A genome engineering technique developed at UT Southwestern Medical Center helped make the institution a research partner in a new $185 million National Institutes of Health (NIH) initiative to build on findings of the Human Genome Project.
A team of UT Southwestern faculty led by Gary Hon, Ph.D., Assistant Professor in the Cecil H. and Ida Green Center for Reproductive Biology Sciences, has been awarded a five-year, $8.8 million grant to participate in the National Human Genome Research Institute’s Impact of Genomic Variation on Function (IGVF) Consortium, which seeks to understand how developmental variants contribute to developmental diseases.
The UTSW team, which also includes principal investigators Nikhil Munshi, M.D., Ph.D., Associate Professor of Internal Medicine and Molecular Biology, and W. Lee Kraus, Ph.D., Professor and Director of the Green Center, will combine molecular biology, genomics, high throughput screens, and computational analyses to focus specifically on potential disease-causing genetic variations in the cardiovascular, nervous, and placental systems.
Mosaic-seq, a technique used for this work, was developed by Dr. Hon, Assistant Professor of Obstetrics and Gynecology and member of the Lyda Hill Department of Bioinformatics. Dr. Hon also is a member of the Harold C. Simmons Comprehensive Cancer Center and is a Cancer Prevention and Research Institute of Texas Scholar who was recruited to UT Southwestern in 2014 with a $2 million grant.
Mosaic-seq allows high throughput analysis of the molecular events that occur during programming of embryonic stem cells into other cell types. This technique uses single-cell sequencing to study different regions of the genome at the same time. Just one experiment can perturb thousands of regions in the genome to better understand their function. With Mosaic-seq, researchers no longer have to study one region at a time. Dr. Hon’s laboratory received national attention in 2017 for this powerful advancement, part of his team’s grant application.
Thirty research sites across the U.S. – including Harvard, Stanford, and Yale universities – will collaborate in the IGVF Consortium to study noncoding regions of the human genome that are known to contribute to genetic diseases such as congenital heart disease, autoimmune disease, and blood disorders.
Dr. Hon said the IGVF Consortium is the National Human Genome Research Institute’s next step to unveiling the genome’s role in disease.
“The Human Genome Project told us that most of the genome doesn’t contain genes. One big surprise from genome-wide association studies is that gene-poor regions contain many disease signatures,” Dr. Hon said. “It turns out that the signatures largely overlap with DNA elements, found by the Encyclopedia of DNA Elements (ENCODE) Consortium, that control when genes turn on. The goal of this consortium is to fill in the gaps, linking DNA sequences to genes, cell phenotypes, and disease. Ultimately, this knowledge will allow us to interpret the disease potential of any person’s genome sequence.”
Dr. Munshi said he is especially interested in what light the project can shed on congenital heart disease.
“There are mutations in the noncoding part of the genome that seem to be associated with congenital heart disease, but we don’t have a smoking gun linking those mutations with the defects,” he said. “We will test whether these mutations in the noncoding part of the genome have a functional impact on heart development. We will reiterate that, testing for the neuronal system and the placental system.”
Dr. Kraus, a Professor of Obstetrics and Gynecology and Pharmacology who holds the Cecil H. and Ida Green Distinguished Chair in Reproductive Biology Sciences, will use additional CRISPR-based technologies to study how genetic variation in non-coding RNAs originating from the regulatory elements impacts the development of the placenta, a key organ that supports the fetus as it grows, as well as the heart and central nervous system.
“Studying the role of genetic variation in the embryonic development of these key organs could point the way to understanding human diseases in adults,” Dr. Kraus said.
Dr. Munshi said the (IGVF) Consortium initiative potentially could fill in huge pieces of the puzzle for many diseases.
“If we can determine all of the noncoding elements in the genome that impact a particular developmental pathway, then those could become candidates for disease-associated mutations,” he said. “By generating catalogs of tens of thousands of functional variants, we don’t have to search the billons of base pairs to find where the disease-causing mutations might lie. We can really focus the search on these tens of thousands of variants. It really gives us an encyclopedia to narrow the search.”
