Cancer Genetics and Comparative Genomics

National Human Genome Research Institute

Investigators

Linked publications & trials

Abstract

Canine Genetics The tremendous phenotypic diversity of modern dog breeds represents the end point of a 20,000-year experiment. Each breed has undergone strong artificial selection for morphologic and behavioral traits to create populations that are unique in size, shape, behavioral responses and disease susceptibility. As a result, there is strong phenotypic homogeneity within breeds, offering a unique lens for genetic studies of associated variants. These observations continue to be explored, in depth, by the Ostrander lab. Canine Whole Genome Sequence We have continued our leadership role with Dog10K, an International Consortium involving 18 labs that aims to generate whole genome sequence (WGS) across the Canidae. Thus far, about 4000 canines have been completed by the community as a whole, with nearly 2000 done by Dog10K. These data are being analyzed in depth by Dog10K investigators to fully characterize the canine genome. A paper summarizing this data is in progress. Sequence data and associated VCF files have all been publicly released. Our ultimate goal is to sequence (20x) multiple dogs from multiple members of each of the 300 registered breeds from the U.S., Africa, Europe, and Asia, as well as mixed breeds, village dogs, and wild canids (Ostrander et al., 2019). As a result of this project, we have recently published a chromosome-level highly contiguous genome assembly of the initial reference Boxer, created with long-read technologies that increase sequence contiguity, closed gaps and improve gene annotation (accession GCF_000002285.5) (Jagannathan et al., 2021). As the Ostrander lab generates more sequence, particularly on rare breeds, that data will be incorporated into a large data set that encompasses all dogs sequenced to date. Phylogenetic Studies Using genetic distance measures and genome-wide haplotype sharing we previously published evidence of phenotypic, behavioral, and geographic patterns of breed development (Parker et al., 2017). We now expand our studies with a focus on small sets of breeds. We know that where humans travel they bring their dogs. We've been part of in-depth studies of Patagonian sheepdogs, whose origins we trace to a now extinct UK herding dog from South American (Barrios et al., 2022), providing insights as to human migration in these regions. Ongoing studies focus on Arctic Dogs, a large cohort of ancient dogs from the Americas, modern dogs from Eastern Europe, and modern dogs from the Galapagos Islands. Morphology We previously documented over 91 million canine genome variants for studies of breed morphology, thus creating the largest catalog of genomic variation for a companion animal species to date (Plassais et al., 2019). Using both selective sweep analyses and genome wide association studies (GWAS) we identify strong impact variants associated with 16 phenotypes, including body weight variation, which highlights genes that, when mutated in humans, contribute to fatty acid metabolism, obesity and metabolic syndrome. Other variants, such as those controlling ear size and shape, produce hearing disorders when mutated in humans. In our most recent study, we identify the much sought after variants in the IGF1 gene that control a large portion of canine body size, tracing their origins to ancient wolves from 50K years ago, thus providing a blueprint for similar human studies (Plassais et al.,2022). Canine Cancer We are mapping risk variants for histiocytic sarcoma (HS) and invasive urothelial cancer (iUC), and have begun detailed studies of dogs sampled from Chernobyl Nuclear Power Plant region. HS in humans is a rare, aggressive cancer of dendritic cells and macrophages that accounts for <1% of hematopoietic malignancies in humans. In dogs it is a histologically and clinically similar disease which kills 25% of Bernese Mountain Dogs and 20% of Flat Coated Retrievers (FCR). We used a multi-omics approach to find germline regulatory variants associated with HS and other hematopoietic malignancies in FCR (Evans et al., 2021), identifying PIK3R6 and TNFAIP6 genes as risk loci. Together these loci account for a striking 35% of disease risk. Variants at the PIK2R6 locus co-localize with susceptibility loci for two other hematopoietic malignancies, hemangiosarcoma and B-cell lymphoma, in the closely related golden retriever breed, thus revealing the risk contribution this single locus makes to multiple hematological cancers. Our Chernobyl study is the first of its kind, characterizing the genetic structure of three free-roaming dog populations living 15-45 km from the disaster site, including dogs living within the power plant itself. We also studied several hundred breed dogs, and free breeding dogs from adjacent countries. Our long term goal is to find genes permitting survival of dog populations in what remains a hostile radioactive environment. Comparing genome-wide profiles from the above populations, we observe that dogs from the power plant and Chernobyl City are genetically distinct. Analysis of shared ancestral segments provides information regarding western breed introgression into Chernobyl populations. Additional population studies provide insights as to how mapping studies may ideally be designed. The identification of genetic variants, particularly from dogs living in the still radioactive power plant, provide insights as to how humans could survive any future nuclear exposures. Aging Epigenetic estimators of age (known as clocks) may permit cross species interventions that slow or reverse aging. Previous epigenetic clocks only applied to a single species at a time. However, we describe epigenetic clocks that apply to both dogs and humans. To do this we compared common methylation changes in aging mice, humans and dogs. A comparison between dogs and humans reveals a nonlinear relationship that translates dog-to-human years with the timing of major physiological milestones (Wang et al., 2020). Conserved changes occur primarily in developmental gene networks. By extension, our work this year with the Horvath lab generated clocks using a mammalian methylation array that includes DNA sequences conserved across all mammalian species (Horvath et al., 2022). Canine epigenetic clocks were constructed that estimate average age and average time to death. We also present two highly accurate human-dog dual species epigenetic clocks (R = 0.97), which may facilitate the ready translation from canine to human use, or vice versa, of antiaging treatments being developed for longevity and preventive medicine. Behavior Recent behavioral experiments are aimed at understanding how cross-breed behaviors have evolved. Some likely developed a single time in one lineage of dogs and distributed to other breeds, while others likely evolved multiple times in multiple geographic regions. A natural outgrowth of this work has been our continued collaborations aimed at finding genes controlling breed-specific behaviors. This year we focused on the canine equivalent of Attention Deficit Hyperactivity Disorder (ADHD). By working with canine and human behavioral experts we identified a rigorous set of criteria that described breeds with ADHD-like traits. Studies are ongoing to map the underlying genes. We also undertook studies of obsessive compulsive disorder (OCD), expanding an existing collection of dogs exhibiting a well-defined set of OCD-like traits that, again, reflect similar human disorders. The Ostrander lab remains at the forefront of canine genetics and its application to studies of human health, behavior, and development. Our multi-pronged approach to canine genetics demonstrates the utility of the canine system for continued studies aimed at developing a genetic understanding of humans and their pets.