Maintaining genetic diversity in dog breeds is an important consideration for the management of inherited diseases. We evaluated genetic diversity in Border Collies using molecular and genealogical methods, and examined changes to genetic diversity when carriers for Trapped Neutrophil Syndrome (TNS) and Neuronal Ceroid Lipofuscinosis (NCL) are removed from the genotyped population. Genotype data for 255 Border Collies and a pedigree database of 83,996 Border Collies were used for analysis. Molecular estimates revealed a mean multi-locus heterozygosity (MLH) of 0.311 (SD 0.027), 20.79% of the genome consisted of runs of homozygosity (ROH ) > 1 Mb, effective population size (Ne) was 84.7, and mean inbreeding (F) was 0.052 (SD 0.083). For 227 genotyped Border Collies that had available pedigree information (GenoPed), molecular and pedigree estimates of diversity were compared. A reference population (dogs born between 2005 and 2015, inclusive; N = 13,523; RefPop) and their ancestors (N = 12,478) were used to evaluate the diversity of the population that are contributing to the current generation. The reference population had a Ne of 123.5, a mean F of 0.095 (SD 0.082), 2276 founders (f), 205.5 effective founders (fe), 28 effective ancestors (fa) and 10.65 (SD 2.82) founder genomes (Ng). Removing TNS and NCL carriers from the genotyped population had a small impact on diversity measures (ROH > 1 Mb, MLH, heterozygosity), however, there was a loss of > 10% minor allele frequency for 89 SNPs around the TNS mutation (maximum loss of 12.7%), and a loss of > 5% for 5 SNPs around the NCL mutation (maximum 5.18%). A common ancestor was identified for 38 TNS-affected dogs and 64 TNS carriers, and a different common ancestor was identified for 33 NCL-affected dogs and 28 carriers, with some overlap of prominent individuals between both pedigrees. Overall, Border Collies have a high level of genetic diversity compared to other breeds.

Objectives The aims of this study were to (1) describe the results of a survey on the clinical features of lymphoma in Australian Border Collies and (2) investigate familial clustering of lymphoma‐affected dogs by means of pedigree analyses. Methods Clinical and pedigree information was collected from surveys completed by owners or breeders of Australian Border Collies. Relationships between dogs were derived from pedigree data and kinship was analysed by network and cluster‐based algorithms. Results A total of 246 respondents completed the survey and 57 lymphoma‐affected Australian Border Collies were identified. The mean age of diagnosis was 9.16 (SD ± 3.43) years and the median was 9.7 years (range 2–15 years). The odds of female dogs affected with lymphoma were twice those of males in the reported data (OR = 2.06; 95% CI = 1.13–3.73; P = 0.02). Multicentric, high‐grade B‐cell lymphoma was the most common form in these dogs. Pedigree analyses identified 21 affected dogs that descended from two sires and 28 cases with a common female ancestor. Average inbreeding between both affected and unaffected dogs was similar (0.16, SD ± 0.06 and 0.15, SD ± 0.06, respectively). Conclusion The survey confirmed the presence of a relatively large number of cases of lymphoma in Australian Border Collies, consistent with our previous report of increased risk in this breed. Some dogs were diagnosed at a very young age, but the age ranged over the normal lifespan. Pedigree analyses identified multiple cases within family groups, suggesting a heritable component of the disease in this breed.

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BACKGROUND: Prostate cancer (PCa) is a significant health burden for African men, with mortality rates more than double global averages. The prostate specific Anoctamin 7 (ANO7) gene linked with poor patient outcomes, has recently been identified as the target for an African-specific protein-truncating PCa risk allele. METHODS: Here we determined the role of ANO7 in a study of 889 men from southern Africa, leveraging exomic genotyping array PCa case-control data (n=780, 17 ANO7 alleles) and deep sequenced whole genome data for germline and tumour ANO7 interrogation (n=109), while providing clinicopathologically matched European derived sequence data comparative analyses (n=57). Associated predicted deleterious variants (PDVs) were further assessed for impact using computational protein structure analysis. RESULTS: Notably rare in European patients, we found the common African PDV p.Ile740Leu variant (rs74804606) to be associated with PCa risk in our case-control analysis (Wilcoxon rank-sum test, false discovery rate/FDR=0.03), while sequencing revealed cooccurrence with the recently reported African-specific deleterious risk variant p.Ser914* (rs60985508). Additional findings include, a novel protein truncating African-specific frameshift variant p.Asp789Leu, African-relevant PDVs associated with altered protein structure at Ca2+-binding sites, early-onset PCa associated with PDVs and germline structural variants in Africans (Linear regression models, -6.42 years, 95% CI=-10.68 to -2.16, P-value=0.003) and ANO7 as an inter-chromosomal PCa-related gene fusion partner in African derived tumours. CONCLUSIONS: Here we provide not only validation for ANO7 as an African-relevant protein-altering PCa risk locus, but additional evidence for a role of inherited and acquired ANO7 variance in the observed phenotypic heterogeneity and African ancestral health disparity.