The effect of genetic bottlenecks and inbreeding on the incidence of two major autoimmune diseases in standard poodles, sebaceous adenitis and Addison’s disease

Abstract

BackgroundSebaceous adenitis (SA) and Addison’s disease (AD) increased rapidly in incidence among Standard Poodles after the mid-twentieth century. Previous attempts to identify specific genetic causes using genome wide association studies and interrogation of the dog leukocyte antigen (DLA) region have been non-productive. However, such studies led us to hypothesize that positive selection for desired phenotypic traits that arose in the mid-twentieth century led to intense inbreeding and the inadvertent amplification of AD and SA associated traits.ResultsThis hypothesis was tested with genetic studies of 761 Standard, Miniature, and Miniature/Standard Poodle crosses from the USA, Canada and Europe, coupled with extensive pedigree analysis of thousands more dogs. Genome-wide diversity across the world-wide population was measured using a panel of 33 short tandem repeat (STR) loci. Allele frequency data were also used to determine the internal relatedness of individual dogs within the population as a whole. Assays based on linkage between STR genomic loci and DLA genes were used to identify class I and II haplotypes and disease associations. Genetic diversity statistics based on genomic STR markers indicated that Standard Poodles from North America and Europe were closely related and reasonably diverse across the breed. However, genetic diversity statistics, internal relatedness, principal coordinate analysis, and DLA haplotype frequencies showed a marked imbalance with 30 % of the diversity in 70 % of the dogs. Standard Poodles with SA and AD were strongly linked to this inbred population, with dogs suffering with SA being the most inbred. No single strong association was found between STR defined DLA class I or II haplotypes and SA or AD in the breed as a whole, although certain haplotypes present in a minority of the population appeared to confer moderate degrees of risk or protection against either or both diseases. Dogs possessing minor DLA class I haplotypes were half as likely to develop SA or AD as dogs with common haplotypes. Miniature/Standard Poodle crosses being used for outcrossing were more genetically diverse than Standard Poodles and genetically distinguishable across the genome and in the DLA class I and II region.ConclusionsAncestral genetic polymorphisms responsible for SA and AD entered Standard Poodles through separate lineages, AD earlier and SA later, and were increasingly fixed by a period of close linebreeding that was related to popular bloodlines from the mid-twentieth century. This event has become known as the midcentury bottleneck or MCB. Sustained positive selection resulted in a marked imbalance in genetic diversity across the genome and in the DLA class I and II region. Both SA and AD were concentrated among the most inbred dogs, with genetic outliers being relatively disease free. No specific genetic markers other than those reflecting the degree of inbreeding were consistently associated with either disease. Standard Poodles as a whole remain genetically diverse, but steps should...

Evaluation of the genetic basis of primary hypoadrenocorticism in Standard Poodles using SNP array genotyping and whole-genome sequencing

“…One recent study examining the effects of genetic bottlenecks within the breed is consistent with our GWAS findings (Pedersen et al 2015). By genotyping 33 highly discriminatory microsatellite markers in samples acquired across North America and Europe, the study authors determined that Standard Poodle dogs with AD tend to be highly inbred.…”

Isolation and characterization of canine placenta‐derived mesenchymal stromal cells for the treatment of neurological disorders in dogs

“…Total genomic DNA was isolated from fetal tissue, maternal blood, and cultured cells from male placentas as previously described . Total genomic DNA was used in PCR reactions under previously described conditions with 38 diagnostic autosomal short tandem repeat (STR) markers distributed across the entire canine genome , seven Y chromosome canine specific markers , and an additional gender identification marker . PCR amplicons were visualized on an ABI3730 DNA analyzer (Applied Biosystems) and analyzed using STR and software .…”

Cicatricial Alopecia Research Foundation meeting, May 2016: Progress towards the diagnosis, treatment and cure of primary cicatricial alopecias

“…Sebaceous adenitis in dogs can progress to scarring alopecia . Dogs possessing minor DLA class I haplotypes were half as likely to develop sebaceous adenitis as dogs with common haplotypes suggesting a genetic component to this canine disease.…”

“…Sebaceous adenitis is a lymphoplasmacytic inflammatory skin disease of unknown aetiology that leads to a poor hair coat in young adult to middle aged dogs . Sebaceous adenitis can be somewhat breed specific, notably affecting standard poodles, miniature poodles and beagles . Sebaceous adenitis in dogs can progress to scarring alopecia .…”