Dr. Mark Clement, Department of Computer Science
Many of the most serious medical problems that plague humanity are caused by problems in the genetic regulatory network. Heart disease, cancer and many other maladies could be cured if we understood how genes interact with each other in order to produce different symptoms. Many of these problems are hard to deal with because all of the 20,000 or so genes in the human genome may be responsible for part of the problem. Down Syndrome is caused by three copies of chromosome 21 and results in heart defects, decreased brain function and abnormal jaw and finger proportions. Because the problem is limited to the 200 or so genes on chromosome 21, this problem provides a simplified arena where new algorithms for understanding gene regulatory networks can be developed. Our laboratory has developed an active group of around 10 undergraduate students who have developed novel approaches to understanding the Down Syndrome regulatory network. They have identified several genes that seem to be implicated in the interacting between chromosome 21 genes and jaw development genes. Our collaborator at Purdue/Indiana University has invited students travel to his laboratory to experimentally validate the computational methods we have used through wet lab experiments. This has provided a truly unique interdisciplinary experience that energizes researchers on both sides of the collaboration.
Several techniques have been used to experimentally determine the structure of pathways and the impact of genetic changes on protein production. Microarrays are available that can experimentally determine the concentration of mRNA at different times in the development of an organism. When microarray experiments were performed with Down Syndrome mice at various stages of development, no appreciable differences were seen between the levels of mRNA in normal mice. We hypothesize that some small increase or decrease in one of the products of a gene on chromosome 21 must disproportionately impact one of the pathways leading to symptoms commonly seen in Down Syndrome. If this project is successful, it could lead to treatments for Down Syndrome children during the developmental stages so the symptoms could be minimized. Some preliminary research has found that treatments that inject certain proteins into the brains of Down Syndrome mice during early developmental stages have resulted in more normal brain development in these mice.
This Mentoring Environment has allowed students to develop software to perform this pathway analysis. Most of the raw data has already been gathered and senior level Computer Science Students have performed the analysis. We are currently collaborating with Dr. Randall Roper from Indiana University/Purdue University at Indianapolis. Dr Roper breeds Down Syndrome mice and has produced microarray that our students have analyzed.
This mentored learning experience had the following specific aims:
Allow students to travel to perform wet lab experiments to validate their computational experiments.
Involve a large number (10+) of undergraduates in a research experience.
Develop pathway analysis software that can be used in investigating the causes of Down Syndrome
Submit a NIH grant proposal with the preliminary results obtained from this research.
Evaluation of how well the academic objectives of the proposal were met
Nathaniel Gustafson and Kendell Clement traveled to Purdue Indiana University Indianapolis and performed dissections and became familiar with the wet lab experiments being performed. We would have liked to have more students participate, but they were not able to fit it into their schedules. 8 students were involved heavily in the mentoring environment with several others involved peripherally. Two software projects were developed: Pathgen (http://dna.cs.byu.edu/pathgen) allows users to search for connections between genes. AIRNet analyzes microarray data and infers gene regulatory structures from the data. A NIH grant proposal was submitted with the preliminary results. Reviews have been received and we are currently in the process of resubmitting the proposal.
Evaluation of the mentoring environment
Our laboratory became the center of focus for students involved in the research. We had weekly meetings, but students were interacting throughout the week. The funds were used to hire students that kept things moving. They were able to mentor the other students involved in the project.
List of students who participated and what academic deliverables they have produced or it is anticipated they will produce
Nathaniel Gustafson, Amanda Berbert, Amy Glaves, Ryan Seamons, Gabe Proulx, Steven Flygare, Chris Merris, Kendell Clement. The following academic deliverables were produced in addition to the two software products discussed previously.
“Pathgen: Gene Regulatory Network Tool”, Kendell Clement, Nathaniel Gustafson, Chris Merris, Steven Flygare, Kenneth Sundberg, Mark Clement, Quinn Snell, Jared Allen, Randall J. Roper, Proceedings of the 2008 Joint RECOMB Satellite Conference on REGULATORY GENOMICS and SYSTEMS BIOLOGY, Broad Institute, MIT, Boston MA pp 123
“Asynchronous Inference of Regulatory Networks”, David Oviatt, Kenneth Sundberg, Mark Clement, Quinn Snell, Randall Roper, Jared Allen, Proceedings of the 2008 Joint RECOMB Satellite Conference on REGULATORY GENOMICS and SYSTEMS BIOLOGY, Broad Institute, MIT, Boston MA pp 199. Cat 3
Genome Scale Systems Biology for Down Syndrome, NSF MCB, $159,508 Genome Scale Regulatory Networks for Down Syndrome, NIH R21, $250,000
Description of the results/findings of the project
We have identified a number of pathways in the gene regulatory network that appear to be important in the development of Down Syndrome phenotypes. We also produced software that will be useful to other projects.
Summary account of how funds were used
Funds were used for student wages for research assistants and for travel.