Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Quantifying neutralising antibody responses against SARS-CoV-2 in dried blood spots (DBS) and paired sera

The ongoing SARS-CoV-2 pandemic was initially managed by non-pharmaceutical interventions such as diagnostic testing, isolation of positive cases, physical distancing and lockdowns. The advent of vaccines has provided crucial protection against SARS-CoV-2. Neutralising antibody (nAb) responses are a key correlate of protection, and therefore measuring nAb responses is essential for monitoring vaccine efficacy. Fingerstick dried blood spots (DBS) are ideal for use in large-scale sero-surveillance because they are inexpensive, offer the option of self-collection and can be transported and stored at ambient temperatures. Such advantages also make DBS appealing to use in resource-limited settings and in potential future pandemics. In this study, nAb responses in sera, venous blood and fingerstick blood stored on filter paper were measured. Samples were collected from SARS-CoV-2 acutely infected individuals, SARS-CoV-2 convalescent individuals and SARS-CoV-2 vaccinated individuals. Good agreement was observed between the nAb responses measured in eluted DBS and paired sera. Stability of nAb responses was also observed in sera stored on filter paper at room temperature for 28 days. Overall, this study provides support for the use of filter paper as a viable sample collection method to study nAb responses.</p

Data from: SIDER: an R package for predicting trophic discrimination factors of consumers based on their ecology and phylogenetic relatedness

Stable isotope mixing models (SIMMs) are an important tool used to study species’ trophic ecology. These models are dependent on, and sensitive to, the choice of trophic discrimination factors (TDF) representing the offset in stable isotope delta values between a consumer and their food source when they are at equilibrium. Ideally, controlled feeding trials should be conducted to determine the appropriate TDF for each consumer, tissue type, food source, and isotope combination used in a study. In reality however, this is often not feasible nor practical. In the absence of species-specific information, many researchers either default to an average TDF value for the major taxonomic group of their consumer, or they choose the nearest phylogenetic neighbour for which a TDF is available. Here, we present the SIDER package for R, which uses a phylogenetic regression model based on a compiled dataset to impute (estimate) a TDF of a consumer. We apply information on the tissue type and feeding ecology of the consumer, all of which are known to affect TDFs, using Bayesian inference. Presently, our approach can estimate TDFs for two commonly used isotopes (nitrogen and carbon), for species of mammals and birds with or without previous TDF information. The estimated posterior probability provides both a mean and variance, reflecting the uncertainty of the estimate, and can be subsequently used in the current suite of SIMM software. SIDER allows users to place a greater degree of confidence on their choice of TDF and its associated uncertainty, thereby leading to more robust predictions about trophic relationships in cases where study-specific data from feeding trials is unavailable. The underlying database can be updated readily to incorporate more stable isotope tracers, replicates and taxonomic groups to further increase the confidence in dietary estimates from stable isotope mixing models, as this information becomes available

Ecology and mode-of-life explain lifespan variation in birds and mammals

Maximum lifespan in birds and mammals varies strongly with body mass such that large species tend to live longer than smaller species. However, many species live far longer than expected given their body mass. This may reflect interspecific variation in extrinsic mortality, as life-history theory predicts investment in long-term survival is under positive selection when extrinsic mortality is reduced. Here, we investigate how multiple ecological and mode-of-life traits that should reduce extrinsic mortality (including volancy (flight capability), activity period, foraging environment and fossoriality), simultaneously influence lifespan across endotherms. Using novel phylogenetic comparative analyses and to our knowledge, the most species analysed to date (n = 1368), we show that, over and above the effect of body mass, the most important factor enabling longer lifespan is the ability to fly. Within volant species, lifespan depended upon when (day, night, dusk or dawn), but not where (in the air, in trees or on the ground), species are active. However, the opposite was true for non-volant species, where lifespan correlated positively with both arboreality and fossoriality. Our results highlight that when studying the molecular basis behind cellular processes such as those underlying lifespan, it is important to consider the ecological selection pressures that shaped them over evolutionary time

A comparison of overall plumage characteristics between male (top row) and female (bottom row) flowerpeckers from mainland Sulawesi (left column) and the Wakatobi archipelago (right column).

<p>A comparison of overall plumage characteristics between male (top row) and female (bottom row) flowerpeckers from mainland Sulawesi (left column) and the Wakatobi archipelago (right column).</p

Map showing the Sulawesi region of Indonesia and study sites.

<p>Above: location and outline of the Sulawesi region of Indonesia (dashed lines) and the study area (square). Below: enlarged view of the study area showing peninsular south-east Sulawesi, Buton and the Wakatobi Islands; closed circles indicate sampling sites.</p

Morphological comparisons of adult male and female birds between Sulawesi and Wakatobi populations showing the mean and standard error for each character.

<p>*All characters are presented in units of millimetres except weight which is presented in grams.</p

Molecular and Phenotypic Data Support the Recognition of the Wakatobi Flowerpecker (Dicaeum kuehni) from the Unique and Understudied Sulawesi Region

Accurate estimates of species richness are essential to macroecological and macroevolutionary research, as well as to the effective management and conservation of biodiversity. The resolution of taxonomic relationships is therefore of vital importance. While molecular methods have revolutionised taxonomy, contemporary species delimitation requires an integrative, multi-disciplinary approach. Despite boasting a remarkably high level of endemism, the avifauna of the Sulawesi region of Indonesia remains poorly studied. Previous studies of avian diversity in Sulawesi have focussed predominantly on phenotypic characteristics, thus potentially overlooking any genetically distinct lineages. Grey-sided Flowerpecker Dicaeum celebicum populations from the Wakatobi archipelago were originally described as a separate species from those on nearby mainland Sulawesi. However, for reasons that remain unknown, the Wakatobi populations were reclassified as a subspecies of the mainland form. Combining estimates of genetic divergence with phylogenetic and morphological analyses, we reassessed the status of Wakatobi populations. Our results describe the Wakatobi populations as a separate species to those on mainland Sulawesi; reproductively isolated, genetically and morphologically distinct. We therefore recommend the reclassification of these populations to their original status of Dicaeum kuehni and propose the vernacular name ‘Wakatobi Flowerpecker’. In consideration of our findings and the lack of integrative ornithological research within the Sulawesi region, we believe species richness and avian endemism within the region are underestimated.Copyright 2014 Kelly et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The attached file is the published version of the article