N.L. prepares to raise the bar in bench-to-bedside genomics

The new multimillion dollar Centre for Translational Genomics is operated by Eastern Health and housed, here, on the third floor of the new medical building of the Faculty of Medicine, Memorial University, St. John’s. Photo credit: MUN

The pieces are coming together that could soon make Newfoundland and Labrador a leader in bench-to- bedside genomics, with the capacity to attract significant research and to change the lives of many Canadians and others with genetic-based disorders.

Central to this vision, doggedly pursued for a decade by molecular geneticists, Drs. Darren O’Rielly, at Eastern Health, and Terry-Lynn Young, at Memorial University, is the new multimillion-dollar Centre for Translational Genomics in St. John’s. A joint initiative by Eastern Health and Memorial University, the CTG will be operated by Eastern Health.

The CTG’s suite of gene sequencing equipment, housed in the university’s medical school, is now undergoing validation. The star of the impressive collection is an Illumina NovaSeq 6000, the highest throughput second-generation sequencer on the market. 

Dr. O’Rielly, now the centre’s director, expects all systems will be firing by fall, or early next year, for a phase-one focus on hereditary diseases.

When it comes to capability, he said, “We have a full gamut for a comprehensive array of services to both researchers as well as clinicians,” he said.

For two molecular geneticists, Dr. Terry-Lynn Young, Memorial University and Dr. Darren O’Rielly, Eastern Health, the new Centre for Translational Genomics is a dream come true for their home province, Newfoundland and Labrador.

When fully operational, the CTG, will offer clinical germline and somatic testing, in addition to a range of different sequencing options. Germline mutations are inherited while somatic ones are not. Somatic testing is usually done on tumors, often to provide personalized care.

No longer will the majority of samples have to be shipped outside the region for sequencing and analysis. This change alone, once the CTG is fully functioning, promises faster turnaround times for researchers, clinicians and patients.

Primarily conceived as a Newfoundland and Labrador enterprise, the centre has a close secondary aim to serve Atlantic Canada. To help realize the project, Genome Atlantic supplied a letter of support to tap the Atlantic Canada Opportunities Agency’s (ACOA’s) Atlantic Innovation Fund.

In addition, Genome Atlantic accessed its Genomics Opportunity Review Program to fund a business case assessment to support the ACOA submission. “That was really helpful,” said Project Co-Lead, Dr. Young. “It gave both us and our funders, and the institutions involved, confidence that what we were building would actually have clients at the end of the day, besides just Eastern Health – just the health care providers.”  

Funding for the CTG came from the Atlantic Canada Opportunities Agency, via its Regional Economic Growth Through Innovation program; from the Government of Newfoundland and Labrador, through the Department of Industry, Energy and Technology; and from the Health Care Foundation of Newfoundland and Labrador, as  well as the Janeway Children’s Hospital Foundation, the Dr. H. Bliss Murphy Cancer Care Foundation, Eastern Health and Memorial University.

“In phase two, which is focused on sporadic diseases that includes most cancers,” Dr. Rielly explained, “there is an opportunity to partner with several of the different big pharma companies. And there’s also other companies in this realm, within Atlantic Canada, that have expressed an interest and willingness to use our centre as well.”

Generating researcher interest in the new centre should pose few difficulties, given the province’s extensive population of genomic isolates – that is, inhabitants separated into distinct groups that have historically avoided genetic mixing through intermarriage for various reasons, including geography. Sometimes referred to as Newfoundland and Labrador’s founder population, it includes the province’s indigenous residents and those whose trace their ancestry to the European settlers. For anyone in genetic research, this is a dream population begging for study.

Equally attractive will be integrated research and clinical services, a key objective that Drs. O’Rielly and Young are working hard to facilitate.

They are hoping to significantly cut the time between the discovery of a gene-caused medical condition and the clinical response, by periodically re-analyzing sequencing data on patients. This would be done as new knowledge is translated from peer-reviewed research in the literature and in-house data confirm a genetic variant to be the source of a specific medical disorder. The move would end the need for multiple retests and shave years off the current gap between gene discovery and clinical action.

Dr. Young traces the impetus for the CTG to her experience with Arrhythmogenic Right Ventricular Cardiomyopathy or ARVC, a genetic heart disease that can trigger sudden death. It affects a great many Newfoundlanders and Labradorians, and in 2008 Dr. Young and her colleagues chased the cause to a single mutation on a single gene, TMEM43.

The potential hit home, she said, “once we realized if we could connect both the research side and the diagnostic side…we could really make a huge impact.”  They connected those dots and today, a simple blood test can diagnose ARVC, and an implanted defibrillator can protect sufferers from cardiac death.

With the centre established, work is now focused on generating projects, building networks of researchers and bioinformaticians as well as partnerships and collaborations to actualize their vision of a centre for Canadian excellence in translational genomics. Work is proceeding apace on all fronts.

“We’ve got a huge project now with the Terry Fox Institute Marathon of Hope Initiative, where they’re looking at all the different types of mutations that happen to single genes and to many genes within tumors, cells and tissues,” said Dr. Young. “All the Atlantic provinces are working together as one node,” Dr. O’Rielly said. The massive project is being divided up among different institutions in the region to keep the work in Atlantic Canada, he added.  The Atlantic node of the initiative is Dr. Sherri Christian, Department of Biochemistry, Memorial University.

Collaborations and partnerships have already been established with colleagues at the IWK Health Centre in Halifax, N.S. Dr. O’Rielly said they are looking at common challenges, sharing resources and datasets, as well as working to establish common practices, so that the CGT can eventually process samples from the IWK seamlessly and the two organizations can provide backup for each other.

Undoubtedly, the centre will be a regional asset, but the major beneficiaries are expected to be Newfoundlanders and Labradorians, due to their close proximity to the CTG and their ease of access to the new services provided through Eastern Health. Research on the province’s genetic isolates, which includes most of its residents, is also expected to grow exponentially now because of the CTG.


Genomic Evaluations On the Way for Milking Shorthorns

After many years in the background of Canada’s Holstein-dominated dairy industry, Milking Shorthorns have begun to attract the attention of a growing number of dairy producers.

Breeders, represented by the P.E.I.-based Canadian Milking Shorthorn Society, are seizing the moment to elevate their dairy breed with genomic evaluations. The move will level the playing field for Milking Shorthorns with Canada’s five other established breeds of dairy cattle. These animals, all registered, have genomic evaluations accessible through Lactanet, a farmer-run organization. 

Ryan Barrett, the society’s secretary-manager and an enthusiastic booster of Milking Shorthorns, explained: “we want to build a reference population in order to hopefully start offering genomic evaluations for our breed very soon.”

To get started, the society landed a grant through the Small-Scale Climate Change Fund set up by Genome Atlantic and supported by Research Nova Scotia. The money has allowed the society to begin work with Milking Shorthorn breeders in the Maritimes to genotype their animals  – that is, to do a complete genetic workup on each animal by way of DNA analysis.

Milking Shorthorn dairy cattle on pasture at Oceanbrae Farms near Miscouche, Eastern Prince County, P.E.I. Photo credit: Ryan Barrett.

This groundwork will supply a template for additional genotyping of other Milking Shorthorn dairy cattle across the country, as well as for testing genetic material from existing gene banks.

The aim is to help breeders improve the quality of their Milking Shorthorn herds through genomic selection, a faster, more precise and reliable way to improve dairy herds with desired attributes that generally revolve around milk production, reproduction, longevity and health.

Why the revived interest in the Milking Shorthorn? The breed, once known as Durhams or Dual-Purpose Shorthorns and considered one of the oldest recognized cattle breeds in the world, are gaining new recognition for their climate-friendly qualities in an era of climate change. With greater efficiency they turn forage into milk with higher percentages of fat and protein than the industry standard Holstein breed.

Rated ideal for farms using rotational grazing, Mr. Barrett said the Milking Shorthorn “generally last longer, have fewer health and breeding problems and have a quiet temperament.” He added, “While Milking Shorthorns rarely produce as much milk as Holsteins, they make up for it with lower input costs.”  

Even by 2022 standards, Milking Shorthorns are high achievers, which is perhaps all the more surprising for a breed developed in the late 1700s in Northwest England in the Valley of the Tees River, bordering the counties of Durham, Northumberland and York. 

“In recent years, we have seen more Canadian dairy producers who have started to reconsider the Milking Shorthorn, either as part of a mixed herd or as a dominant breed in their herd,” said Mr. Barrett.

Without the benefit of genomics, he explained, genetic evaluations must rely solely on information about an animal’s lineage and its progeny’s performance.

“Depending on how much data has gone into that animal’s genetic evaluation, the reliability of an individual animal’s evaluation will vary,” he said. “For example: a proven sire with thousands of daughters across the country will have a reliability over 95 per cent. On the other hand, a newborn calf only has the average performance of its parents, so it starts with a reliability of 30-40 per cent. “

With this method, the reliability of the rating depends on the time it takes to establish the data.

By comparison, genomics substantially improves the reliability factor while dramatically reducing the time involved to supply results with greater precision. “By doing a genomic test of an individual animal from a hair or other tissue sample and identifying how that animal will code for more than 65,000 markers (SNPs) that are commonly used in dairy cattle,” he said, “we can compare that animal’s genetic profile against other genetic profiles, identify individual SNP’s or groups of SNPs with favourable or unfavourable performance for a number of traits and improve the reliability of genetic evaluation without that animal having to be calved, and having a milk record etc. This provides the dairy producer with more reliable information to chose how to breed his cattle, which cattle to keep for replacements, which to sell, etc.”

The Canadian Milking Shorthorn Society is betting that genomic evaluations for the Milking Shorthorn will ensure the moderate-sized cows with the climate friendly advantage will gain even greater traction on Canadian dairy farms.

Certainly, the Milking Shorthorn is a firm favourite with Mr. Barrett and his family. His grandfather, Keith, purchased his first one in 1950 and since then the breed has remained at the heart of Oceanbrae Farms, now run part-time by Mr. Barrett and full-time by his brother, Matt, and their father, Fred, on the southern shore of Malpeque Bay, near Miscouche, in Eastern Prince County.

Oceanbrae Farms was recognized for having a Master Breeder herd in 2008 and the operation is said to be in the running to claim the title again this year, a significant year for Milking Shorthorn advocates everywhere.

This year marks the 200th anniversary of the Coates Herd Book, the first cattle herd book ever produced, “Containing the pedigrees of Short-Horned Bulls and Cows Etc. of the Improved Durham Breed.” It is a reminder of how important genetic improvement has been for the Shorthorn breed and the potential that lies ahead with genomic evaluation.