Analysis

Reduced mutation rate in exons due to differential mismatch repair

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Abstract

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.

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Acknowledgements

We acknowledge funding from the 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 634143 (MedBioinformatics) and by the European Research Council (Consolidator Grant 682398). IRB Barcelona is the 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.S. is supported by an EMBO Long-Term Fellowship (ALTF 568-2014) cofunded by the European Commission (EMBOCOFUND2012, GA-2012-600394) with support from Marie Curie Actions. A.G.-P. is supported by a Ramón y Cajal contract from the Spanish Ministry of Economy and Competitiveness (RYC-2013-14554). We acknowledge the contribution of I. Reyes-Salazar to refactoring and cleaning all code produced in the study for publication. We are grateful to B. Campbell and U. Tabori for help in obtaining the mutation calls for bMMRD samples sequenced by the International BMMRD Consortium. The results published here are in part based upon data generated by the TCGA Research Network (http://cancergenome.nih.gov/).

Author information

Author notes

    • Joan Frigola
    •  & Radhakrishnan Sabarinathan

    These authors contributed equally to this work.

Affiliations

  1. Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.

    • Joan Frigola
    • , Radhakrishnan Sabarinathan
    • , Loris Mularoni
    • , Ferran Muiños
    • , Abel Gonzalez-Perez
    •  & Núria López-Bigas
  2. Research Program on Biomedical Informatics, Universitat Pompeu Fabra, Barcelona, Spain.

    • Joan Frigola
    • , Radhakrishnan Sabarinathan
    • , Loris Mularoni
    • , Ferran Muiños
    • , Abel Gonzalez-Perez
    •  & Núria López-Bigas
  3. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.

    • Núria López-Bigas

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Contributions

J.F. and R.S. participated in the design and execution of analyses, produced the figures, participated in the interpretation of results and edited the manuscript. L.M. developed computational code employed in the analyses. F.M. developed the statistical framework to compute the significance of the decreased exonic mutation burden and its correlation with chromatin features. A.G.-P. participated in the design of analyses, the interpretation of results, the oversight of analyses, and drafted and edited the manuscript. N.L.-B. conceived the study, participated in the design of analyses, oversaw the study and the interpretation of results, and drafted and edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Núria López-Bigas.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–7

  2. 2.

    Life Sciences Reporting Summary

Excel files

  1. 1.

    Supplementary Table 1

    Coverage of several chromatin features of exons and introns across the structure of genes.

  2. 2.

    Supplementary Table 2

    Difference in exonic and intronic coverage (Mann–Whitney P value) and mean exonic coverage across the genic structure.

  3. 3.

    Supplementary Table 3

    Decreased exonic mutation rate across clusters of tumors.

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    Supplementary Table 4

    Decreased exonic mutation burden across groups of genes with different mutation rate covariate values.

  5. 5.

    Supplementary Table 5

    Decreased exonic mutation burden for individual tumors.

  6. 6.

    Supplementary Table 6

    Correlation of decreased exonic mutation burden and the exonic enrichment for several histone marks.