SickKids researchers sequence genome of Canadian beaver

They were diligent, methodical, meticulous. They overcame obstacles large and small and applied available resources to try to achieve an ambitious goal. When they needed to move beyond existing resources, they pushed the limits and modified them. Channelling some of the most distinctive traits of the quintessentially Canadian symbol they were studying, a team of Canadian scientists has made an indelible mark on the history of this country – and beyond – just in time to kick off the country’s 150th anniversary.

A team of researchers from The Centre for Applied Genomics (TCAG) at The Hospital for Sick Children (SickKids) has successfully sequenced the genome of Castor canadensis – the Canadian beaver. In fact, the beaver in question is none other than Ward, a 10-year-old resident of the Toronto Zoo.  The research, published in the January 16 online edition of G3: Genes|Genomes|Genetics, is a partnership with the Ontario Institute for Cancer Research (OICR), the Royal Ontario Museum (ROM), the University of Toronto and the Toronto Zoo.


Video and feature photo courtesy of SickKids 

Interview with the Researchers

Lead authors, Drs. Stephen Scherer and Si Lok, shed s ome light on why their world-leading research team undertook this unusual project, and how understanding the fundamentals of what makes Ward, Ward, could help scientists advance research into human conditions like autism.

Why did you choose to study the beaver?

S.S.: We could have done this genome research project using DNA from any human or from someone with one of the conditions we study like autism – but by going this route there was even more potential for broader impact! We started exploring our options and realized that our national symbol, the beaver, had not been sequenced yet. This is the most important animal in Canadian history, so to know about its genome allows us to better understand how it all came about: its history, how it relates to its environment. The genome is a starting point.

TCAG sequences about 10,000 genomes a year. One of the areas of focus is how genes play a role in the development of autism in humans. What’s the connection between sequencing a beaver’s genome and helping families understand why autism may affect one child in the family, but not another?

S.S.: There are some families who we know have autism or some other developmental disorder because of the genetics, but we haven’t found the genetic alteration yet. The novel genome-assembly approach that we’ve developed for the beaver project will provide another vantage point.

S.L.: The Human Genome Project led many people to think genetic sequencing is a done deal, but it’s really not. What’s typically done is genome ‘re-sequencing’. The genomes of only a small number of people are actually fully sequenced – less than a dozen in the world. For all the others, to make it cost-effective, we quickly sequence billions of fragments but align them by comparison to a reference genome. It’s really a comparative approach analogous to tracing a picture. But ultimately, we can’t just look at the tracings. We need to see all the underlying unique pieces too, and there are lots of them.

The sequencing of Ward’s genome was done the way we’d eventually like to do everyone’s – it’s called de novo sequencing. It’s a completely original process, which allowed us to build Ward’s unique genome from the ground up, so we would not use any preconception of another genome.

S.S.: Our new genome-assembly technique allows us to find new types of genetic variations we haven’t seen before using the current technologies, so we think our yield in explaining autism will go up. We are already applying the technique in our human sequencing projects, as well as for other animals. It’s very exciting.

Why is the method so important?

S.S.: At TCAG, we’re generating a genome product that is really, really good, but it’s not perfect. To find all the genetic variants we need to fully understand things like cancer or autism, we needed a much better approach.

We were able to take samples from the beaver, find the DNA and put it into the latest genome sequencing machines, which generated the three billion chemical letters of information that comprise the beaver genome. What’s unique about the project is we had to develop some new methods to actually stitch together all of those three billion chemical letters of information into a complete ‘jigsaw puzzle’. At the end of the day, we were able to generate the complete genome sequence of what we believe is the most important animal in Canada.

With new technologies and new sets of analytical experiments we’ve developed here, we can now apply what we learned in the beaver sequencing project to those human sequencing projects we are doing here at the same time.

What does this study show us about the beaver?

S.S.: What we found is that the beaver genome is roughly the same size as the human genome, maybe a little smaller. That’s not really surprising to us; if you look at any mammalian genome sequence – mouse, rat, chimpanzee – and compare it to humans, they’re roughly the same size.

We were able to clearly describe the genes that are important to rodents, and most importantly to the beaver. We identified the genes involved in dentition and enamel deposition, a defining characteristic of rodents, and particularly of beavers. Rodents are classified by their teeth structure, and beavers seem to take this to the extreme because their teeth continuously grow so they can chop down trees. They incorporate a special kind of enamel to strengthen the teeth, and iron, to sharpen them. The mechanism resembles a self-sharpening ice skate, which gets sharper as you skate.

This is really about the power of genetics. We’ve never sequenced any genomes with the quality that we’ve had with the beaver. It’s exciting because it allows us to see some things for the very first time.

Why did you do it now?

S.S.: Dr. Lok and I went to graduate school and did our PhDs at SickKids under Dr. Lap-Chee Tsui, the world-famous Canadian geneticist who discovered the cystic fibrosis gene in 1989. As Canadians, we wanted to give back in some way, above and beyond our typical research. Last year we recognized that the coming sesquicentennial of Canada, new technologies, and our ideas provided the ‘perfect storm’ for us to make a lasting contribution to the scientific world, to our future research, and to the sense of Canadian characteristics of hard work, loyalty, and pride in our heritage. Buy-in from our TCAG team and other Canadian scientists was instantaneous.

Scherer is Director of TCAG and Senior Scientist at SickKids. He is also Director of the McLaughlin Centre and Professor in the Department of Molecular Genetics at the University of Toronto.

Lok is Senior Project Manager and Lead in Technology Development at TCAG.

This study was supported by Genome Canada, Ontario Genomics, Canada Foundation for Innovation, the Government of Ontario, the Lau Family Endowment and SickKids Foundation.

 

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Read more Healthier, Wealthier, Smarter blog posts on our Healthier, Wealthier, Smarter site and share your insights on Twitter with the hashtag, #onHWS. To learn more about how health research makes Ontario healthier, wealthier, and smarter, check out our website and our other blog posts and videos.

Health & Community Leaders Talk: Paul Kurdyak

By Dr. Paul Kurdyak, Director, Health Outcomes for the Medical Psychiatry Alliance (MPA); Medical Director, Performance Improvement at the Centre for Addiction and Mental Health (CAMH).

What does health research mean to you?

Health research is a very broad topic, but to me, it means research aimed at finding ways to improve the health and well-being of individuals suffering from medical conditions, including mental illnesses and addictions. The burden of mental illness is high. Patients who are dealing with a physical health issue on top of their mental illness experience greater impact on their ability to function and on their quality of life. In Ontario, we spend billions of dollars on individuals living with combined mental and physical illness, but are not seeing great quality of care or outcomes. This is the worst case scenario – spending a lot of money to achieve poor health outcomes.

We know what needs to be done based on existing evidence, but we fall short on delivering evidence-based care. For example, we know that getting adequate and timely care for young Ontarians being diagnosed for the first time with schizophrenia is critical to achieve good outcomes. Our research shows that many of these young Ontarians are not receiving adequate physician follow-up. Patients with schizophrenia have double the amount of health care costs compared to those who don’t have this condition – and the costs are related to their physical health care in addition to their mental health. Despite these high health care costs, these patients have a shorter life expectancy – by up to 20 years — compared to individuals who don’t have a severe mental illness. This is unacceptable.

The Medical Psychiatry Alliance (MPA) was established in January 2014 with a six-year mandate, to kick start a transformation in Ontario that will help increase access to quality, integrated mental and physical health care. The MPA is the first of its kind in Canada with this urgent mandate. It is a unique collaboration between The Centre for Addiction and Mental Health, The Hospital for Sick Children, Trillium Health Partners and the University of Toronto. Currently, the MPA is systematically generating evidence for the best models of integrated care in which to treat Ontarians, which we hope will reduce the burden of cost for patients and for the health system overall.

 

How does health research contribute to a healthier, wealthier, smarter Ontario?

The best health care policy is based on sound evidence. The MPA is leading the analysis of the impact of integrated care on patient outcomes, with an emphasis on rigorous research methods to determine system-level impact using data from the Institute for Clinical Evaluative Sciences. I am the Director of Health Outcomes for this arm of research under the MPA’s mandate.

Recently, our research discovered that treating psychotic illnesses cost the province of Ontario just under $2.1 billion in 2012, which was about four per cent of the total provincial health budget. We already knew costs for treating psychotic illnesses were high, but what our research now shows is how early patients start incurring long-term care and medical care costs. Patients with psychotic illnesses as young as 46 are in long-term care facilities and are generating high medical care costs, which is about 20 years earlier than the general population. The needs of patients with chronic psychotic illnesses change over time, and those needs become more complex as people age.

The MPA’s new models of clinical care, currently rolling out as pilot initiatives at CAMH, SickKids and Trillium Health Partners, hope to better serve the needs of these patients. These new models of care are backed by innovative new education programs spearheaded by U of T, to train learners and healthcare providers and equip them with the training and tools they need to better care for patients with complex needs.

If we are successful in increasing access to integrated health services for those with severe mental illness, we will be helping Ontarians live longer and healthier lives, with improved quality of life. Moreover, we have demonstrated that we are not getting very good outcomes despite very high costs. We hope to show that providing integrated, high quality health care for individuals with mental illnesses and addictions will improve health outcomes, quality of life, and reduce costs.

 

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Read more Health and Community Leaders Talk blog posts on our Healthier, Wealthier, Smarter site and share your insights on Twitter with the hashtag, #onHWS. To learn more about how health research makes Ontario healthier, wealthier, and smarter, check out our website and our other blog posts and videos.