Olfactory Receptor–Gene Clusters, Genomic-Inversion Polymorphisms, and Common Chromosome Rearrangements

Abstract

The olfactory receptor (OR)-gene superfamily is the largest in the mammalian genome. Several of the human OR genes appear in clusters with > or = 10 members located on almost all human chromosomes, and some chromosomes contain more than one cluster. We demonstrate, by experimental and in silico data, that unequal crossovers between two OR gene clusters in 8p are responsible for the formation of three recurrent chromosome macrorearrangements and a submicroscopic inversion polymorphism. The first two macrorearrangements are the inverted duplication of 8p, inv dup(8p), which is associated with a distinct phenotype, and a supernumerary marker chromosome, +der(8)(8p23.1pter), which is also a recurrent rearrangement and is associated with minor anomalies. We demonstrate that it is the reciprocal of the inv dup(8p). The third macrorearrangment is a recurrent 8p23 interstitial deletion associated with heart defect. Since inv dup(8p)s originate consistently in maternal meiosis, we investigated the maternal chromosomes 8 in eight mothers of subjects with inv dup(8p) and in the mother of one subject with +der(8), by means of probes included between the two 8p-OR gene clusters. All the mothers were heterozygous for an 8p submicroscopic inversion that was delimited by the 8p-OR gene clusters and was present, in heterozygous state, in 26% of a population of European descent. Thus, inversion heterozygosity may cause susceptibility to unequal recombination, leading to the formation of the inv dup(8p) or to its reciprocal product, the +der(8p). After the Yp inversion polymorphism, which is the preferential background for the PRKX/PRKY translocation in XX males and XY females, the OR-8p inversion is the second genomic polymorphism that confers susceptibility to the formation of common chromosome rearrangements. Accordingly, it may be possible to develop a profile of the individual risk of having progeny with chromosome rearrangements.

Expansion of a 12-kb VNTR containing the REXO1L1 gene cluster underlies the microscopically visible euchromatic variant of 8q21.2

“…39 Interestingly, a diploid REXO1L2P median copy number of 172, almost identical to the 173 in our controls, was found using sequencing in 159 ethnically diverse subjects from the 1000 Genomes Project, 32 and the Database of Genomic Structural Variation records 272 copies, within the EV range, of a 7-kb segment including the REXO1L1 gene in a Southern Kalahari hunter-gatherer (KB1). 40 RP11-96G1 at 8q21.2 is the third most common benign CNV identified by Whitby et al 34 using BAC array CGH and, like the second most common (RP11-122N11 at 8p23.1), becomes microscopically visible at high copy number, 31 contains tandemly repeated DNA families, 27 predisposes to polymorphic inversions 41 and has been associated with neocentromere formation. 42 The 8q21.2 VNTR is one of the nine autosomal tandem arrays 42 kb that contain a single gene and show CNV.…”

Inverted duplications deletions: underdiagnosed rearrangements??

“…1A), constituted by complex repeats containing olfactory receptor gene clusters lying at 8 and 12 Mb on the short arm of chromosome 8 and flanking a single copy region (6,9). The rearrangement was the result of non-allelic homologous recombination (NAHR) leading to the formation of a dicentric (qter->p23.1::p23.…”

Diagnosis and fine mapping of a deletion in distal 11q in two Chinese patients with developmental delay

“…Alternatively, some smaller deletions are likely to occur through different mechanisms; for example, chromosome recombinations can be mediated by palindromic AT-rich repeats, low copy repeats or olfactory receptor gene clusters. [8][9][10] Consequently, there are likely to be multiple mechanisms that result in the generation of deletions in long arm of chromosome 11.…”