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

Relationship between grain colour and preharvest sprouting-resistance in wheat Relação entre cor de grão e resistência à germinação pré-colheita em trigo

Since red alleles (R) of the genes that control grain colour are important for the improvement of preharvest sprouting resistance in wheat and there are three independently inherited loci, on chromosomes 3A, 3B and 3D of hexaploid wheat, it is possible to vary the dosage of dominant alleles in a breeding program. The objective of this work was to evaluate the dosage effect of R genes on preharvest sprouting, in a single seed descent population, named TRL, derived from the cross between Timgalen, white-grained wheat, and RL 4137, red-grained wheat. The study was carried out using sprouting data in ripe ears obtained under artificial conditions in a rainfall simulator over three years. According to the results there is a significant effect on preharvest sprouting provided by colour and a weaker effect of increasing R dosage. However, the significant residual genotypic variation between red lines and all lines (reds and whites) at 0.1% level showed that preharvest sprouting was also controlled by other genes. There are no significant correlations between sprouting and date of ripeness or between ripeness, R dosage and colour intensity.<br>Uma vez que os alelos dominantes para cor vermelha (R), dos genes que controlam a cor do grão, têm importância no incremento da resistência à germinação pré-colheita, em trigo, e há três locos herdados independentemente, nos cromossomos 3A, 3B e 3D do trigo hexaplóide, é possível variar sua dosagem em um programa de melhoramento. O objetivo deste trabalho foi avaliar o efeito de dosagem dos genes R na germinação pré-colheita, em uma população de descendência por semente única, batizada de TRL, derivada do cruzamento entre Timgalen, trigo de grão branco, e RL 4137, trigo de grão vermelho. O estudo utilizou dados de germinação em espigas maduras, obtidos sob condições artificiais em um simulador de chuva, em três anos. De acordo com os resultados, o efeito da cor de grão e, menos acentuadamente, da dosagem dos alelos dominantes, sobre a germinação pré-colheita foi significativo. Entretanto, a variação genotípica residual, entre as linhas vermelhas e entre as linhas vermelhas e brancas, significativa a 0,1%, mostra que a germinação pré-colheita é também controlada por outros genes. Não foi constatada correlação significativa entre germinação na espiga e data de maturação ou entre maturação, dosagem de R e intensidade de cor