Response to cytosolic DNA is a major way of type I IFN-production and is triggered by several DNA/RNA sensing pathways, including the STING-mediated pathway. STING (Tmem173/ MPYS/ MITA), a tetraspanning membrane-resident sensor, directly binds certain cyclic dinucleotides (CDNs) such as c-di-AMP and c-di-GAMP,or interacts with upstream “DNA sensors”, such as IFI16 or cGAS, a nucleotidyl transferase that generates cGMP-AMP (cGAMP), which in turn binds and activates STING. Given that excessive levels of IFN-I contributes to the development of autoimmunity, chronic inflammation and sepsis, expression of this cytokine must be tightly regulated. To further understand the mechanism of host responses to cytosolic DNA using genetic approach, we used evolutionary divergent wild derived mice of MOLF strain to map, identify and characterize novel mutations at the N-terminal domain (NTD) of STING, one of the main DNA-sensors and mediator of responses to DNA. These mutations confer low production of IFN in MOLF macrophages. Despite defective IFN-production, MOLF exhibit high levels of IL6 in response to DNA thus revealing the complexity of STING-mediated responses. The novelty of these studies in that i) they highlight for the first time functional importance of NTD of STING while recent studies focused exclusively on the C-terminal region of STING; ii) they describe novel model of DNA-response that is polarized from IFN towards other cytokines; iii) they show that the mutant allele is inherited in a dominant manner thus alluding to a possible mechanism of STING-mediated signal transduction; iv) they present evidence of other (novel) sensors of DNA that could be identified via unbiased genetic approach. To characterize these novel components of the DNA-response, we performed linkage analysis of the trait and identified several loci conferring the trait. Identification of these genes will be insightful for translational research relevant to human health.