Genome

Researchers discover one million new components of the human genome

Christopher.Sorensen — Thu, 08 Feb 2024 19:16:32 +0000

Researchers discover one million new components of the human genome

Christopher.Sorensen Thu, 02/08/2024 - 14:16

Cutline

Timothy Hughes, professor and chair of �山ǿ��’s department of molecular genetics in the Temerty Faculty of Medicine, is the principal researcher on a study that found nearly one million new exons, or stretches of DNA that are expressed in mature RNA (photo courtesy of the Donnelly Centre)

Anika Hazra

Topic

Breaking Research

Temerty Faculty of Medicine

Donnelly Centre for Cellular & Biomolecular Research

Genome

Molecular Genetics

Research & Innovation

Subheadline

“We’ve started to chip away at the dark genome by finding nearly one million previously unknown exons through a method called exon trapping”

Researchers at the University of Toronto’s Donnelly Centre for Cellular and Biomolecular Research have found nearly one million new exons – stretches of DNA that are expressed in mature RNA – in the human genome.

There are around 20,000 protein-coding genes in humans that contain approximately 180,000 known internal exons. These protein-coding regions account for only one per cent of the entire human genome. The vast majority of what remains is a mystery – aptly referred to as the “dark genome.“

“We’ve started to chip away at the dark genome by finding nearly one million previously unknown exons through a method called exon trapping,” said Timothy Hughes, principal investigator on the study and professor and chair of the department of molecular genetics in �山ǿ��’s Temerty Faculty of Medicine.

“The technique involves an assay with plasmids to find exons in DNA fragments of unknown composition,” said Hughes, who holds the Canada Research Chair in decoding gene regulation and the John W. Billes Chair of Medical Research at �山ǿ��. “While exon trapping is not widely used anymore, it proved to be effective when used in combination with high-throughput sequencing to scan the entire human genome.”

The findings were published recently in the journal Genome Research.

Exons are segments of the genome that can encode proteins to direct tissue development and biological processes within the body. They are considered to be autonomous if they don’t require external assistance to splice into a mature RNA transcript, which is then translated into a protein.

The team behind the study was driven to test the exon definition model that guides research in molecular genetics after questioning one of its assumptions – that the accurate removal of non-protein-coding intron regions of the genome is aided by clear and consistent indicators of where exons begin and end. This assumption does not seem to hold in all cases as the splicing of exons does not always go smoothly, sometimes resulting in mature RNA transcripts that contain non-functional components.

“Almost none of the newly discovered exons are found consistently across genomes of different species,” said Hughes. “They seem to appear in the human genome mainly due to random mutation and are unlikely to play a significant role in our biology. This is evidence that evolution in humans involves a lot of trial and error – most likely enabled by the vast size of our genome.”

It is helpful to document randomly mutated exons within the human genome as their translation could potentially be harmful. Long non-coding RNA exons, which are autonomous but often have no known function, have been connected to the development of cancer. Of the roughly 1.25 million known and unknown exons the team found through exon trapping, almost four per cent were long non-coding RNA exons.

In addition, the exons residing within non-coding introns, called pseudoexons, can mutate to make a weak splice site stronger. This results in the exon being included in a mature RNA transcript, potentially leading to disease.

“This is an interesting study that broadens our knowledge of sequences across the human genome that have the potential to be recognized as exons in transcribed RNA,” said Benjamin Blencowe, professor of molecular genetics in �山ǿ��’s Temerty Faculty of Medicine, who was not involved in the study. “While the significance of the majority of the newly detected exons is unclear, some of them may be activated in certain contexts – for example, by disease mutations – and therefore cataloguing them is important. This study will further serve as a valuable resource facilitating ongoing efforts directed at deciphering the splicing code.”

A stronger understanding of the factors impacting exon inclusion in mature RNA can help improve programs like SpliceAI, a widely used tool for predicting splice sites and aberrant splicing. SpliceAI can be trained on new data such as that produced through this study to refine its prediction capabilities.

“SpliceAI often doesn’t provide details on the characteristics of exons and has a poor ability to predict splicing in exons that aren’t already catalogued,” said Hughes. “Our exon trapping data contains biologically meaningful information that can be fed into SpliceAI and other splicing predictors to open up new paths for exploring the dark genome.”

The research was supported by the Canadian Institutes of Health Research and the U.S. National Institutes of Health.

�山ǿ�� researchers use deep DNA sequencing to find TB "super-spreader" in northern Quebec

Christopher.Sorensen — Tue, 04 Feb 2020 16:44:28 +0000

�山ǿ�� researchers use deep DNA sequencing to find TB "super-spreader" in northern Quebec

Christopher.Sorensen Tue, 02/04/2020 - 11:44

Cutline

The study focused on an outbreak of tuberculosis in the Nunavik region of Quebec and was done in collaboration with Kuujjuaq-based Nunavik Regional Board of Health and Social Services (photo by Cyrielle Beaubois via Getty Images)

Françoise Makanda

Topic

Our Community

Dalla Lana School of Public Health

Genome

Research & Innovation

A University of Toronto-led research team used deep sequencing of DNA to find a previously undetected tuberculosis super-spreader – an unusually contagious person – in a Nunavik, Que. outbreak.

It is the first time the technique has been used in connection with tuberculosis transmission in Canada. The researcher’s findings were published today in the eLIFE journal.

“Super-spreading may be playing a key role in transmission in these outbreaks up north,” says the study’s lead author Robyn Lee (left), an assistant professor at the Dalla Lana School of Public Health.

“If we can identify specific factors that are associated with super-spreading in Nunavik – when a patient with these characteristics comes into clinic and is diagnosed with tuberculosis, we can ideally triage their contacts and have them tested more quickly to help break the chains of transmission.”

According to the Canadian Tuberculosis Reporting System, Nunavik’s rate of infections was 304.0 per 100,000 inhabitants in 2016 while Canada’s overall rate was 4.8 per 100,000 habitants.

The researchers found one additional super-spreader who potentially led to 17 additional cases or 35 per cent of the outbreak between 2011 and 2012. With the routine sequencing approach, researchers had also previously identified another super-spreader who may have transmitted up to 19 additional cases.

“Most of these new cases had attended the same social community gathering houses which were suspected venues of transmission during the outbreak,” Lee says.

Deep sequencing helped identify variations in patients’ bacterial DNA that found the super-spreader. People living with tuberculosis are not necessarily infected with a single bacterium, says Lee. They may have more than one strain to start with, or the strain may change over time. At times, they can spread different strains to others.

Lee also says that deep sequencing may provide extra information for public health specialists during outbreaks that happen over short time periods. Recognizing symptoms, early identification and prompt diagnosis are key to reducing tuberculosis transmission and prevent large numbers of people from becoming infected, she adds.

“Typically, with ‘routine’ whole-genome sequencing, we sequence the genome about 50 to 100 times and we come up with a consensus sequence representing a patient’s bacteria,” says Lee.

“We compare consensus sequences from different patients to understand transmission. By sequencing the genome from 500 to 1,000 times – 10 to 20 times more than we would usually sequence – we were able to look for variation in the bacteria within the patient and be confident that this variation is something that’s real and not a potential mistake caused by the sequencing or the way we analyze the data.”

The study was done in collaboration with the Nunavik Regional Board of Health and Social Services, the Harvard T.H. Chan School of Public Health and McGill University. It was funded by the National Institutes of Health and Canadian Institutes of Health Research.

�山ǿ��'s Sloan Foundation fellow on how tiny bugs and simple worms offer clues to infectious diseases

noreen.rasbach — Mon, 18 Mar 2019 18:15:45 +0000

�山ǿ��'s Sloan Foundation fellow on how tiny bugs and simple worms offer clues to infectious diseases

noreen.rasbach Mon, 03/18/2019 - 14:15

Cutline

Aaron Reinke is an assistant professor of molecular genetics at �山ǿ��'s Faculty of Medicine (photo by Calvin Mok)

Topic

Research & Innovation

Microsporidia are one-cell parasites that can cause stomach pain, weight loss and eye inflammation, among other symptoms. They can be fatal in people with weakened immune systems, including the malnourished and those with AIDS. They also infect insects — and Aaron Reinke studies that process in worms to better understand how these parasites make people and animals sick.

Reinke is an assistant professor of molecular genetics at the University of Toronto's Faculty of Medicine, where he set up a laboratory in 2017 after postdoctoral studies at the University of California, San Diego (USCD). He was recently �山ǿ��’s sole recipient of an Alfred P. Sloan Foundation fellowship, a prestigious early-career award that comes with a US$70,000 prize.

Reinke spoke with writer Jim Oldfield about how microsporidia infect worms, why we should care about these parasites, and how immunity to disease-causing agents can be inherited.

Tell us about your research.

Broadly, we’re interested in how parasites interact with their hosts, to understand how pathogens evolve. We study microsporidia in particular, a unicellular organism that is related to fungi and extremely common. It can cause disease and death in humans, and in animals it has figured out how to infect just about every species. It affects livestock and aquiculture production, and it’s been implicated in the collapse of honeybee colonies, so there are practical reasons to understand these parasites as well. And although there are thousands of species, we don’t know much about them, since they only live inside host cells and have been very hard to study.

So how do you overcome those challenges?

Well, we now have genome sequences for about two dozen species of microsporidia, which aids genomic studies. And these parasites have very small genomes, roughly 2,000 genes, which makes it easy to sequence more of them. As well, we now have a system that has let us identify a set of proteins expressed by microsporidia genomes. This system, which I developed as a postdoc in the lab of Emily Troemel at UCSD, lets us see the proteins these parasites put into host cells. With biochemical techniques we can label those new proteins and then study their different properties and effects in the host cell. We also have a great host for studying this interaction – C. elegans, a worm that is a powerful experimental model because it shares a lot of biology with humans.

What have you found in C. elegans?

We’re now able to look at multiple wild strains of C. elegans, which allows us to see how the worms have evolved resistance to infection. We are experimenting with pools of worm strains and we have genomic ways of reading out which strains do better or worse under infection with different microsporidia. We have identified strains of C. elegans that are resistant and susceptible to different species of microsporidia, and we’re starting to identify the genes responsible for the phenotypes we observe.

You’re also studying inherited immunity. Can you tell us about that?

Researchers are increasingly seeing environmental effects that impact the next generation in both people and other animals. There have been many studies on how immunity is passed along between generations, including in invertebrates such as mollusks, bees and butterflies. But we don’t know how this works, and it’s hard to study in these organisms due to lack of tools and long generation times.

The advantage with worms is that we can go through a generation in three days and use genetics to identify the genes involved, so they are an amazing model. We can infect animals and isolate their progeny, and we see the progeny are more resistant to infections. We are now characterizing this response and identifying how immunity is transferred. Understanding this process will provide insight on how this happens in other animals, and it may help us understand other types of inherited environmental effects, which are potentially conserved in humans.

How do you like Canada?

I grew up in Montana, so I’d been to Canada before and I’ve found living here great. Toronto is an excellent environment to do science, and I’ve found that �山ǿ��’s department of molecular genetics gives new investigators time to develop a research program before asking too much in terms of teaching and committee work. So I’ve been writing a lot of grants and recruiting lab members. We’re at a nice size now, with three grad students, two postdocs and two technicians.

We’ll just keep on asking basic science questions here in the MaRS building and hope people continue to take interest in what we’re doing.

�山ǿ�� researchers publish long-awaited cannabis genome map

noreen.rasbach — Wed, 28 Nov 2018 21:19:39 +0000

�山ǿ�� researchers publish long-awaited cannabis genome map

noreen.rasbach Wed, 11/28/2018 - 16:19

Cutline

The world's first cannabis chromosome map reveals the plant’s evolutionary past and points to its future as potential medicine (photo by Michael Fischer via Pexels)

Jovana Drinjakovic

Topic

Global Lens

Donnelly Centre for Cellular & Biomolecular Research

Research & Innovation

Subheadline

Map reveals how hemp and marijuana evolved as separate strains with distinct chemical properties

THC and CBD, bioactive substances produced by cannabis and sought by medical patients and recreational users, sprung to life thanks to ancient colonization of the plant’s genome by viruses, University of Toronto researchers have found.

The finding is only one of the insights revealed by the long-awaited cannabis genome map detailing gene arrangement on the chromosomes, published recently in the journal Genome Research. Among other revelations are discovery of a gene responsible for the production of cannabichromene, or CBC, a lesser known cannabinoid, as the active substances in cannabis are known, and new insights into how strain potency is determined.

“The chromosome map is an important foundational resource for further research which, despite cannabis’s widespread use, has lagged behind other crops due to restrictive legislation,” says Tim Hughes, a professor in the Donnelly Centre for Cellular and Biomolecular Research and co-leader of the study. Hughes is also a professor in the department of molecular genetics and senior fellow at the Canadian Institute for Advancement of Research.

The researchers expect the map will speed up breeding efforts to create new strains with desired medical properties as well as varieties that can be grown more sustainably, or with increased resistance to diseases and pests.

The study was a three-part collaboration between Tim Hughes’s team, with graduate student Kaitlin Laverty spearheading the computational work behind genome assembly, and those of Jonathan Page, of Aurora Cannabis and the University of British Columbia, and Harm van Bakel, of the Icahn School of Medicine at Mount Sinai in New York.

Hughes, Page and van Bakel first got together in 2011 when they released the first draft of cannabis genome, which was too fragmented to reveal gene position on chromosomes.

The new map reveals how hemp and marijuana, which belong to the same species Cannabis sativa, evolved as separate strains with distinct chemical properties. Cannabis plants grown for drug use are abundant in psychoactive tetrahydrocannabinol, or THC, whereas hemp produces cannabidiol, or CBD, popular of late for its medicinal potential. Some people use CBD to relieve pain and it is also being tested as a treatment for epilepsy, schizophrenia and Alzheimer’s.

The enzymes making THC and CBD are encoded by THCA and CBDA synthase genes, respectively. Both are found on chromosome 6 of the ten chromosomes the cannabis genome is packaged into. There, the enzyme genes are surrounded by vast swaths of garbled DNA that came from viruses that colonized the genome millions of years ago. This viral DNA, or retroelements as it is known, made copies of itself that spread across the genome by jumping into other sites in the host cell’s DNA.

“Plant genomes can contain millions of retroelement copies,” says van Bakel. “This means that linking genes on chromosomes is analogous to assembling a huge puzzle where three quarters of the pieces are nearly the same colour. The combination of a genetic map and PacBio sequencing technology allowed us to increase the size of the puzzle pieces and find enough distinguishing features to facilitate the assembly process and pinpoint the synthase genes.”

The researchers believe that gene duplication of the ancestral synthase gene and expanding retroelements drove ancient cannabis to split into chemically distinct types. Humans subsequently selected for plants containing desirable chemistry such as high THC.

The gene sequences for the THCA and CBDA synthases are nearly identical, supporting the idea that they come from the same gene that was duplicated millions of years ago. Over time, one or both gene copies became scrambled by invading retroelements, and by evolving separately, they eventually came to produce two different enzymes – CBDA synthase found in hemp (fibre-type), and THCA synthase in drug-type (marijuana).

Because the enzymes are so similar at the DNA level, until this study it was not even clear if they are encoded by separate genes or by two versions of the same gene. Adding to the confusion was the fact that most strains produce both CBD and THC despite breeders’ efforts to grow hemp varieties free from the mind-altering THC for users looking to avoid it.

The chromosome map now clearly shows that two distinct genes are at play, which should make it possible to separate them during breeding to grow plants without THC.

Some psychoactive effects in medical strains could be coming from CBC, a lesser known cannabinoid that has unusual pharmacology including anti-inflammatory properties. The discovery of the gene responsible for CBC synthesis will make it possible for breeders to tailor its content in future varieties.

“Mainstream science has still not done enough because of research restrictions,” says Page. “Legalization and looming ease of research regulation really provide for opportunities for more research to be done. And Canada is leading the way.”

The study was supported by the Canadian Institutes of Health and Research.

�山ǿ�� study bridges a divide in cell aging in neurodegenerative diseases

noreen.rasbach — Tue, 20 Nov 2018 05:00:00 +0000

�山ǿ�� study bridges a divide in cell aging in neurodegenerative diseases

noreen.rasbach Tue, 11/20/2018 - 00:00

Cutline

From left, doctoral students Amanda Hall and Lauren Ostrowski and Associate Professor Karim Mekhail (photo by Jim Oldfield)

Topic

Research & Innovation

Research from the University of Toronto has shown that in some neurodegenerative diseases, two hallmarks of cell aging – protein aggregation and a type of DNA instability – are linked. They were previously thought to be unconnected.

The researchers used cellular models of amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia and found that the gumming up of certain proteins undermines the stability of ribosomal DNA repeats – repetitive genetic sequences essential for manufacturing all proteins and cells.

“We found that protein aggregates shorten the lifespan of the cell by compromising the stability of the highly repetitive ribosomal DNA sequences,” says Karim Mekhail, an associate professor in the Faculty of Medicine’s department of laboratory medicine and pathobiology who holds the Canada Research Chair in Spatial Genome Organization.

“That these two major mechanisms of cell aging are connected points to strategies that may hit two birds with one stone in neurodegeneration.”

The journal Communications Biology published the results earlier this month.

Repetitive DNA sequences comprise over half of the genome in some organisms, and they are essential to cell function. But they are susceptible to reorganization, which can lead to chromosomal rearrangements, premature cell aging and disease.

Mekhail and his team, including doctoral students Lauren Ostrowski and Amanda Hall, first found that trouble-making proteins – which emerge from repetitive DNA sequences called transposons – aggregate in yeast cells humanized with mutations found in patients suffering from ALS and ataxia. They then mapped how the aggregates destabilize ribosomal DNA repeats and lead to premature yeast cell aging, before confirming the findings in human cells.

The work took more than four years. “This story was full of surprises,” says Mekhail. “The findings may seem obvious in retrospect, but if you’d told us in the beginning that there was crosstalk between protein aggregation and destabilization of DNA, we’d have thought that was absurd. Lauren and Amanda really had to persevere.”

To identify new and urgently needed therapeutic approaches, the researchers are now testing if drugs that disrupt transposon protein aggregates restore genome stability and cell lifespan in various neurodegenerative diseases.

The research was funded by the Canada Research Chairs program, the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada and the Ontario Ministry of Research and Innovation.

Gene genies: How Toronto became a global hub for genetic research

noreen.rasbach — Fri, 21 Sep 2018 20:38:56 +0000

Gene genies: How Toronto became a global hub for genetic research

noreen.rasbach Fri, 09/21/2018 - 16:38

Cutline

“It’s mind-boggling how fast the technology has improved,” says Stephen Scherer about sequencing a person's genetic information

Chris Sorensen

Topic

Global Lens

Artificial Intelligence

Faculty of Applied Science & Engineering

Research & Innovation

Startups

Stephen Scherer has had a finger on the pulse of genomic research for over 20 years. But that didn’t prepare him for what happened while he was vacationing at his Ontario cottage last summer.

“I had four consecutive days where people came and asked, on behalf of their relatives, about a genetic test – asking what does this mean?” says Scherer, a University Professor at the University of Toronto who is a director at �山ǿ��’s McLaughlin Centre and the Hospital for Sick Children’s Centre for Applied Genomics.

The sudden rise in dockside queries is a result of the increasing ease of reading one’s genetic information. In a lab at SickKids’ Peter Gilgan Centre for Research and Learning, for example, it now costs about $1,000 to sequence an individual’s entire genome – a process that takes about a week. By contrast, it took researchers about $3 billion and 15 years to create a reference genome for the Human Genome Project, published in 2003.

“I couldn’t imagine, even a few years ago, we would be doing this,” Scherer says. “It’s mind-boggling how fast the technology has improved.”

Yet, what hasn’t improved quite so rapidly is our understanding of all that data. Recent research has shown our genomes are far more complex than previously thought. That, in turn, means much more work is necessary to decode our genomic “blueprints” so we know when mutations are something to worry about, and how prevent them from becoming full-blown illnesses.

Getting there will require tapping the expertise – and, critically, data – of researchers and clinicians who work in a wide swath of medical fields.

It’s an interdiscipinary challenge �山ǿ�� and its partner hospitals are in a unique position to tackle.

“We think �山ǿ�� is the right place to do this,” Scherer says. “The breadth of research here is so vast and the university has a single medical school, which is a huge advantage since people who are doing cancer research or autism research are actually meeting around the same tables.

“We really see this concept of precision medicine driven by the engine of genome sequencing.”

Toronto has another reason to be optimistic about its chances to be a leader in genomic medicine: The city already has a long history of research excellence when it comes to understanding our genes and genomes.

In the mid-1980s, for example, �山ǿ�� University Professor Tak Mak discovered the T-Cell receptor, beating labs around the world and establishing a cornerstone of modern immunology. And he did it despite being turned down for a grant related to the work.

“It was a sunny Sunday afternoon in the summer of 1983,” Mak, who is also a senior scientist at the Princess Margaret Cancer Centre, recalled in a 2011 article published by the Proceedings of the National Academy of Sciences of the United States of America. “I walked into the lab, and there was a stack about two feet high of computer sheets comparing the sequences of our T cell-specific genes to everything in the gene bank.

“After scanning through hundreds of pages, I held up one sheet, looked at it from an angle, and there it was … I stared at it for a long time and finally said to myself, ‘I can't believe it. This could be the human TCR.’”

Other local success stories in the field were equally as momentous: In 1989, �山ǿ�� University Professor Emeritus Lap-Chee Tsui, who was previously the geneticist-in-chief at the Hospital for Sick Children, discovered the mutation in the gene responsible for cystic fibrosis, a genetic disease that affects about one out of every 2,000 Canadians – mostly children; in the mid-1990s, �山ǿ�� University Professor Peter St George Hyslop discovered the genes responsible for early-onset Alzheimer’s.

Scherer, too, has made several key contributions. In 2004, he co-authored a landmark study about copy-number variations, or repeated or deleted copies of entire genes that vary by individual. Then, earlier this year, Scherer and fellow researchers released a first-ever study as part of the Personal Genome Project (PGP) Canada. The paper, published in the Canadian Medical Association Journal, found all of the project’s 56 participants – all reasonably healthy – possessed “clinically relevant” genomic information.

While the PGP study noted there remains much ambiguity – some variants in the genome can lead directly to disease or genetic disorders, others appear to merely raise risks, still others seem to have no effect at all – it nevertheless concluded “these findings suggest that whole genome sequencing can benefit routine health care in Canada’s future.”

Scherer, for one, envisions a day when every child will have their genome sequenced upon being born – a sort of genetic instruction booklet. “That’s what we’re preparing for here at SickKids – essentially every child would have their genome done as a framework so they can use it in decision-making throughout their lifetime,” he says.

Beyond the hospital, there are also a growing number of private companies who offer direct-to-consumer genetic testing. The Silicon Valley startup 23andMe, for example, built an international business with five million users straddling nearly 50 countries in just over a decade. It has even attracted the interest of drug giant GlaxoSmithKline, which wants to use the company’s genetic database to find new drug targets.

No wonder, then, genetic counsellors – �山ǿ�� offers a two-year master’s program – occupy one of the fastest growing job categories in the United States, according to numbers compiled by the U.S. Bureau of Labor Statistics.

From a research perspective, meantime, there’s hardly a facet of medicine, from autism to heart disease, that hasn’t been informed by the growing ocean of genetic data.

Michael Sefton is a member of the department of chemical engineering and applied chemistry and executive director of Medicine by Design (photo by Neil Ta)

University Professor Michael Sefton, the executive director of �山ǿ��’s Medicine by Design initiative, says genomic information is core to everything researchers do in the cutting-edge field of regenerative medicine, which aims to regrow, repair or replace damaged or diseased cells, organs and tissues.

“Some of the projects don’t worry so much about what the genes are up to, but will instead have a protein-centred perspective or are looking at how the cells interact,” says Sefton, who also holds appointments in the Institute of Biomaterials & Biomedical Engineering and the department of chemical engineering and applied chemistry.

“But if you scratch the surface, they are unwittingly using the genome information to understand what’s going on.”

As for the idea of Toronto becoming a leader in genomic-inspired medical research, Sefton says the interdisciplinary approach taken by Medicine by Design, made possible by a $114-million grant from the federal government, the largest in �山ǿ��’s history, proves Toronto is indeed a place where it’s possible for researchers to successfully work together across institutional boundaries.

Says Sefton, “We talk to each other, we collaborate – we’re Canadian.”

Toronto may also have a technological advantage in the race to develop genomic medicine. In recent years, the city has become an important hub for artificial intelligence, or AI, research in fields like deep learning, which was pioneered by people like �山ǿ�� University Professor Emeritus Geoffrey Hinton. The technology, which mimics the way the human brain learns, is capable of recognizing patterns in extremely large data sets – like the human genome.

Deep Genomics, for example, is a startup spun out of research by �山ǿ�� Professor Brendan Frey that uses deep learning to search for clues about genetic diseases and potential treatments. It’s so far raised more than US$10 million in financing.

“Right now we look for bazooka wounds in the genes,” Scherer says. “But to find the subtle variations, we need to use machine learning.

“This is an area where Toronto could be a world leader.”

This story first appeared in the Faculty of Medicine's 2018 Dean's Report. Read the report.

Why we're sequencing the genomes of Canada's iconic species

noreen.rasbach — Thu, 28 Jun 2018 12:38:54 +0000

Why we're sequencing the genomes of Canada's iconic species

noreen.rasbach Thu, 06/28/2018 - 08:38

Cutline

The Canada 150 Sequencing Initiative will sequence the genomes of 150 organisms important to Canadians, publishing the results in public databases (photo by Shutterstock)

Topic

Our Community

Genome

Research & Innovation

The Conversation

Last year, to commemorate Canada’s 150th birthday – and to lay a foundation for Canadian research excellence for the next 150 years – a group of scientists in our country embarked upon the Canada 150 Sequencing Initiative (CanSeq150).

Motivated by our nation’s curiosity about the animal that most shaped our history, we sequenced the genome – the genetic instruction book – of the Canadian beaver (Castor canadensis) in time for Canada’s sesquicentennial. We’ve also begun sequencing 34 other species, including the Canada jay (Perisoreus canadensis) and the Canada lynx (Lynx canadensis).

Our goal is to sequence the genomes of 150 organisms important to Canada – and Canadians.

We are accepting proposals from researchers who present the best cases for the historical or immediate importance to Canada of each proposed organism. As new species are chosen, Canada’s Genomics Enterprise (CGEn) will announce additional species selected to undergo whole genome sequencing on its website.

A Canada lynx (photo by Eric Kilby via Flickr)

Some of these genomes will be sequenced in a way that allows us to develop and test new technologies or methods to analyze the genetic sequence. We also hope that by better understanding the genomes of other species – and our own – we can better understand ourselves and our place in natural history.

Scientists learn and teach Theodosius Dobzhansky’s famous 20^thcentury concept: “Nothing in biology makes sense except in the light of evolution.”

In the 21^stcentury, with the vision that genomic sequences will enable better biological and medical studies, we might consider updating Dobzhansky’s insight to include genome sequence as well as evolution.

The CanSeq150 approach builds on past experience and provides inspiration for new submissions. For example, when the severe acute respiratory syndrome (SARS)-associated coronavirus threatened the health of Canadians in 2003, researchers mobilized to sequence the viral genome to aid in diagnosis and vaccine development.

No bird brain

We’re now working on generating a genomic sequence of Perisoreus Canadensis – the Canada jay – that can be used as a reference for other studies. (Known as the gray jay for 60 years, the American Ornithologists' Union recently reverted to its original name.)

The Canada jay inhabits all 13 provinces and territories, and figures strongly in First Nations folklore, where it is called the Wisakedjak, or whiskey jack. There is strong support for its designation as Canada’s national bird.

A pair of Canada jays feed their nestlings in Algonquin Park (photo by Dan Strickland via Wikimedia)

A fascinating attribute of the Canada jay is its superior intelligence. It has developed a highly complex food-stockpiling strategy across widely scattered sites that keeps the bird alive through the winter breeding season. Each Canada jay can retrieve thousands of saliva-coated food caches each season by memory and pattern recognition – all hard-wired by its brain structure and encoded by its genome.

Nature and nurture

Long before Canada was a country, early accounting ledgers of the Hudson Bay Company show the Canada lynx and the snowshoe hare were in an obligate relationship.

The two animals share identical geographic range, covering the Canadian boreal forest. Deduced from historical fur harvest records, hare and lynx populations were found to oscillate in tightly linked 10-year cycles.

The genomes of the lynx and the hare can enlighten researchers on how the changing environment induces hormones and contributes to the cyclical declines in reproductive fitness in the hare population.

The genetic changes encoding the environmental sensors that underlie seasonal coat colour changes in the snowshoe hare, among other physiological and environmental relationships, will be revealed.

Life’s code

The genome provides cells with directions like a blueprint, or orchestral score, for all aspects of development throughout the life of the organism.

Humans inherit half of their DNA from each parent, as they did from their parents, and so on, right back to the origin of Homo sapiens. The genomic information embedded in this DNA ties together the millions of species of Charles Darwin’s tree of life.

We have ample examples demonstrating how decoding human genomes can reveal the underpinnings of diseases and disorders, such as cancer and autism, and enable diagnostics for early detection. Medical or pharmaceutical treatments increasingly target specific features of a disease, such as the proteins a cell expresses on its surface.

By definition, genome sequencing provides far better coverage of a genome’s genetic markers than earlier technologies. We will be sequencing whales and trout, bear and sheep, maple trees and fungus, in order to discover genomic DNA bar codes – DNA markers covering all the cell’s chromosomes – that are important for selection and adaptation, and can be used in breeding and conservation.

Gift to science

I teach my own students that as some applications of genomic science are becoming rather effortless, we are now only limited by our creativity.

To encourage such creativity, we believe that the first crack at studying a given new genome sequence should be made by researchers who best understand the organism’s unique biological, cultural, economic, societal and historical role.

For CanSeq150, we will sequence the genomes of 150 organisms brought forward by Canadian researchers.

We believe that those same scientists can best harness the genome sequence information for our country – and for the world.

These experiences will influence decisions for future projects, including those related to human disease. The typical cost of a genome project will be $3,000, and while this cost will be borne by CGEn and its partners, the studies will be led by the researchers who submit the genomes for sequencing.

Results from CanSeq150 will be available to researchers worldwide through public databases, such as the National Center for Biotechnology Information.

With our “updated” (genome-based) view of Dobzhanksy’s evolutionary biology concept, we aspire to promote scientific discovery altruistically. Understanding the intersections among the CanSeq150 species – and others – will surely help us become wiser custodians of our heritage.

Stephen W. Scherer, is the director of the McLaughlin Centre for Molecular Medicine at the University of Toronto.

This article was originally published on The Conversation. Read the original article.

Personal Genome Project shows whole genome sequencing may transform how Canadians manage their own health care

noreen.rasbach — Mon, 05 Feb 2018 15:57:20 +0000

Personal Genome Project shows whole genome sequencing may transform how Canadians manage their own health care

noreen.rasbach Mon, 02/05/2018 - 10:57

Cutline

“Though we’ve identified clinically relevant genomic information for all participants, each of their genomes has even more information that we can’t interpret yet,” says Stephen Scherer, director of �山ǿ��'s McLaughlin Centre (photo by J.P. Moczulski)

Topic

Research & Innovation

Stephen Scherer

Researchers from the University of Toronto and the Hospital for Sick Children (SickKids) behind the Personal Genome Project Canada are predicting that whole genome sequencing will likely become part of mainstream health care in the foreseeable future.

In the first-ever study from the Personal Genome Project Canada (PGP-C), the researchers found 25 per cent of participants to date had genomic information indicating they could be at risk for future disease and even more were found to have genetic variants that would be relevant for family planning or newborn screening. All participants had genomic information associated with risks for adverse drug reactions or altered drug effectiveness, with 23 per cent of participants identified as being at risk for severe, potentially life-threatening adverse drug reactions.

The study was published Feb. 3 online in CMAJ (the Canadian Medical Association Journal).

PGP-C is a comprehensive public data resource that integrates participants’ whole genome sequencing data with their health information to advance scientific understanding of genetic and environmental contributions to human health and disease. All of the project’s inaugural 56 participants have clinically relevant information in their genomes, highlighting the potential of using whole genome sequencing data proactively for precision medicine and to reduce the risk of therapeutic failure.

“Though we’ve identified clinically relevant genomic information for all participants, each of their genomes has even more information that we can’t interpret yet,” says Stephen Scherer, director of �山ǿ��'s McLaughlin Centre and senior scientist and director of The Centre for Applied Genomics (TCAG) at SickKids.

Read an article in the Globe and Mail about the study and Personal Genome Project Canada

“As we analyze more samples, we continuously learn more about the human genome which will allow us to eventually take full advantage of the wealth of information it contains. That’s why the goal of the project is to sequence thousands of genomes each year.”

PGP-C is the Canadian arm of the global Personal Genome Project, a collaborative academic research effort that started with Harvard Medical School’s Personal Genome Project in 2005. A priority of the Personal Genome Project is to share information collected from the localized projects with researchers around the world to drive new knowledge about human biology.

Participants were required to undergo an extensive consent process as all data, including results from their whole genome sequencing, combined with personal and family history, is available online. Each participant had access to genetic counselling to appropriately contextualize the results of their genetic testing.

“Genetic counsellors play an important role in communicating and interpreting these results appropriately,” said Professor Trevor Young, dean of �山ǿ��'s Faculty of Medicine, which runs Ontario’s only academic training program for genetic counselling. “The demand for these specialized skills is only going to rise given the massive increase in the number of genome-wide tests now being used in hospitals.”

Interested in publicly funded research in Canada? Learn more at �山ǿ��’s #supportthereport advocacy campaign

The cost of whole genome sequencing has fallen dramatically since PGP-C began recruiting and analyzing samples in 2012 and further still from when the project was conceptualized in 2007. Signs indicate the technology will continue to become more affordable and accessible, which the authors expect will transform whole genome sequencing into more of a mainstream practice for the general population. As a result, frontline health-care providers may become involved in interpreting and delivering resulting genomic information in the near future.

The work was funded by the University of Toronto’s McLaughlin Centre, the Canada Foundation for Innovation, Genome Canada-Ontario Genomics, the Government of Ontario, the Canadian Institutes of Health Research (CIHR), Medcan Health Management Inc. and SickKids Foundation.

Read the full study in CMAJ

�山ǿ�� scientists help discover how to turn off CRISPR

ullahnor — Fri, 09 Dec 2016 16:55:21 +0000

�山ǿ�� scientists help discover how to turn off CRISPR ullahnor Fri, 12/09/2016 - 11:55

Heidi Singer

Author legacy

Heidi Singer

Subheadline

Researchers are part of an international team that has made gene editing safer and more precise, offering promise for new therapies

CRISPR genome editing is quickly revolutionizing biomedical research, but the new technology is not yet exact. The technique can inadvertently make excessive or unwanted changes in the genome and create off-target mutations, limiting safety and efficacy.

Now, researchers at the University of Toronto and University of Massachusetts Medical School have discovered the first known “off-switches” for CRISPR gene-editing activity, providing greater control and a much-needed “safety valve,” according to a new study featured on the cover of Cell.

The scientists found three proteins that block CRISPR, known as anti-CRISPRs.

�山ǿ�� Faculty of Medicine's Alan Davidson, a professor of molecular genetics and biochemistry, and Karen Maxwell, an assistant professor of biochemistry, made the discovery with UMass researcher Erik J. Sontheimer.

“CRISPR is very powerful, but we have to be able to turn it off,” says Davidson. “This is a very fundamental addition to the toolbox which should give researchers more confidence to use gene editing.”

Professor Alan Davidson (left) and Assistant Professor Karen Maxwell are part of a research team that has discovered the first known “off-switches” for CRISPR gene editing

A simple and efficient way of editing the genome, CRISPR is changing biomedical research by making it far easier to inactivate or edit genes in a cell line for study. Work that used to take months or years to perform can now be done in weeks.

Scientists are developing CRISPR to target specific cell types, tissues or organs where a disease occurs. But sometimes, CRISPR hits the wrong target, causing unintended damage.

“CRISPR activity in these other cells, tissues or organs is at best useless and at worst a safety risk,” says Sontheimer. “But if you could build an off-switch that keeps Cas9 (the enzyme that cuts the DNA for editing) inactive everywhere except the intended target tissue, then the tissue specificity will be improved.”

The new paper not only identifies that “off switch” but it shows that CRISPR inhibitors have evolved naturally and can be identified and exploited.

The “off switch” will allow researchers to be more precise in their use of CRISPR. If they only want to use it during one stage of a cell’s life – such as when the DNA is replicating – they can turn it off during all other stages, reducing the chance of unwanted consequences.

A major way of delivering CRISPR into the body is through inactivated viruses that can be programmed to attach themselves to target cells. The challenge is that viruses can’t be engineered to be 100 per cent specific.

Researchers in muscular dystrophy, for example, want to target muscle cells. But a particular virus known for its ability to target muscle cells also attaches itself to liver cells, where it could cause unintended damage. The “off switch” could allow researchers to release “anti-CRISPR” proteins into the body to turn off CRISPR activity in liver cells, offering a new layer of protection against mistakes.

“Knowing we have a safety valve will allow people to develop many more uses for CRISPR,” says Maxwell. “Things that may have been too risky previously might be possible now.”

The “off switch” could be used across the board for any application of CRISPR technology to target specific cells or tissues. For the researchers, the next step is to widen the “off switch” to include other types of CRISPR systems.

�山ǿ�� to sequence genomes of 10,000 people per year: “Information is the new oil,” say University of Toronto scientists

lanthierj — Wed, 14 Sep 2016 19:52:23 +0000

�山ǿ�� to sequence genomes of 10,000 people per year: “Information is the new oil,” say University of Toronto scientists

lanthierj Wed, 09/14/2016 - 15:52

Cutline

(all photos by Johnny Guatto)

Heidi Singer

Author legacy

Heidi Singer

Topic

City & Culture

Hospital for Sick Children

Research & Innovation

Subheadline

City becomes one of the world’s leading producers of biodata

The University of Toronto today launched a massive project to sequence the whole genomes of 10,000 people per year – positioning Toronto as a leader in the global race to understand complex diseases.

With the population of Toronto among the most diverse in the world, the project will provide an unusual breadth of genetic material to study, said Professor Stephen Scherer, director of �山ǿ��’s McLaughlin Centre and the Centre for Applied Genomics at The Hospital for Sick Children (SickKids).

He said the move will accelerate the big data revolution and create a new generation of precision therapies.

“With sequencing now married to large-scale computation, I believe we in Toronto can help lead the way for precision medicine. Genomic information is the new oil. It’s the resource that’s going to drive technology in the new era.

“We’re generating the oil that researchers will use to enable discoveries and to create new products in software, biotechnology and information management that will realize precision medicine.”

Genome

Researchers discover one million new components of the human genome

�山ǿ�� researchers use deep DNA sequencing to find TB "super-​spreader" in northern Quebec

�山ǿ��'s Sloan Foundation fellow on how tiny bugs and simple worms offer clues to infectious diseases

�山ǿ�� researchers publish long-awaited cannabis genome map

�山ǿ�� study bridges a divide in cell aging in neurodegenerative diseases

Gene genies: How Toronto became a global hub for genetic research

Why we're sequencing the genomes of Canada's iconic species

No bird brain

Nature and nurture

Life’s code

Gift to science

Personal Genome Project shows whole genome sequencing may transform how Canadians manage their own health care

Read an article in the Globe and Mail about the study and Personal Genome Project Canada

Interested in publicly funded research in Canada? Learn more at �山ǿ��’s #supportthereport advocacy campaign

Read the full study in CMAJ

�山ǿ�� scientists help discover how to turn off CRISPR

�山ǿ�� to sequence genomes of 10,000 people per year: “Information is the new oil,” say University of Toronto scientists

Read more about Scherer's research

�山ǿ�� researchers use deep DNA sequencing to find TB "super-spreader" in northern Quebec