A Short History of Mapping
Reading The Human Blueprint
Pines, Maya, ed. "Blazing a Genetic Trail." Bethesda, MD:
Howard Hughes Medical Institute, 1991.
"All human disease is genetic in origin," Nobel laureate Paul
Berg of Stanford University told a cancer symposium a few years
ago. Berg was exaggerating only slightly. It has become increasingly evident
that virtually all human afflictions, from cancer to psychological
disorders and susceptibility to infection, are rooted in our genes.
"What we need to do now is find those genes," claims James Watson, who
shared a Nobel Prize for deciphering the structure of DNA and who now
directs the National Center for Human Genome Research at the National
Institutes of Health.
The necessary guide will be a map fixing each of the estimated 50,000
to 100,000 human genes to its correct location on the chromosomes.
"Like the system of interstate highways spanning our country, the map
of the human genome will be completed stretch by stretch,"
says. He expects that this map, the goal of the federally funded
Human Genome Project, will provide the key to understanding the nearly
4,000 known genetic disorders and the countless diseases whose origin
may be due in part to genetic malfunctions, as well as the astonishing
variety of normal human traits.
Such a map has been on the wish lists of molecular explorers for
years. Without it, nailing the culprits responsible for genetic
diseases requires not only hard work, ingenuity, and determination,
but more than a little luck. Although researchers were aided by luck
when they found the general location of the gene for Huntington's
disease (HD) on chromosome 4 in 1983, for instance, since that time
they have spent eight years painstakingly slogging through the target
area at the tip of the chromosome and still have no gene in sight.
Yet single-gene diseases such as HD are relatively easy targets.
Disorders that seem to be caused by the interplay of several genes,
hypertension, atherosclerosis, and most forms of cancer and mental
illness, are much more difficult to track down. Having a map of the
entire human genome will make it theoretically possible to identify
every gene that contributes to them.
A gene map can also lead researchers to new frontiers in drug
development. Once all the genes are identified and their bases are
sequenced, it will be possible to produce virtually any human
protein-valuable natural pharmaceuticals, such as tissue plasminogen
activator, interferon, and erythropoietin - as well as new molecules
designed specifically to block disease-producing proteins.
The NIH gene-mapping project officially began in October, 1990. But
the map of the human genome has been in the making for a good part of
the century. It started in 1911, when the gene responsible for
red-green color blindness was assigned to the X chromosome following
the observation that this disorder was passed on to sons by mothers
who saw colors normally. Some other disorders that affect only males
were likewise mapped to the X chromosome on the theory that females,
who have two X chromosomes, were protected from these disorders by a
normal copy of the gene on their second X chromosome unlike males, who
have one X and one Y chromosome.
The other 22 pairs of chromosomes remained virtually uncharted until
the late 1960s. Then biologists fused human and mouse cells to create
uneasy hybrid cells that cast off human chromosomes until only one or
a few remained. Any recognizable human proteins in these hybrid cells
thus had to be produced by genes located on the remaining human
chromosomes. This strategy allowed scientists to assign about 100
genes to specific chromosomes.
Map-making really took off in the early 1970s, when geneticists
discovered characteristic light and dark stripes or bands across each
chromosome after it was stained with a chemical. These bands, which
fluoresced under ultraviolet light, provided the chromosomal
equivalent of latitudes. They made it easier to identify individual
human chromosomes in hybrid cells and served as rough landmarks on the
chromosomes, leading to the assignment of some 1,000 genes to specific
Around the same time,
recombinant DNA technology began to
revolutionize biology by allowing researchers to snip out pieces of
DNA and splice them into bacteria, where they could be grown, or
cloned, in large quantities. This led to two new mapping strategies.
In one, in situ hybridization, scientists stop the division of human
cells in such a way that each chromosome is clearly visible under a
light microscope. Then they use probes to find the location of any
DNA fragment on these chromosomes. Originally these probes were
radioactively labeled, but chemically-tagged probes that can be made
to fluoresce have been found to yield far more accurate and rapid
The other strategy is to use DNA variations as markers on the human
genome, as proposed by Botstein, White, Skolnick, and Davis in 1980.
This has resulted in a flood of new markers and an explosion in the
knowledge of genes' chromosomal whereabouts. The number of genes
mapped grew from 579 in 1981 to 1,879 in 1991. Gene mappers, who used
to meet to coordinate their findings every year or so, now update the
map every day via electronic databases.
Meanwhile, scientists learned to sequence the genes they isolated.
This became possible in the mid-1970s when Frederick Sanger at
Cambridge University and Walter
Gilbert and Allan Maxam at Harvard University developed efficient
new methods for determining the order of bases in a strand of DNA.
Automated high-speed sequencing by machine followed in the 1980s.
Now, once a new gene has been identified, it is immediately sequenced
to understand the nature of the protein it codes for and to identify
mutations that are related to disease.
Sequencing the entire genome, however, means sequencing at least 3
billion base pairs of DNA - a chromosome of each type, or half the
total number of chromosomes in a human cell. This remains a daunting
Generally the most interesting or accessible genes have been located
first, creating a disparity among chromosomal maps. While the map of
the X chromosome appears to be as densely populated as the New York
coast, for instance, chromosome 18 looks as lonesome as central South
The Human Genome Project should even out the map by sending explorers
into chromosomal terra incognito. "The project really isn't doing
anything new. What it's doing is creating order and accountability,"
says geneticist Eric Lander of the Whitehead Institute.
This orderly process is expected to produce a genetic linkage map in
which the positions of genes for specific traits and diseases are
superimposed on a grid of evenly spaced markers along the chromosomes.
The project's five-year goal is to cover the entire genome with 1,500
genetic markers placed at equal intervals. Scientists will be able to
determine any gene's location relative to these markers.
In addition, the project will create a physical map that shows actual
distances along the chromosomes in terms of base pairs.
The physical map probably will be constructed of long overlapping
stretches of DNA cloned in yeast and known as yeast artificial
chromosomes (YACs). Developed in 1987 by Maynard Olson, now an HHMI
investigator at Washington University in St. Louis, YACs make it
possible to clone and store very large DNA segments - much larger than
those that can be cloned in bacteria. The technique has reduced the
number of DNA pieces that need to be placed in the right order from
about 100,000 to 10,000. Recently, Olson assembled a YAC library of
the entire genome and distributed it for the use of gene mappers.
At least two approaches have been developed to unite the genetic
linkage map and the physical map so that a researcher can easily move
back and forth between the two. One is to dot both maps with a new
kind of marker known as sequence-tagged sites, or STSs - long
sequences of DNA that generally occur only once in the whole human
genome and can be used as common reference points. The other approach
is to plot the position of existing genetic markers onto the physical
map by means of in situ hybridization.
Meanwhile, new strategies promise to speed up sequencing
significantly. Some researchers have reported that it may not be
necessary to sequence every base but to sequence certain pivotal
regions of DNA and fill in the blanks later. Moreover, automated
sequencing and computer software designed specifically for genome
analysis are already reducing sequencing time. As the pace of mapping
and sequencing quickens, so does the pace of data collection. The
Genome Data Base, developed by The Johns Hopkins University in
collaboration with HHMI, integrates various kinds of mapping and
sequencing data, as well as the constantly evolving genetic linkage
map. The Paris-based Centre d'Etude du Polymorphisme Humain collates
data from laboratories around the world to develop a series of
consensus maps for each chromosome. Another international body, the
Human Genome Organisation, is starting to coordinate gene-mapping
efforts in 42 nations.
The Genome Project has often been criticized as the intrusion of "Big
Science" on the traditionally "small science" of biology. However,
"everyone's beginning to realize this isn't at all like putting up a
space station or erecting a supercolliding superconductor," says Glen
Evans of the Salk Institute in La Jolla, California. "We're not going
to undertake large-scale sequencing until new technology makes it
cheap to do," explains
If a map of the genome and sets of overlapping clones had been
available when researchers set out to find the cystic fibrosis gene,
their task would have taken only a fraction of the time and cost,
points out Thomas Caskey, of the HHMI unit at the Baylor College of
Medicine. "The investigators wouldn't have had to clone region after
region looking for the gene," he says. "They could have just reached
into the freezer and pulled out two markers flanking it. The same
would be true for many other diseases. And remember, once we make
this map, we will never have to do it again."
Go to next story: What can we expect from the Human Genome Project
See Graphics Gallery:
Comparative Scale of Mapping,
Sequences of Base Pairs
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