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Establishing causal links between non-coding variants and human phenotypes is an increasing challenge. Here we introduce a high-throughput mouse reporter assay for assessing the pathogenic potential of human enhancer variants in vivo and examine nearly a thousand variants in an enhancer repeatedly linked to polydactyly. We show that 71% of all rare non-coding variants previously proposed as causal led to reporter gene expression in a pattern consistent with their pathogenic role. Variants observed to alter enhancer activity were further confirmed to cause polydactyly in knock-in mice. We also used combinatorial and single-nucleotide mutagenesis to evaluate the in vivo impact of mutations affecting all positions of the enhancer and identified additional functional substitutions, including potentially pathogenic variants hitherto not observed in humans. Our results uncover the functional consequences of hundreds of mutations in a phenotype-associated enhancer and establish a widely applicable strategy for systematic in vivo evaluation of human enhancer variants.

[1] A new conceptual model that facilitates the inference of the vigor of severe convective storms, producing tornadoes and large hail, by using satellite-retrieved vertical profiles of cloud top temperature (T)-particle effective radius (r e ) relations is presented and tested. The driving force of these severe weather phenomena is the high updraft speed, which can sustain the growth of large hailstones and provide the upward motion that is necessary to evacuate the violently converging air of a tornado. Stronger updrafts are revealed by the delayed growth of r e to greater heights and lower T, because there is less time for the cloud and raindrops to grow by coalescence. The strong updrafts also delay the development of a mixed phase cloud and its eventual glaciation to colder temperatures. Analysis of case studies making use of these and related criteria show that they can be used to identify clouds that possess a significant risk of large hail and tornadoes. Although the strength and direction of the wind shear are major modulating factors, it appears that they are manifested in the updraft intensity and cloud shapes and hence in the T-r e profiles. It is observed that the severe storm T-r e signature is an extensive property of the clouds that develop ahead in space and time of the actual hail or tornadic storm, suggesting that the probabilities of large hail and tornadoes can be obtained at substantial lead times. Analysis of geostationary satellite time series indicates lead times of up to 2 h.

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Abstract. Coupled atmosphere-fire models can now generate forecasts in real time, owing to recent advances in computational capabilities. WRF-SFIRE consists of the Weather Research and Forecasting (WRF) model coupled with the fire-spread model SFIRE. This paper presents new developments, which were introduced as a response to the needs of the community interested in operational testing of WRF-SFIRE. These developments include a fuel-moisture model and a fuel-moisture-data-assimilation system based on the Remote Automated Weather Stations (RAWS) observations, allowing for fire simulations across landscapes and time scales of varying fuel-moisture conditions. The paper also describes the implementation of a coupling with the atmospheric chemistry and aerosol schemes in WRF-Chem, which allows for a simulation of smoke dispersion and effects of fires on air quality. There is also a data-assimilation method, which provides the capability of starting the fire simulations from an observed fire perimeter, instead of an ignition point. Finally, an example of operational deployment in Israel, utilizing some of the new visualization and datamanagement tools, is presented.