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

A model for the impact of herbicide tolerance on the performance of oilseed rape as a volunteer weed

The introduction of genetically modified, herbicide‐tolerant, oilseed rape into the agricultural environment will have ramifications beyond weed control of the crop. Herbicide‐tolerant rape will undoubtedly become part of established volunteer weed populations that occur in many cereal rotations, but its longevity in these populations and its impact as a weed and contaminant of future oilseed rape crops is uncertain. A life cycle model of volunteer oilseed rape was therefore constructed, incorporating existing information on physiological processes such as emergence pattern, longevity of buried seed, death rates of various structures and flowering and seeding as functions of density. The model was designed to allow interaction with control factors such as harvesting efficiency, herbicide treatment, ploughing and the sequence of crops in the rotation. Many of the physiological parameters (including seed decay rates, fecundity at high density) are uncertain, simply through lack of information in the appropriate context. Other parameters such as harvesting efficiency and herbicide kill rates, are inherently variable in farming. Accordingly, a Monte‐Carlo approach, in which the model was run many times with different random realisations of parameter sets, was used to expose factors to which the seedbank was sensitive. Sets of 1250 realisations were compared for each of two extreme conditions: where herbicide could be used according to current intensive farming practice and where it was not an option (representing total herbicide tolerance). Modelled seedbank numbers after 5 yr ranged from 10‐3to 104m‐2, realistic values found in arable soils. The use of herbicide, together with efficient harvesting of seed, clearly has an important suppressive effect on the oilseed rape seedbank, keeping it lower than 102m‐2(a typical sowing rate) after 5 yr in more than 80% of realisations. In the absence of herbicide, seedbanks were invariably greater, but their absolute value depended strongly on harvesting efficiency and the extent to which high density of plants suppressed fecundity. Analysis of the time series from the simulations showed that the seedbank levels fluctuated by orders in magnitude from year to year in the absence of herbicide use. The sensitivity analysis of the life‐cycle model led to the development of a simplified model for the seedbank dynamics. The model shows that the essential features of the dynamics result from an interaction between density‐dependent fecundity and the perturbations due to management. Therefore predictions of the effect of herbicide tolerance on seedbank dynamics are highly uncertain without knowledge of the density dependence of fecundity. Furthermore, the sensitivity to management practices suggests that seedbank levels will be substantially more difficult to control if the efficacy of herbicide is compromised. It is concluded that the model and Monte‐Carlo approach have many potential uses in exploring the effects of management, cultivar physiology and the nature of the transgenes

Risks from transgenic crops

No abstract available

How to catch all those mutations--the report of the third Human Variome Project Meeting, UNESCO Paris, May 2010

The third Human Variome Project (HVP) Meeting "Integration and Implementation" was held under UNESCO Patronage in Paris, France, at the UNESCO Headquarters May 10-14, 2010. The major aims of the HVP are the collection, curation, and distribution of all human genetic variation affecting health. The HVP has drawn together disparate groups, by country, gene of interest, and expertise, who are working for the common good with the shared goal of pushing the boundaries of the human variome and collaborating to avoid unnecessary duplication. The meeting addressed the 12 key areas that form the current framework of HVP activities: Ethics; Nomenclature and Standards; Publication, Credit and Incentives; Data Collection from Clinics; Overall Data Integration and Access-Peripheral Systems/Software; Data Collection from Laboratories; Assessment of Pathogenicity; Country Specific Collection; Translation to Healthcare and Personalized Medicine; Data Transfer, Databasing, and Curation; Overall Data Integration and Access-Central Systems; and Funding Mechanisms and Sustainability. In addition, three societies that support the goals and the mission of HVP also held their own Workshops with the view to advance disease-specific variation data collection and utilization: the International Society for Gastrointestinal Hereditary Tumours, the Micronutrient Genomics Project, and the Neurogenetics Consortium.Genetics of disease, diagnosis and treatmen