SPERM BASED ASSAYS measure DE NOVO RATE OF DUPLICATIONS AND DELETIONS AT HOT SPOTS

Letter abstract

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Nature Genetics 40, 90 - 95 (2007)
Published online: 2 December 2007 | doi:10.1038/ng.2007.40


Germline rates of de novo meiotic deletions and duplications causing several genomic disorders
Daniel J Turner1, Marcos Miretti1, Diana Rajan1, Heike Fiegler1, Nigel P Carter1, Martyn L Blayney2, Stephan Beck3 & Matthew E Hurles1

Top of pageMeiotic 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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Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, CB10 1SA, UK.
Bourn Hall Clinic, Bourn, Cambridge CB23 2TN, UK.
University College London Cancer Institute, University College London, London WC1E 6DD, UK.
Correspondence to: Matthew E Hurles1 e-mail: meh@sanger.ac.uk