Capsule Biosynthesis Genes and Repeat-Unit Polysaccharide Structures

<p>Shown are the <i>cps</i> gene clusters for cases discussed in the text, together with the polysaccharide structure of the encoded repeat unit where known [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0020031#pgen-0020031-b031" target="_blank">31</a>] (the full set is shown in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0020031#pgen-0020031-sg001" target="_blank">Figure S1</a>). Genes are represented on the forward and reverse strands by boxes coloured according to the gene key, with gene designations indicated above each box. Grey blocks indicate regions of sequence similarity between gene clusters. Repeat-unit structures are displayed with the linkage to undecaprenyl pyrophosphate at the right-hand side (not necessarily the case for the published structures [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0020031#pgen-0020031-b031" target="_blank">31</a>]), so residue numbers are counted from right to left. Monosaccharides are represented as shapes coloured according to the structure key. Housekeeping sugars are coloured grey. Non-housekeeping sugar colours correspond to the associated sugar biosynthesis gene colours. Glycerol, choline, and acetate are indicated as text. Also shown are the nature of linkages with the associated gene, and the linkages between repeat units created by the Wzy polymerase. Gene designations are in parentheses where their substrate specificity is unclear.</p

Representation of the Wzx/Wzy-Dependent Pathway for Biosynthesis of CPS 9A

<div><p>Pictured is a hypothetical model for capsule biosynthesis in S. pneumoniae based on a mixture of experimental evidence and speculation. For a recent review, see Yother [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0020031#pgen-0020031-b015" target="_blank">15</a>].</p><p>(1) Non-housekeeping nucleotide sugar biosynthesis.</p><p>(2) The initial transferase (WchA in this case) links the initial sugar as a sugar phosphate (Glc-P) to a membrane-associated lipid carrier (widely assumed to be undecaprenyl phosphate).</p><p>(3) Glycosyl transferases sequentially link further sugars to generate repeat unit.</p><p>(4) Wzx flippase transports the repeat unit across the cytoplasmic membrane.</p><p>(5) Wzy polymerase links individual repeat units to form lipid-linked CPS.</p><p>(6) Wzd/Wze complex translocates mature CPS to the cell surface and may be responsible for the attachment to peptidoglycan. The complex of WchA, Wzy, Wzx, Wzd, and Wze shown in the membrane is based on that in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0020031#pgen-0020031-g002" target="_blank">Figure 2</a> of Whitfield and Paiment [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0020031#pgen-0020031-b047" target="_blank">47</a>] for the related Escherichia coli Type 1 capsule.</p></div

Schema of instrumental variable analyses conducted in order to infer the potential causal relations between DNA methylation, gene expression, BMI, and adiposity-related disease.

<p>Schema of instrumental variable analyses conducted in order to infer the potential causal relations between DNA methylation, gene expression, BMI, and adiposity-related disease.</p

Fifty novel replicated differentially methylated CpGs associated with BMI sorted by <i>p-</i>value in the discovery cohorts.

<p>Fifty novel replicated differentially methylated CpGs associated with BMI sorted by <i>p-</i>value in the discovery cohorts.</p

Annotated genes of replicated differentially methylated CpGs identified in the BMI epigenome-wide association study.

<p>Genes are grouped by association with gene expression, association of gene expression with BMI, and Mendelian randomization analyses for causal support. Duplicate gene names within the same group are not shown. Figure does not include 18 intergenic CpGs without a gene annotation. BMI, body mass index; EWAS, epigenome-wide association study.</p

Study characteristics of the Framingham Heart Study and Lothian Birth Cohort participants (discovery cohorts) at the time of DNA methylation assays.

<p>Study characteristics of the Framingham Heart Study and Lothian Birth Cohort participants (discovery cohorts) at the time of DNA methylation assays.</p

Series of analyses conducted for the epigenome-wide association study of body mass index.

<p>ARIC, Atherosclerosis Risk in Communities; BMI, body mass index; DHS, DNase I hypersensitive site; FHS, Framingham Heart Study; GO, Gene Ontology; GOLDN, Genetics of Lipid Lowering Drugs and Diet Network; GWAS, genome-wide association study; LBC, Lothian Birth Cohorts; MR, Mendelian randomization; PIVUS, Prospective Investigation of the Vasculature in Uppsala Seniors; TSS, transcription start site.</p

Association results from 11 replicated CpGs with significant three-way associations in whole blood between CpG methylation and BMI, CpG methylation and gene expression, and gene expression and BMI.

<p>Association results from 11 replicated CpGs with significant three-way associations in whole blood between CpG methylation and BMI, CpG methylation and gene expression, and gene expression and BMI.</p

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease