Genomic Copy Number Variation in Horses and Their Impact on Susceptibility to Recurrent Airway Obstruction

Overrepresentation of immunity-related genes in copy number variable regions (CNVRs) in human and animal genomes is well-documented and thought to provide adaptive flexibility and modulate predisposition to diseases. Here we studied possible involvement of CNVRs in susceptibility to equine recurrent airway obstruction (RAO) – an asthma-like debilitating inflammatory disease in horses. First, we generated a 258-CNVR map for the horse genome based on the analysis of 36 horses of 16 breeds by CGH on a 500,000-element whole-genome tiling array. The data were merged with previously published horse CNVs and a composite genome-wide database of over 1,500 CNVRs was generated. This serves as a critical foundation for the discovery of variants contributing to equine diseases/disorders. Next, array CGH was conducted in 16 severely RAO-affected and 6 age-matched control horses of various breeds. The study cohort showed 363 CNVRs, 58 of which were unique to RAO cases and 12 shared between two or more affected animals. The majority (73%) of unique CNVRs involved genes including immunity-related BTNL2, FAM19A1, and LINGO2. Notably, a massive loss in a miRNA gene cluster in chr15 partially overlapped with a previously detected RAO candidate region. A significant loss in chr24 involved SPI2 and SERPINA1 genes, deficiency of which has been associated with chronic obstructive pulmonary disease in humans. Among common CNVRs, extreme log2 ratios in RAO cases but not in controls were seen in an olfactory receptor cluster in chr12. The findings support the genetic heterogeneity of RAO susceptibility and do not exclude the involvement of CNVs.