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Newly Funded Genome Canada Projects Focus on Proteomics, Rare Disease, Crop Genomics

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CHICAGO (GenomeWeb) – Genome Canada, in conjunction with several provincial governments and private organizations, last week announced C$255 million ($207 million) in funding for two initiatives that seek to advance precision medicine and genomic technology.

Under the first initiative, Genome Canada, the Canadian Institutes of Health Research, and other partners will provide C$162 million over four years to fund 15 precision medicine and genomics projects underway across Canada. For the second, Genome Canada and others are providing C$93 million to support 10 ongoing technology development efforts.

Notably, Genome Canada, in conjunction with Genome British Columbia, is ponying up C$11.1 million on the technology side to extend the University of Victoria-Genome BC Proteomics Centre in Victoria, British Columbia into a nationwide entity called the Pan-Canadian Proteomics Centre.

This newly branded center is dedicated to services, collaborations, and technology development, according to its director, Christoph Borchers. Teams at different sites are concentrating on different aspects of proteomics.

An earlier round of funding allowed the program to expand from Victoria to the University of British Columbia in Vancouver. Now, the Proteomics Centre will establish new nodes at the Hospital for Sick Children in Toronto and at Jewish General Hospital in Montreal. The Montreal site, which is affiliated with McGill University, will set up a new clinical proteomics program, Borchers said.

The funding is partly for providing services to academia and partly for specific technology development projects, which cover bioinformatics, structural proteomics, quantitative proteomics, and clinical proteomics, according to Borchers.

The decision to go nationwide is based largely on the demand for proteomic services, as well as the broadening of the field. "It's widening the services that we can offer and we add more capacity," Borchers said.

"Proteomics is pretty broad right now," he said. "In the beginning, it was just protein identification. Now, we can do protein quantification in a targeted and untargeted way."

UVic and UBC do not have all the expertise the Pan-Canadian Proteomics Centre now needs, such as in structural proteomics and in detecting protein-protein interactions, according to Borchers, which the new sites will provide. SickKids in Toronto, for example, has experts in BioID, a computer-aided method developed at Sanford Research in Sioux Falls, South Dakota, to screen for protein-protein interactions.

He said the McGill site at Jewish General Hospital was added in order to develop clinical assays that can be used to analyze patient samples routinely.

Borchers called the Pan-Canadian Proteomics Centre "more or less a one-stop shop" for all sorts of proteomic services. "Someone comes in and wants to have a quantitative proteomics analysis and also might ask, 'Can you tell me about this protein-protein interaction using BioID?'" he said. The different sites can send samples and information to each other, making it easier to run an experiment in one location and analyze it elsewhere.

This geographic diversification also helps the Proteomic Centre — which dates to 1982 — increase its pool of potential collaborative partners.

Genome Canada said that the Pan-Canadian Proteomics Centre has committed to more than 60 projects over the next four years, with a combined value of upwards of C$7.8 million. The organization plans to develop at least 1,400 new assays, move about 150 assays into clinical practice, and introduce 11 new software tools. The center also expects to start developing proteogenomics technologies.

In precision medicine, provincial organizations Ontario Genomics, Genome Alberta, and Genome British Columbia are teaming to provide C$12.9 million to Care4Rare Canada to support a new program called C4R-Solve, which seeks to apply multi-omics research to diagnose rare genetic diseases. This program includes researchers from the Children's Hospital of Eastern Ontario Research Institute in Ottawa, Toronto's SickKids, the University of Calgary in Alberta, and UBC.

C4R-Solve researchers will be studying transcriptomics, metabolomics, lipidomics, and deep whole-exome data to detect mosaicism, according to principal investigator Kym Boycott, a senior scientist at the CHEO Research Institute and co-chair of the International Rare Disease Research Consortium's diagnostics committee. They will be in search of new disease and mutational mechanisms.

"Part of the benefit, of course, would be improved diagnostics for rare disease, but actually, we're very interested in what we call 'solving the unsolved patient,'" Boycott said. In this context, this refers to patients who have had exome sequencing done but the test turned up no disease-related mutations.

These are patients who are suspected to have a genetic disease but DNA sequencing could not find a mutation, Boycott said. "So where are those mutational mechanisms hiding? We're interested in those difficult-to-solve patients. Nobody knows how best to approach that kind of patient who's unsolved."

Right now, diagnostic exome sequencing in Canada has a success rate of only about 25 to 30 percent, she said. By taking a multi-omic approach, Boycott hopes to reach 60 percent by the end of the four-year grant period.

If this happens, the three provincial genomics organizations expect their investment will pay off in the form of at least C$28 million in annual savings from faster, more accurate diagnoses and from more efficient, widely available sequencing services.

The study already has a nationwide cohort of 1,000 patients whose cases remain unsolved after exome sequencing. The goal is not only to deliver a molecular diagnosis to a subset of those patients, Boycott said, but also to establish when to use which diagnostic approach. For example, the researchers want to determine when clinicians should order a genome sequence or a transcriptome analysis, or when they should suspect mosaicism.

"Have we missed long-range rearrangements, which we might only pick up with a genome in a de novo assembly? Are we missing splicing mutations, which we'll only get by transcriptome? Are we missing mosaicism, which we'll only get by deep whole-exome sequencing?" Boycott explained.

As part of the grant, C4R-Solve partners in Alberta and Ontario — in conjunction with provincial health ministries — also will build a Canada-wide network called Genomics4RD to coordinate data sharing, which should help embed exome sequencing into clinical workflows.

"We do a lot of international data sharing in the rare disease space, including Matchmaker Exchange, which helps us identify additional patients with changes in the same gene and overlapping clinical presentation," Boycott said.

iThe project aims both to gain new insights into mutational mechanisms and to give patients access to genome-wide sequencing testing, Boycott said, which should increase diagnostic rates.

She noted that researchers must demonstrate utility and cost effectiveness before payors will reimburse for such tests. "This is around bringing the things that we have proven are quite effective — which is exome sequencing — into the clinic," Boycott said.

C4R-Solve is the third round of funding from Genome Canada and its provincial affiliates for the Care4Rare Canada Consortium, which grew out of the FORGE (Finding of Rare Disease Genes) Canada project. By the end of the project, the consortium will have had a decade's worth of funding.

Last month, Genome Canada also teamed with Genome BC and Genome Prairie — covering Manitoba and Saskatchewan — to provide C$800,000 in funding to help build a Canadian online bioinformatics resource for the DivSeek initiative. DivSeek — short for Diversity Seek — was established in 2015 to support the genomic characterization of the 7 million crop accessions stored at gene banks around the world.

This DivSeek Canada project is a two-year "parallel initiative" to the global DivSeek community, according to co-investigator and technical project leader Richard Bruskiewich, CEO of Star Informatics, a biomedical and bioscientific IT company on Vancouver Island. Bruskiewich also holds an adjunct faculty appointment in the botany department at the University of British Columbia.

A team led by UBC botanist and bioinformatician Loren Rieseberg will build this resource — which will initially include tools for the sunflower, flax, and lentil breeding communities — on Compute Canada's high-throughput research computing infrastructure. DivSeek Canada may later be extended to other Canadian crops, Bruskiewich said.

"It really is about developing a platform to host the data and the tools that will meet the mission objectives, which are to increase the access to plant breeders to the genomic information that's being generated," Bruskiewich said.

His office at UBC in Vancouver is just a five-minute walk from a year-old Compute Canada hub at Simon Fraser University. "We're going to try to build a web portal that will tie into the high-performance computing machines that they have just installed," Bruskiewich said.

The researchers will seek to improve data aggregation for the three crops. "One of the key problems that plant breeders often face is that they don't know where to get data because it's all over the world," Bruskiewich said. "Some of it maybe was published in a scientific paper and wasn't fully let out of the bag by the researchers."

The crops they picked do not have large, organized genomics communities like corn or wheat, and the researchers plan to implement workflows for association genetics for them.

"We are going to focus mostly on the next level, which is crop communities that aren't so large, don't have a lot of bioinformaticians at their disposal, and therefore don't have as much capacity to use the data effectively," Bruskiewich said.

For each crop, he said, DivSeek will have an association genetics map, and the quantitative trait loci will be indexed by ontology related to crops and traits. By integrating experimental results from breeders, he said, the hope is that breeders will get interested in the DivSeek resource.

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