Germline mutations are the principal cause of heritable disease and the ultimate source of evolutionary change. Similarly, somatic mutations are the primary cause of cancer and may contribute to the burden of human disease more broadly than previously appreciated. Here, we review recent insights into the rates, spectrum, and determinants of genomic mutations and how these parameters inform our understanding of both Mendelian and complex human diseases. We also consider models for conceptualizing mutational consequences and outline several key areas for future research, including the development of new technologies to access and quantify the full spectrum of mutations, as well as to better interpret the consequences of mutations with respect to molecular functionality, evolutionary fitness, and disease pathogenicity.
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