, evidence suggested that signals for AN would be detected with increased power5. We present a GWAS of 3,495 AN cases and 10,982 controls with one genome-wide significant locus (index variant rs4622308, p=4.3x10-9) in a region (chr12:56,372,585-56,482,185) which includes six genes. The SNP-chip heritability [Formula] of AN from these data is 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability stems from common genetic variation. Using these GWAS results, we also find significant positive genetic correlations with schizophrenia, neuroticism, educational attainment, and HDL cholesterol, and significant negative genetic correlations with body mass, insulin, glucose, and lipid phenotypes. Our results support the reconceptualization of AN as a disorder with both psychiatric and metabolic components.

genomics↗