Analysis of genomic copy number variation in equine recurrent airway obstruction (heaves)

Abstract

We explored the involvement of genomic copy number variants (CNVs) in susceptibility to recurrent airway obstruction (RAO), or heaves-an asthmalike inflammatory disease in horses. Analysis of 16 RAO-susceptible (cases) and six RAO-resistant (control) horses on a custom-made whole-genome 400K equine tiling array identified 245 CNV regions (CNVRs), 197 previously known and 48 new, distributed on all horse autosomes and the X chromosome. Among the new CNVRs, 30 were exclusively found in RAO cases and were further analyzed by quantitative PCR, including additional cases and controls. Suggestive association (P = 0.03; corrected P = 0.06) was found between RAO and a loss on chromosome 5 involving NME7, a gene necessary for ciliary functions in lungs and involved in primary ciliary dyskinesia in humans. The CNVR could be a potential marker for RAO susceptibility but needs further study in additional RAO cohorts. Other CNVRs were not associated with RAO, although several involved genes of interest, such as SPI2/SERPINA1 from the serpin gene family, which are associated with chronic obstructive pulmonary disease and asthma in humans. The SPI2/SERPINA1 CNVR showed striking variation among horses, but it was not significantly different between RAO cases and controls. The findings provide baseline information on the relationship between CNVs and RAO susceptibility. Discovery of new CNVs and the use of a larger population of RAO-affected and control horses are needed to shed more light on their significance in modulating this complex and heterogeneous disease.

Inter- and intra-breed genome-wide copy number diversity in a large cohort of European equine breeds

“…To further verify the accuracy of CNVR prediction, RT-qPCR was used to validate four genomic regions containing common segment CNVs of different sizes detected in this study (from 12kb to 2Mb length). The CNVR located within Olfr4F21 gene on ECA1 and OR8S1 gene on ECA6 were already detected in previous studies [15,20], whereas the remaining two were novel CNVRs. The CNVRs represented a different state of the segment CNVs (signal gain and loss in relation to the average signal of the reference; Additional file 4: Table S3).…”

“…The current publicly available database of genetic variants in the equine genome contains 25,756,212 SNP and 3,663,455 insertion/deletions polymorphisms "INDELs", accessed from the Genome Variation Map (http://bigd.big.ac.cn/gvm/home). Until now, CNVs identified in nearly 45 different horse breeds occupy about 1-3% of their genome and there are more CNVs residing in genes (~80%) than in intergenic regions (~20%) [5,7,[15][16][17][18][19]. In horses, the average range for CNV size remains between 1kb to 4.84Mb with CNV losses generally dominating over gains in comparison with a reference Thoroughbred genome [7,[15][16][17].…”

“…Until now, CNVs identified in nearly 45 different horse breeds occupy about 1-3% of their genome and there are more CNVs residing in genes (~80%) than in intergenic regions (~20%) [5,7,[15][16][17][18][19]. In horses, the average range for CNV size remains between 1kb to 4.84Mb with CNV losses generally dominating over gains in comparison with a reference Thoroughbred genome [7,[15][16][17]. The majority of the actual number of identified specific CNVs in horses has been reported using a limited number of individuals [7,17,20].…”

Inter- and intra-breed genome-wide copy number diversity in a large cohort of European equine breeds

“…The current publicly available database of genetic variants in the equine genome contains 25,756,212 SNP and 3,663,455 insertion/deletions polymorphisms "INDELs", accessed from the Genome Variation Map (http://bigd.big.ac.cn/gvm/home). Until now, CNVs identified in nearly 45 different horse breeds occupy about 1-3% of their genome and there are more CNVs residing in genes (~80%) than in intergenic regions (~20%) [5,7,[15][16][17][18][19]. In horses, the average range for CNV size remains between 1kb to 4.84Mb with CNV losses generally dominating over gains in comparison with a reference Thoroughbred genome [7,[15][16][17].…”

“…Until now, CNVs identified in nearly 45 different horse breeds occupy about 1-3% of their genome and there are more CNVs residing in genes (~80%) than in intergenic regions (~20%) [5,7,[15][16][17][18][19]. In horses, the average range for CNV size remains between 1kb to 4.84Mb with CNV losses generally dominating over gains in comparison with a reference Thoroughbred genome [7,[15][16][17]. However, the majority of the actual number of identified specific CNVs in horses has been reported using a limited number of individuals [7,17,20].…”