The avalanche of genome data grows daily. The new challenge will be to use
this vast reservoir of data to explore how DNA and proteins work with each other
and the environment to create complex, dynamic living systems. Systematic
studies of function on a grand scale - Functional Genomics - will be the focus of
biological explorations in this century and beyond. These explorations will
encompass studies in transcriptomics, proteomics, structural genomics, new
experimental methodologies, and comparative genomics:
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Transcriptomics involves large-scale analysis of messenger RNAs
transcribed from active genes to follow when, where, and under what conditions
genes are expressed.
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Studying protein expression and function--or
proteomics--can bring
researchers closer to what is actually happening in the cell than mRNA
gene-expression studies. This capability has applications to drug design.
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Structural genomics initiatives are being launched worldwide to
generate the 3-D (three-dimensional) structures of one or more proteins from each protein family,
thus offering clues to function and biological targets for drug design.
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Experimental methods for understanding the function of DNA sequences and
the proteins they encode (a more direct definition of Functional Genomics),
including knockout studies to inactivate genes
in living organisms and monitor any changes that could reveal their functions.
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Comparative genomics—analyzing DNA sequence patterns of humans and
well-studied model organisms side-by-side—has become one of the most powerful
strategies for identifying human genes and interpreting their function. Having
come a long way from its initial use of finding genes, comparative genomics
is now concentrating on finding regulatory regions.
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Metabolomics is the
study of the metabolic profile of a given cell, tissue, fluid, organ or
organism at a given point in time. The metabolome (that includes proteins,
RNA, DNA, various substrates and small circuits of pathway networks)
represents the collection of all metabolites (small molecules that are the
intermediates and products of metabolism) in a biological organism.

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Nutrigenomics applies
genomics, transcriptomics, proteomics and metabolomics to human nutrition,
especially the relationship between nutrition and health. Nutrigenomics is associated with the issue of
personalized nutrition, since claims are being made that differences in
genotype should result in differences in the diet and health relationship.
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Epigenomics
is the study of epigenetic changes (mainly DNA methylation and modification
of histones; see under "cells and within cells, epigenetics") on a
genome-wide scale.
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Neurogenomics. The
last ten years of the 20th century constituted "The Decade of the Brain". The time now seems ripe to begin a 21st century unification of genomics and
neuroscience with one goal being to understand how only ~21,000 human genes
contribute to the structure and function of an organ containing a trillion
neurons with 1015 estimated connections. The full-scale application
of genomics and bioinformatics technologies to brain research could lead to a
new kind of systems neuroscience akin to the reconceptualization of "systems
biology" in the genome era.
Neurogenomics is the study
of how the genome as a whole contributes to the evolution, development,
structure and function of the nervous system. It includes investigations of how
genome products (transcriptomes and proteomes) vary in time and space. Neurogenomics differs markedly from the application of genome sciences to other
systems, particularly in the spatial category, because anatomy and connectivity
are paramount to our understanding of function in the nervous system.
Neurogenomics focuses
on the contributions of genome-based research efforts in uncovering the
molecular pathways and processes that underlie psychiatric and neurodegenerative
disorders in the mammalian CNS. Although it has long been thought that many
diseases of the CNS in humans had a genetic component, the polygenic nature of
these conditions made identification of specific genes challenging. The virtual
completion of the human and mouse genome projects combined with advances in
transgenic mouse technologies now affords the possibility of integrating
often-times quite disparate fields of research to provide unique insights into
the molecular basis of aberrant CNS function. Neurogenomics areas include:
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Neurophenomics. Following
the sequencing of the human and mouse genomes, the next major step is to assign
a
function to each of the identified genes. The currency of gene function is the
mutation. The majority of mutations that have been found in humans is
single-base pair mutations. Phenotype-driven approaches are important for
bridging the gap between gene identification and understanding gene function.
Knowledge of the genetics of nervous system function and regulation of behavior
will lead to improved understanding of normal and abnormal brain function and
behavior, enhanced diagnostics, and more effective therapeutics. Forward genetic
strategies are being used to identify genes involved in nervous system function
and behavior. Thus, while various genetic engineering strategies provide
information about gene function through knockout technologies, to best model
human disease mutagenesis programs that employ single-base pair lesions are
desirable and often focus on the use of N-ethyl-N-nitrosourea (ENU) to induce
single-base pair lesions in the genome and allow for an unbiased approach which
involves screening potentially mutant lines for a host of neuro-behavioral, -physiological,
and -anatomical phenotypes. For instance, ENU-mutagenized C57BL/6J mice are
being used to identify neurobehavioral mutations in five domains (the phenotypic
screens focus on neuroendocrine and behavioral responses to stress, learning and
memory, psychostimulant response, vision, and circadian rhythm), and a
three-generation breeding scheme to produce homozygous mutants to recover both
recessive and dominant mutations. Whole-genome and regional approaches as well
as large-scale mutagenesis programs are thus being used (see
http://www.tnmouse.org/neuromutagenesis/).
This field is called Neurophenomics. Furthermore, in this endeavour, issues such as administration, bio-informatics,
power of phenotypic screens to detect behavioral outliers, and identifying the
mutant gene are important. A further
interesting contribution in this area concerns a
saturation screen of the druggable mouse genome to identify novel drug targets
for neuropsychiatric disease. For this, a large-scale phenotypic
screen in mice has been undertaken to identify genes that regulate neuropsychiatric behavior. The screen is based on the production and phenotypic
analysis of mouse knockouts of all genes that are members of gene families whose
protein products are considered to be tractable for drug development (see figure
below). The
knockout animals are subjected to a behavioral screen that includes tests for
anxiety, depression, psychosis, pain, circadian rhythms and cognition. To date
more than 1,250 genes have been knocked out and screened with a goal of
completing 3,750 additional genes. Another aspect of
Neurogenomics is the need for model organisms intermediate between mice and
humans that can be investigated using genetic approaches. Genome mapping in
non-human primates provides these models, and will be particularly important
for the investigation of brain and behavior. Such mapping and sequencing
projects are underway in a wide range of primate species, including the vervet
monkey. Several decades of studies in well-characterized vervet colonies have
demonstrated heritability for a wide range of behavioral phenotypes. These
highly inbred colonies are equivalent to human population isolates, and are thus
particularly powerful for genome-wide genetic mapping of such phenotypes. Indeed
the vervet offers an ideal test for a phenomic approach to the investigation of
complex traits; the phenome is the comprehensive representation of phenotypes,
and a phenomic approach to genetic mapping involves simultaneous analysis of the
whole phenome by performing genome-wide genotyping of an entire study population.
For the investigation of brain and behavior, the evaluation of the vervet
phenome can include, for example, neuroimaging, gene expression profiling, and
pharmacologic interventions, in addition to existing behavioral assessments.

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Pharmacogenomics (that
combines medicine, pharmacology and genomics) tries to understand the
correlation between an individual patient's genetic make-up (genotype) and
their response to drug treatment. Some drugs work well in some patient
populations and not as well in others. Studying the genetic basis of a
response of a patient to therapeutics allows drug developers to more effectively design
therapeutic treatments.
Thus, through pharmacogenomics, drugs might one day be tailor-made for
individuals and their conditions, allowing prescription of the most effective
drug dosage and a reduction of unwanted side
effects. Pharmacogenomics is therefore the use of genetic information to
predict drug response. The term drug response includes two facets: drug
effectiveness (efficacy) and drug side effects. It is estimated that, on
average, as much as forty percent of the medicines that individuals take
every day are not effective. In fact, for certain medications, the estimate
of non-effectiveness is well over 50%. Every drug simply does not work for
every individual and many people are exposed to the problematic side effects
of drugs while receiving little or no benefit. Pharmacogenomics tries to
identify people whose genetic profiles or "bar codes" predict that they are
inappropriate for a given medication, whether due to poor efficacy and/or
adverse side effects. Pharmacogenomics allows physicians to prescribe with
greater confidence, and pharmaceutical companies to more effectively target
drugs where they will do the most good. The current one-size-fits-all
approach to medicine will be augmented increasingly by diagnostic analysis
that, for many drugs and many patients, will validate the appropriateness of
certain medications before they are administered. One approach to
pharmacogenomics is to directly study the genetic component of the problem
(the DNA itself) to understand the way in which variations in DNA sequences
contribute to phenotypic traits such as common diseases and drug responses.
See also under "Pharmacogenomics".
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