Genomic diversity and population structure of the Leonberger dog breed

Abstract

Background Leonberger is a giant dog breed formed in the 1850s in Germany. Its post-World War II popularity has resulted in a current global population of ~ 30,000 dogs. The breed has predispositions to neurodegenerative disorders and cancer, which is likely due in large part to limited genetic diversity. However, to date there is no scientific literature on the overall demography and genomic architecture of this breed. Results We assessed extensive pedigree records, SNP array genotype data, and whole-genome sequences (WGS) on 142,072, 1203 and 39 Leonberger dogs, respectively. Pedigree analyses identified 22 founder animals and revealed an apparent popular sire effect. The average pedigree-based inbreeding coefficient of 0.29 and average kinship of 0.31 show a dramatic loss of genetic diversity. The observed average life span decreased over time from 9.4 years in 1989 to 7.7 years in 2004. A global health survey confirmed a high prevalence of cancer and neurological disorders. Analysis of SNP-based runs of homozygosity (ROH) identified 125,653 ROH with an average length of 5.88 Mb, and confirmed an average inbreeding coefficient of 0.28. Genome-wide filtering of the WGS data revealed 28 non-protein-changing variants that were present in all Leonberger individuals and a list of 22 potentially pathogenic variants for neurological disorders of which 50% occurred only in Leonbergers and 50% occurred rarely in other breeds. Furthermore, one of the two mtDNA haplogroups detected was present in one dog only. Conclusions The increasing size of the Leonberger population has been accompanied by a considerable loss of genetic diversity after the bottleneck that occurred in the 1940s due to the intensive use of popular sires resulting in high levels of inbreeding. This might explain the high prevalence of certain disorders; however, genomic data provide no evidence for fixed coding variants that explain these predispositions. The list of candidate causative variants for polyneuropathy needs to be further evaluated. Preserving the current genetic diversity is possible by increasing the number of individuals for breeding while restricting the number of litters per sire/dam. In addition, outcrossing would help optimize long-term genetic diversity and contribute to the sustainability and health of the population.

A CNTNAP1 Missense Variant Is Associated with Canine Laryngeal Paralysis and Polyneuropathy

“…The neurological diseases identified in humans associated with variants in CNTNAP1 support our recent speculation, based on the enrichment of this allele in Leonbergers [7], that the herein-described missense variant predicted in silico to be deleterious represents a promising candidate causative mutation for inherited neurological disorders in dogs. The striking genetic association data implicate that this mutation affects the function of the encoded protein, although we have not studied this further.…”

“…To date, variants in ARHGEF10 [8] and GJA9 [9] have already been associated with certain forms of the disorder and designated with breed-specific names Leonberger polyneuropathy type 1 (LPN1; OMIA 001917-9615) and Leonberger polyneuropathy type 2 (LPN2; OMIA 002119-9615), respectively. These two variants, however, do not explain all the phenotypically described cases in Leonbergers [7]. The ARHGEF10 variant has also been reported in the related Saint Bernard breed, but again it did not explain all LPPN cases [8].…”

“…Late-onset forms, e.g., geriatric onset laryngeal paralysis polyneuropathy (GOLPP), are also observed in various breeds including Labrador retrievers [6]. Leonberger dogs are known to be susceptible to LPPN; recently, a short list of potentially pathogenic variants for neurological disorders in this breed derived from whole-genome sequencing has been presented [7]. To date, variants in ARHGEF10 [8] and GJA9 [9] have already been associated with certain forms of the disorder and designated with breed-specific names Leonberger polyneuropathy type 1 (LPN1; OMIA 001917-9615) and Leonberger polyneuropathy type 2 (LPN2; OMIA 002119-9615), respectively.…”

The effect of inbreeding, body size and morphology on health in dog breeds

“…These factors have all contributed to high levels of inbreeding within breeds. The level of inbreeding can be estimated using pedigrees, which were commonly used to determine the coefficient of inbreeding (F p ) within individuals and breeds [3]; however, unless calculations include the complete pedigree [4,5], F p may underrepresent the actual inbreeding by 5-10 fold [6][7][8]. More recently, measurement of genetic inbreeding levels through direct genotype-based methods has become a feasible option.…”

“…More recently, measurement of genetic inbreeding levels through direct genotype-based methods has become a feasible option. Such approaches to determine inbreeding have provided evidence that dog breeds [4,5,8,9] have levels of inbreeding that are considered extremely high (> 0.1) in other species and where the effects of inbreeding depression are expected to occur [10][11][12].…”