Current sequencing technologies make it possible to obtain the entire genetic code of an individual or agriculturally important plant in a matter of days. Typically, millions of genomic changes are identified, each of which must be examined and interpreted to detect the handful of variants with significant clinical or agricultural consequences. Often the process detects DNA variants that are not well understood because they have not been studied. A DNA variant of uncertain significance, or VUS, undergoes extensive analysis and testing to determine whether it has a role in the development of a trait or disease.

The VUS interpretation process is critically important yet, at times, painstakingly slow. Enormous amounts of genomic data are being generated in clinical and research laboratories like HudsonAlpha, meaning the number of variants awaiting deeper categorization continues to grow.

During a CODE project, trained faculty facilitators mentor their students in research projects to characterize DNA variants of uncertain significance previously identified at HudsonAlpha or curated from public databases. Analyzing a VUS involves both computational and experimental research to explain how a specific change in the DNA sequence might affect the function of a protein and, in turn, the health of a human, plant, or animal. Students are encouraged to study genes that are of interest to them. CODE facilitators have taught these research projects as labs, units in a related class, individual assignments, or full-semester courses.

 Recognizing that many universities and colleges have minimal budgets for lab-based research, CODE utilizes computer-based toolsets that require minimal startup expenses but allow for real and significant contributions to science. Facilitators from participating schools will be trained in the DNA variant analysis pipeline during a two-day workshop led by HudsonAlpha researchers and educators.

HudsonAlpha provides facilitators and students with sequence data (gathered from de-identified patient samples) and any relevant background information. In addition, a series of online video and print tutorials developed at HudsonAlpha support facilitators as they guide students through the analysis pipeline. Students use publicly available databases and specialized software to examine each DNA variant and its surrounding sequence, align multiple DNA and protein sequences to study evolutionary conservation and structural comparison, model the protein’s structure, and run molecular dynamics simulations. Finally, they use this information to make predictions regarding the functional consequence of the DNA variant. Some schools may extend the research beyond CODE and combine computational analyses with biochemical, molecular, and physiological techniques to experimentally test a student’s predictions.

 Students are encouraged to document their work and findings related to their genetic variant in a written report to be submitted to and discussed with the HudsonAlpha team. All student and faculty participants are invited to attend an annual symposium at HudsonAlpha to share their work, interact with other participating institutions, and learn from researchers in the field. Participating colleges and universities are encouraged to incorporate this project into their course curriculum, providing students with credit hours towards their degree and authentic research experience. A clearly defined policy of authorship sharing for resulting scientific publications and intellectual property rights has been established, designed to recognize the important role students and advisors will play in contributing to the scientific body of knowledge.