Stephanie Morris, PhD, is a Program Director in NHGRI’s Division of Genome Sciences. She manages a portfolio of grants and initiatives in technology development and functional genomics, including the ENCODE program. Below, Dr. Morris describes a new program launched by NHGRI — the Impact of Genomic Variation on Function Consortium — which aims to advance understanding of genome function and its contributions to human health and disease.
ASHG: What is the central problem that the Impact of Genomic Variation on Function Consortium (IGVF) will tackle?
Morris: The IGVF consortium’s goal is to understand how DNA variations across one’s genome (a person’s complete set of DNA, including genes) affect genome function, which in turn affects a person’s health and likelihood for developing certain diseases. Genomic variants are the differences that appear in the “letters” of the DNA sequence — the As, Cs, Gs and Ts that make up the genetic code. The order of these letters is commonly regarded as the recipe for life, and genome function is the output of this recipe. Ultimately, the genome’s role is to provide instructions on how to make all of the different cells in a body and put them together to make a person.
Our DNA sequence is more than 99.9 percent identical to other people; the small variations, along with environment, determine a person’s physical features and their risk for developing certain diseases. Researchers spent many years identifying genomic variation between people and populations, and also associating particular variations with specific diseases. Their efforts have led to breakthroughs in our ability to detect variations from one individual to the next; as a result, researchers have identified millions of genomic variants. This is essentially the difference between our genomes, which can vary in size, and determine if they have an impact on our health. Research efforts have also increased our ability to determine the specific variations associated with disease. The genomic community has identified tens of thousands of these disease-associated variants. The National Human Genome Research Institute (NHGRI) recognizes the challenge of interpreting how these variants influence a person’s health. The IGVF consortium, in partnership with others, will focus on this main problem and how best to address it.
ASHG: What opportunities are available to researchers who are interested in the IGVF consortium?
Morris: To ensure that the genomics workforce is represented by people from across cultures and populations, NHGRI is on a mission to have the genomics workforce reflect the diversity of the human population. The IGVF consortium will require a broad range of approaches and expertise to address the scientific problem, and a diverse workforce will enable new and different perspectives and approaches. In addition to genomics, the study may require expertise in applying new technologies and knowledge from other fields, including machine learning/artificial intelligence, cell biology and gene regulation. NHGRI can better recruit these types of expertise when we encourage a broader range of people to apply. Our goal is to hear from new and early-stage investigators, including those who have not previously participated in an NHGRI-consortium or program. NHGRI is making a concerted effort to receive applications from investigators with underrepresented demographic or institutional backgrounds. Our teams should involve experienced investigators who may be new to genomic science. NHGRI recognizes that the genomics field needs new ways of thinking, and the field can only progress by intentionally pushing for such diversity.
ASHG: What knowledge will the studies from the consortium add to the field of genomics?
Morris: The IGVF consortium will help researchers and clinicians interpret a greater portion of the available information on genomic variants and how they relate to specific diseases. Some genomic changes have no effect on a gene, while others will change a gene’s function or activity. The IGVF consortium has five objectives that will improve our understanding of which genomic changes are important and how they work:
- The consortium will use model systems of the human genome to make experimental changes in the genomic sequence and learn which changes matter and what they do.
- The consortium will identify where and when genes function.
- Because current laboratory approaches cannot test for all variants, the consortium will develop predictive models of the impact of genomic variation on genome function.
- The consortium seeks to understand how combined elements in genomic recipes work together to create even more complex outcomes in the human body.
- The consortium will develop a catalog of how genomic variation impacts function. The IGVF will share this catalog and their approaches with the broader research community, which will allow others to perform related studies.
ASHG: How will results from the studies be integrated into healthcare?
Morris: The IGVF consortium will provide new lines of evidence that clinicians can consider when they determine how genomic variation may affect patient health. Today, clinicians rely on statistical correlations that link genomic variation to disease, which have proven valuable. However, of the tens of thousands of disease-associated variants, researchers have only specifically identified a small number of these variants. The consortium will study and characterize thousands of genomic variants and determine which of these directly impact health and disease, which will greatly expand the evidence available to clinicians. Ultimately, the IGVF consortium intends to partner with organizations offering resources that develop and catalog genomic variant association with several diseases, such as ClinGen. This way, the consortium will share new evidence with clinicians in a manner that they could readily put to use.