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

Independent effects of familiarity and mating preferences for ornamental traits on mating decisions in guppies

The avoidance of familiar individuals as mates can act to maximize the benefits of polyandry or might help to minimize inbreeding in small or highly philopatric populations. As previous mates are also familiar, the effects of familiarity and mating history can often be confounded. Here, we disentangle these effects on mating decisions in the guppy, Poecilia reticulata, and examine their influence on sexual selection. In 3 experiments, males and females were 1) able to mate, 2) had visual and olfactory contact, or 3) had visual contact only. Familiarity was successfully acquired via visual cues, and females were in all cases more likely to mate with unfamiliar than with familiar males, indicating that familiarity is a more important determinant of mating outcome than mating history. Males did not court unfamiliar females any more than familiar females and did not differentially allocate sperm. Familiarity did not alter the strength of sexual selection on male coloration: we found overall positive selection for bright, large males. Female preferences for unfamiliar males and ornamental traits may therefore be largely independent. Copyright 2006.mate choice; mating history; polymorphism; polyandry; sexual selection; sperm competition