Monthly Archives

December 2017

Happy 2018 from the Karlsson lab cryptogenomicists

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Happy 2018 from the Karlsson Lab!

Our holiday card is out, featuring the remarkable illustrations of Kathleen Morrill. In this year’s card, we set out as intrepid explorers to swab and sequence the fantastic beasts of lore (and poke gentle fun at our far-ranging projects and diverse mix of species). This year’s card is accompanied by our field guide “Fantastic Beasts and How to Swab Them”.

Studying Cancer In Dogs

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Kate Megquier, DVM

When people hear that I am a veterinarian, they are often surprised to learn that I work in a genetics lab, rather than in the clinic with a white coat and a stethoscope. I began studying the genomic basis of cancers in dogs when I was in veterinary school because I wanted to help further translational research – that is, I wanted to help make discoveries that could be translated into new clinical treatments and diagnostics for pets. Along the way, I have come to understand that this research is also important from a comparative medicine perspective: understanding cancer in dogs can also teach us about cancer in people. It’s a win-win scenario!

In this post, I’d like to give you a brief overview of how our lab studies cancer in dogs, and hint at a few exciting new studies that we will be starting in the near future!

Inherited risk factors

One way that we study cancers in dogs is by looking for genetic risk factors that predispose them to developing cancer. Genetic risk factors for cancer tend to run in highly related dog breeds, meaning that these risk factors are passed down (inherited) from generation to generation. This is somewhat similar to how cancers can run in human families – for example, you may have heard about how individuals in families with an inherited mutation in a BRCA gene often have an elevated risk of breast, ovarian, or prostate cancer.

When we look for inherited risk factors, we search the entire genome for regions that contain mutations with different frequencies in dogs with and without cancer. This is called a genome-wide association study. These regions harbor genetic variants that affect the risk of developing cancer. We work with collaborators to understand the inherited risk factors behind multiple cancer types. Interestingly, risk factors for a given cancer sometimes differ across breeds who all get the same cancer type. For example, we’ve shown that three breeds predisposed to osteosarcoma have different genetic risk factors, but these risk factors impact genes that work together. Studying whether carrying these risk factors can predict the development of disease or how the disease will act clinically will aid in developing new diagnostic tests. In addition, we are continuing to investigate what these genetic changes are doing at the cellular level that is leading to cancer. Knowing this will help to better understand the underlying disease and potentially to develop new therapies in the future.


It is now well-known that exposure to certain agents called carcinogens (think tobacco smoke, asbestos, or radiation, to name only a few) can increase the risk of developing cancer. Because our dogs live in the same environment as we do, studying how these agents affect the risk of cancer in our dogs not only helps us to keep them safe, but can also help to identify agents that may be harmful to humans. Tobacco smoke is one example of a shared environmental exposure leading to cancer. One of the best-known risk factors in human respiratory tract cancers, it has been shown to increase the risk of nasal and sinus cancer as well as lung cancer in dogs. Because many dogs live their entire lives with the same owner in the same house, their exposure to certain types of carcinogens can be tracked, either with owner questionnaires or with publicly available information on pollution levels and other risk factors in the area that they live. In addition, recent research has shown that silicone rubber (you know, those LIVESTRONG bracelets?) can be used as a passive sampler to track exposure to various compounds. We are excited to be planning a pilot study looking at whether silicone collar tags can be used to track environmental exposure levels of various compounds in dogs, so stay tuned for that!

Somatic mutations

In addition to inherited mutations, we are also interested in mutations that occur during the lifetime of a cell, called somatic mutations. These can arise from either genetic (for example, faulty DNA repair genes) or environmental (carcinogen exposure) causes. This type of mutation is what is being referred to when doctors perform sequencing of a tumor.

Somatic mutations are important in understanding the behavior of a tumor clinically. Two important types of gene that are frequently mutated in cancers are oncogenes and tumor suppressors, and these are often described using the analogy of the cell as a car. Oncogenes are like the gas pedal – the tumor wants to go fast, meaning that it wants to proliferate and divide. A mutation in an oncogene causes the gas pedal to be stuck down, and cells proliferate out of control. Tumor suppressors, on the other hand, are like the brakes in this analogy – these are genes that can stop uncontrolled cell division and induce apoptosis (cell death). Many cancers disable the brakes through mutation or deletion of these tumor suppressor genes.

Treating cancer

Traditionally, cancer has been treated in three ways: surgical removal of the tumor, irradiation of the tumor site, and chemotherapy, which targets all fast-dividing cells. But cancer cells aren’t the only ones in the body that divide fast. This is also true for hair, immune cells and the cells lining the gut. The fact that the chemotherapy also harms these cell types leads to side effects such as increased risk of infection, nausea, and sometimes hair loss. Recently, however, new drugs called “targeted therapies” have begun to be designed. These drugs can target cancer cells with a particular mutation, and spare the normal tissue. Going back to our car analogy, it’s as if knowing how the cancer disabled the brakes allows us to selectively re-engage them, rather than having to target all fast-moving cars.

This is one of the goals of precision medicine – to be able to sequence a patient’s tumor and select a targeted therapy specifically designed for the mutations in that tumor, without causing damage to the normal tissue. There are a number of targeted therapies already in use in human medicine, for example, the drug vemurafenib targets a mutation in a gene called BRAF in patients with melanoma. A few have been approved for use in veterinary medicine, for example, toceranib is used to treat dogs with mast cell tumors. The more we know about the underlying mutations in different types of cancer, the better we can design targeted therapies for these mutations and help to treat more patients. Dogs will be important in this effort both for veterinary medicine and for human medicine, as many cancers that are rare in people are actually common and more easily studied in dogs.

Liquid biopsy

In order to sequence somatic mutations, we need to be able to sample the tumor’s DNA. Usually, this means that a tumor biopsy must be performed, and DNA prepared directly from a portion of tumor tissue. Recent advances in sequencing techniques are allowing researchers to sequence the tumor from fragments of DNA floating in the bloodstream, rather than having to physically sample the tumor itself so that the patient doesn’t need to undergo surgery. This technique, called “liquid biopsy,” opens up many possibilities, including improved diagnostic tests, repeated sampling of tumor DNA over the course of therapy to monitor response and development of chemotherapy resistance, and monitoring patients in remission for signs of relapse. We are very excited to be piloting the use of this technique to sequence tumor DNA in dogs, with the help of the Adalsteinsson lab, who are pioneering this technique at the Broad Institute. Stay tuned for more information on this pilot study as it unfolds!

This has been a bit of a whirlwind tour of some the things we look at now and are planning to look at in our canine cancer studies. I hope to write in more detail about some of these topics in the future as we embark on our new studies and publish new findings.



Introducing the Working Dog Project

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Jessica Hekman, DVM

I am a new face at Karlsson Lab, the lab behind Darwin’s Dogs. I finished my Ph.D. this summer and started here as a postdoc in September. When I arrived, our fearless leader Elinor announced that she had just started up an exciting new project and that she wanted me to be its team leader. On my first day I was suddenly swimming (though not quite drowning) in a wash of information about the new Working Dog Project.

The problem this project is tackling is a complex one: why do only about 50% of the dogs chosen to train as working (assistance, guide, sniffing, police, military, etc) dogs succeed in their programs? We depend on these dogs in so many ways – you may not even be aware of the ways dogs keep you safe – but they are very expensive to train. It’s a great waste of resources when a dog washes out of one of these programs. Not to mention, the dog would be happier going straight to the life he’ll do best in rather than struggling in a training program for which he turns out not to be suited! (You may have read the story of Lulu, a dog who recently because internet famous after her exit from a bomb-sniffing program.)

Environment (how these dogs are raised and trained) certainly has a lot to do with which dogs succeed and which fail, but so does genetics, and genetics is what we do at Karlsson Lab. So we’re diving in to the problem of figuring out the genetics affecting success and failure in working dogs.

The predisposition of a dog to succeed in any given working dog program is the very definition of a “complex trait”: a trait affected by many different genes, interacting with each other and with the environment in unpredictable ways. These are the types of problems that attract our lab; we also study cancer and OCD, which are also both great examples of complex traits. Understanding the genetics behind these kinds of traits is super difficult, because untangling the effects of genetics and environment is not a straightforward problem.

The approach Karlsson Lab takes to most of these complex trait problems is sample size: get as many samples as possible and hope that they swamp the environmental effects. This is, of course, the approach we’re taking with the Darwin’s Dogs project and its task of finding genes associated with different behavioral traits in dogs. The Working Dogs Project is very similar to Darwin’s Dogs, in fact, in its focus on behavioral traits. Darwin’s Dogs uses a massive number of survey questions from owners to characterize each dog’s behavior (thank you all so much for all of this data!). The technical term for this is “phenotyping” – describing the characteristics that we’re interested in (versus “genotyping,” describing the genetics that we will use in our analysis).

Unlike Darwin’s Dogs, however, we can’t ask the trainers of working dogs to fill out a massive survey about their dogs. If we did, we’d get many fewer responses, and remember that a large sample size is one of our goals. (I like to say we want “zillions” of working dogs, while Elinor will simply say we want “all of them.”) We have to work with the data that the different training organizations already collect.

This is the central challenge of the Working Dog Project. There are lots of different kinds of working dogs out there! Are the behaviors that make a dog a bad fit for a bomb sniffing job the same behaviors that make them a bad fit for a guide dog job? (Some behaviors yes, some no.) There are also a lot of different working dog training programs, and they all collect different data about their dogs. Can I compare these different pieces of data, or are they apples and oranges? My first job is to start learning about what kinds of data different groups collect, and try to make sense of it for a rigorous analysis.

When it comes to collecting DNA samples from working dogs, we have a number of initial collaborators who have been great so far. The time will come when we will be finding other groups to help with this, once we have our feet under us a bit more. It’s a funny world, in which collecting and sequencing DNA isn’t the hard part of a project! Welcome to the Genomic Era.

I would be remiss if I didn’t thank our funders. The Theriogenology Foundation and AKC Reunite have been very generous in supporting our first two years. Thank you so much to them.

To stay in touch with the Working Dog Project, I encourage you to join our mailing list, which we will use to send out updates and to ask for working dog DNA samples when we’re ready for them. We’ll also let you know here on the Darwin’s Dogs blog what’s going on, of course.

Wish us luck!