The SARS-CoV-2 virus, the causative agent of COVID-19, is undergoing constant mutation. Here, we utilized an integrative approach combining epidemiology, virus genome sequencing, clinical... Show moreThe SARS-CoV-2 virus, the causative agent of COVID-19, is undergoing constant mutation. Here, we utilized an integrative approach combining epidemiology, virus genome sequencing, clinical phenotyping, and experimental validation to locate mutations of clinical importance. We identified 35 recurrent variants, some of which are associated with clinical phenotypes related to severity. One variant, containing a deletion in the Nsp1-coding region (Δ500-532), was found in more than 20% of our sequenced samples and associates with higher RT-PCR cycle thresholds and lower serum IFN-β levels of infected patients. Deletion variants in this locus were found in 37 countries worldwide, and viruses isolated from clinical samples or engineered by reverse genetics with related deletions in Nsp1 also induce lower IFN-β responses in infected Calu-3 cells. Taken together, our virologic surveillance characterizes recurrent genetic diversity and identified mutations in Nsp1 of biological and clinical importance, which collectively may aid molecular diagnostics and drug design. Show less
Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can... Show moreLeptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 x 10(-16), n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity. Show less
The implementation of strict emission control measures in Beijing and surrounding regions during the 2015 China Victory Day Parade provided a valuable opportunity to investigate related air quality... Show moreThe implementation of strict emission control measures in Beijing and surrounding regions during the 2015 China Victory Day Parade provided a valuable opportunity to investigate related air quality improvements in a megacity. We measured NH3, NO2 and PM2.5 at multiple sites in and outside Beijing and summarized concentrations of PM2.5, PM10, NO2, SO2 and CO in 291 cities across China from a national urban air quality monitoring network between August and September 2015. Consistently significant reductions of 12-35% for NH3 and 33-59% for NO2 in different areas of Beijing during the emission control period (referred to as the Parade Blue period) were observed compared with measurements in the pre- and post-Parade Blue periods without emission controls. Average NH3 and NO2 concentrations at sites near traffic were strongly correlated and showed positive and significant responses to traffic reduction measures, suggesting that traffic is an important source of both NH3 and NOx in urban Beijing. Daily concentrations of PM2.5 and secondary inorganic aerosol (sulfate, ammonium and nitrate) at the urban and rural sites both decreased during the Parade Blue period. During (after) the emission control period, concentrations of PM2.5, PM10, NO2, SO2 and CO from the national city-monitoring network showed the largest decrease (increase) of 34-72% (50-214 %) in Beijing, a smaller decrease (a moderate increase) of 1-32% (16-44 %) in emission control regions outside Beijing and an increase (decrease) of 6-16% (2-7 %) in non-emission-control regions of China. Integrated analysis of modelling and monitoring results demonstrated that emission control measures made a major contribution to air quality improvement in Beijing compared with a minor contribution from favourable meteorological conditions during the Parade Blue period. These results show that controls of secondary aerosol precursors (NH3, SO2 and NOx) locally and regionally are key to curbing air pollution in Beijing and probably in other mega cities worldwide. Show less
