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Germline rates of de novo meiotic deletions and duplications causing several genomic disorders


Meiotic recombination between highly similar duplicated sequences (nonallelic homologous recombination, NAHR) generates deletions, duplications, inversions and translocations, and it is responsible for genetic diseases known as 'genomic disorders', most of which are caused by altered copy number of dosage-sensitive genes. NAHR hot spots have been identified within some duplicated sequences. We have developed sperm-based assays to measure the de novo rate of reciprocal deletions and duplications at four NAHR hot spots. We used these assays to dissect the relative rates of NAHR between different pairs of duplicated sequences. We show that (i) these NAHR hot spots are specific to meiosis, (ii) deletions are generated at a higher rate than their reciprocal duplications in the male germline and (iii) some of these genomic disorders are likely to have been underascertained clinically, most notably that resulting from the duplication of 7q11, the reciprocal of the deletion causing Williams-Beuren syndrome.

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Figure 1: Different classes of NAHR.
Figure 2: Assaying NAHR using real-time PCR.
Figure 3: Male meiotic rates of deletions and duplications caused by NAHR.
Figure 4: Morphology of NAHR hot spots.
Figure 5: Haplotypes of NAHR breakpoints at CMT1A REP.

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The authors are grateful to L. Osborne for information on WBS-LCR duplications, C. May for advice on sperm recombination assays, and J. Lupski and A. Jeffreys for comments on an earlier version of the manuscript. We would like to thank the sperm donors themselves and the staff at the Bourn Clinic. This work was funded by the Wellcome Trust.

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Authors and Affiliations



M.E.H. and D.J.T. designed this study, M.L.B., S.B. and M.M. performed sample collection, and N.P.C., H.F. and D.R. carried out array–CGH experiments. All other experiments were performed by D.J.T. M.E.H. and D.J.T. performed the analysis and wrote the manuscript.

Corresponding author

Correspondence to Matthew E Hurles.

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Turner, D., Miretti, M., Rajan, D. et al. Germline rates of de novo meiotic deletions and duplications causing several genomic disorders. Nat Genet 40, 90–95 (2008).

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