Philip Hieter,
Mark Boguski
P. Hieter is at the Center for Molecular Medicine and
Therapeutics, Department of Medical Genetics, University of British
Columbia, Vancouver, BC, V6T124 Canada. M. Boguski is at the National
Center for Biotechnology Information, National Institutes of Health,
Bethesda, MD, USA 20892.
"Functional genomics" is
a term that has taken root in the scientific community. What exactly do
people mean when they refer to functional genomics? An informal poll of
colleagues indicates that the term is widely used, but has many
different interpretations. There is even some sentiment that the term
is unnecessary and that it does nothing more than refer to biological
research as a whole. Perusal of the several hundred functional genomics
websites that have sprung up over the last 12 months clearly
demonstrates that interpretations of the term are diverse and
highlights the substantial degree of "hype" that is being used to
promote the functional genomics approach, with little data to support
it. Nevertheless, the concept of functional genomics has arrived and it
is stimulating the creation of new ideas and approaches to understanding biological mechanisms in the context of knowledge of
whole genome structure.
To fully understand functional genomics, we must examine its roots. The
term "genome" itself is more than 75 years old and refers to an
organism's complete set of genes and chromosomes. The term
"genomics" was coined rather recently (in 1986) by Thomas Roderick
to describe the scientific discipline of mapping, sequencing, and
analyzing genomes and to provide a name for the new journal Genomics (1). The term has become universally
accepted over the past decade. Genomics is now undergoing, however, a
transition or expansion from the mapping and sequencing of genomes (the
original stated goals of the Human Genome Project) to an emphasis on
genome function. To reflect this shift, genome analysis may now be
divided into "structural genomics" and "functional genomics."
Structural genomics represents an initial phase of genome analysis and
has a clear end point--the construction of high-resolution genetic, physical, and transcript maps of an organism. The ultimate physical map
of an organism is its complete DNA sequence.
Functional genomics represents a new phase of genome
analysis. It provides a fertile ground for (and will require) creative thinking in developing innovative technologies that make use of the
vast resource of structural genomics information. Specifically, functional genomics refers to the development and application of global
(genome-wide or system-wide) experimental approaches to assess gene
function by making use of the information and reagents provided by
structural genomics. It is characterized by high throughput or
large-scale experimental methodologies combined with statistical and
computational analysis of the results. The fundamental strategy in a
functional genomics approach is to expand the scope of biological investigation from studying single genes or proteins to studying all
genes or proteins at once in a systematic fashion. Computational biology will perform a critical and expanding role in this area: whereas structural genomics has been characterized by data management, functional genomics will be characterized by mining the data sets for
particularly valuable information. Functional genomics promises to
rapidly narrow the gap between sequence and function and to yield new
insights into the behavior of biological systems.
Several recent studies fall under the operational definition of
functional genomics. The recent completion (2) of the genome sequence of the budding yeast Saccharomyces cerevisiae (in
other words, completion of the structural genomics phase) has provided the raw material to begin exploring the potential power of functional genomics approaches. An international consortium of yeast biologists is
systematically constructing a comprehensive set of yeast strains, each
of which will be deleted for one of the roughly 6000 predicted genes
(3). Individual yeast open reading frames (ORFs) are being
systematically replaced by oligonucleotide "bar codes," which can
be used in a polymerase chain reaction (PCR) or DNA microarray assay
for revealing those strains that survive under particular conditions
(4). This reference collection will be made publicly
available as soon as it is finished and will provide yeast researchers
specializing in the study of a particular cellular process or class of
genes the opportunity to devise assays or genetic screens utilizing the
strain set. Three recently devised methods for obtaining genome-wide
mRNA expression data, oligonucleotide "chips" (5), SAGE
(6) and DNA microarrays (7), are particularly powerful in the context of knowing the entire genome sequence (and thus
all genes) (8). The report by De Risi et al. in
this issue (9) provides a powerful example of the way in
which the DNA microarray methodology can provide a global view of
changes in gene expression patterns in response to physiological shifts or manipulation of transcriptional regulators. The SAGE method, in the
context of nearly comprehensive expressed sequence tag (EST) data, has
also been elegantly applied to analysis of genes differentially
expressed in human cancer (10).
In addition, knowledge of the yeast genome sequence has made feasible
the systematic analysis of protein-protein interactions for all 6000 yeast proteins by means of the two-hybrid method (11).
Analysis of all 18 million pair-wise combinations is under way.
Furthermore, partial protein sequences from high-resolution, two-dimensional gels and electrospray mass spectrometry of protein complexes can be used to unambiguously assign peptides to specific gene
sequences in the context of the whole genome sequence (12, 13).
As Peter Goodfellow has said (14), the central belief
embedded in functional genomics is that the complete sequence of the genomes of many organisms, including humans, will change the way we do
biology. Daniel Tosteson, dean of the Harvard Medical School, described
the situation more explicitly: "In the past we have had functions in
search of sequences. In the future, pathology and physiology will
become `functionators' for the sequences" (15).
Traditional disciplines are already adopting a genome-scale viewpoint
when it comes to approaching research problems. One example is the
Cancer Genome Anatomy Project (CGAP), which seeks to foster
infrastructure and new methodologies for cancer detection, diagnosis,
prognosis, and therapy (16). Functional genomics will not
only make traditional research approaches more productive and
efficient, but will also supplement the detailed understanding of gene
function provided by traditional approaches with a powerful new
perspective on the holistic operation of biological systems. Functional
genomics, however, will not replace the time-honored use of genetics,
biochemistry, cell biology, and structural studies in gaining a
detailed understanding of biological mechanisms. The extent to which
any functional genomics approach actually defines the function of a
particular protein (or set of proteins) will vary depending on the
method and gene involved. In general, the functional information gained
will provide a framework and a starting point for further analysis
(17, 18), much like a primary genetic screen identifies
candidate genes that require extensive subsequent validation.
We are entering a phase in which we shall see more functional genomics
data and hear less hype. Despite the unprecedented volume of data being
generated from individual experiments, rigorous, reproducable design
must be the watchword, so that emerging technologies can be fairly
evaluated. The traditional format of scientific publication cannot
reflect the scope and depth of data being produced. Summaries of
results and conclusions in publications are certainly of interest, but
are not very useful for subsequent analysis or utilization of the data
by others and may not even be adequate for effective peer review. A key
issue regarding the access to data from publicly funded, genome-scale,
functional analyses must be addressed. A great legacy of the structural
genomics era is the philosophy and practice of the public release of
data that we hope will carry over to the functional genomics age. The
timely submission of expression data, for example, in some standard
format independent of specific technique, would lead to the most
effective analysis and utilization of the results by the scientific
community.
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We thank J. Roskams, S. Fields, and D. Bassett for critical
reading of the manuscript and helpful
input.
Volume 278, Number 5338
Issue of 24 October 1997,
pp. 601 - 602
©1997 by The American Association for the Advancement of Science.
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Copyright © 1997 by the American Association for the Advancement of Science.