Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements

Area of Science:

• Genetics
• Genomics
• Human Genetics

Background:

• The olfactory receptor (OR) gene superfamily is the largest in the mammalian genome.
• Human OR genes form clusters on chromosomes, with some chromosomes containing multiple clusters.
• Recurrent chromosome rearrangements in 8p are observed, associated with specific phenotypes.

Purpose of the Study:

• To investigate the molecular mechanisms underlying recurrent chromosome macrorearrangements in 8p.
• To identify genetic factors predisposing to these rearrangements.
• To explore the role of olfactory receptor gene clusters in chromosome instability.

Main Methods:

• Experimental and in silico analyses of olfactory receptor (OR) gene clusters.
• Characterization of chromosome macrorearrangements including inverted duplication of 8p (inv dup(8p)) and supernumerary marker chromosome (+der(8)).
• Investigation of maternal chromosome 8 using probes within 8p-OR gene clusters to detect submicroscopic inversions.

Main Results:

• Unequal crossovers between 8p OR gene clusters cause three recurrent chromosome macrorearrangements: inv dup(8p), +der(8)(8p23.1pter), and an 8p23 interstitial deletion.
• Maternal heterozygosity for a submicroscopic 8p inversion, delimited by OR gene clusters, was identified in mothers of affected individuals.
• This 8p inversion polymorphism is present in 26% of the European descent population and confers susceptibility to unequal recombination.

Conclusions:

• 8p inversion heterozygosity predisposes individuals to unequal recombination events, leading to recurrent chromosome rearrangements like inv dup(8p) and its reciprocal product.
• The OR-8p inversion is the second identified genomic polymorphism that increases susceptibility to common chromosome rearrangements.
• This finding may enable the development of risk profiles for individuals having offspring with chromosome rearrangements.