While recent studies have identified higher than anticipated heterogeneity of mutation rate across genomic regions, mutations in exons and introns are assumed to be generated at the same rate. Here we find fewer somatic mutations in exons than expected from their sequence content and demonstrate that this is not due to purifying selection. Instead, we show that it is caused by higher mismatch-repair activity in exonic than in intronic regions. Our findings have important implications for understanding of mutational and DNA repair processes and knowledge of the evolution of eukaryotic genes, and they have practical ramifications for the study of evolution of both tumors and species.

We acknowledge funding from Spanish Ministry of Economy and Competitiveness (SAF2015-66084-R, MINECO/FEDER, UE), La Fundació la Marató de TV3, EU H2020 Programme 2014-2020 under grant agreements no. 634143 (MedBioinformatics) and by the European Research Council (Consolidator Grant 682398). IRB Barcelona is a recipient of a Severo Ochoa Centre of Excellence Award from the Spanish Ministry of Economy and Competitiveness (MINECO; Government of Spain) and is supported by CERCA (Generalitat de Catalunya). R. Sabarinathan is supported by an EMBO Long-Term Fellowship (ALTF 568-2014) co-funded by the European Commission (EMBOCOFUND2012, GA-2012-600394) support from Marie Curie Actions. A.Gonzalez-Perez is supported by a Ramón y Cajal contract