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

Gondwanide continental collision and the origin of Patagonia

A review of the post-Cambrian igneous, structural and metamorphic history of Patagonia, largely revealed by a five-year programme of U–Pb zircon dating (32 samples), geochemical and isotope analysis, results in a new Late Palaeozoic collision model as the probable cause of the Gondwanide fold belts of South America and South Africa. In the northeastern part of the North Patagonian Massif, Cambro-Ordovician metasediments with a Gondwana provenance are intruded by Mid Ordovician granites analogous to those of the Famatinian arc of NW Argentina; this area is interpreted as Gondwana continental crust at least from Devonian times, probably underlain by Neoproterozoic crystalline basement affected by both Pampean and Famatinian events, with a Cambrian rifting episode previously identified in the basement of the Sierra de la Ventana. In the Devonian (following collision of the Argentine Precordillera terrane to the north), the site of magmatism jumped to the western and southwestern margins of the North Patagonian Massif, although as yet the tectonics of this magmatic event are poorly constrained. This was followed by Early Carboniferous I-type granites representing a subduction-related magmatic are and Mid Carboniferous S-type granites representing crustal anatexis. The disposition of these rocks implies that the North Patagonian Massif was in the upper plate, with northeasterly subduction beneath Gondwana prior to the collision of a southern landmass represented by the Deseado Massif and its probable extension in southeastern Patagonia. This ‘Deseado terrane’ may have originally rifted off from a similar position during the Cambrian episode. Intense metamorphism and granite emplacement in the upper plate continued into the Early Permian. Known aspects of Late Palaeozoic sedimentation, metamorphism, and deformation in the Sierra de la Ventana and adjacent Cape Fold Belt of South Africa are encompassed within this model. It is also compatible with modern geophysical and palaeomagnetic data that do not support previous hypotheses of southward-directed subduction and collision along the northern limit of Patagonia. Subsequent Permian break-off of the subducted plate, perhaps with delamination of the lower part of the upper plate, allowed access of heat to the overlying Gondwana margin and resulted in voluminous and widespread silicic plutonism and volcanism throughout Permian and into Triassic times. Thus the new model addresses and attempts to explain three long-standing geological enigmas—the origin of the Gondwanide fold belts, the origin of Patagonia, and the cause of widespread Permian silicic magmatism (Choiyoi province) in southern South America. Differing significantly from previous models, it has new implications for the crustal structure, mineral resources, and plant and animal distribution in this part of Gondwana, since the southern landmass would have had an independent evolution throughout the Early Palaeozoic

Early Carboniferous sub- to mid-alkaline magmatism in the Eastern Sierras Pampeanas, NW Argentina: a record of crustal growth by the incorporation of mantle-derived material in an extensional setting

A recently discovered granitic intrusion at Cerro La Gloria in western Sierra de Famatina (NW Argentina) is representative of sub- to mid-alkaline Carboniferous magmatism in the region. The main rock type consists of microcline, quartz and plagioclase, with amphibole, magnetite, ilmenite, biotite, epidote, zircon, allanite and sphene as accessory minerals. We report a U–Pb zircon SHRIMP age for the pluton of 349 ± 3 Ma (MSWD = 1.1), i.e., Tournaisian. Whole-rock chemical composition and Nd isotope analyses are compatible with an origin by melting of older mafic material in the lower crust (εNdt between − 0.58 and + 0.46 and TDM values of about 1.1 Ga). The pluton is intruded by penecontemporaneous to late alkaline mafic dykes that are classified as back-arc basalts. Coeval, Early Carboniferous A-type granites occur farther east in the Sierras Pampeanas, probably generated during lithospheric stretching. Overall, the Early Carboniferous granitic rocks show a west-to-east mineralogical and isotopic zonation indicating that magma genesis involved a greater contribution of juvenile material of mantle character to the west. Based on the observed patterns of geochronology, geochemistry and field relationships we suggest that A-type magma genesis in the Eastern Sierras Pampeanas was linked to an Andean-type margin where the lithospheric mantle played a role in its generation