Download On Mapping the Human Genome

CLIN. CHEM. 33/3, 349-351 (1987)
On Mapping the Human Genome
Ed. note: This well-written anonymous (doubtless midtiauthored) piece, excerpted from an Office of Technology
Assessment proposal, is presented here by permission of
Robert Cook-Deegan, Mi)., project director.
Mapping the human genome is increasingly
a topic for
discussion at professional scientific meetings of molecular
biologists and geneticists. Scientists and clinicians appear to
agree on two general objectives. These are to understand (a)
how genes relate to human disease, and (b) the relationship
between genetics and other scientific fields such as ecology,
psychology, physiology, and biochemistry.
Scientists directly involved disagree about how to achieve
these objectives. They differ in their assessments of competing technical means to construct a map of all human genes,
the importance of having such a map, and the costs and time
scale of making a complete map. Cost estimates of $300
million to $3 billion have been postulated as necessary to
construct the complete DNA sequence alone (without accounting for necessary genetic, biochemical, physiological,
and medical research necessary to interpret the resulting
sequence). Different sources have estimated the effort would
take from two to 20 years. Several areas of uncertainty
and
divergent opinion surround policy on mapping the human
genome.
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Should there be a special national commitment to map
the human genome? If so, what should its technical objective
be: a complete sequence, a map of all human genetic
diseases, a map of all genes of interest, or a map that could
be used to guide efforts to attain these objectives?
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If there were to be such an effort, who should fund and
coordinate it?
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What techniques might be used, what technologies must
be developed, and what are the likely technological spinoffs?
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How many scientists and technicians would be needed?
Are they already available and trained?
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When should a special effort be started (if ever), and how
long would it take?
Some disagreement arises from differing judgments about
what kind of map is desirable. Other concerns focus on
consequences of mounting large targeted scientific efforts.
Some scientists fear that a major national commitment to
human gene mapping would displace other research that is
of higher priority. Others aver that a national commitment
would hasten advances in a field with diverse clinical
applications and great potential for human benefit, would
encourage technolgical growth in a strategically important
area of biotechnology, would foster international and interagency cooperation, and would sustain public support for
relevant research.
At present, approximately one-thirtieth of one percent of
the human genome has been sequenced. Several hundred of
the 50 000 to 100 000 human genes have been located or
“mapped” (one-fourth of one percent of all genes). Almost
4000 genetic sites-most
associated with human disease-
have been identified (generally by analysis of family pedigrees), but only a small fraction have been actually located
on the chromosomes. In one important sense, the job will
never be complete, because even if there were a full genomic
sequence, understanding
how it relates to disease, normal
function, and environmental forces would always be topics
of inquiry. Yet having a useful genetic map of humans
sooner rather than later could accelerate research in diverse
fields of investigation
and would almost certainly have
significant practical impacts.
What Is a Human Gene Map?
Some of the controversy about approaches to mapping the
human genome stems from different conceptions of what a
human gene map is. There are several varieties, each
requiring a different technical approach and involving a
different level of effort to attain. A genetic map is constructed by using traditional genetic techniques. It is a measurement of how close genes are to one another based on how
often they are associated
with one another. Genes on
different chromosomes frequently separate from one another
in the subsequent generation (because they are independently sorted during cell division), while those that are
located adjacent to one another on the same chromosome are
only rarely separated. Genetic maps can often be used to
verify that a gene is on a particular chromosome, for
example, but finding the specific location within a chromesome can be difficult using traditional genetics (especially in
humans where experimental
matings are not possible).
“Distance” on a genetic map only approximately
corresponds to physical distance along a chromosome. This is
because some parts of DNA are particularly susceptible to
rearrangement
during cell divisions, resulting in a high
frequency of separation for genes on opposite sides of the
break point. Other stretches of DNA are unusually resistant
to rearrangement, and so genes in these areas seem to be
closer to each other than they actually are.
A physical map is one that identifies areas of interest on
the chromosomes according to their location (rather than
how often they are found together). The complete nucleotide
sequence of all the DNA in an organism is the ultimate
physical map, but other types of physical maps also exist. In
humans, for example, there are ka,yotype maps that show
all 46 chromosomes and also a number of “bands” (subregions) found on those chromosomes. Most human chromosomes contain several hundred million nucleotide base pairs
in a linear sequence, and each chromosome band roughly
corresponds to 1 million to 10 million base pairs (and 10 to
100 genes). Several hundred human genes have been traced
to their locations on the chromosomes.
Other maps correlate known chromosomal positions to
sites where DNA is cut by enzymes that recognize specific
sequences of four to seven base pairs. Such maps can be
constructed
relatively rapidly when combined with new
cloning methods. Still others can locate particular regions of
CLINICALCHEMISTRY,Vol. 33, No. 3, 1987 349
DNA that differ among individuals in the same species. In
humans,
for example, investigators
can identify several
genetic regions that differ among individuals in the same
family. These regions can be located on the chromosomes,
and the same methods can be used to find disease genes
located nearby (in genetic “distance”).
Just as different geographic maps are useful for different
purposes, the different varieties of gene maps differ in their
level of detail, clinical relevance, and scientific import. Road
maps are most useful for travel by automobile, for example,
but are not useful for those needing geomorphologic data to
seek new oil deposits. Some of the debate about mapping the
human genome centers on which type of map should be
constructed
first and how the different maps should be
related to one another and to the large body of relevant
scientific and medical knowledge.
Choices about the kind of map to be developed matter,
because they determine the technology to be used, the rate
of attaining
a complete map, and the potential utility of
having a complete map. A complete nucleotide sequence
would contribute substantially
to creation of all of the other
types of maps, but its completion might require considerably
greater effort (this is a point of disagreement
among scientists), and it would have to be supplemented
by an even
greater effort to study the structure and function of genes
with clinical or scientific import. Only a small portion of the
human genome is known to be related to disease or to code
for proteins or other products. A complete sequence thus
might contain large expanses of DNA whose significance
would be difficult to assess in light of current knowledge.
Some have argued that it would be simpler to do a complete
nucleotide sequence than to identify all genes of interest,
locate them, and determine their sequence. They argue that
the effort to identify genes of interest, clone them, and
prepare them for sequencing would be much greater than
simply finding the total sequence and working from the
total sequence to define regions of interest identified by
other means. Others argue that the amount of “interesting”
DNA is only 3 to 5% the total, and a less “brute force”
approach to constructing
a gene map should be followed.
They assert that a map can only be useful if it is continually
related to relevant scientific and clinical information about
physiology and pathology.
Why Map the Human Genome?
Mapping the human genome is an attractive goal because
of the contribution
it would make to scientific knowledge
and its likely contributions
to medical practice, industrial
application,
and hazard prevention.
Each of the benefits
would arise from the process of constructing
a map of the
human genome, regardless
of the time scale or precise
nature of the effort. Funding levels and priority within
agencies will determine
the pace of discovery, and the
particular agencies (and nations) funding and coordinating
that research
will influence the relevance of the effort
devoted to these different possible applications.
Efforts directed at scientific questions
of comparative
biology of
species, for example, would entail an emphasis on descriptive genetics of different organisms, while clinical applications would necessitate family studies and medical investigation. Industrial applications would likely center on possible products that could be profitably produced by using the
technologies used to explore the human gene map.
Scientific and technical advances. Availability of a map of
the human genome would permit more precise comparison
350 CLINICAL CHEMISTRY, Vol. 33, No. 3, 1987
of different species. The genetics of some bacteria, yeast,
nematodes, fruit flies, and mice are relatively well characterized. Work on the major histocompatibility
complex of
mice, for example, has greatly aided analysis of analogous
regions in humans (called the “lILA region” in humans).
Such work on both mice and humans has led to dramatic
medical advances in understanding
immunological
disease
and in organ transplantation.
The human gene map would
permit greater understanding
of how humans differ from
other animals, and it would aid analysis of genetic characteristics of human populations in different environments.
Construction
of the human gene map would also foster
development
of new techniques
for identifying
genes of
interest, locating them, and studying how they work. This
would build on current knowledge of other fields as well as
previous work in genetics. A gene map is merely a tool for
further understanding
physiology and disease, but it is an
important one.
Clinical implications. A complete gene map would locate
genes causing human disease. The most recent compendium
of genetic diseases in humans lists almost 4000 different
genetic locations related to human disease. Most of these
genetic diseases are caused by genes that have not been
located and whose function is only poorly understood (they
are known only by their inheritance
pattern or some other
indirect indicator). A gene map would be a powerful tool for
more quickly locating disease-related
genes. Knowing the
gene location makes developing a definitive diagnostic test
more likely by narrowing the region to be studied, with the
eventual prospect of treatment
(not necessarily involving
gene therapy).
Knowing the location of a gene does not, however, necessarily lead to understanding
its /iinction. For genes directly
causing disease, a means of diagnosis does not imply that
there is a way to treat the disease or slow its progression. It
is now possible, for example, to make the specific diagnosis
of Huntington’s disease, Duchenne muscular dystrophy, and
cystic fibrosis in some families by using genetic markers.
But subsequent medical treatments cannot prevent most
symptoms, and prospects of gene therapy in the foreseeable
future are remote for these diseases because they are so
poorly understood. (The functions of the defective genes are
not understood for any of these three diseases.) Thus it is
possible to detect the abnormality,
but not to understand
how it relates to symptoms or to thwart its ill effects.
However, knowing the location and sequence of a gene
can make rapid progress in understanding
(and possible
treatment)
more likely. The gene causing chronic granulematous disease, for example, has been found. Scientists
determined the gene’s sequence and from that deduced the
structure
of the protein product, which had never been
described. This marked the first time a genetic disease had
been “studied backwards”-starting
from the gene rather
than from knowledge about biochemistry. This offers a new
and specific diagnostic test, a new avenue for understanding
the disease, and a promising pathway for possibly discovering a means of preventing or treating symptoms.
Knowing a gene’s location can also have clinical benefits,
even if the disease process cannot be arrested.
Genetic
diagnosis of cystic fibrosis, for example, has been shown to
result in improved health of those affected by alerting
physicians
and family members early to the diagnosis,
permitting anticipation and treatment of associated medical
problems.
Industrial applications. Construction of a gene map could
also have commercial implications. The products first developed by using recombinant
DNA have been products of
human genes (e.g., insulin, interferons, interleukins).
Genes
first cloned and marketed have been those with known
function and anticipated
clinical benefit. The explosive
growth in knowledge about human genetics undoubtedly
will generate many more such prospects for clinical application and consequent commercial potential.
In addition to direct clinical applications, gene mapping is
likely to spawn many new techniques that would also be
commercially
useful. The same methods for doing genetic
sequencing, for example, could be applied to agricultural
or
veterinary
biotechnology.
New techniques for cloning and
for handling long genetic sequences would likewise be of
general scientific benefit and commercial interest. Automation of cell sorting, DNA preparation,
and sequencing would
be widely useful. Nucleotide chemistry, mathematical
algorithms for sorting and matching, and other necessary steps
to making a complete gene map would generate new ideas
for yet other commercial applications.
Information
for government
oversight and regulation.
Having a complete gene map would aid those investigating
mutational
effects of new drugs and environmental
exposure to chemicals, radiation,
and infectious agents. Existence of a genetic map would not only provide a standard for
analysis of genetic effects of environmental
exposure, but
the process of generating
a gene map would also generate
new technologies to permit quantitative
evaluation of genetic damage. This would be useful in assessing previous
exposures to agents that cause mutations
(alterations
of
DNA), estimating
the effects of possible exposures, and
monitoring public health. These capabilities would assist in
more specific enforcement
of laws to control pollution and
workplace exposures.
Risks. The foremost argument
against
mapping
the
genome to date is not against the map itself, but against an
accelerated project to develop it. Some scientists fear that a
special program on mapping the genome would displace
funding for other projects of greater scientific interest.
Other scientists are concerned that an effort to understand the genetics of humans could overwhelm efforts to
understand
the genetics of other species, or that focus on
gene mapping may detract attention from other aspects of
human genetics such as population genetics. One letter to
Nature highlighted
the folly of sequencing
“the” human
genome when there are over 5 billion individual humans,
and recognition
of genetic heterogeneity
among species,
rather than uniformity, is the salient discovery of modern
genetics. Such scientists believe that true understanding
of
genetics (including
human genetics) depends on understanding other organisms, and that a special effort would
likely make funding short for other endeavors-not
only
because of the funding competition noted above, but also
because the pool of talent is finite and a major project would
tap a significant fraction of promising investigators
in the
relevant disciplines.
The style of research in molecular biology is also seen as
threatened
by a major project to map the human genome.
Molecular biology has been called a “cottage industry,” with
the most prominent investigators
well known to one another
and much of the scientific interchange
taking place informally among colleagues. A major project could threaten
this, altering relationships
and requiring more formal coordination and information-exchange
mechanisms.
Another
objection centers not on gene mapping but
against intensified studies of human genetics. Some social
critics assert that the study of human genetics will ineluctably lead to errant applications.
They cite the examples of
Nazi eugenics and anti-immigration
and sterilization
laws
in the United States during the early decades of this
century. Such critics may object (although they have not yet
taken a position on this particular
topic) to any special
project to map the human genome because the existence of
map would bring unanticipated
applications they regard as
undesirable.
[A short section here discusses
and private U.S. institutes.]
the role of U.S. agencies
International
cooperation and industrial competition. The
nature and size of the task of mapping the human genome
make it a prime candidate for international
scientific cooperation. European
science and technology agencies have
expressed great interest in mapping the genome, but are
looking to the United States to provide leadership. Japan is
independently
mounting an effort to sequence parts of the
genome. Interest in the United States and Europe appears
to emanate primarily from medical and scientific communities, while the Japanese effort appears to have emanated
from the interests
of several companies.
The Japanese
interests to date center on developing new technology to
sequence nucleotides,
and its application to mapping the
human genome is only one of many that are possible. The
Japanese
effort thus appears to anticipate
technological
spinoffs in the manufacture
and design of goods derived
from biotechnology. The Japanese government has nonetheless expressed interest in an international
cooperative scientific effort. This effort is likely to involve achieving a balance
between proprietary
secrecy and the traditional
free exchange of scientific information.
This balance would be
difficult even within one country, but would be even more
difficult among several national governments (each with its
own industrial, nationalistic,
and scientific objectives). Yet
the advantages
may suffice to overcome the barriers.
CLINICAL CHEMISTRY, Vol. 33, No. 3, 1987 351