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Genetic Variation Influences Response to Environmental Exposure

By Omari J. Bandele
February 2010

Threadgill spoke to a diverse group of scientists gathered in the Keystone conference room and, by a voice link, to scientists off-site. (Photo courtesy of Steve McCaw)

David Balshaw
Host David Balshaw, center, sat with colleagues from the NIEHS Division of Extramural Research and Training - sponsors of the Keystone Seminar Series. (Photo courtesy of Steve McCaw)

A better understanding of genetic variation, Threadgill noted, could help scientists conducting clinical trials anticipate adverse reactions to drugs, as in the example mentioned in his slide, above. (Photo courtesy of Steve McCaw)

Stan Stasiewicz
Biologist Stan Stasiewicz of the NIEHS Host Susceptibility Branch was one of several veteran bench scientists on hand to learn about Threadgill's work refining mouse strains to enhance extrapolation to human health. (Photo courtesy of Steve McCaw)

On Jan. 14, NIEHS grantee David Threadgill, Ph.D., explored "Preclinical Modeling of Environmental Exposures" during the latest installment of the NIEHS Keystone Science Lecture Series, hosted by Program Administrator David Balshaw, Ph.D. Threadgill's research focuses on understanding how genetic variations within the human population modulate response to environmental exposure and how to utilize new mouse strains that more closely approximate this modulation in laboratory experiments.

"We need to rethink the way experimental mouse models are used in order to better model the human population," Threadgill argued. "This will allow us to obtain more relevant information and improve our understanding of the human response to environmental exposure."

Expanding toxicology studies to include genetic variation

Early in his presentation, Threadgill( Exit NIEHS, who is chair of the Department of Genetics at North Carolina State University, observed that most toxicological studies focus primarily on dose-response curves and other dose-based parameters, largely overlooking the contribution of genetic variation to the observed responses.

To address this shortcoming, Threadgill and colleagues in the Collaborative Cross project developed genetically diverse populations of mouse strains that capture variability across the entire mouse genome. He believes these mice will improve predictions of how human genetic variation modulates susceptibility to environmental risk factors. "Every human is a carrier of a specific genome, and that genome dictates how individuals respond to an environmental exposure," Threadgill explained. "We can synthetically model this in the laboratory."

Threadgill highlighted the fact that the common inbred - genetically identical - mouse strains widely used as experimental models represent only 30% of the genetic variation known to exist in the mouse genome. This inherent limitation reduces the utility of these common inbred mouse strains in studies that examine the effect of genetic variation in a population.

Translating work with mosaic strains into potential applications with humans

The genetically diverse mouse models were generated by mating eight different inbred strains. This approach produced hundreds of mosaic strains, which represent 90% of the genetic variation found in mice and capture a large number of unique allele combinations not present in existing mouse models. According to Threadgill, these mosaics are better models for the human population. He believes they will allow investigators to interrogate genes in concert with environmental perturbations to examine the responses in an individual and a population.

Using this experimental model, Threadgill and colleagues demonstrated that the genetic makeup of mice influenced their propensity to exercise, as well as their clinical outcomes. Overall, physical activity correlated with weight loss. However, some outliers were highly active yet still gained weight - while others that were less active maintained or lost weight when provided the opportunity to exercise. Threadgill contends that novel allele combinations contributed to these unexpected cases and that this scenario may also occur in the human population.

Threadgill believes variations in allele combinations contributed to the unexpected cases also seen in a study involving severe acute respiratory syndrome (SARS) and other infectious agents. In this study, lung function was used as an indicator of the level of sickness in the mice. Researchers found that as some strains lost weight during infection, the mice still had normal pulmonary pathology - while others showed the opposite pattern.

In conclusion, Threadgill provided examples of planned projects where the mosaic strains could aid in explaining clinical cases that may be influenced by human genetic diversity. One such study - through the Women's Health Initiative - involves the increased incidence of breast cancer observed in women on postmenopausal hormone replacement. Using his mouse models, Threadgill hopes to elucidate whether this phenomenon represents a general population risk or whether it is possible to identify a subset of women who are genetically susceptible to adverse effects from hormone replacement.

(Omari J. Bandele, Ph.D., is a postdoctoral fellow in the NIEHS Laboratory of Molecular Genetics Environmental Genomics Group.)

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