The billions of chemical units of DNA that make up a human genome work in often mysterious ways in providing the instructions to build and operate all the cells in the human body. The Human Genome Project, which determined the order of those chemical units (also called nucleotides or bases), was completed nearly 13 years ago. So, what is left to understand? As it turns out - a ton! In fact, genome scientists are just beginning to scratch the surface of understanding all the intricacies of human genome function and how genomic differences influence health and disease.
The genome is not organized in a simple way - for example, it does not partition into a 'protein' part, a 'regulatory' part, a 'cancer' part, or a 'heart disease' part. Rather, different functions are encoded by bits of DNA that are essentially interspersed across the genome. This leaves researchers the challenging task of scanning the genome base-by-base, looking for clues in the DNA that might indicate the presence of functional elements. Such elements include genes that code for proteins and regulatory sequences that turn those genes on and off.
NHGRI's largest program dedicated to understanding how the human genome works is the ENCyclopedia of DNA Elements (ENCODE) Project. ENCODE was conceived just as the Human Genome Project was ending, aiming to build a robust understanding about the human genome beyond its sequence. The overarching goals of ENCODE included identifying and developing the best laboratory and computational techniques for finding functional DNA elements, applying them to analyze the human genome, and making the resulting data widely available.
Because the human genome is large and complex, ENCODE was started as a pilot in 2003, with an initial focus on a defined 1% of the human genome. After completing the pilot, ENCODE expanded in 2007 to work on the entire human genome, publishing a large set of findings in 2012. Substantial amounts of additional data and insights have been generated since then. At the same time, there is a growing need to understand what the genomic elements catalogued by ENCODE actually do.
To take stock of ENCODE's accomplishments to date and to help frame NHGRI's future research efforts in this area, the Institute held the program review workshop "From Genome Function to Biomedical Insight: ENCODE and Beyond" in March 2015. The recommendations emanating from this workshop included continuing genome-wide identification and cataloging of functional elements in the human genome - activities that were pursued in all previous phases of ENCODE. A new high-priority recommendation called for expanding efforts to understand how the functional genomic elements actually work. Such an effort will require that researchers test the catalogued elements to determine what roles, if any, they play in human biology. In addition, future efforts should examine the function of the elements in a range of biological conditions and diseases.
Following the workshop's recommendations, NHGRI will issue funding opportunity announcements (FOAs) for a five-part ENCODE program that includes: Functional Element Mapping Centers, Functional Element Characterization Centers, Computational Analysis Centers, a Data Analysis Center, and a Data Coordination Center. Through awards issued in response to these FOAs, expected to be made later this year, NHGRI hopes to continue ENCODE's strong tradition as a dynamic and productive research program.
In 2015, NHGRI launched two other programs to explore the function of the human genome. The Genomics of Gene Regulation (GGR) program aims to decipher the language of how and when genes are turned on and off, and how the molecules that regulate this activity work together. GGR will thus help scientists understand how regulatory elements and genes interact. In another program, NHGRI and the National Cancer Institute have awarded grants for developing new computational approaches that integrate data from many sources to help determine the functional consequences of genomic variants - differences in DNA between individuals. Such data would narrow the set of genomic variants, millions of which are known, down to a smaller number that might be relevant to human health and disease.
Through all these efforts, NHGRI hopes to foster research that increases our knowledge about functional elements in the human genome by cataloguing them, determining what they do, and establishing their connection to human biology. This body of work reflects yet another layer of complexity associated with the human genome. Fully understanding all of the genome's complexity will require the effort of multiple generations of scientists - well beyond my lifetime - but NHGRI envisions playing a leadership role for these efforts over the long haul.
Posted: February 2, 2016