Abstract
Whole exome sequencing (WES) has become a common tool for identifying genetic causes of human inherited disorders, and it has also recently been applied to canine genome research. We conducted WES analysis of neuroaxonal dystrophy (NAD), a neurodegenerative disease that sporadically occurs worldwide in Papillon dogs. The disease is considered an autosomal recessive monogenic disease, which is histopathologically characterized by severe axonal swelling, known as “spheroids,” throughout the nervous system. By sequencing all eleven DNA samples from one NAD-affected Papillon dog and her parents, two unrelated NAD-affected Papillon dogs, and six unaffected control Papillon dogs, we identified 10 candidate mutations. Among them, three candidates were determined to be “deleterious” by in silico pathogenesis evaluation. By subsequent massive screening by TaqMan genotyping analysis, only the PLA2G6 c.1579G>A mutation had an association with the presence or absence of the disease, suggesting that it may be a causal mutation of canine NAD. As a human homologue of this gene is a causative gene for infantile neuroaxonal dystrophy, this canine phenotype may serve as a good animal model for human disease. The results of this study also indicate that WES analysis is a powerful tool for exploring canine hereditary diseases, especially in rare monogenic hereditary diseases.
Highlights
Whole exome sequencing (WES), a technique for sequencing all the exons of protein-coding genes, has become a powerful and common tool for identifying causative genes of inherited disorders
In the present study, using WES analysis and TaqMan genotyping assays, we identified the PLA2G6 c.1579G>A missense mutation in Papillon dog neuroaxonal dystrophy (NAD)
As only the PLA2G6 c.1579G>A mutation had an association with the presence or absence of the disease, we assumed that this mutation might be a causal mutation of canine NAD
Summary
Whole exome sequencing (WES), a technique for sequencing all the exons of protein-coding genes, has become a powerful and common tool for identifying causative genes of inherited disorders. Since the first isolation of a causative mutation in 2010 [1], more than 150 mutations of human inherited disorders have been identified by WES analysis [2]. When compared with whole genome sequencing, WES requires less monetary cost and results in a higher quality of sequence coverage, as it targets only 1 to 2 per cent of the total genome. The application of WES analysis has been expanded to several domestic species, as the genomic databases of non-human animals have become more accurate. The genome sequence database for domestic dogs (Canis familiaris) has been updated and improved several times since the first publication of a high-quality draft genome sequence in 2005 [3]. The WES enrichment kit based on the latest version of the canine reference genome, CanFam3.1 [4], was designed in 2014 [4], making it much easier to identify genetic mutations in inherited diseases [5] [6]
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