Dr. Christine Queitsch: 'It is quite clear that the approaches used to interpret these variants and commonly used cell lines are not sufficient. Human cell lines are not human beings.'
There are about 8.2 billion people in the world and each one has their own set of common and rare genetic variants. Moreover, environmental exposures determine each person’s risk of disease and potential prognosis.
This presents both challenges and opportunities for researchers, as articulated in the white paper, “Understanding Genetic Variants in Context,” published December 3 in the journal eLife. Authors include several BBI faculty; Christine Queitsch, Ph.D., is a Corresponding Author.
“Our white paper states the challenges as we see them,” said Queitsch, a professor in the UW Department of Genome Sciences. “There are so many variants in human populations and we do not yet understand their effects on phenotype and disease risk. Variant mapping is about 10 years old, and although we have made great strides, it is quite clear that the approaches used to interpret these variants and commonly used cell lines are not sufficient. Human cell lines are not human beings.”
In addition to Queitsch, other BBI authors are: First Author Nasa Sinnott-Armstrong, Lea M Starita, Cole Trapnell, Judit Villen, and Doug Fowler; Stan Fields of UW Medicine, and Frederick (“Fritz”) Roth from University of Toronto and now with University of Pittsburgh. Most are Principal Investigators on the UW’s Center for Excellence in Genome Sciences, one of several such centers funded by the NIH’s National Human Genome Research Institute.
“We wanted to use this paper to think about where we are as a field and where we need to be,” she said. “We wanted to explore what has happened theoretically, but also technology-wise, in the field, and how could this inform our own research, our own efforts, moving forward.”
Moving forward, the authors state, means pursuing “mechanistic insights into variant effects to separate confounding from causal association, conducting multiplex assays of variant effect (MAVEs) in context offers the promise of scale and systematic analysis.”
“The more contextual multiplex variant functional data becomes available, the more modeling approaches that rely on vast datasets, such as machine learning and artificial intelligence, can be used to infer variant-specific and context-dependent biological mechanisms, thereby informing individualized predictions of disease risk for rare and common diseases and facilitating their prevention and treatment,” the paper states.
Moreover, their paper emphasizes the significant role the environment plays in the effects of genetic variants.
“Because human genetic makeup has not fundamentally changed in the last 50 years, changing environmental context has either altered the genetic contributions of a subset of polymorphisms or shifted the liability threshold for these disorders,” the authors write. “Fundamental recent changes to environmental context include altered pathogen exposure and microbiomes through increased hygiene, refrigeration, and antibiotics; radical dietary shifts toward industrially produced food; and environmental stress through artificial light, house dust, and harmful chemicals. Although we posit that environmental context is more crucial than genetic or developmental context for understanding variant penetrance and expressivity, environment is also the hardest context to fully define and measure in the laboratory.”
One can argue that the paper’s thesis is found in the Abstract: “Having a unified understanding of the molecular, physiological, and environmental processes governing the interpretation of genetic variants is sorely needed for the field, and this perspective argues for feasible approaches by which the combined interpretation of cellular, animal, and epidemiological data can yield that knowledge.”
So, what will it take to achieve that “combined interpretation of cellular, animal, and epidemiological data can yield that knowledge?”
“That depends to a great extent on how much the taxpayer – and the government of the United States of America – is willing to invest in this problem,” Queitsch said. “It is the fundamental challenge of our time.”
