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Introduction

It has been 25 years since the first complete genome of an organism was sequenced—that of the bacteria Haemophilus influenzae in 1995 (Fleishmann et al., 1995). It was followed quickly by the genomes of other bacteria and then organisms of increasing complexity—the nematode Caenorhabditis elegans in 1998 (C. elegans Sequencing Consortium, 1998), the fruit fly Drosophila melanogaster in 2000 (Adams et al., 2000), the laboratory mouse Mus musculus in 2002 (Chinwalla et al., 2002), and humans in 2004 (International Human Genome Sequencing, 2004). The ability to sequence whole genomes of organisms—a process that has become faster and less expensive with each passing year—has opened a golden age of biology, with researchers discovering much that had previously been out of their reach.

However, as pointed out by Donal Manahan, director of the Division of Integrative Organismal Systems at the National Science Foundation (NSF), even after decades of intense work, researchers still do not understand the functions of all of the genes in any organism and exactly how the information in genes is transformed into an organism’s phenotype, its physical characteristics. “Why has this been so complicated?” he asked. “It’s fair to say that this might be viewed by many as the biggest gap in biological knowledge—our inability to predict the phenotype of a cell or an organism from what we know about its genome and its environment.”

Manahan was speaking at the opening session of a workshop at the National Academies of Sciences, Engineering, and Medicine in Washington, DC. Held from February 10–12, 2020, the workshop was sponsored by NSF with the goal of determining the current state of the science of

functional genomics. Functional genomics was defined in the context of this workshop as the biological field concerned with understanding the connection between the information contained in an organism’s genome and its physical characteristics. Understanding phenotypes from genomic information is increasingly done with broad genome-wide-, or “-omics-,” style approaches. The workshop aimed to understand what is needed for the field of functional genomics to move forward (see the Statement of Task in Appendix A).

IMPORTANCE OF FUNCTIONAL GENOMICS

In his remarks, Manahan mentioned an interesting editorial published in Nature Genetics titled “A Focus on Function” (2000). The article recommended a focus on developing a “molecular intelligence,” the ability of researchers to understand and predict how genes contribute to physiological processes. But what is most striking about the article, he said, is that it was published 20 years ago, in July 2000. So even at the beginning of the 21st century, there was a community conversation about function. “And here we are 20 years later hopefully narrowing that down in many ways.”

NSF funded the workshop, Manahan said, because it is interested in obtaining guidance from the scientific community concerning how to move the field of functional genomics forward. The information NSF sought from functional genomics researchers “will help us develop new approaches as a community, to address how best to develop a predictive understanding of properties of living systems.”

Gene Robinson of the University of Illinois at Urbana-Champaign, who chaired the workshop’s organizing committee, then offered some additional background concerning the workshop. The field of genomics has two main thrusts: discovery genomics and functional genomics. Discovery genomics is “roaring ahead,” he said, and is well into the 21st century. Functional genomics, by contrast, has barely made it into this century. Most of the tools and techniques available in functional genomics allow researchers to work only at the level of single genes or small numbers of genes, while researchers in discovery genomics have the tools to see patterns at a much larger scale. It is one of the holy grails in biology, Robinson said, to be able to predict function from genetic sequence, including understanding the role of the environment and its interaction with the genome. “In order to be able to do this, we need these large-scale, discovery-oriented projects,” and those in turn will require the development of much better tools. “That’s what we’re calling functional genomics.”

WORKSHOP OUTLINE AND OBJECTIVES

Robinson then listed the workshop’s objectives for the audience. They were to

• Understand the successes and failures in functional genomics research in a variety of research organisms—what tools helped investigators succeed and what tools still do not exist or need development for future research success.
• Discuss considerations for selecting experimental systems as well as research approaches that leverage all functional genomics–related scientific disciplines.
• Understand research strategies for determining factors (genetic, epigenetic, environmental, etc.) that influence phenotype.
• Discuss possible “rules of life” to guide baseline and comparative questions across the different realms of microbes, animals, and plants.
• Look at advantages and disadvantages of currently available consortia and databases as well as discuss emerging tools and databases that might not be widely available.
• Think critically about the training needs for future genotype-to-phenotype researchers.
• Discuss short- and medium-term research and knowledge goals, noting potential strategies to reach these goals.

With that, Robinson provided a quick outline of how the workshop would proceed. The first day would begin with a keynote address designed to set the stage for the rest of the workshop. It would be followed by individual sessions that focused on case studies of building and using functional genomics tools, defining “model systems,” understanding the contributions of non-protein-coding DNA to phenotype, and the societal and ethical implications of functional genomics research.

This proceedings was prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. The planning committee’s role was limited to planning and convening the workshop. The views contained in the proceedings are those of individual workshop participants and do not necessarily represent the views of all workshop participants, the planning committee, or the National Academies.

The organization of this proceedings roughly follows the organization of the workshop itself. Chapter 2 contains a description of the first keynote talk by Aviv Regev of the Broad Institute and the Massachusetts Institute of Technology. Chapter 3 reports on a series of presentations and

the ensuing discussion on case studies of building tools for use in functional genomics research in various organisms. The talks reported in Chapter 4 focus on understanding the contributions of non-protein-coding DNA to determining phenotype, while those in Chapter 5 describe research aimed at understanding the environmental regulation of gene function.

Chapter 6 recounts the workshop’s second keynote presentation, this one by Patricia Wittkopp of the University of Michigan. Chapter 7 covers a session that was devoted to interpreting and validating results from high-throughput screening approaches, while Chapter 8 describes presentations and a panel discussion focused on large databases and consortia. Chapter 9 describes several big-picture challenges in functional genomics research: education and training, determining and defining “model organisms,” and the social and ethical implications of functional genomics research. Chapter 10 offers a brief wrap-up of the workshop and a look to the future.