Karl received a BS in mathematics in 1991 from the University of Wisconsin–Milwaukee, and a PhD in statistics in 1997 from the University of California, Berkeley; his PhD advisor was Terry Speed. He was a postdoctoral fellow with James Weber at the Marshfield Clinic Research Foundation, 1997–1999. He was a faculty member in the Department of Biostatistics at Johns Hopkins University, 1999–2007. In 2007, he moved to the University of Wisconsin–Madison.
Karl is an applied statistician focusing on problems in genetics and genomics, particularly the analysis of meiotic recombination and the genetics of complex traits in experimental organisms. He is an enthusiastic advocate for open science, open software, reproducible research, and interactive data visualization.