Genome-wide patterns and properties of de novo mutations in humans

L.C. Francioli, P.P. Polak, A. Koren, A. Menelaou, S. Chun, I. Renkens, C.M. van Duijn, M.A. Swertz, C. Wijmenga, G.J. van Ommen, P.E. Slagboom, D.I. Boomsma, K. Ye, V. Guryev, P.F. Arndt, W.P. Kloosterman, P.I.W. Bakker, S.R. Sunyaev, F. Dijk, P.B.T. NeerincxS.L. Pulit, P. Deelen, C.C. Elbers, P.F. Palamara, I. Pe'er, A. Abdellaoui, M. van Oven, M. Vermaat, M. Li, J.F.J. Laros, M. Stoneking, P. de Knijff, M. Kayser, J.H. Veldink, L.H. Van den Berg, H. Byelas, J.T. den Dunnen, M. Dijkstra, N. Amin, K.J. van der Velde, J.J. Hottenga, J. van Setten, E.M. van Leeuwen, A. Kanterakis, V.M. Kattenberg, L.C. Karssen, B.D.C. van Schaik, J. Bot, I.J. Nijman, D. van Enckevort, H. Mei, V. Koval, K. Estrada, C. Medina-Gomez, E.W. Lameijer, M.H. Moed, J.Y. Hehir-Kwa, R.E. Handsaker, S.A. McCarroll, D. Vuzman, M. Sohail, F. Hormozdiari, T. Marschall, A. Schönhuth, M. Beekman, A.J. de Craen, H.E.D. Suchiman, A. Hofman, B. Oostra, A. Isaacs, F. Rivadeneira, A.G. Uitterlinden, G. Willemsen, M. Platteel, S.J. Pitts, S. Potluri, P. Sundar, D.R. Cox, Q. Li, Y. Li, Y. Du, R. Chen, H. Cao, N. Li, S. Cao, J. Wang, J.A. Bovenberg, M. Brandsma

Research output: Contribution to JournalArticleAcademicpeer-review


Mutations create variation in the population, fuel evolution and cause genetic diseases. Current knowledge about de novo mutations is incomplete and mostly indirect. Here we analyze 11,020 de novo mutations from the whole genomes of 250 families. We show that de novo mutations in the offspring of older fathers are not only more numerous but also occur more frequently in early-replicating, genic regions. Functional regions exhibit higher mutation rates due to CpG dinucleotides and show signatures of transcription-coupled repair, whereas mutation clusters with a unique signature point to a new mutational mechanism. Mutation and recombination rates independently associate with nucleotide diversity, and regional variation in human-chimpanzee divergence is only partly explained by heterogeneity in mutation rate. Finally, we provide a genome-wide mutation rate map for medical and population genetics applications. Our results provide new insights and refine long-standing hypotheses about human mutagenesis.
Original languageEnglish
Pages (from-to)822-826
Number of pages5
JournalNature Genetics
Issue number7
Publication statusPublished - 2015

Cohort Studies

  • Netherlands Twin Register (NTR)


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