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This paper describes a computationally efficient framework for uncertainty studies in global and regional climate change. In this framework, the Massachusetts Institute of Technology (MIT) Integrated Global System Model (IGSM), an integrated assessment model that couples an Earth system model of intermediate complexity to a human activity model, is linked to the National Center for Atmospheric Research (NCAR) Community Atmosphere Model (CAM). Since the MIT IGSM-CAM framework (version 1.0) incorporates a human activity model, it is possible to analyze uncertainties in emissions resulting from both uncertainties in the underlying socio-economic characteristics of the economic model and in the choice of climate-related policies. Another major feature is the flexibility to vary key climate parameters controlling the climate system response to changes in greenhouse gases and aerosols concentrations, e.g., climate sensitivity, ocean heat uptake rate, and strength of the aerosol forcing. The IGSM-CAM is not only able to realistically simulate the present-day mean climate and the observed trends at the global and continental scale, but it also simulates ENSO variability with realistic time scales, seasonality and patterns of SST anomalies, albeit with stronger magnitudes than observed. The IGSM-CAM shares the same general strengths and limitations as the Coupled Model Intercomparison Project Phase 3 (CMIP3) models in simulating present-day annual mean surface temperature and precipitation. Over land, the IGSM-CAM shows similar biases to the NCAR Community Climate System Model (CCSM) version 3, which shares the same atmospheric model. This study also presents 21st century simulations based on two emissions scenarios (unconstrained scenario and stabilization scenario at 660 ppm CO2-equivalent) similar to, respectively, the Representative Concentration Pathways RCP8.5 and RCP4.5 scenarios, and three sets of climate parameters. Results of the simulations with the chosen climate parameters provide a good approximation for the median, and the 5th and 95th percentiles of the probability distribution of 21st century changes in global mean surface air temperature from previous work with the IGSM. Because the IGSM-CAM framework only considers one particular climate model, it cannot be used to assess the structural modeling uncertainty arising from differences in the parameterization suites of climate models. However, comparison of the IGSM-CAM projections with simulations of 31 CMIP5 models under the RCP4.5 and RCP8.5 scenarios show that the range of warming at the continental scale shows very good agreement between the two ensemble simulations, except over Antarctica, where the IGSM-CAM overestimates the warming. This demonstrates that by sampling the climate system response, the IGSM-CAM, even though it relies on one single climate model, can essentially reproduce the range of future continental warming simulated by more than 30 different models. Precipitation changes projected in the IGSM-CAM simulations and the CMIP5 multi-model ensemble both display a large uncertainty at the continental scale. The two ensemble simulations show good agreement over Asia and Europe. However, the ranges of precipitation changes do not overlap - but display similar size - over Africa and South America, two continents where models generally show little agreement in the sign of precipitation changes and where CCSM3 tends to be an outlier. Overall, the IGSM-CAM provides an efficient and consistent framework to explore the large uncertainty in future projections of global and regional climate change associated with uncertainty in the climate response and projected emissions. [ABSTRACT FROM AUTHOR]