Unlocking mysteries of trait and disease heritability in dogs

“How do genes control physical, behavioral, and disease traits?” is a perennial question for geneticist Elaine Ostrander, Chief and Distinguished Senior Investigator of the Cancer Genetics and Comparative Genomics Branch at the National Human Genome Research Institute of the National Institutes of Health and Section Head of Comparative Genetics. Ostrander, who is known for her seminal discoveries in trait heritability in dogs and humans, tracked the history of dog breeds to address questions in morphology, behavior, and disease variation. She also mapped important cancer genes in canines and humans, advancing the knowledge of how complex diseases are inherited. 

Developing a canine genetic model from scratch

Ostrander started her scientific journey by investigating the relationship between the DNA structure and transcription in yeast during her PhD and postdoctoral years. Learning about the discovery of microsatellites steered her into mammalian research. “It became immediately clear that microsatellites were polymorphic in a population that they were useful for studying variation, but they were also stable enough to track inheritance of sections of DNA within a family. Suddenly, it became possible to make a genetic map of any mammal you cared about,” she recalls.

For Ostrander and Jasper Rine, that choice of mammal was a dog. While other scientists studying genetics were mapping genes in flies, worms, yeast, and humans, Ostrander, working in Jasper Rine’s research group at the University of California, Berkeley, began to construct a genetic map of the dog genome, with a long-term goal of using the map to find genes that distinguish breed appearance and behavior as well as genes associated with disease susceptibility. Continuing this work in her own research group at Fred Hutchinson Cancer Center, Ostrander created the first linkage maps in dogs in the early 90s. A decade later, her foundational work snowballed into a modern canine genetics project establishing dogs as a genetic model system. “Ostrander’s work built the stage and collected, in collaboration with several institutions, the first whole genome sequence of a domestic dog, the Boxer, in 2005. The subsequent decade was populated by an explosion of publications and genome developments led by her research group and collaborators,” says Bridgett vonHoldt, Associate Professor of Ecology and Evolutionary Biology at Princeton University and a long-time collaborator of Ostrander.

According to Leonid Kruglyak, Professor of Human Genetics and Biological Chemistry at the University of California, Los Angeles and Howard Hughes Medical Institute Investigator who nominated Ostrander for this honor, “Ostrander is without a doubt the leader in the field of canine genetics and genomics.” Leading an international consortium, Ostrander helped generate a global public repository consisting of genomes from 2,000 individual canids—including 1,611 dogs of known breeds (321 breeds), 309 village dogs, 63 wolves, and 4 coyotes—to address questions surrounding domestication, behavior, morphology, and disease susceptibility.

“Dogs were an obvious choice because the dog breed structure makes it easier to find genes responsible for traits. To be a member of a breed, parents and grandparents must be members of the same breed, making each breed a closed population,” explains Ostrander. Tapping into breed structure, where breed appearance and behavior remain intact generation after generation, Ostrander’s group identified genes responsible for the remarkable differences in size and shape between breeds. Her work showed that a single allele of IGF-1 is a major determinant of size in small breeds and that coat variation is determined by variants in just three genes. By identifying the time when variants first showed up in ancient DNA, her work takes a holistic view of morphology and behavior across different canid species.

Studying man’s best friend to understand humans

In addition to genes in dogs, Ostrander extensively studied human cancer genes in her laboratory at the Fred Hutchinson Cancer Research Center, focusing on human breast and prostate cancer. Her group was one of the first to describe a role for BRCA1 and BRCA2 mutations in women from the general population at risk for breast and ovarian cancer. Her expertise in dog genetics dovetailed well with this work, as she ended up discovering cancer-causing DNA variants in both humans and dogs. “Most things that dogs get, humans also get—they get the same cancers and diabetes; they also get many of the same neuromuscular, kidney and heart diseases. Some breeds are at an extraordinary risk for certain types of cancer. For instance, a Scottish Terrier is at 20-fold higher risk of getting bladder cancer than any mixed breed dog. Therefore, the underlying genetics must be really strong and profound,” explains Ostrander.

In an effort to explore the history between the dog and cancer genomes, her group used a multi-omics approach that was largely unexplored in the canine model to create the largest catalog of canine whole-genome, transcriptome, and chromatin immunoprecipitation sequencing. Such resources allow scientists today to identify common cancer-causing alleles in dog breeds and link them to human malignancies. For example, Ostrander identified two regions in the canine genome that explain a risk for developing a lethal histiocytic sarcoma, which also occurs in humans. By understanding genes in these risk regions in cancer-related pathways, her work empowered new diagnostics and therapeutic strategies for human cancers.

Ostrander’s group also studies aging and survival-related genes. “Big dogs do not live as long as little dogs. We would like to know why that happens,” she says. To solve this puzzle, Ostrander collaborated with international researchers looking for dog samples in the most unlikely places. “We are studying DNA samples from over 400 dogs, sampled by collaborators, from the exclusion zone around the Chernobyl nuclear power plant. We are looking for changes in DNA that dogs have accumulated over 15 generations which allows them to survive in this radioactive environment,” says Ostrander.  

A champion in all walks of life

Ostrander has contributed greatly to the scientific community through making her cutting-edge research in dog genetics accessible to the general public. A big proponent of community outreach, she takes pride in regularly engaging with dog groups, breed clubs, professional dog trainers’ associations, and families to help answer questions about behavior and diseases.

In addition to being a pioneer in science, Ostrander is also at the top of her game in powerlifting. She is a nationally ranked powerlifter, competing as a Masters lifter for five years. With a growing accumulation of first- and second-place medals, Ostrander looks forward to a time when she trains Masters lifters herself.  

Join us in congratulating Elaine Ostrander, who received the Edward Novitski Prize at The Allied Genetics Conference 2024 in Metro Washington, DC.

2024 GSA Awards Seminar Series

On June 13, at 1:00 p.m. EDT, Elaine Ostrander will join us to discuss how domestic dogs are among the most variable mammalian land-based species on earth and the genetic underpinnings of that variation, including breed-associated morphology, behavior, and disease susceptibility. Save the date and register here!

Sejal Davla, PhD, is a neuroscientist, science writer, and data scientist with expertise in research in a variety of life sciences. She has more than a decade of experience studying the brain by using cutting-edge methodologies in microscopy, molecular biology, genetics, and biochemistry, and is a motivated storyteller and science communicator.