Canine Genetics The tremendous phenotypic diversity of modern dog breeds represents the end point of a >15,000-year experiment. Each breed has undergone strong artificial selection in which dog fanciers selected for many traits including body size, fur color, skull shape, and even behavior, to create novel breeds. As a result, there is strong phenotypic homogeneity within breeds including breed-associated genetic diseases such as cancer. These traits are explored in depth in the Ostrander lab. Canine Whole Genome Sequence Drs. Bob Wayne, Guo-Dong Wang and Elaine Ostrander organized a June 2016 meeting in Beijing with 18 other labs to establish a collaboration aimed at generating whole genome sequence (WGS) for 10,000 dogs in the next five years. Our goal is to sequence (20-30x) 10,000 unrelated dogs from each of 300 registered breeds from the U.S., Africa, Europe, and Asia. Dogs from non-breed working populations, as well as free breeding, semi-feral populations from around the world are also being collected. This effort is a partnership with the Chinese Academy of Sciences (Ostrander et al., 2019; Wang et al., 2019). Our own collection efforts this year have included Mexico, Chile, Italy, and many others. The Ostrander lab has catalogued WGS sequence from over 1000 canines thus far (Plassais et al., 2019). We have used our data to identify genes associated with a myriad of morphologic traits and aging, providing insights into human growth and development (Plassais et al., 2019) (Whitaker et al., 2019). Canine Population Structure and Mendelian Disease Gene Mapping Ostrander lab Staff Scientist Heidi Parker has undertaken and continued a large and continuous study of canine breed structure (Parker et al., 2017) in order to better inform our disease mapping studies. We assembled the most diverse dataset of dog breeds in existence reflecting extensive phenotypic variation and heritage. We continue to uncover geographic patterns of development and independent origins of common traits. Our analyses characterized the complexities of breed development, resolving longstanding questions regarding individual breed origination, the effect of migration on geographically distinct breeds and, by inference, transfer of trait and disease alleles among dog breeds. We have shown we can track the history of variant alleles, offering predictions as to additional breeds where these diseases may appear next. This work is foundational to all studies in disease mapping in dog breeds, as it informs study design by determining how breeds should be partitioned or grouped for analyses. We used this type of information to to contribute to various disease gene mapping studies. For instance, our collaborative studies with Jeff Schoenebeck this year, led by his postdoc (Marchant et al., 2019), demonstrated that a missense variant in the ADAMTS3 gene is associated with Upper Airway Syndrome in the Norwich Terrier, but not Norfolk Terrier. Dog Origins A natural outgrowth of this work has been our continued collaborations to better understand the process of domestication. Such studies highlight genes and regions of genes that are particularly malleable, providing insights into the genes that are likely most important in understanding human variation (Pilot et al., 2018; Schweizer et al., 2018; Talenti et al., 2018). One important lesson from these studies is that dog breed formation mirrors human migration patterns. Thus, one excellent way to better understand the migration of peoples and disease alleles in early human history is to follow the patterns that define dog breed development. We show this is true, for instance, in a new study of Italian breeds, where there is clear evidence of co-development of early dog and human populations (Talenti et al., 2018). Dog Behavior and Human Syndromes In a study led by collaborator Bridget vonHoldt (vonHoldt et al., 2017) we previously demonstrated the molecular underpinnings of behavioral characteristics associated with domestication. We analyzed a 5Mb genomic region in the dog genome under positive selection in domestication. Deletion of this region is linked to Williams-Beuren syndrome (WBS) in humans, a multi-system congenital disorder characterized by hyper-social behavior. This study associated quantitative data on behavioral phenotypes symptomatic of WBS in humans with structural changes in the WBS locus in dogs, showing that hyper-sociability, a central feature of WBS, is also a core element of domestication that distinguishes dogs from wolves (vonHoldt et al., 2017). This year we continued that work, showing that homozygosity of various mobile element insertions associated with the WBSCR17 gene could predict success in assistance dog training programs (Tandon et al., 2019). We also did a whole genome comparison of two types of dog breeds: those that are highly athletic and include the sport-hunting breeds versus the terriers which are known for their hyperactivity (Kim et al., 2018). These are groups at the ends of a continuum in both form and function. We found that genes underlying cardiovascular, muscular, and neuronal functions are under strong selection in sport-hunting breeds and observed a significant association of one gene with breed-specific accomplishments in competitive obstacle course events and problem solving in athletics. In terms of terriers, in results we are now expanding, we found associations with genes that are associated with human hyperactivity and panic response. These results demonstrate how strong behavioral selection alters physiology to create breeds with distinct capabilities, and further established the dog as a system for identifying behavioral genes of interest to human health and biology. This paper was featured on the cover of PNAS. Studies continue with a focus on obsessive behaviors. We remain firmly committed to mapping of canine cancer genes. Ongoing studies include those with a focus on histiocytic sarcoma, invasive bladder cancer and gastric cancer. We have just submitted a paper examining changes in canine bladder tumors that either have or lack the distinguishing BRAFV595E mutation observed in humans as BRAFV600E. We have manuscripts in preparation on other topics and have expanded our network of collaborators, particularly for histiocytic sarcoma. We have also expanded our network of sample collection, participating in various dog shows and events to greatly expand our dataset, particularly for our gastric cancer studies. We have summarized our viewpoints and the strengths of the dog model for studies of human cancer in a review by Ostrander et al., 2019. Lastly, we take our responsibility to aid those working in other fields with genomic sequencing issues. Towards that end we contributed to studies on the Tasmanian Devil (Margres et al., 2018), an offshoot of our own interests in canine venereal transmissible tumors (CTVT) and the feline genome project (Genova et al., 2018).
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