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The rate of meiotic gene conversion varies by sex and age

Nature Genetics volume 48, pages 1377–1384 (2016)Cite this article

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An Author Correction to this article was published on 20 September 2018

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Abstract

Meiotic recombination involves a combination of gene conversion and crossover events that, along with mutations, produce germline genetic diversity. Here we report the discovery of 3,176 SNP and 61 indel gene conversions. Our estimate of the non-crossover (NCO) gene conversion rate (G) is 7.0 for SNPs and 5.8 for indels per megabase per generation, and the GC bias is 67.6%. For indels, we demonstrate a 65.6% preference for the shorter allele. NCO gene conversions from mothers are longer than those from fathers, and G is 2.17 times greater in mothers. Notably, G increases with the age of mothers, but not the age of fathers. A disproportionate number of NCO gene conversions in older mothers occur outside double-strand break (DSB) regions and in regions with relatively low GC content. This points to age-related changes in the mechanisms of meiotic gene conversion in oocytes.

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Figure 1: The study design and method used for detecting gene conversions.
Figure 2: The NCO gene conversion rate, G.
Figure 3: NCO gene conversion rate G as a function of the GC content of the neighboring 100 bp.
Figure 4: Maternal age increase in complex crossovers.

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Change history

  • 20 September 2018

    In the version of this article published, statements about the impact of insertions and deletions on gene conversions were incorrect. We reported a bias toward deletions, whereas in fact the bias was toward insertions. We are deeply indebted to Laurent Duret and Brice Letcher for noticing this mistake in our manuscript. Full details can be found in the correction notice.

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Acknowledgements

This work was supported in part by the NIH (NIDA) (R01-DA017932).

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Authors and Affiliations

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

    Bjarni V Halldorsson, Marteinn T Hardarson, Birte Kehr, Unnur Styrkarsdottir, Arnaldur Gylfason, Gudmar Thorleifsson, Florian Zink, Adalbjorg Jonasdottir, Aslaug Jonasdottir, Patrick Sulem, Gisli Masson, Unnur Thorsteinsdottir, Agnar Helgason, Augustine Kong, Daniel F Gudbjartsson & Kari Stefansson

  2. School of Science and Engineering, Reykjavik University, Reykjavik, Iceland

    Bjarni V Halldorsson

  3. Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland

    Unnur Thorsteinsdottir & Kari Stefansson

  4. Department of Anthropology, University of Iceland, Reykjavik, Iceland

    Agnar Helgason

  5. School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland

    Daniel F Gudbjartsson

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Contributions

B.V.H., D.F.G. and K.S. designed the experiments. B.V.H. wrote the first draft of the manuscript. B.V.H., M.T.H., B.K., U.S., P.S., A.H., A.K., D.F.G. and K.S. reviewed and contributed to subsequent drafts of the manuscript. B.V.H., M.T.H. and A.G. implemented the methodology. B.V.H., M.T.H. and B.K. prepared tables and figures. Aslaug Jonasdottir and Adalbjorg Jonasdottir performed the Sanger sequencing. U.T. oversaw the operations of the genotyping facility. B.V.H., M.T.H., F.Z., G.T., A.G. and G.M. processed the data. B.V.H. and M.T.H. analyzed the data. All authors contributed to the final version of the manuscript.

Corresponding authors

Correspondence to Bjarni V Halldorsson or Kari Stefansson.

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Competing interests

All authors are employees of deCODE Genetics/Amgen.

Integrated supplementary information

Supplementary Figure 1 Repair mechanisms of DNA double-strand breaks.

Small gray boxes show regions where heteroduplex DNA is formed. DSBs are resolved via either synthesis-dependent strand annealing (SDSA) or double Holliday junctions (dHjs). dHjs result in either dissolution or resolution; resolution results in either crossover (CO) or non-crossover (NCO).

Supplementary Figure 2 Odds ratio of an NCO gene conversion being in a male DSB region and a crossover recombination hotspot as a function of mother’s age in the chip data set.

Error bars, 95% confidence intervals. The dotted lines represent linear models.

Supplementary Figure 3 Crossover recombination rate of NCO gene conversions in the chip data set.

Error bars, 95% confidence intervals. The dotted line represents a linear model.

Supplementary Figure 4 MPPs by local GC content.

(a) Distribution of SNP MPPs by local GC content. (b) Probability that a SNP MPP is in a DSB region by local GC content.

Supplementary Figure 5 Number of verified gene-converted MPPs per event as a function of mother’s age in the chip data set.

Error bars, 95% confidence intervals. The dotted line represents a linear model.

Supplementary Figure 6 Detection of complex crossover gene conversions.

Two equally parsimonious locations exist to place a crossover recombination. The navy blue haplotype represents the background haplotype, and the cyan haplotype represents the other haplotype. The location of gene conversion depends on the assignment of the background haplotype.

Supplementary Figure 7 Schematic overview of the algorithm for detecting gene conversions.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7, Supplementary Tables 1–10 and Supplementary Note. (PDF 2505 kb)

Supplementary Data

Gene conversion MPPs. Data set of all gene conversion MPPs found and neighboring MPPs. (XLSX 1263 kb)

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Halldorsson, B., Hardarson, M., Kehr, B. et al. The rate of meiotic gene conversion varies by sex and age. Nat Genet 48, 1377–1384 (2016). https://doi.org/10.1038/ng.3669

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