An Evolutionarily Recent, Deleterious Mutation Causes Bardet-Biedl Syndrome in the Hungarian Puli
Bardet-Biedl syndrome is a recessive ciliopathy characterized by a wide range of clinical features including retinopathy, obesity, polydactyly, renal dysfunction, and hypogonadism in humans. In this study, we report the natural occurrence of Bardet-Biedl syndrome in the domestic dog. Like the human counterpart, the disease in dogs causes retinopathy, infertility, and obesity. To identify the genetic cause of disease, we analyzed 170K SNP genotyping array data produced from Illumina's CanineHD BeadChip array in conjunction with whole-genome sequence data. With the inclusion of parent-affected offspring data, we filtered variants from candidate gene regions to a single nonsense SNP in BBS4. We experimentally validated and genotyped this SNP for 3 affected and 42 non-affected Hungarian Puli and also accepted genotypes from whole-genome sequencing data if it passed quality filtering in dogs of other breeds. With a total of 81 genotyped dogs, we find that the SNP has a significant association with disease (PCHISQ = 2.907e-11). When looking at the array data, we noticed that the mother of an affected individual appears homozygous for the haplotype despite being heterozygous for the SNP. This suggests that this deleterious mutation arose relatively recently and that there are two versions of an otherwise seemingly identical haplotype, one with the mutation and the other without. From this study, we have shown that the technique of combining various types of data and utilizing parent-proband samples has enabled the identification of a relatively new mutation using a modest number of affected samples. This is especially important for mapping rare disease genes where samples are often limited. We have also provided breeders with a means to prevent propagation of disease and for scientists to create an animal model to study the disease and its significant phenotypes.