A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC

DE BAKKER* PI, MCVEAN G*, SABETI PC*, MIRETTI MM*, GREEN T, MARCHINI J ET AL.

NATURE GENETICS

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2006 vol. 38 p. 1166 - 1172

1061-4036

de Bakker* PI, McVean G*, Sabeti PC*, Miretti MM*, Green T, Marchini J, Ke X, Monsuur AJ, Whittaker P, Delgado M, Morrison J, Richardson A, Walsh EC, Gao X, Galver L, Hart J, Hafler DA, Pericak-Vance M, Todd JA, Daly MJ, Trowsdale J, Wijmenga C, Vyse TJ, Beck S, Murray SS, Carrington M, Gregory S, Deloukas P, Rioux JD. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nature Genetics, Oct;38(10):1166-1172, 2006 (*joint first authors) 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 spermbased 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.