Five Stanford Medicine faculty members received more than $ 40 million from the National Institutes of Health as part of a five-year, $ 180 million effort to understand how the human genome changes – those that affect sequence DNA, the three-dimensional structure and pattern of the chemical tags that regulate gene expression along its length – influence human health and disease.

The research should help clinicians better predict an individual’s risk of disease and provide clues to the molecular causes of poorly understood diseases.

The new consortium, the Impact of Genomic Variation on Function, brings together researchers from 30 institutions to identify, map and catalog regions of the human genome essential for its function. The goal of the consortium is an extension of decades-long efforts to find out how a person’s genetic code, associated with environment and lifestyle, affects that person’s likelihood of developing a wide variety of conditions.

The researchers are Professor of Genetics Mike Cherry, PhD; assistant professor of genetics Jesse Engreitz, PhD; assistant professor of genetics and computer science Anshul Kundaje, PhD; assistant professor of pathology Ansuman Satpathy, MD, PhD; and professor of cardiovascular medicine Thomas Quertermous, MD.

Since the first sequencing of the human genome in the early 2000s, researchers have identified tens of thousands of variations associated with the disease, typically by comparing the complete DNA sequences of many people and identifying specific changes that occur more commonly in people with a disease or medical condition.

Some of the variations identified alter the structure – and therefore the physiological function – of the protein encoded by a gene in the DNA sequence. Others occur in regulatory regions that control how and when certain genes are expressed. Still others alter the three-dimensional structure of the genome or the prevalence of chemical tags on DNA that control gene function.

In some cases, these changes may be directly linked through molecular pathways to the development of a disease under study. Sickle cell anemia, for example, is caused by a single mutation in the gene that encodes a protein in red blood cells called beta hemoglobin. Mutated beta hemoglobin molecules fold back incorrectly, forcing the red blood cell into a sickle shape which inefficiently delivers oxygen and causes pain, fatigue, and other symptoms in patients.

Zoom on the variants

But more than 90% of the variants occur in non-coding regions of the genome, and it is still unclear whether or how many of them are linked to specific disease processes. Consortium members will use laboratory methods and computer modeling to discover the functions of these variants.

Satpathy received $ 13 million to launch the Single-Cell Mapping Center for Human Regulatory Elements and Gene Activity. Researchers at the center will generate an open-source map detailing the elements of genetic regulation, the three-dimensional structure of chromatin, and gene and protein expression profiles of individual cells in a variety of organ systems and tissue types, both in healthy people and those with various diseases related to the immune system.

Engreitz and Quertermous were awarded nearly $ 8.5 million to jointly lead the Stanford Center for Connecting DNA Variants to Function and Phenotype. Their goal is to interpret how non-coding regions of the human genome are associated with the development of specific heart disease in adults and children. They will use genetic mapping, genetic engineering and computer methods to understand the link between genomic variation in regulatory elements of cardiovascular cells and their structure and function. These new connections will be used to catalog the effect of variants in many human cell types and diseases.

“It is a great pleasure to be part of this network of highly accomplished scientists in a joint effort to decipher the regulatory framework of the human genome,” Quertermous said. “The consortium’s knowledge will dramatically accelerate efforts to understand how single-nucleotide changes affect human traits and complex diseases. ”

Likewise, Kundaje received nearly $ 4 million to predict the effects of genetic variation depending on its context and location in regulatory regions. “Ultimately, our machine learning models will generate a high-resolution functional sequence map of the human genome that will identify, for any cell type, cell state or location in the body, which non-coding variants affect the regulation of which. neighboring genes, and what those effects are, “Kundaje said.” Such a map will allow us to take advantage of the recent explosion in genome sequencing and molecular profiling techniques to understand the genetic basis of the disease. “

Over $ 18 million has been awarded to Cherry and Mark Gerstein, PhD, professor of biomedical informatics, molecular biophysics, biochemistry and informatics at Yale University, to co-lead an administration and coordination center Datas. They will evaluate and coordinate the use of data and new software generated by the consortium and maintain a database of results for use by the biomedical research community.

“The guiding principles of this consortium are open science, open data and open source software,” Cherry said. “This is a critical part of the consortium, bringing together researchers from across the country to generate complex types of data through new experimental tests, many of which focus on the level of gene expression of a single cell. The center will help make this complex, high-quality data interoperable, findable and accessible. “