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.
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, CB10 1SA, UK.
Daniel J
DJ
Turner
Marcos
M
Miretti
Diana
D
Rajan
Heike
H
Fiegler
Nigel P
NP
Carter
Martyn L
ML
Blayney
Stephan
S
Beck
Matthew E
ME
Hurles
D002872:Chromosome Deletion; D002897:Chromosomes, Human, Pair 7; D020440:Gene Duplication; D006801:Humans; D008297:Male; D008540:Meiosis; D008969:Molecular Sequence Data; D011995:Recombination, Genetic; D013094:Spermatozoa / Q000166:cytology; D018980:Williams Syndrome / Q000235:genetics