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Genome-wide maps of recombination and chromosome segregation in human oocytes and embryos show selection for maternal recombination rates

Nature Genetics volume 47, pages 727735 (2015) | Download Citation

Abstract

Crossover recombination reshuffles genes and prevents errors in segregation that lead to extra or missing chromosomes (aneuploidy) in human eggs, a major cause of pregnancy failure and congenital disorders. Here we generate genome-wide maps of crossovers and chromosome segregation patterns by recovering all three products of single female meioses. Genotyping >4 million informative SNPs from 23 complete meioses allowed us to map 2,032 maternal and 1,342 paternal crossovers and to infer the segregation patterns of 529 chromosome pairs. We uncover a new reverse chromosome segregation pattern in which both homologs separate their sister chromatids at meiosis I; detect selection for higher recombination rates in the female germ line by the elimination of aneuploid embryos; and report chromosomal drive against non-recombinant chromatids at meiosis II. Collectively, our findings show that recombination not only affects homolog segregation at meiosis I but also the fate of sister chromatids at meiosis II.

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Acknowledgements

We gratefully acknowledge C. May, A. Eyre-Walker, J. Gruhn, R. Rowsey, J. Turner, F. Cole and members of the Hoffmann laboratory for discussion and critical reading of the manuscript. We thank Y. Hou, W. Fan and S. Xie for freely sharing data and discussion on their study of female pronucleus–PB trios. Financial support for this research was provided by the UK Medical Research Council (Senior Research Fellowship to E.R.H.; G0902043) and a European Molecular Biology Organization (EMBO) Young Investigator award to E.R.H.

Author information

Author notes

    • Christian S Ottolini
    • , Louise J Newnham
    •  & Antonio Capalbo

    These authors contributed equally to this work.

Affiliations

  1. The Bridge Centre, London, UK.

    • Christian S Ottolini
    • , Karen Sage
    • , Michael C Summers
    •  & Alan H Handyside
  2. School of Biosciences, University of Kent, Canterbury, UK.

    • Christian S Ottolini
    • , Darren K Griffin
    • , Michael C Summers
    •  & Alan H Handyside
  3. Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, UK.

    • Louise J Newnham
    • , Alex D Herbert
    •  & Eva R Hoffmann
  4. GENERA (Gynecology, Endocrinology and Assisted Reproduction), Centers for Reproductive Medicine, Rome, Italy.

    • Antonio Capalbo
    • , Danilo Cimadomo
    • , Laura Rienzi
    •  & Filippo M Ubaldi
  5. Illumina, Inc., Fulbourn, UK.

    • Senthilkumar A Natesan
    • , Hrishikesh A Joshi
    • , Alan R Thornhill
    •  & Alan H Handyside
  6. Department of Mathematics and Statistics, University of Indiana, Bloomington, Indiana, USA.

    • Elizabeth Housworth
  7. Institute of Integrative and Comparative Biology, University of Leeds, Leeds, UK.

    • Alan H Handyside

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Contributions

A.C., C.S.O., D.C., L.R., F.M.U., K.S., M.C.S. and A.R.T. were responsible for donor consenting, oocyte collection and oocyte activation. L.R., F.M.U., A.H.H. and K.S. oversaw ethical and legal regulation in Italy and the UK. A.C., C.S.O., S.A.N., H.A.J. and D.C. carried out amplification, SNP array and aCGH experiments. A.H.H., L.J.N., C.S.O. and E.R.H. analyzed the encoded data. E.R.H. and A.D.H. carried out data analysis and simulations. E.R.H. and E.H. carried out statistical analyses. E.R.H., A.H.H. and L.J.N. generated the figures. E.R.H., A.H.H., L.J.N. and C.S.O. wrote the manuscript. A.H.H., C.S.O., D.K.G., A.C., L.J.N. and E.R.H. edited the manuscript. All authors proofread and accepted the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Alan H Handyside or Eva R Hoffmann.

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DOI

https://doi.org/10.1038/ng.3306

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