Abstract

De novo mutations (DNMs) cause a large proportion of severe rare diseases of childhood. DNMs that occur early may result in mosaicism of both somatic and germ cells. Such early mutations can cause recurrence of disease. We scanned 1,007 sibling pairs from 251 families and identified 878 DNMs shared by siblings (ssDNMs) at 448 genomic sites. We estimated DNM recurrence probability based on parental mosaicism, sharing of DNMs among siblings, parent-of-origin, mutation type and genomic position. We detected 57.2% of ssDNMs in the parental blood. The recurrence probability of a DNM decreases by 2.27% per year for paternal DNMs and 1.78% per year for maternal DNMs. Maternal ssDNMs are more likely to be T>C mutations than paternal ssDNMs, and less likely to be C>T mutations. Depending on the properties of the DNM, the recurrence probability ranges from 0.011% to 28.5%. We have launched an online calculator to allow estimation of DNM recurrence probability for research purposes.

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Data availability

Access to these data is controlled, the DNMs are a subset of the sequence variants deposited to the European Nucleotide Archive (PRJEB15197).

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References

  1. 1.

    Tang, W. W. C., Kobayashi, T., Irie, N., Dietmann, S. & Surani, M. A. Specification and epigenetic programming of the human germ line. Nat. Rev. Genet. 17, 585–600 (2016).

  2. 2.

    De Felici M. in Oogenesis, 19–38 (Coticchio, G., Albertini, D. F. & de Santis, L. (Eds.); Springer Verlag, London; 2013).

  3. 3.

    Biesecker, L. G. & Spinner, N. B. A genomic view of mosaicism and human disease. Nat. Rev. Genet. 14, 307–320 (2013).

  4. 4.

    Samuels, M. E. & Friedman, J. M. Genetic mosaics and the germ line lineage. Genes (Basel) 6, 216–237 (2015).

  5. 5.

    Ju, Y. S. et al. Somatic mutations reveal asymmetric cellular dynamics in the early human embryo. Nature 543, 714–718 (2017).

  6. 6.

    Woodworth, M. B., Cirskis, K. M. & Walsh, C. A. Building a lineage from single cells: genetic techniques for cell lineage tracking. Nat. Rev. Genet. 18, 230–244 (2017).

  7. 7.

    Lodato, M. A. et al. Somatic mutation in single human neurons tracks developmental and transcriptional history. Science 350, 94–98 (2015).

  8. 8.

    Rahbari, R. et al. Timing, rates and spectra of human germline mutation. Nat. Genet. 48, 126–133 (2015).

  9. 9.

    Acuna-Hidalgo, R. et al. Post-zygotic point mutations are an underrecognized source of de novo genomic variation. Am. J. Hum. Genet. 97, 67–74 (2015).

  10. 10.

    Campbell, I. M. et al. Parent of origin, mosaicism, and recurrence risk: probabilistic modeling explains the broken symmetry of transmission genetics. Am. J. Hum. Genet. 95, 345–359 (2014).

  11. 11.

    Campbell, I. M. et al. Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders. Am. J. Hum. Genet. 95, 173–182 (2014).

  12. 12.

    Helderman-van Den Enden, A. T. J. M. et al. Recurrence risk due to germ line mosaicism: Duchenne and Becker muscular dystrophy. Clin. Genet. 75, 465–472 (2009).

  13. 13.

    Bakker, E. et al. Germinal mosaicism increases the recurrence risk for new Duchenne muscular dystrophy mutations. J. Med. Genet. 26, 553–559 (1989).

  14. 14.

    Mari, F. et al. Germline mosaicism in Rett syndrome identified by prenatal diagnosis. Clin. Genet. 67, 258–260 (2005).

  15. 15.

    Rose, V. M. et al. Germ-line mosaicism in tuberous sclerosis: how common? Am. J. Hum. Genet. 64, 986–992 (1999).

  16. 16.

    Verhoef, S. et al. High rate of mosaicism in tuberous sclerosis complex. Am. J. Hum. Genet. 64, 1632–1637 (1999).

  17. 17.

    Pyott, S. M. et al. Recurrence of perinatal lethal osteogenesis imperfecta in sibships: parsing the risk between parental mosaicism for dominant mutations and autosomal recessive inheritance. Genet. Med. 13, 125–130 (2011).

  18. 18.

    Jónsson, H. et al. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature 549, 519–522 (2017).

  19. 19.

    Kong, A. et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature 488, 471–475 (2012).

  20. 20.

    Scally, A. Mutation rates and the evolution of germline structure. Philos. Trans. R. Soc. Lond. B 371, 20150137 (2016).

  21. 21.

    Wong, W. S. W. et al. New observations on maternal age effect on germline de novo mutations. Nat. Commun. 7, 10486 (2016).

  22. 22.

    Maher, G. J. et al. Visualizing the origins of selfish de novo mutations in individual seminiferous tubules of human testes. Proc. Natl Acad. Sci. USA 113, 2454–2459 (2016).

  23. 23.

    Saitsu, H. et al. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nat. Genet. 40, 782–788 (2008).

  24. 24.

    Allen, A. S. et al. De novo mutations in epileptic encephalopathies. Nature 501, 217–221 (2013).

  25. 25.

    Scally, A. et al. Insights into hominid evolution from the gorilla genome sequence. Nature 483, 169–175 (2012).

  26. 26.

    Jónsson, H. et al. Whole genome characterization of sequence diversity of 15,220 Icelanders. Sci. Data 4, 170115 (2017).

  27. 27.

    Busing, F., Meijer, E. & Van Der Leeden, R. Delete-m jackknife for unequal m. Stat Comput 9, 2–7 (1999).

  28. 28.

    Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

  29. 29.

    Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

  30. 30.

    Eggertsson, H. P. et al. Graphtyper enables population-scale genotyping using pangenome graphs. Nat. Genet. 49, 1654–1660 (2017).

  31. 31.

    Stamatakis, A. RAxML version 8: A tool for phylogenetic analysis and post-analysis of large phylogenies. Bioinformatics 30, 1312–1313 (2014).

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Acknowledgements

We thank all of the participants in this study. The study was performed in collaboration with Illumina.

Author information

Affiliations

  1. deCODE genetics/Amgen Inc., Reykjavik, Iceland

    • Hákon Jónsson
    • , Patrick Sulem
    • , Gudny A. Arnadottir
    • , Gunnar Pálsson
    • , Hannes P. Eggertsson
    • , Snaedis Kristmundsdottir
    • , Florian Zink
    • , Birte Kehr
    • , Kristjan E. Hjorleifsson
    • , Brynjar Ö. Jensson
    • , Ingileif Jonsdottir
    • , Sigurjon Axel Gudjonsson
    • , Arnaldur Gylfason
    • , Adalbjorg Jonasdottir
    • , Aslaug Jonasdottir
    • , Simon N. Stacey
    • , Olafur Th. Magnusson
    • , Unnur Thorsteinsdottir
    • , Gisli Masson
    • , Augustine Kong
    • , Bjarni V. Halldorsson
    • , Agnar Helgason
    • , Daniel F. Gudbjartsson
    •  & Kari Stefansson
  2. Department of Pediatrics, Landspitali University Hospital, Reykjavik, Iceland

    • Sigurdur Einar Marelsson
  3. Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland

    • Unnur Thorsteinsdottir
    •  & Kari Stefansson
  4. School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland

    • Augustine Kong
    •  & Daniel F. Gudbjartsson
  5. School of Science and Engineering, Reykjavik University, Reykjavík, Iceland

    • Bjarni V. Halldorsson
  6. Department of Anthropology, University of Iceland, Reykjavik, Iceland

    • Agnar Helgason

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Contributions

H.J., G.A.A., F.Z., B.K., K.E.H., B.Ö.J. and D.F.G. analyzed the data. H.J., G.P., H.P.E., S.K., F.Z., B.K., A.G. and D.F.G. conceived methods for analyzing data. Ad.J., As.J. and O.Th.M. performed experiments. P.S., G.A.A., B.Ö.J., I.J., S.E.M. and S.A.G. collected samples and information. H.J., P.S., O.Th.M., U.T., G.M., B.V.H., D.F.G. and K.S. designed the study. H.J., P.S., D.F.G. and K.S. wrote the manuscript with input from G.A.A., G.P., K.E.H., S.N.S., U.T., A.K., B.V.H. and A.H.

Competing interests

All of the authors except S.E.M. are employees of deCODE Genetics/Amgen, Inc.

Corresponding authors

Correspondence to Daniel F. Gudbjartsson or Kari Stefansson.

Integrated supplementary information

  1. Supplementary Figure 1 Germ cell lineages of parents with nine offspring.

    a,b, The male and female germ cell lineages of a nine-offspring family. c,d, The paternal and maternal germ cell lineages of a nine-offspring family. Purple and green text correspond to DNMs determined by the trio and sibling approach, respectively. Percentages are paternal and maternal imbalances, respectively. The paternal imbalance serves as a background rate for the maternal DNMs, and vice versa. In addition to ssDNMs, we incorporated DNMs that are somatic mosaic in the parent (≥4 reads supporting the alternative allele in the parent). DNM sites are ordered according to carrier frequency, from high (top) to low (bottom) frequency.

  2. Supplementary Figure 2 Germ cell lineages of nine-offspring parents.

    a,b, The male and female germ cell lineages of a nine-offspring family. c,d, The paternal and maternal germ cell lineages of a nine-offspring family. Purple and green text correspond to DNMs determined by the trio and sibling approach, respectively. Percentages are paternal and maternal allelic imbalances, respectively. The paternal allelic imbalance serves as a background rate for the maternal DNMs, and vice versa. In addition to ssDNMs, we incorporated DNMs that are somatic mosaic in the parent (≥4 reads supporting the alternative allele in the parent). DNM sites are ordered according to carrier frequency, from high (top) to low (bottom) frequency.

  3. Supplementary Figure 3 ssDNM rate against allelic imbalance in parents for various subsets.

    a, Restricting to DNMs determined by the trio approach and DNMs from the sibling approach in which the allelic balance difference between carriers and parents was rejected. A two-sided Fisher test was used for the allelic balance test difference. The P values were adjusted with Holm multiple-testing correction using the number of DNMs found solely by the sibling approach. b, In addition to rejecting the null hypothesis as in a, we required DNMs determined by the sibling approach to have at least two siblings who were non-carriers despite having the same haplotype background as the DNM carriers (absent). For a and b, the analysis was restricted to deep-sequenced parents (13 parent pairs and 518 sibling pairs). c, Same as in a except that all sibling pairs were used (238 parent pairs and 518 sibling pairs). d, Same as in b except that all sibling pairs were used (238 parent pairs and 518 sibling pairs). The center values are means and error bars are 95% CIs.

  4. Supplementary Figure 4 The power of the sibling method.

    The power of detecting a DNM segregating in the parental germline conditional on DNM transmission.

  5. Supplementary Figure 5 Targeted resequencing of DNM sites from the 10- and 17-sibling families.

    a, The allelic imbalance from targeted resequencing against carrier status determined from whole-genome sequencing. In a, sites with over 100× coverage were used, resulting in 657 genotypes from 27 offspring from two parent pairs. In a, the hinges are the first and third quantiles, and notches are ±1.58 × IQR/√n, where IQR is the interquartile range and n is the number in each category. be, Targeted resequenced imbalance of the parents against the imbalance from whole-genome sequencing.

  6. Supplementary Figure 6 A schematic overview of the recurrence calculator.

    The green and orange states represent the intermediate analysis steps and datasets, respectively.

  7. Supplementary Figure 7 SMPP as a function of reads supporting the alternative allele.

    The vertical error bars are the 95% CIs assessed by the jackknife procedure. The center values are the means. 13 parent pairs and 1,517 sibling trios were used in the 200× subset, and 54 parent pairs and 241 sibling trios were used in the 30× subset.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–7, Supplementary Tables 1–5 and Supplementary Note

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DOI

https://doi.org/10.1038/s41588-018-0259-9