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 hospitalization2,3,4 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

Effaced preservation in the Ediacara biota and its implications for the early macrofossil record

Abstract: Ediacaran structures known as 'pizza discs' or Ivesheadia have long been considered enigmatic. They are amongst the oldest known members of the Ediacara biota, apparently restricted to the Avalonian successions of Newfoundland and the UK, c. 579-560Ma. Here, we suggest that these impressions are taphomorphs, resulting from the post-mortem decay of the frondose Ediacaran biota. Ediacaran fossils range from well-preserved, high-fidelity variants to almost completely effaced specimens. The effaced specimens are inferred to have undergone modification of their original morphology by post-mortem microbial decay on the sea floor, combined with sediment trapping and binding. In this style of preservation, morphological details within the organism became variously subdued as a function of the extent of organic decay prior to casting by overlying sediments. Decay and effacement were progressive in nature, producing a continuum of grades of preservation on Ediacaran bedding planes. Fossils preserved by such 'effaced preservation' are those that have suffered these processes to the extent that only their gross form can be determined. We suggest that the lack of detailed morphology in effaced specimens renders such fossils unsuitable for use as type material, as it is possible that several taxa may, upon degradation and burial, generate similar morphological taphomorphs. We here reinterpret the genus Ivesheadia as a taphomorph resulting from extensive post-mortem decay of frondose organisms. Blackbrookia, Pseudovendia and Shepshedia from beds of comparable age in England are likewise regarded as taphomorphs broadly related to Charnia or Charniodiscus spp. To reflect the suggestion that such impressions are likely to be taphomorphs, and not taxonomically discrete, we propose the term ivesheadiomorphs to incorporate all such effaced taphonomic expressions of Ediacaran macrofossil taxa in Avalonian assemblages. Our recognition of effaced preservation has significant implications for Ediacaran taxonomy, and consequently for measures of Ediacaran diversity and disparity. It is implied that Avalonian assemblages preserve both organisms that were alive and organisms that were already dead at the time of burial. As such, the fossil assemblages cannot be taken to represent census populations of living organisms, as in prior interpretations. © The Palaeontological Association