Convergent Evolution of Pain-Inducing Defensive Venom Components in Spitting Cobras

Preprint 20 páginas. The molecular data associated with species tree generation have been deposited to the nucleotide database of NCBI and the accession numbers are displayed in Table S7. The transcriptome data have been deposited in the SRA and TSA databases of NCBI and are associated with the BioProject accession number PRJA506018. Mass spectrometry data and database search results for top-down and bottom-up proteomic experiments are publicly available in the MassIVE repository under accession number MSV000081885 and in proteomXchange with accession number PXD008597.Convergent evolution provides unparalleled insights into the selective drivers underlying evolutionary change. While snakes use venom primarily for predation, and venom composition often reflects diet specificity, three lineages of spitting cobras have independently evolved the ability to use venom as a defensive projectile. Using gene, protein and functional analyses, we show that the three spitting lineages possess venom characterized by an upregulation of PLA2 toxins, which potentiate the action of venom cytotoxins to activate mammalian sensory neurons and cause enhanced pain. These repeated independent changes provide a fascinating example of convergent evolution across multiple phenotypic levels driven by exaptations. Notably, the timing of their origins suggests that defensive venom spitting may have evolved in response to the emergence of bipedal hominids in Africa and Asia.This work was funded from a studentship supported by Elizabeth Artin Kazandjian to T.D.K., grant PE 2600/1 from the German Research Foundation (DFG) to D.P., grant OPUS 1354156 from the US National Science Foundation to H.W.G., grants FAPESP 2017/18922-2 and 2019/05026-4 from the São Paulo Research Foundation to R.R.d.S, grants RPG-2012-627 and RFG-10193 from the Leverhulme Trust to R.A.H. and W.W., grant MR/L01839X/1 from the UK Medical Research Council to J.M.G., R.A.H., J.J.C. and N.R.C., fellowship DE160101142 from the Australian Research Council, and fellowship FRIPRO-YRT #287462 and grant DP160104025 from the Research Council of Norway to E.A.B.U., and a Sir Henry Dale Fellowship (200517/Z/16/Z) jointly funded by the Wellcome Trust and Royal Society to N.R.C.N

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