Cancer Genetics and Comparative Genomics

National Human Genome Research Institute

Investigators

Linked publications & trials

Abstract

Canine Genetics The domestic dog is increasingly accepted as a uniquely informative model system. The Ostrander lab is proud to work with dog owners from all over the world who wish to be collaborators on dog genetic studies. In sampling pet dog DNA, we seek to understand how dog breeds have been shaped by humans, why some breeds are prone to specific diseases, and what accounts for the striking differences in appearance and behavior between breeds. The latter category includes genes that, when otherwise mutated, are often responsible for human disease or syndromes. Our work aligns with the NHGRI strategic plan which includes a focus on “…using genomics to understand biology, to enhance knowledge about disease, and to improve human health.” Canine whole genome sequence and studies of constraint The Dog10K consortium, co-headed by Dr. Ostrander, completed and published a first installment of our data, providing sequence and detailed analysis of 2000 canids (Meadows et al., 2023). We have used that data in a study of “genome constraint” across the dog genome in an effort to identify previously undetected genes that are responsible for morphological phenotypes, some of which, when mutated, are deleterious. Typically, breed standard phenotypes such as stature, pelage, and craniofacial structure are analyzed through genetic association studies. However, such analyses are limited to assayed phenotypes only, leaving difficult-to-measure phenotypic subtleties easily overlooked. We investigated coding variation using whole DNA sequence from over 2000 dogs, leading to discoveries of variants related to craniofacial morphology and stature. Among the newly found variants is a splice-acceptor change in the PDGFRA gene which is associated with a bifid or split nose, a characteristic trait of Çatalburun dogs, implicating the gene's role in midline closure. In humans the gene is associated with cleft lip and palate but is incompletely penetrant. Dogs thus offer an opportunity to study genetic background factors affecting penetrance of the gene. In addition, we found dogs with bifid noses who do not have mutations in PDGFRA, offering an opportunity to identify additional cleft lip genes of likely relevance to humans. Canine cancers Naturally occurring canine invasive urinary carcinoma (iUC) closely resembles human muscle invasive bladder cancer in terms of histopathology, metastases, response to therapy, and low survival rate. The heterogeneous nature of the disease has led to the association of large numbers of risk loci in humans; however, most are of small effect. In dogs, distinct breeds show markedly different rates of iUC, thus presenting an opportunity to identify additional risk factors and overcome the locus heterogeneity encountered in human mapping studies. Because diseases in dogs are naturally occurring we rely on interaction and participation of dog owners and breeders as well as their veterinarians to gather samples and phenotypes of our study dogs. In collaboration with investigators at Purdue College of Veterinary Medicine we identified a homozygous protein altering point mutation within the NIPAL1 gene which increases risk by eight-fold (OR = 8.42, CI = 3.12-22.71), accounting for nearly 30% of iUC risk in the Shetland Sheepdog. Inclusion of six additional loci accounts for most of the disease risk in the breed and explains nearly 75% of the iUC phenotypes in this study. When combined with sequence data from tumors, we show that variation in the MAPK signaling pathway is an overarching cause of iUC susceptibility in dogs. This offers a chance to develop improved therapeutics. We have also been fortunate to collaborate with previous Ostrander lab postdoc Dr. Jacquelyn Evans, now on the faculty at Cornell University College of Veterinary Medicine, to undertake similar experiments in Belgian breeds at risk for gastric cancer. This work identifies 15 risk loci. Of particular interest are HDAC2 putative regulatory variants. Also noted are PDZRN3 and KLHL29, which have not yet been associated with human gastric cancer. These studies highlight the value of citizen science in helping advance our understanding of human cancers. In distinct but parallel studies on histiocytic sarcoma, collaborations at Michigan State University reveal insights into the molecular pathogenesis of the disease, including potential approaches to therapy. Specifically, the results reveal significant up-regulation of molecular pathways involving the FOXM1, AURKB,, PLK1, and E2F genes in tumors and cell lines. This, again, speaks to the power of working with pet owners to open new avenues for studies of cancer genetics. Aging We concluded our aging studies this year with an examination of chronological versus biological aging in dogs. Chronological age reveals the number of years an individual has lived since birth while biological age is reflective of physiological decline. Differing rates of physiological decline are related to longevity and result from genetics, environment, behavior, and disease. The creation of methylation biological age predictors is a long-standing challenge in aging research due to the lack of individual pre-mortem longevity data. The consistent differences in longevity between domestic dog breeds enable the construction of biological age estimators which can, in turn, be contrasted with methylation measurements to elucidate mechanisms of biological aging. We drew on three flagship methylation studies using distinct measurement platforms and tissues to assess the feasibility of creating biological age methylation clocks in the dog. We expanded epigenetic clock building strategies to accommodate phylogenetic relationships between individuals, thus controlling for the use of breed standard metrics. We observe that biological age methylation clocks are affected by population stratification and require heavy parameterization to achieve effective predictors. Dogs as sentinels for radiation exposure The 1986 the Chernobyl nuclear disaster initiated a series of catastrophic events resulting in long-term and widespread environmental radioactive contamination. In a paper published in Science Advances (Spatola et al., 2023), we characterized the genetic structure of the dogs living within the contaminated region representing three free-roaming populations: those within the power plant itself, those 15 to 45 kilometers from the disaster site, and dogs from other parts of Eastern Europe. Genome-wide profiles from Chernobyl purebred and free-breeding dogs reveal that dogs from the power plant and Chernobyl City are genetically distinct, with the former displaying increased intrapopulation genetic similarity and differentiation. Analysis of shared ancestral genome segments highlights differences in the extent and timing of western breed introgression while kinship analysis revealed 15 families, with the largest spanning all collection sites within the radioactive exclusion zone, reflecting migration of dogs between the power plant and Chernobyl City. This year we are building on that data to look for both historical mutations that might have occurred at the time of the explosion and been propagated through the intervening 15 generations, or mutations that continue to occur today, particularly in the dogs living in the power plant, due to ongoing ionizing radiation exposure. This work is in progress. Breed specific and anomalous behaviors We recently released a study with previous Ostrander lab postdoc Dr. Jaemin Kim (Jeong et al., 2025) in which we looked for genes that contribute to herding behaviors in Border Collies. Comparison of the whole-genome sequences of herding and non-herding breeds revealed signatures of positive selection associated with pathways underlying social interaction and cognitive functions. Of the strong selective sweep signals found, haplotypes within ephrin type-B receptor 1 (EPHB1), which is linked to locomotor hyperactivity and spatial memory, were particularly compelling. They showed evidence of segregation within breed lineages of conformation versus working lines of Border Collies. Interestingly, other genes in the ephrin pathway were identified in studies of herding dogs we published in Cell (Dutrow et al., 2022) In general, both studies provide a foundation for current studies of repetitive behaviors. In the last two years we have undertaken a large behavioral study with the goal of identifying genetic factors related to anomalous repetitive behaviors, which maybe abnormal extensions of normal herding behaviors, in Border Collies and Shetland Sheepdogs. This work is in progress. Other isolated populations Dogs can be found wherever humans go, ending up in places that have previously been devoid of large predators. This is the case we describe in our study of dogs from the Galápagos Islands, which was published this year in Current Biology (Spatola et al., 2025). We know that dogs arrived on the Galapagos with explorers and occupied the Islands at least since the 1830s; however, it was not until the 1900s that dog populations grew substantially, endangering wildlife and spreading disease. In 1981, efforts to control the canine population size began. Yet, there exist large free-roaming dog populations on at least two of the islands. We thus performed a complete genomic analysis of the current Galápagos dog population, as well as historical Galápagos dogs, testing for population structure, admixture, and shared ancestry. Our results indicate that modern Galápagos dogs are recently admixed with purebred dogs but show no evidence of a population bottleneck, suggesting that they continue to migrate to the islands despite regulations prohibiting such. Additionally, identity-by-descent analyses reveal evidence of shared shepherd-dog ancestry in the historical dogs. The results of this study provide mechanisms and statistical approaches for further studies of isolated populations that have undergone population bottlenecks, regardless of species, and highlight the role of Shepherd dogs in the development of many dog populations. American ancient dog populations Studies of ancient dogs help us understand the migration of early peoples since “where people go, so go their dogs.” In a major study this year, published in Science (Feuerborn et al., 2025), we examined the origins and diversity of Greenland’s sled dogs using both modern and ancient DNA samples. We found distinct regional populations and evidence for two migrations of dogs into Greenland with the Inuit from what is now Canada. Furthermore, we found that there is minimal European ancestry in present day Greenland sled dogs and limited recent inbreeding, despite low heterozygosity. Ongoing studies focus on not only Greenland sled dogs but also other populations (Coutinho-Lima et al., 2024; Manin et al., 2025), exploring how human and animal co-migration shaped the survival of historical humans.