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 hospitalization2–4 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

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

Agrarian Dreams, Agricultural Realities: Agricultural Land Conversion in Mexico's Chihuahuan Desert

This dissertation examines the drivers and socioeconomic process of the conversion of rangeland to irrigated crops in Janos County, Chihuahua since 1970. The research was motivated by a desire to understand why irrigated agriculture was expanding in this site when there were no such expansions in adjacent regions. I analyze the historical roots of agricultural expansion as well as the contemporary social and economic dynamics that propel it today. Data came from 166 interviews with landowners, ex-landowners, laborers, and local officials, as well as from historical land records. Results reveal the importance Mexico’s national land reform (~1920-1992) in breaking up large ranches and creating opportunities for small farms to become established, even if many of those small farms—especially on ejidos—ultimately failed. I attribute the majority of rangeland-to-cropland conversion to Mennonites, whose commodity farms have proliferated through both in-migration and capitalist investment of agricultural profits. My research contributes to the wide-ranging literature on Mexico’s ejido system through the analysis of dynamics on the arid lands ejidos in Janos County. The Janos ejidos differ from the preponderance of cases in the literature in that they were founded through very different mechanisms and have seen far higher rates of land sales and consolidation. I contribute to the literature on agricultural frontiers by discussing agricultural expansion in arid rangelands rather than in tropical forests, where most of the literature is centered. The contrast between stagnating agriculture on the ejidos and expanding agriculture by Mennonites reveals both the importance of capital access in desert farming and the prominent role that social and cultural capital play in improving access to agriculture. In Janos, addressing the ‘agrarian question’ entails a close examination of capital access as well as intragroup social dynamics. Commercial cattle grazing has been the dominant land use there for at least 300 years, though the percentage of land under crops has expanded significantly in recent decades, irrigated with groundwater from a declining aquifer. The proliferation of irrigated agriculture has roots in Mexico’s national land reform, which ran nearly from the end of the Revolution in 1920 until 1992. The land reform fractured the vast cattle ranches that had previously dominated Janos County and redistributed a third of the land area in the form of 14 ejidos. The land reform also incentivized ranchers to sell land rather than have it expropriated by the government, which enabled groups of Mennonites from central Chihuahua to buy thousands of hectares at a time starting in the 1950s. Those parcels became the first four Mennonite colonies in Janos County and the hubs of ongoing cropland expansion. The process of ejido formation in Janos County was different than in most studies of central and southern Mexico, with profound impacts for land use and rights ownership. Ejidos here were not formed through restitution of land rights to long-term residents, indigenous communities, or even occupiers. Instead, land rights on new ejidos were given to landless laborers who had signed petitions demanding land through the land reform process, laborers who were most often living more than hundred kilometers from Janos County and had never been there. The freshly minted ejidatarios who came to Janos County to begin their new agrarian lives lacked the equipment, the investment capital, the farming expertise, and the social relations with each other needed to establish farms. While government support for these communities was significant, it was only sporadically sufficient to establish agricultural livelihoods. Out-migration and land sales were rampant, particularly after Mexico’s neoliberal policy reforms of the late 1980s and 1990s. There has been significant consolidation of land control on the ejidos since the 1990s, which has facilitated the ability of some households to earn a modest living from cattle or crops. On nearly every ejido, there remains land officially designated for farming that is still used only for cattle grazing. Founders of the first four Mennonite colonies in Janos County had come from Mennonite communities in west-central Chihuahua, and those communities had been founded by Mennonites immigrating from Canada in the 1920s. Mennonites in Janos County are Mexican citizens or dual Mexican-Canadian citizens but are in nearly every way deliberately distinct from mainstream Mexican society. They still speak Spanish as a second language, if at all, and they live in clearly defined colonies with their own churches, schools, businesses, and minute governmental institutions. They are also farmers first and foremost, though there is some economic diversification. Mennonite settlers arrived to Janos with sufficient economic means to establish irrigated farms – mostly modest – and construct functioning community centers with minimal state support. Mennonite colonies are ethnic enclaves that maintain high stocks of social and cultural capital that improve access to farming and foster loyalty to the home community and to farming as a livelihood. Social practices of cooperation and preferential treatment reduce the economic burden of establishing new farms or expanding existing farms, such as sharing farm machinery and paying each other for land or expensive services in annual installments without interest. Mennonites also have their own sources of formal and informal credit that are difficult for outsiders to access. The Mennonite agricultural access regime has enabled farmers to gradually intensify and expand their farming operations over time. Mennonites now routinely tap into international markets to grow genetically modified cotton, in addition to chili peppers, onions, and other crops that are planted, weeded, and harvested by migrant workers from southern and central Mexico. Agricultural production in my focal communities was always of ubiquitous commodities produced primarily for the market, but since the 1990s there has been something of an agrarian transformation underway. The area of irrigated crops has expanded rapidly, driven in part by economic differentiation of farmers and consolidation of landownership. The national neoliberal policy changes in the 1990s enabled these changes, as they served to increase the costs of agricultural production, significantly alter credit access, open new agricultural markets, and legalize the sale and rental of ejido land rights. While rising production costs drove some ejidatario and Mennonite farmers to sell out and migrate, new markets and sources of credit enabled wealthier Mennonite farmers to intensify and expand their operations. Increased farm profits among the emerging Mennonite elite were plowed back into purchases of ejido parcels and new blocks of ranchland outside the original colonies. The expansion drove up property values, further incentivizing ejidatarios and ranchers alike to sell land to Mennonites. High property values and competition for land are major barriers to entry for young would-be farmers, breeding new concerns over social justice and community values. Meanwhile, irrigated agriculture continues to expand outward from the original Mennonite colonies and the aquifer continues to fall

Save water or save wildlife? Water use and conservation in the central Sierran foothill oak woodlands of California, USA

More frequent drought is projected for California. As water supplies constrict, and urban growth and out-migration spread to rural areas, trade-offs in water use for agriculture, biodiversity conservation, fire hazard reduction, residential development, and quality of life will be exacerbated. The California Black Rail (Laterallus jamaicensis coturniculus), state listed as “Threatened,” depends on leaks from antiquated irrigation district irrigation systems for much of its remnant small wetland habitat in the north central Sierra Nevada foothills. Residents of the 1295 km² foothill habitat distribution of the Black Rail were surveyed about water use. Results show that the most Black Rail habitat is owned by those purchasing water to irrigate pasture, a use that commonly creates wetlands from leaks and tailwater. Promoting wildlife, agricultural production, and preventing wildfire are common resident goals that call for abundant and inexpensive water; social and economic pressures encourage reduction in water use and the repair of leaks that benefit wildlife and greenery. Broad inflexible state interventions to curtail water use are likely to create a multitude of unintended consequences, including loss of biodiversity and environmental quality, and alienation of residents as valued ecosystem services literally dry up. Adaptive and proactive policies are needed that consider the linkages in the social-ecological system, are sensitive to local conditions, prevent landscape dewatering, and recognize the beneficial use of water to support ecosystem services such as wildlife habitat. Much Black Rail habitat is anthropogenic, created at the nexus of local governance, plentiful water, agricultural practices, historical events, and changing land uses. This history should be recognized and leveraged rather than ignored in a rush to “save” water by unraveling the social-ecological system that created the landscape. Policy and governance needs to identify and prioritize habitat areas to maintain during drought.This project was funded as part of the NSF Coupled Human Natural Systems Program, Project Award Number 1115069, Wetlands in a Working Landscape, with Professor Steve Beissinger as Principal Investigator. J.L. Oviedo’s involvement in this study was also funded by the Salvador de Madariaga program (grant number PRX16/00452) of the Spanish Ministry of Education, Culture and Sports.Peer reviewe

Integrating social and ecological data to model metapopulation dynamics in coupled human and natural systems

Editors’ Note: Papers in this Special Feature are linked online in a virtual table of contents at: www.wiley.com/go/ecologyjournal[EN] Understanding how metapopulations persist in dynamic working landscapes requires assessing the behaviors of key actors that change patches as well as intrinsic factors driving turnover. Coupled human and natural systems (CHANS) research uses a multidisciplinary approach to identify the key actors, processes, and feedbacks that drive metapopulation and landscape dynamics. We describe a framework for modeling metapopulations in CHANS that integrates ecological and social data by coupling stochastic patch occupancy models of metapopulation dynamics with agent-based models of land-use change. We then apply this framework to metapopulations of the threatened black rail (Laterallus jamaicensis) and widespread Virginia rail (Rallus limicola) that inhabit patchy, irrigation-fed wetlands in the rangelands of the California Sierra Nevada foothills. We collected data from five diverse sources (rail occupancy surveys, land-use change mapping, a survey of landowner decision making, climate and reservoir databases, and mosquito trapping and West Nile virus testing) and integrated them into an agent-based stochastic patch occupancy model. We used the model to (1) quantify the drivers of metapopulation dynamics, and the potential interactions and feedbacks among them; (2) test predictions of the behavior of metapopulations in dynamic working landscapes; and (3) evaluate the impact of three policy options on metapopulation persistence (irrigation district water cutbacks during drought, incentives for landowners to create wetlands, and incentives for landowners to protect wetlands). Complex metapopulation dynamics emerged when landscapes functioned as CHANS, highlighting the importance of integrating human activities and other ecological processes into metapopulation models. Rail metapopulations were strongly top-down regulated by precipitation, and the black rail's decade-long decline was caused by the combination of West Nile virus and drought. Theoretical predictions of the two metapopulations’ responses to dynamic landscapes and incentive programs were complicated by heterogeneity in patch quality and CHANS couplings, respectively. Irrigation cutbacks during drought posed a serious extinction risk that neither incentive policy effectively ameliorated

Whole-genome sequencing reveals host factors underlying critical COVID-19

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization 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