The Behavioral and Functional Genetics Lab of Karl J. Clark, Ph.D., focuses on the development of genome engineering tools to interrogate the genetics of stress response and characterize patients' variant alleles that potentially contribute to a wide range of rare disorders. Dr. Clark's lab has four actively funded research projects and welcomes students to participate directly in these projects or to develop related projects that would blossom within the lab's rich workspace.
- Identifying genes that play roles in modulating the stress response. Researchers in Dr. Clark's lab have developed novel behavioral assays that allow for detection of phenotypic changes in larval zebrafish. They have used genome engineering to create novel mutations in critical hypothalamic-pituitary-adrenal (HPA) axis genes to validate behavioral suite, and now are producing conditional gene knockouts to further characterize HPA axis genes and to identify novel genetic modifiers involved in stress response.
- Expanding the leading edge of current genome engineering technologies to modify DNA and RNA in the mitochondria. Healthy mitochondria are critically important for health, including neural functioning and cortisol production. Mitochondrial disease affects about 1 in 5,000 people and can occur due to a wide number of potential defects in mitochondrial genes encoded by the nuclear or mitochondrial genome. Collectively, rare disease impacts about 25 million people in the US or about 1 in 17 individuals. However, the specific molecular cause of rare disorders may impact only a handful of individuals. This can make clinical diagnosis next to impossible. Patients from around the world travel to Mayo Clinic for diagnosis of rare disorders.
- Testing patient variants that may be contributing to rare disease. Dr. Clark's lab collaborates with the Center for Individualized Medicine's Translational Genomics Program. To understand the roles that patients' mutations play in the pathogenesis of rare disorders, researchers use a wide array of technologies including the development of cell culture or zebrafish models, which leverages genome engineering expertise. By characterizing biological consequences of patients' variant nucleotide sequences in various disease models and functional assays, the lab contributes to the diagnosis and understanding of rare disorders.
- Learning how early-life environmental stimuli are recorded to create long-lasting changes in the biology of animals. Advances in DNA sequencing, RNA sequencing and other big data analyses have provided new tools to aid in the diagnosis of the underlying causes of rare disorders. However, simply identifying a change such as a new DNA variant is not enough to know if that is the cause or simply an inconsequential change to the DNA. Therefore, functional testing in cells or animal models can help in the interpretation of newly identified DNA variants.
- Understanding how stressors and the body's response to stressors contribute to the onset and severity of disease. The clinical significance of stress-aggravated disorders is extremely high. Stress aggravation can occur when a stressor is too strong (acute), occurs too often (chronic), or alters long-term responses to future stressors through neural network or epigenetic transcriptome changes. The genetic and environmental interactions of the stress response system and the system's role in disease progression depend on heritable genetic factors, life-priming events and later life events that may trigger disease onset. Normal life-priming promotes adaptive resilience to stressors; however, both low and high exposures to stress can be maladaptive to the developing stress response system.
- Developing and testing cutting-edge genome engineering technologies that can be used to efficiently produce targeted integrations and conditional mutants in zebrafish. New genome engineering tools have become important for both understanding mechanisms of disease and for their potential to be used in targeted genetic or cellular therapies.
Significance to patient care
Dr. Clark's Behavioral and Functional Genetics laboratory contributes to the development of tools and research that aid in the better understanding of how the stress response system develops, how stress signaling impacts patients, and how defects in the mitochondrial genome might be corrected, and help identify variants that may contribute to rare disorders.
- President, International Behavioural and Neural Genetics Society, 2020-2022
- Co-founder, Lifengine Technologies, Inc., 2016
- Recipient, Outstanding Junior Faculty Travel Award, International Behavioural and Neural Genetics Society, 2014
- Recipient, Young Investigator Travel Award, Mini Convention: Frontiers in Addiction Research, National Institute on Drug Abuse, 2010
- Co-founder, Recombinetics Inc., 2008